A magnetically drivable nanovehicle for curcumin with antioxidant capacity and MRI relaxation properties

Curcumin possesses wide-ranging anti-inflammatory and anti-cancer properties and its biological activity can be linked to its potent antioxidant capacity. Superparamagnetic maghemite (gamma-Fe2O3), called surface-active maghemite nanoparticles (SAMNs) were surface-modified with curcumin molecules, due to the presence of under-coordinated Fe-III atoms on the nanoparticle surface. The so-obtained curcumin-modified SAMNs (SAMN@curcumin) had a mean size of 13 +/- 4 nm. SAMN@curcumin was characterized by transmission and scanning electron microscopy, UV/Vis, FTIR, and Mossbauer spectroscopy, X-ray powder diffraction, bulk susceptibility (SQUID), and relaxometry measurements (MRI imaging). The high negative contrast proclivity of SAMN@curcumin to act as potential contrast agent in MRI screenings was also tested. Moreover, the redox properties of bound curcumin were probed by electrochemistry. SAMN@curcumin was studied in the presence of different electroactive molecules, namely hydroquinone, NADH and ferrocyanide, to assess its redox behavior. Finally, SAMN@curcumin was electrochemically probed in the presence of hydrogen peroxide, demonstrating the stability and reactivity of bound curcumin.

Investigation of the dielectric relaxation processes in PbZr0.65Ti0.35O3-BaFe12O19 multiferroic ceramic composites

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

L-Carnitine supplementation impairs endothelium-dependent relaxation in mesenteric arteries from rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Nuclear magnetic relaxation for the spin-degenerate Anderson model

A renormalization-group calculation of the temperature-dependent nuclear spin relaxation rate for a magnetic impurity in a metallic host is reported. The calculation follows a simplified procedure, which produces accurate rates in the low-temperature Fermi-liquid regime, although yielding only qualitatively reliable results at higher temperatures. In all cases considered, as the temperature T diminishes, the rates peak before decaying linearly to zero in the Fermi-liquid range. For T → 0, the results agree very well with Shiba's expression relating the low-temperature coefficient of the relaxation rate to the squared zero-temperature susceptibility. In the Kondo limit, the enhanced susceptibility associated with the Kondo resonance produces a very sharp peak in the relaxation rate near the Kondo temperature. © 1991.

Oxygen mobility in Bi:Sr:Ca:Cu:O ceramic measured using anelastic relaxation methods

Since the discovery of YBaCuO, experiments have shown that its superconducting properties are strongly affected by the oxygen content. More recently, anelastic relaxation measurements in La2CuO4+δ, showed that the decrease in the oxygen content can be related to two events. One is the decrease in mobility between two adjacent CuO planes, and the other is the increase in the number of tilting patterns of the CuO6 octahedra. In the case of the bismuth-based ceramic, it is known that the oxygen content, within some limits, does not affect its superconducting properties. In order to evaluate the mobility and the effect of the oxygen content on this material we have prepared BSCCO ceramic and tested regarding its internal friction and electrical resistivity as a function of the temperature while the oxygen content was being reduced by a sequence of vacuum annelaing at 620 K. The samples were prepared in the Bi:Sr:Ca:Cu = 2212 and 2223 proportion, using powder obtained by the sol-gel route and conventional solid state reaction. The anelastic relaxation measurements were performed using a torsion pendulum operating with frequency about 15-35 Hz between 77 to 700 K. The diffraction pattern of the as sintered and the vacuum annealed material were also presented. The results have shown complex anelastic relaxation structures that were associated to the jump of interstitial oxygen atoms between two adjacent CuO planes. The vacuum annealing showed to be deleterious to the critical temperature of the superconducting ceramic.

Coupling between respiratory and sympathetic activities as a novel mechanism underpinning neurogenic hypertension

Enhanced sympathetic outflow to the heart and resistance vessels greatly contributes to the onset and maintenance of neurogenic hypertension. There is a consensus that the development of hypertension (clinical and experimental) is associated with an impairment of sympathetic reflex control by arterial baroreceptors. More recently, chronic peripheral chemoreflex activation, as observed in obstructive sleep apnea, has been proposed as another important risk factor for hypertension. In this review, we present and discuss recent experimental evidence showing that changes in the respiratory pattern, elicited by chronic intermittent hypoxia, play a key role in increasing sympathetic activity and arterial pressure in rats. This concept parallels results observed in other models of neurogenic hypertension, such as spontaneously hypertensive rats and rats with angiotensin II–salt-induced hypertension, pointing out alterations in the central coupling of respiratory and sympathetic activities as a novel mechanism underlying the development of neurogenic hypertension.

Neurogenic neuroprotection: Future perspectives

Neurogenic neuroprotection elicited by deep brain stimulation is emerging as a promising approach for treating patients with ischemic brain lesions. In rats, stimulation of the fastigial nucleus, but not dentate nucleus, has been shown to reduce the volume of focal infarction. Protection of neural tissue is a rapid intervention that has a relatively long-lasting effect, rendering fastigial nucleus stimulation (FNS) a potentially valuable method for clinical application. We review some of the main findings of animal experimental research from a clinical perspective. Results: Although the complete mechanisms of neuroprotection induced by FNS remain unclear, important data has been presented in the last two decades. The acute effect of electrical stimulation of the fastigial nucleus is likely mediated by a prolonged opening of potassium channels, and the sustained effect appears to be linked to inhibition of the apoptotic cascade. A better understanding of the cellular and molecular mechanisms underlying neurogenic neuroprotection by stimulation of deep brain nuclei, with special attention to the fastigial nucleus, can contribute toward improving neurological outcomes in ischemic brain insults.

Ethanol induces vascular relaxation via redox-sensitive and nitric oxide-dependent pathways

We investigated the role of reactive oxygen species (ROS) and nitric oxide (NO) in ethanol-induced relaxation. Vascular reactivity experiments showed that ethanol (0.03-200 mmol/L) induced relaxation in endothelium-intact and denuded rat aortic rings isolated from male Wistar rats. Pre-incubation of intact or denuded rings with L-NAME (non selective NOS inhibitor, 100 mu mol/L), 7-nitroindazole (selective nNOS inhibitor, 100 mu mol/L), ODQ (selective inhibitor of guanylyl cyclase enzyme, I mu mol/L), glibenclamide (selective blocker of ATP-sensitive K+ channels, 3 mu mol/L) and 4-aminopyridine (selective blocker of voltage-dependent K+ channels, 4-AP, 1 mmol/L) reduced ethanol-induced relaxation. Similarly, tiron (superoxide anion (O-2(-)) scavenger, 1 mmol/L) and catalase (hydrogen peroxide (H2O2) scavenger, 300 U/mL) reduced ethanol-induced relaxation to a similar extent in both endothelium-intact and denuded rings. Finally, prodifen (non-selective cytochrome P450 enzymes inhibitor, 10 mu mol/L) and 4-methylpyrazole (selective alcohol dehydrogenase inhibitor, 10 mu mol/L) reduced ethanol-induced relaxation. In cultured aortic vascular smooth muscle cells (VSMCs), ethanol stimulated generation of NO, which was significantly inhibited by L-NAME. In endothelial cells, flow cytometry studies showed that ethanol increased cytosolic Ca2+ concentration ([Ca2+]c), O-2(-) and cytosolic NO concentration ([NO]c). Tiron inhibited ethanol-induced increase in [Ca-2]c and [NO]c. The major new finding of this work is that ethanol induces relaxation via redox-sensitive and NO-cGMP-dependent pathways through direct effects on ROS production and NO signaling. These findings identify putative molecular mechanisms whereby ethanol, at pharmacological concentrations, influences vascular reactivity. (C) 2011 Elsevier Inc. All rights reserved.

A new NO donor failed to release NO and to induce relaxation in the rat basilar artery

Nitric oxide (NO)-donors are pharmacologically active substances that in vivo or in vitro release NO. Their most common side effect is headache caused by cerebral vasodilatation. We previously demonstrated that the new NO-donor Ru(terpy)(bdq)NO](3+) (Terpy), synthesized in our laboratory, induces relaxation of rat aorta. This study aimed to verify the effect of Terpy and sodium nitroprusside (SNP) in basilar artery. We conducted vascular reactivity experiments on endothelium-denuded basilar rings. The concentrations of iron (Fe) and ruthenium (Ru) complex were analyzed in basilar artery lysates after incubation with NO donors by mass spectrometry. We also evaluated the NO released from SNP and Terpy by using confocal microscopy. Interestingly, Terpy did not induce relaxation of the basilar artery. SNP induced relaxation in a concentration-dependent way. NO donors cross the membrane of vascular smooth muscle and entered the cell. In spite of its permeability, Terpy did not release NO in the basilar artery. Otherwise, SNP released NO in the basilar artery cells cytoplasm. Taken together, our results demonstrate that the new NO donor (Terpy) failed to release NO and to induce relaxation in the basilar artery. The NO donor SNP induces vascular relaxation due to NO release in the vascular smooth muscle cells. (C) 2011 Elsevier B.V. All rights reserved.

Impaired beta-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K-Ca channel activity

beta-Adrenoceptor (beta-AR)-mediated relaxation plays an important role in the regulation of vascular tone. beta-AR-mediated vascular relaxation is reduced in various disease states and aging. We hypothesized that beta-AR-mediated vasodilatation is impaired in DOCA-salt hypertension due to alterations in the cAMP pathway. beta-AR-mediated relaxation was determined in small mesenteric arteries from DOCA-salt hypertensive and control uninephrectomized (Uni) rats. To exclude nitric oxide (NO) and cyclooxygenase (COX) pathways, relaxation responses were determined in the presence of L-NNA and indomethacin, NO synthase inhibitor and COX inhibitors, respectively. Isoprenaline (ISO)-induced relaxation was reduced in arteries from DOCA-salt compared to Uni rats. Protein kinase A (PKA) inhibitors (H89 or Rp-cAMPS) or adenylyl cyclase inhibitor (SQ22536) did not abolish the difference in ISO-induced relaxation between the groups. Forskolin (adenylyl cyclase activator)-induced relaxation was similar between the groups. The inhibition of IKCa/SKCa channels (TRAM-34 plus UCL1684) or BKCa channels (iberiotoxin) reduced ISO-induced relaxation only in Uni rats and abolished the relaxation differences between the groups. The expression of SKCa channel was decreased in DOCA-salt arteries. The expression of BKCa channel a subunit was increased whereas the expression of BKCa channel p subunit was decreased in DOCA-salt arteries. The expression of receptor for activated C kinase 1 (RACK1), which is a binding protein for BKG, channel and negatively modulates its activity, was increased in DOCA-salt arteries. These results suggest that the impairment of beta-AR-mediated relaxation in DOCA-salt mesenteric arteries may be attributable to altered IKCa/SKCa and/or BKCa channels activities rather than cAMP/PKA pathway. Impaired beta-AR-stimulated BKCa channel activity may be due to the imbalance between its subunit expressions and RACK1 upregulation. (C) 2012 Elsevier Ltd. All rights reserved.

Aorta from angiotensin II hypertensive mice exhibit preserved nitroxyl anion mediated relaxation responses

Hypertension is a disorder affecting millions worldwide, and is a leading cause of death and debilitation in the United States. It is widely accepted that during hypertension and other cardiovascular diseases the vasculature exhibits endothelial dysfunction; a deficit in the relaxatory ability of the vessel, attributed to a lack of nitric oxide (NO) bioavailability. Recently, the one electron redox variant of NO, nitroxyl anion (NO-) has emerged as an endothelium-derived relaxing factor (EDRF) and a candidate for endothelium-derived hyperpolarizing factor (EDRF). NO- is thought to exist protonated (HNO) in vivo, which would make this species more resistant to scavenging. However, no studies have investigated the role of this redox species during hypertension, and whether the vasculature loses the ability to relax to HNO. Thus, we hypothesize that aorta from angiotensin II (AngII)-hypertensive mice will exhibit a preserved relaxation response to Angeli's Salt, an HNO donor. Male C57B16 mice, aged 12-14 weeks were implanted with mini-osmotic pumps containing AngII (90 ng/min, 14 days plus high salt chow) or sham surgery. Aorta were excised, cleaned and used to perform functional studies in a myograph. We found that aorta from AngII-hypertensive mice exhibited a significant endothelial dysfunction as demonstrated by a decrease in acetylcholine (ACh)-mediated relaxation. However, vessels from hypertensive mice exhibited a preserved response to Angeli's Salt (AS), the HNO donor. To confirm that relaxation responses to HNO were maintained, concentration response curves (CRCs) to ACh were performed in the presence of scavengers to both NO and HNO (carboxy-PTIO and L-cys, resp.). We found that ACh-mediated relaxation responses were significantly decreased in aorta from sham and almost completely abolished in aorta from AngII-treated mice. Vessels incubated with L-cys exhibited a modest decrease in ACh-mediated relaxations responses. These data demonstrate that aorta from AngII-treated hypertensive mice exhibit a preserved relaxation response to AS, an HNO donor, regardless of a significant endothelial dysfunction. (C) 2011 Elsevier Ltd. All rights reserved,

Relaxation of Adaptive Evolution during the HIV-1 Infection Owing to Reduction of CD4+T Cell Counts

Background: The first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. In order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. The diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection. Results: Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N)/d(S)>1) was detected in the viruses within each host in all time points. In the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. In both patients X4 variants never reached high frequencies during infection time. The recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time. Conclusion: Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. The dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection.

Exercise training improves relaxation response and SOD-1 expression in aortic and mesenteric rings from high caloric diet-fed rats

Abstract Background Obesity has been associated with a variety of disease such as type II diabetes mellitus, arterial hypertension and atherosclerosis. Evidences have shown that exercise training promotes beneficial effects on these disorders, but the underlying mechanisms are not fully understood. The aim of this study was to investigate whether physical preconditioning prevents the deleterious effect of high caloric diet in vascular reactivity of rat aortic and mesenteric rings. Methods Male Wistar rats were divided into sedentary (SD); trained (TR); sedentary diet (SDD) and trained diet (TRD) groups. Run training (RT) was performed in sessions of 60 min, 5 days/week for 12 weeks (70–80% VO2max). Triglycerides, glucose, insulin and nitrite/nitrate concentrations (NOx-) were measured. Concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP) were obtained. Expression of Cu/Zn superoxide dismutase (SOD-1) was assessed by Western blotting. Results High caloric diet increased triglycerides concentration (SDD: 216 ± 25 mg/dl) and exercise training restored to the baseline value (TRD: 89 ± 9 mg/dl). Physical preconditioning significantly reduced insulin levels in both groups (TR: 0.54 ± 0.1 and TRD: 1.24 ± 0.3 ng/ml) as compared to sedentary animals (SD: 0.87 ± 0.1 and SDD: 2.57 ± 0.3 ng/ml). On the other hand, glucose concentration was slightly increased by high caloric diet, and RT did not modify this parameter (SD: 126 ± 6; TR: 140 ± 8; SDD: 156 ± 8 and TRD 153 ± 9 mg/dl). Neither high caloric diet nor RT modified NOx- levels (SD: 27 ± 4; TR: 28 ± 6; SDD: 27 ± 3 and TRD: 30 ± 2 μM). Functional assays showed that high caloric diet impaired the relaxing response to ACh in mesenteric (about 13%), but not in aortic rings. RT improved the relaxing responses to ACh either in aortic (28%, for TR and 16%, to TRD groups) or mesenteric rings (10%, for TR and 17%, to TRD groups) that was accompanied by up-regulation of SOD-1 expression and reduction in triglycerides levels. Conclusion The improvement in endothelial function by physical preconditioning in mesenteric and aortic arteries from high caloric fed-rats was directly related to an increase in NO bioavailability to the smooth muscle mostly due to SOD-1 up regulation.

Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats

Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.

Resistance exercise acutely enhances mesenteric artery insulin-induced relaxation in healthy rats

AIMS: We evaluated the mechanisms involved in insulin-induced vasodilatation after acute resistance exercise in healthy rats. MAIN METHODS: Wistar rats were divided into 3 groups: control (CT), electrically stimulated (ES) and resistance exercise (RE). Immediately after acute RE (15 sets with 10 repetitions at 70% of maximal intensity), the animals were sacrificed and rings of mesenteric artery were mounted in an isometric system. After this, concentration-response curves to insulin were performed in control condition and in the presence of LY294002 (PI3K inhibitor), L-NAME (NOS inhibitor), L-NAME+TEA (K(+) channels inhibitor), LY294002+BQ123 (ET-A antagonist) or ouabain (Na(+)/K(+) ATPase inhibitor). KEY FINDINGS: Acute RE increased insulin-induced vasorelaxation as compared to control (CT: Rmax=7.3 ± 0.4% and RE: Rmax=15.8 ± 0.8%; p<0.001). NOS inhibition reduced (p<0.001) this vasorelaxation from both groups (CT: Rmax=2.0 ± 0.3%, and RE: Rmax=-1.2 ± 0.1%), while PI3K inhibition abolished the vasorelaxation in CT (Rmax=-0.1±0.3%, p<0.001), and caused vasoconstriction in RE (Rmax=-6.5 ± 0.6%). That insulin-induced vasoconstriction on PI3K inhibition was abolished (p<0.001) by the ET-A antagonist (Rmax=2.9 ± 0.4%). Additionally, acute RE enhanced (p<0.001) the functional activity of the ouabain-sensitive Na(+)/K(+) ATPase activity (Rmax=10.7 ± 0.4%) and of the K(+) channels (Rmax=-6.1±0.5%; p<0.001) in the insulin-induced vasorelaxation as compared to CT. SIGNIFICANCE: Such results suggest that acute RE promotes enhanced insulin-induced vasodilatation, which could act as a fine tuning to vascular tone.