Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

Synopsis Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptintreated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein

Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats

A B S T R A C T Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (Lbuthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation

Sanguis draconis

Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon’s blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0–50 μg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10–50 μg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation

K0S and Λ production in Pb-Pb collisions at sNN−−−−√=2.76 TeV

The ALICE measurement of K0S and Λ production at midrapidity in Pb-Pb collisions at sNN−−−√=2.76  TeV is presented. The transverse momentum (pT) spectra are shown for several collision centrality intervals and in the pT range from 0.4  GeV/c (0.6  GeV/c for Λ) to 12  GeV/c. The pT dependence of the Λ/K0S ratios exhibits maxima in the vicinity of 3  GeV/c, and the positions of the maxima shift towards higher pT with increasing collision centrality. The magnitude of these maxima increases by almost a factor of three between most peripheral and most central Pb-Pb collisions. This baryon excess at intermediate pT is not observed in pp interactions at s√=0.9  TeV and at s√=7  TeV. Qualitatively, the baryon enhancement in heavy-ion collisions is expected from radial flow. However, the measured pT spectra above 2  GeV/c progressively decouple from hydrodynamical-model calculations. For higher values of pT, models that incorporate the influence of the medium on the fragmentation and hadronization processes describe qualitatively the pT dependence of the Λ/K0S ratio

phi-Meson production at forward rapidity in p-Pb collisions at root s(NN)=5.02 TeV and in pp collisions at root s=2.76 TeV

The first study of phi-meson production in p-Pb collisions at forward and backward rapidity, at a nucleonnucleon centre-of-mass energy root s(NN)= 5.02 TeV, has been performed with the ALICE apparatus at the LHC. The phi-mesons have been identified in the dimuon decay channel in the transverse momentum (p(T)) range 1 <p(T) <7GeV/c, both in the p-going (2.03 <y <3.53) and the Pb-going (-4.46 <y <-2.96) directions - where ystands for the rapidity in the nucleon-nucleon centre-of-mass - the integrated luminosity amounting to 5.01 +/- 0.19nb(-1) and 5.81 +/- 0.20nb(-1), respectively, for the two data samples. Differential cross sections as a function of transverse momentum and rapidity are presented. The forward-backward ratio for f-meson production is measured for 2.96Peer reviewe

Measurement of D-s(+) product ion and nuclear modification factor in Pb-Pb collisions at root S-NN=2.76 TeV

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Measurement of transverse energy at midrapidity in Pb-Pb collisions at root s(NN)=2.76 TeV

We report the transverse energy (ET) measured with ALICE at midrapidity in Pb-Pb collisions at root s(NN) = 2.76 TeV as a function of centrality. The transverse energy was measured using identified single-particle tracks. The measurement was cross checked using the electromagnetic calorimeters and the transverse momentum distributions of identified particles previously reported by ALICE. The results are compared to theoretical models as well as to results from other experiments. The mean ET per unit pseudorapidity (eta), , in 0%-5% central collisions is 1737 +/- 6(stat.) +/- 97(sys.) GeV. We find a similar centrality dependence of the shape of as a function of the number of participating nucleons to that seen at lower energies. The growth in at the LHC energies exceeds extrapolations of low-energy data. We observe a nearly linear scaling of with the number of quark participants. With the canonical assumption of a 1 fm/c formation time, we estimate that the energy density in 0%-5% central Pb-Pb collisions at root s(NN) = 2.76 TeV is 12.3 +/- 1.0 GeV/fm(3) and that the energy density at the most central 80 fm(2) of the collision is at least 21.5 +/- 1.7 GeV/fm(3). This is roughly 2.3 times that observed in 0%-5% central Au-Au collisions at root s(NN) = 200 GeV.Peer reviewe

Azimuthally Differential Pion Femtoscopy in Pb-Pb Collisions at root s(NN)=2.76 TeV

We present the first azimuthally differential measurements of the pion source size relative to the second harmonic event plane in Pb-Pb collisions at a center-of-mass energy per nucleon-nucleon pair of root(NN)-N-s = 2.76 TeV. The measurements have been performed in the centrality range 0%-50% and for pion pair transverse momenta 0.2 <k(T) <0.7 GeV/c. We find that the R-side and R-out radii, which characterize the pion source size in the directions perpendicular and parallel to the pion transverse momentum, oscillate out of phase, similar to what was observed at the Relativistic Heavy Ion Collider. The final-state source eccentricity, estimated via R-side oscillations, is found to be significantly smaller than the initial-state source eccentricity, but remains positive-indicating that even after a stronger expansion in the in-plane direction, the pion source at the freeze-out is still elongated in the out-of-plane direction. The 3 + 1D hydrodynamic calculations are in qualitative agreement with observed centrality and transverse momentum R-side oscillations, but systematically underestimate the oscillation magnitude.Peer reviewe

Correlated Event-by-Event Fluctuations of Flow Harmonics in Pb-Pb Collisions at root S-NN=2.76 TeV

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