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Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation–contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.

Increased fructose consumption is among bad nutritional habits that contribute to increased incidence of neurodegenerative diseases. We proposed that coffee, the most popular beverage worldwide, may protect against the progression of Alzheimer's disease (AD). We investigated the protective potential of decaffeinated green coffee bean extract (GCBE) and the possible potentiation of pioglitazone (PIO) effects by decaffeinated GCBE in fructose-induced AD in rats. Twenty-four rats [12-untreated and 12-pre-treated (for 4 weeks) with GCBE] consumed drinking water supplemented with 10% fructose for 18 weeks. Twelve of these rats (6-GCBE-untreated and 6-GCBE-pre-treated) were treated orally with PIO starting on the 13th week for 6 weeks. Prophylactic administration of GCBE attenuated oxidative damage (increased cortical reduced glutathione and superoxide dismutase activity), while decreased malondialdehyde. It retarded the activation of acetylcholine esterase, increased acetylcholine level in the cortex of fructose-induced AD. It also impeded the upregulation of beta-secretase-1and the accumulation of Aβ plaques that were induced by fructose drinking. With PIO therapy, GCBE showed better effects alleviating oxidative stress and Aβ extracellular plaques formation, while improving cholinergic activity, learning, and memory ability. In conclusions, the consumption of GCBE may protect against the development of AD and delay the progression of AD when given with PIO. PRACTICAL APPLICATIONS: Decaffeinated dietary supplement of green coffee bean extract attenuated the deleterious consequences of fructose-induced Alzheimer's disease in rats. It improved the antioxidant status and cortical cholinergic activity, while hindered the changes responsible for amyloid plaque formation. It also improved the impaired learning and memory. These results, if confirmed by clinical studies, may recommend the consumption of decaffeinated green coffee beans extract as dietary supplement or as a regular beverage to protect against AD in individuals with family history or early signs of AD. With pioglitazone, such dietary supplement improved pioglitazone efficacy and delayed the progression of AD.

Objectives: Glycated hemoglobin (HbA1c) is the most commonly used glycemic index among diabetic patients. The present study sought to investigate the relationship between HbA1c and lipid parameters among healthy pregnancies and gestational diabetic cases. Materials and Methods: Seventy-five Saudi pregnant women within the age group of 19 to 43 years were selected for this crosssectional study. The participants were categorized into with and without gestational diabetes (GDM), all of whom were non-smokers; in addition, they neither had a previous history of chronic illnesses nor were they on any medications which could alter lipid profile and HbA1c concentrations. Totally, 75 g of oral glucose tolerance test (OGTT) was utilized to identify 25 women with GDM. All biochemical tests including HbA1c, fasting blood sugar (FBG), total cholesterol (TC), low-density lipoprotein (LDL-cholesterol), triglycerides (TG), and high-density lipoprotein (HDL-cholesterol) were performed by a biochemical auto-analyzer. The collected data were statistically analyzed using a paired student’s t test. The P values of

Depression is the most common illness that affects a large number of individuals in all countries. It is believed that decreased levels of neurotransmitters such as serotonin, norepinephrine and dopamine are the main cause of depression. Selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs), their mechanism is to increase the amount of neurotransmitters in the CNS. Design, synthesis and molecular docking of novel compounds namely amino acetylenic derivatives of aryloxy as isostere for aryloxypropylamine. The reaction of 7-methoxy-2-naphthol with propargylbromide generated 7-methoxy-2-(prop-2-yn-1-yloxy) naphthalene (ZR-1). ZR-1 was subjected to Mannich reaction yielded the derivatives of aryloxybutynylamines (ZR-2 to ZR-7). The Mp, FTIR, 1H-NMR, C13-NMR, DSC, elemental analysis and HPLC were consistent with the assigned structures. The molecular docking results obtained for aminoacetylenic compounds showed that the new novel 7-methoxy-2- {[4- (piperidine) but-2-yn-1-yl]oxy}-naphthalene (ZR-4) provide effective π overlap with binding sites of SERT protein by ionic, hydrogen bonding and overlap of aryl and cyclic amine moieties with the amino acids of transporter protein, which produce the binding energy (-109,69 kcal/mol) for ZR-4 relative to paroxetine (-114.18 kcal/mol), that may lead to promising drug in the treatment of depression.

The present study aims to emphasize the enhanced efficacy of long acting in-situ gel forming implants (ISGFI) based on poly (lactic-co-glycolic acid) (PLGA) matrix to deliver anti-psychotic risperidone over extended time periods with reduced administration frequency. Schizophrenic patients show considerable difficulties in adherence and compliance to oral medications associated with negative outcomes including symptoms exacerbation and psychotic relapse. The studied optimized ISGFI formulation, comprised of 2.85:1 ratio of DMSO solvent:PLGA (type 75:25), was subjected to various characterization studies including morphological real-time changes, scanning electron microscopy and in-vitro drug release study. Pharmacokinetics and behavioral evaluations of anti-psychotic action of ISGFI systems were pursued on healthy and schizophrenia-induced rats respectively then compared to results of marketed microspheres. Morphological observations showed the immediate formation of whitish smooth ISGFI system owing to the rapid PLGA solidification after rapid DMSO dissipation into the external medium. Scanning electron microscopy confirmed the slow gradual biodegradation of the formed ISGFI. The optimized formulation assured its effectiveness to produce satisfactory initial burst and cumulative risperidone release and obviate costs of additional tablets needed during the commercial product use. Pharmacokinetic study manifested the effective performance of ISGFI to extend risperidone release for longer period (72 days) in comparison to the marketed formulations (48 days). Besides, optimized ISGFI were more effective in improving ketamine-induced schizophrenia-like symptoms in experimental rats, particularly in the first week of study period. Meanwhile, in-vitro, pharmacokinetic and pharmacodynamic evaluations had advocated the potential advantages of ISGFI systems for treating schizophrenia with improved adherence and compliance of patients.

Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.

Overwhelming evidence indicates that consumption of fruits and vegetables with antioxidant properties correlates with reduced risk for cancers, including leukemia. Carrots contain beneficial agents, such as β-carotene and polyacetylenes, which could be effective in the treatment of leukemia. This study investigated the effect of carrot juice extracts on myeloid and lymphoid leukemia cell lines together with normal hematopoietic stem cells. Leukemia cell lines and nontumor control cells were treated with carrot juice extracts for up to 72 hours in vitro. Induction of apoptosis was investigated by using annexin V/propidium iodide staining followed by flow cytometric analysis, and results were confirmed by using 4'-6-diamidino-2-phenylindole morphology. Effects on cellular proliferation were investigated via cell cycle analysis and cell counts. Treatment of leukemia cell lines with carrot juice extract induced apoptosis and inhibited progression through the cell cycle. Lymphoid cell lines were affected to a greater extent than were myeloid cell lines, and normal hematopoietic stem cells were less sensitive than most cell lines. This study has shown that extracts from carrots can induce apoptosis and cause cell cycle arrest in leukemia cell lines. The findings suggest that carrots may be an excellent source of bioactive chemicals for the treatment of leukemia.

New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.

Exogam, Diamant, Matière Nucléaire; The structure of the very neutron-deficient rare-earth nuclei has been investigated in the first experiment with the EXOGAM gamma array coupled to the DIAMANT light charged particle detector using radioactive beam of $^{76}$Kr delivered by the SPIRAL facility. Very neutron-deficient Pr, Nd and Pm isotopes have been populated at rather high spin by the reaction $^{76}$Kr + $^{58}$Ni at a beam energy of 328 MeV. We report here the first results of this experiment.

In nanoparticle image velocimentry (nPIV), evanescent wave illumination is used to measure near-wall velocity fields with an out-of-plane resolution of less than 200nm. Similar methodology can be extended for temperature measurements using Brownian motion characteristics of the sub-micron tracer particles in this region. Temperature change affects Brownian motion of tracer particles through a change in Brownian diffusion coefficient and a change in viscosity. The present study tries to numerically investigate the possibilities of utilizing this effect in near-wall thermometry. Synthetic nPIV images of the illuminated particle tracer of 100nm diameter are initially generated. The spatial distribution of the particles takes in to account near wall forces such as buoyancy, electrostatic repulsion and Van Der Waals attraction, in addition to the hindered Brownian motion. Validation studies are carried out using stationary liquids at constant temperatures. It is believed that this observation would help in explaining the anomalous heat transfer characteristics of nanofluids.

The endogenous fatty acid ethanolamide, palmitylethanolamide, alleviated, in a dose-dependent manner, pain behaviors elicited in mice by injections of formalin (5%, intraplantar), acetic acid (0.6%, 0.5 ml per animal, intraperitoneal, i.p.), kaolin (2.5 mg per animal, i.p.), and magnesium sulfate (120 mg per kg, i.p.). The antinociceptive effects of palmitylethanolamide were prevented by the cannabinoid CB2receptor antagonist SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5- (4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], not by the cannabinoid CB1receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide · HCl]. By contrast, palmitylethanolamide had no effect on capsaicin-evoked pain behavior or thermal nociception. The endogenous cannabinoid, anandamide (arachidonylethanolamide), alleviated nociception in all tests (formalin, acetic acid, kaolin, magnesium sulfate, capsaicin and hot plate). These effects were prevented by the cannabinoid CB1receptor antagonist SR141716A, not the cannabinoid CB2receptor antagonist SR141716A. Additional fatty acid ethanolamides (oleylethanolamide, myristylethanolamide, palmitoleylethanolamide, palmitelaidylethanolamide) had little or no effect on formalin-evoked pain behavior, and were not investigated in other pain models. These results support the hypothesis that endogenous palmitylethanolamide participates in the intrinsic control of pain initiation. They also suggest that the putative receptor site activated by palmitylethanolamide may provide a novel target for peripherally acting analgesic drugs. © 2001 Elsevier Science B.V.

The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg-1, intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB1cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB1cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg-1, i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs. © 2006 Nature Publishing Group All rights reserved.