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Zoology     Hybrid Journal   (Followers: 6, SJR: 0.875, h-index: 30)

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Journal Cover   Pharmacological Research
  [SJR: 1.693]   [H-I: 84]   [5 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2586 journals]
  • Classical and atypical agonists activate M1 muscarinic acetylcholine
           receptors through common mechanisms
    • Abstract: Publication date: Available online 13 April 2015
      Source:Pharmacological Research
      Author(s): Alena Randáková , Eva Dolejší , Vladimír Rudajev , Pavel Zimčík , Vladimír Doležal , Esam E. El-Fakahany , Jan Jakubík
      We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline.
      Graphical abstract image

      PubDate: 2015-04-17T05:15:30Z
  • The multifaceted mitochondrion: An attractive candidate for therapeutic
    • Abstract: Publication date: Available online 24 March 2015
      Source:Pharmacological Research
      Author(s): Flavie Strappazzon , Francesco Cecconi
      Mitochondria are considered the powerhouse of the cell and disturbances in mitochondrial functions are involved in several disorders such as neurodegeneration and mitochondrial diseases. This review summarizes pharmacological strategies that aim at modifying the number of mitochondria, their dynamics or the mitochondrial quality-control mechanisms, in several pathological instances in which any of these mechanisms are impaired or abnormal. The interplay between different cellular pathways that involve mitochondria in order to respond to stress is highlighted. Such a high mitochondrial plasticity could be exploited for new treatments.
      Graphical abstract image

      PubDate: 2015-04-04T03:55:44Z
  • Insulin-like growth factor 1 (IGF-1) expression is up-regulated in
    • Abstract: Publication date: July 2013
      Source:Pharmacological Research, Volume 73
      Author(s): Alessio Squassina , Marta Costa , Donatella Congiu , Mirko Manchia , Andrea Angius , Valeria Deiana , Raffaella Ardau , Caterina Chillotti , Giovanni Severino , Stefano Calza , Maria Del Zompo
      Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p =0.005; sample 2, fold change=2.21; p =0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • MicroRNAs as pharmacological targets in endothelial cell function and
    • Abstract: Publication date: September 2013
      Source:Pharmacological Research, Volume 75
      Author(s): Aránzazu Chamorro-Jorganes , Elisa Araldi , Yajaira Suárez
      Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative, migratory and morphogenic capacities of endothelial cells, as well as control of leukocyte trafficking. MicroRNAs are short non-coding RNAs that have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level. This review summarizes the latest insights in the identification of endothelial-specific microRNAs and their targets, as well as their roles in controlling endothelial cell functions in both autocrine and paracrine manner. In addition, we discuss the therapeutic potential for the treatment of endothelial cell dysfunction and associated vascular pathophysiological conditions.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320,
           shows significant therapeutic effects in a mouse model of muscular
    • Abstract: Publication date: September 2011
      Source:Pharmacological Research, Volume 64, Issue 3
      Author(s): Clara Sciorati , Daniela Miglietta , Roberta Buono , Viviana Pisa , Dario Cattaneo , Emanuele Azzoni , Silvia Brunelli , Emilio Clementi
      A resolutive therapy for muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration and in the severe forms to death, is still lacking. Since inflammation and defects in nitric oxide generation are recognized key pathogenic events in muscular dystrophy, we have analysed the effects of a derivative of ibuprofen, NCX 320, belonging to the class of cyclooxygenase inhibiting nitric oxide donator (CINOD), in the α-sarcoglycan null mice, a severe mouse model of dystrophy. NCX 320 was administered daily in the diet for 8months starting 1month from weaning. Muscle functional recovery was evaluated by free wheel and treadmill tests at 8months. Serum creatine kinase activity, as well as the number of diaphragm inflammatory infiltrates and necrotic fibres, was measured as indexes of skeletal muscle damage. Muscle regeneration was evaluated in diaphragm and tibialis anterior muscles, measuring the numbers of centronucleated fibres and of myogenic precursor cells. NCX 320 mitigated muscle damage, reducing significantly serum creatine kinase activity, the number of necrotic fibres and inflammatory infiltrates. Moreover, NCX 320 stimulated muscle regeneration increasing significantly the number of myogenic precursor cells and regenerating fibres. All these effects concurred in inducing a significant improvement of muscle function, as assessed by both free wheel and treadmill tests. These results describe the properties of a new compound incorporating nitric oxide donation together with anti-inflammatory properties, showing that it is effective in slowing muscle dystrophy progression long term. Of importance, this new compound deserves specific attention for its potential in the therapy of muscular dystrophy given that ibuprofen is well tolerated in paediatric patients and with a profile of safety that makes it suitable for chronic treatment such as the one required in muscular dystrophies.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • Nicotinamide-rich diet protects the heart against
           ischaemia–reperfusion in mice: A crucial role for cardiac SUR2A
    • Abstract: Publication date: June 2010
      Source:Pharmacological Research, Volume 61, Issue 6
      Author(s): Andriy Sukhodub , Qingyou Du , Sofija Jovanović , Aleksandar Jovanović
      It is a consensus view that a strategy to increase heart resistance to ischaemia–reperfusion is a warranted. Here, based on our previous study, we have hypothesized that a nicotinamide-rich diet could increase myocardial resistance to ischaemia–reperfusion. Therefore, the purpose of this study was to determine whether nicotinamide-rich diet would increase heart resistance to ischaemia–reperfusion and what is the underlying mechanism. Experiments have been done on mice on control and nicotinamide-rich diet (mice were a week on nicotinamide-rich diet) as well as on transgenic mice overexpressing SUR2A (SUR2A mice), a regulatory subunit of cardioprotective ATP-sensitive K+ (KATP) channels and their littermate controls (WT). The levels of mRNA in heart tissue were measured by real-time RT-PCR, whole heart and single cell resistance to ischaemia–reperfusion and severe hypoxia was measured by TTC staining and laser confocal microscopy, respectively. Nicotinamide-rich diet significantly decreased the size of myocardial infarction induced by ischaemia–reperfusion (from 42.5±4.6% of the area at risk zone in mice on control diet to 26.8±1.8% in mice on nicotinamide-rich diet, n =6–12, P =0.031). The cardioprotective effect of nicotinamide-rich diet was associated with 11.46±1.22 times (n =6) increased mRNA levels of SUR2A in the heart. HMR1098, a selective inhibitor of the sarcolemmal KATP channels opening, abolished cardioprotection afforded by nicotinamide-rich diet. Transgenic mice with a sole increase in SUR2A expression had also increased cardiac resistance to ischaemia–reperfusion. We conclude that nicotinamide-rich diet up-regulate SUR2A and increases heart resistance to ischaemia–reperfusion.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • Enalapril treatment discloses an early role of angiotensin II in
           inflammation- and oxidative stress-related muscle damage in dystrophic mdx
    • Abstract: Publication date: November 2011
      Source:Pharmacological Research, Volume 64, Issue 5
      Author(s): Anna Cozzoli , Beatrice Nico , Valeriana Teresa Sblendorio , Roberta Francesca Capogrosso , Maria Maddalena Dinardo , Vito Longo , Sara Gagliardi , Monica Montagnani , Annamaria De Luca
      Inhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5mg/kg enalapril i.p. for 4–8 weeks have been compared with those of 1mg/kg α-methyl-prednisolone (PDN), as positive control. Enalapril caused a dose-dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-β1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest the ability of enalapril to blunt angiotensin-II dependent activation of pro-inflammatory and pro-oxidant pathways which may be earlier events with respect to the pro-fibrotic ones, and may in part account for both functional impairment and muscle necrosis. The PDN-like profile may corroborate the combined use of the two classes of drugs in DMD patients so to potentiate the beneficial effects at skeletal muscle level, while reducing both spontaneous and PDN-aggravated cardiomyopathy.
      Graphical abstract image Highlights ► An early treatment with enalapril was performed in exercised mdx mice. ► In vivo, enalapril increased mouse fore limb strength dose-dependently. ► Ex vivo, enalapril reduced muscular markers of oxidative stress and inflammation. ► Results corroborate an early role of angiotensin II in muscular dystrophy. ► Pre-clinical evidences of therapeutic interest of ACE inhibitors for therapy of DMD.

      PubDate: 2015-03-18T16:09:25Z
  • Matrix metalloproteinases: Targets for doxycycline to prevent the vascular
           alterations of hypertension
    • Abstract: Publication date: December 2011
      Source:Pharmacological Research, Volume 64, Issue 6
      Author(s): Michele M. Castro , Jose E. Tanus-Santos , Raquel F. Gerlach
      Hypertension is associated with well known structural and functional alterations in both resistance and conduit arteries, which may be the result from long-lasting high blood pressure and may also be the cause of maintained hypertension and its complications. Therefore, in addition to lowering blood pressure, therapeutic strategies targeting the structural and functional modifications found in hypertensive patients may prevent the cardiovascular events and decrease the death rates associated with hypertension. Mounting evidence indicates that many vascular alterations associated with sustained hypertension are due to imbalanced matrix metalloproteinases (MMPs), a family of zinc-endopeptidases that degrade not only proteins of extracellular matrix (ECM) but several other substrates. Recent observations showed that abnormal MMP activity is a feature of the pathogenesis of hypertension and other diseases, thus justifying the development of drugs aiming at MMP downregulation. This review focuses on the extracellular actions of MMPs in hypertension-induced chronic vascular alterations. We then discuss the effects of MMP inhibitors, especially doxycycline, on the vascular changes associated with hypertension. There is now strong evidence that MMP inhibition with doxycycline (and maybe other MMP inhibitors) may attenuate the functional and structural alterations associated with hypertension, including increases in arterial stiffness. These beneficial effects may be, at least in part, independent of their antihypertensive effects.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • Functional expression of choline transporter-like protein 1 (CTL1) in
           small cell lung carcinoma cells: A target molecule for lung cancer therapy
    • Abstract: Publication date: October 2013
      Source:Pharmacological Research, Volume 76
      Author(s): Masato Inazu , Tomoko Yamada , Nobuo Kubota , Tsuyoshi Yamanaka
      Choline is essential for the synthesis of the major membrane phospholipid phosphatidylcholine and the neurotransmitter acetylcholine (ACh). Elevated levels of choline and up-regulated choline kinase activity have been detected in cancer cells. Thus, the intracellular accumulation of choline through choline transporters is the rate-limiting step in phospholipid metabolism and a prerequisite for cancer cell proliferation. However, the uptake system for choline and the functional expression of choline transporters in lung cancer cells are poorly understood. We examined the molecular and functional characterization of choline uptake in the small cell lung carcinoma cell line NCI-H69. Choline uptake was saturable and mediated by a single transport system. Interestingly, removal of Na+ from the uptake buffer strongly enhanced choline uptake. This increase in choline uptake under the Na+-free conditions was inhibited by dimethylamiloride (DMA), a Na+/H+ exchanger (NHE) inhibitor. Various organic cations and the choline analog hemicholinium-3 (HC-3) inhibited the choline uptake and cell viability. A correlation analysis of the potencies of organic cations for the inhibition of choline uptake and cell viability showed a strong correlation (R =0.8077). RT-PCR revealed that choline transporter-like protein 1 (CTL1) mRNA and NHE1 are mainly expressed. HC-3 and CTL1 siRNA inhibited choline uptake and cell viability, and increased caspase-3/7 activity. The conversion of choline to ACh was confirmed, and this conversion was enhanced under Na+-free conditions, which in turn was sensitive to HC-3. These results indicate that choline uptake through CTL1 is used for ACh synthesis. Both an acetylcholinesterase inhibitor (eserine) and a butyrylcholinesterase inhibitor (ethopropazine) increased cell proliferation, and these effects were inhibited by 4-DAMP, a mAChR3 antagonist. We conclude that NCI-H69 cells express the choline transporter CTL1 which uses a directed H+ gradient as a driving force, and its transport functions in co-operation with NHE1. This system primarily supplies choline for the synthesis of ACh and secretes ACh to act as an autocrine/paracrine growth factor, and the functional inhibition of CTL1 could promote apoptotic cell death. Identification of this new CTL1-mediated choline transport system provides a potential new target for therapeutic intervention.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • Long-term liraglutide treatment is associated with increased insulin
           content and secretion in β-cells, and a loss of α-cells in ZDF
    • Abstract: Publication date: October 2013
      Source:Pharmacological Research, Volume 76
      Author(s): Tiffany Schwasinger-Schmidt , David C. Robbins , S. Janette Williams , Lesya Novikova , Lisa Stehno-Bittel
      The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. Our aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8±22.5 and 547.2±33.1mg/dl, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2±0.7 pixel units in vehicle-treated rats, and 54.9±0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the α-cell numbers/area with liraglutide treatment (6.5cells/field), compared to vehicle (17.9cells/field). There was an increase in β-cell numbers, the β- to α-cell ratio that was statistically higher in the liraglutide-treated rats (24.3±4.4) compared to vehicle (9.1±2.8). Disrupted mitochondria were more commonly observed in the α-cells (51.9±10.3% of cells) than in the β-cells (27.2±4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of α- to β-cells was decreased and there was an absolute reduction in islet α-cell content. There was selective disruption of intracellular α-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.
      Graphical abstract image

      PubDate: 2015-03-18T16:09:25Z
  • Cyclooxygenase metabolism mediates vasorelaxation to
           2-arachidonoylglycerol (2-AG) in human mesenteric arteries
    • Abstract: Publication date: March 2014
      Source:Pharmacological Research, Volume 81
      Author(s): Christopher P. Stanley , Saoirse E. O'Sullivan
      Objective The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans. Approach Mesenteric arteries were obtained from patients receiving colorectal surgery and mounted on a myograph. Arteries were contracted and 2-AG concentration–response curves were carried out. Mechanisms of action were characterised pharmacologically. Post hoc analysis was carried out to assess the effects of cardiovascular disease/risk factors on 2-AG responses. Results 2-AG caused vasorelaxation of human mesenteric arteries, independent of cannabinoid receptor or transient receptor potential vanilloid-1 activation, the endothelium, nitric oxide or metabolism via monoacyglycerol lipase or fatty acid amide hydrolase. 2-AG-induced vasorelaxation was reduced in the presence of indomethacin and flurbiprofen, suggesting a role for cyclooxygenase metabolism 2-AG. Responses to 2-AG were also reduced in the presence of Cay10441, L-161982 and potentiated in the presence of AH6809, suggesting that metabolism of 2-AG produces both vasorelaxant and vasoconstrictor prostanoids. Finally, 2-AG-induced vasorelaxation was dependent on potassium efflux and the presence of extracellular calcium. Conclusions We have shown for the first time that 2-AG causes vasorelaxation of human mesenteric arteries. Vasorelaxation is dependent on COX metabolism, activation of prostanoid receptors (EP4 & IP) and ion channel modulation. 2-AG responses are blunted in patients with cardiovascular risk factors.
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      PubDate: 2015-03-18T16:09:25Z
  • Defining the blanks – Pharmacochaperoning of SLC6 transporters and
           ABC transporters
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): Peter Chiba , Michael Freissmuth , Thomas Stockner
      SLC6 family members and ABC transporters represent two extremes: SLC6 transporters are confined to the membrane proper and only expose small segments to the hydrophilic milieu. In ABC transporters the hydrophobic core is connected to a large intracellular (eponymous) ATP binding domain that is comprised of two discontiguous repeats. Accordingly, their folding problem is fundamentally different. This can be gauged from mutations that impair the folding of the encoded protein and give rise to clinically relevant disease phenotypes: in SLC6 transporters, these cluster at the protein–lipid interface on the membrane exposed surface. Mutations in ABC-transporters map to the interface between nucleotide binding domains and the coupling helices, which provide the connection to the hydrophobic core. Folding of these mutated ABC-transporters can be corrected with ligands/substrates that bind to the hydrophobic core. This highlights a pivotal role of the coupling helices in the folding trajectory. In contrast, insights into pharmacochaperoning of SLC6 transporters are limited to monoamine transporters – in particular the serotonin transporter (SERT) – because of their rich pharmacology. Only ligands that stabilize the inward facing conformation act as effective pharmacochaperones. This indicates that the folding trajectory of SERT proceeds via the inward facing conformation. Mutations that impair folding of SLC6 family members can be transmitted as dominant or recessive alleles. The dominant phenotype of the mutation can be rationalized, because SLC6 transporters are exported in oligomeric form from the endoplasmic reticulum (ER). Recessive transmission requires shielding of the unaffected gene product from the mutated transporter in the ER. This can be accounted for by a chaperone-COPII (coatomer protein II) exchange model, where proteinaceous ER-resident chaperones engage various intermediates prior to formation of the oligomeric state and subsequent export from the ER. It is likely that the action of pharmacochaperones is contingent on and modulated by these chaperones.
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      PubDate: 2015-03-18T16:09:25Z
  • Novel therapeutic strategies for ischemic heart disease
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Adam J. Perricone , Richard S. Vander Heide
      Despite significant advances in the physician's ability to initiate myocardial reperfusion and salvage heart tissue, ischemic heart disease remains one of the leading causes of death in the United States. Consequently, alternative therapeutic strategies have been intensively investigated, especially methods of enhancing the heart's resistance to ischemic cell death – so called “cardioprotective” interventions. However, although a great deal has been learned regarding the methods and mechanisms of cardioprotective interventions, an efficacious therapy has yet to be successfully implemented in the clinical arena. This review discusses the current understanding of cardioprotection in the context of ischemic heart disease pathophysiology, highlighting those elements of ischemic heart disease pathophysiology that have received less attention as potential targets of cardioprotective intervention.
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      PubDate: 2015-03-18T16:09:25Z
  • Naltrexone/bupropion for obesity: An investigational combination
           pharmacotherapy for weight loss
    • Abstract: Publication date: June 2014
      Source:Pharmacological Research, Volume 84
      Author(s): Sonja K. Billes , Puspha Sinnayah , Michael A. Cowley
      The mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss.
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      PubDate: 2015-03-18T16:09:25Z
  • α1 and α2-adrenoceptors in the medial amygdaloid nucleus
           modulate differently the cardiovascular responses to restraint stress in
    • Abstract: Publication date: August 2012
      Source:Pharmacological Research, Volume 66, Issue 2
      Author(s): Eduardo Albino Trindade Fortaleza , América Augusto Scopinho , Fernando Morgan de Aguiar Corrêa
      Medial amygdaloid nucleus (MeA) neurotransmission has an inhibitory influence on cardiovascular responses in rats submitted to restraint, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. In the present study, we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during an acute restraint. Male Wistar rats received bilateral microinjections of the selective α1-adrenoceptor antagonist WB4101 (10, 15, and 20nmol/100nL) or the selective α2-adrenoceptor antagonist RX821002 (10, 15, and 20nmol/nL) into the MeA, before the exposure to acute restraint. The injection of WB4101 reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no influence on BP increases observed during the acute restraint. Our findings indicate that α1 and α2-adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that α1-adrenoceptors and α2-adrenoceptors mediate the MeA-related facilitatory and inhibitory influences on restraint-related HR responses, respectively.
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      PubDate: 2015-03-18T16:09:25Z
  • The anabolic/androgenic steroid nandrolone exacerbates gene expression
           modifications induced by mutant SOD1 in muscles of mice models of
           amyotrophic lateral sclerosis
    • Abstract: Publication date: February 2012
      Source:Pharmacological Research, Volume 65, Issue 2
      Author(s): Mariarita Galbiati , Elisa Onesto , Arianna Zito , Valeria Crippa , Paola Rusmini , Raffaella Mariotti , Marina Bentivoglio , Caterina Bendotti , Angelo Poletti
      Anabolic/androgenic steroids (AAS) are drugs that enhance muscle mass, and are often illegally utilized in athletes to improve their performances. Recent data suggest that the increased risk for amyotrophic lateral sclerosis (ALS) in male soccer and football players could be linked to AAS abuse. ALS is a motor neuron disease mainly occurring in sporadic (sALS) forms, but some familial forms (fALS) exist and have been linked to mutations in different genes. Some of these, in their wild type (wt) form, have been proposed as risk factors for sALS, i.e. superoxide dismutase 1 (SOD1) gene, whose mutations are causative of about 20% of fALS. Notably, SOD1 toxicity might occur both in motor neurons and in muscle cells. Using gastrocnemius muscles of mice overexpressing human mutant SOD1 (mutSOD1) at different disease stages, we found that the expression of a selected set of genes associated to muscle atrophy, MyoD, myogenin, atrogin-1, and transforming growth factor (TGF)β1, is up-regulated already at the presymptomatic stage. Atrogin-1 gene expression was increased also in mice overexpressing human wtSOD1. Similar alterations were found in axotomized mouse muscles and in cultured ALS myoblast models. In these ALS models, we then evaluated the pharmacological effects of the synthetic AAS nandrolone on the expression of the genes modified in ALS muscle. Nandrolone administration had no effects on MyoD, myogenin, and atrogin-1 expression, but it significantly increased TGFβ1 expression at disease onset. Altogether, these data suggest that, in fALS, muscle gene expression is altered at early stages, and AAS may exacerbate some of the alterations induced by SOD1 possibly acting as a contributing factor also in sALS.
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      PubDate: 2015-03-18T16:09:25Z
  • Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat
           cerebral cortex
    • Abstract: Publication date: May 2013
      Source:Pharmacological Research, Volume 71
      Author(s): Clarissa Vasconcelos de Oliveira , Vinícius Rafael Funck , Letícia Meier Pereira , Jéssica Grigoletto , Leonardo Magno Rambo , Leandro Rodrigo Ribeiro , Luiz Fernando Freire Royes , Ana Flávia Furian , Mauro Schneider Oliveira
      Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects.
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      PubDate: 2015-03-18T16:09:25Z
  • Erythroid induction of K562 cells treated with mithramycin is associated
           with inhibition of raptor gene transcription and mammalian target of
           rapamycin complex 1 (mTORC1) functions
    • Abstract: Publication date: Available online 3 December 2014
      Source:Pharmacological Research
      Author(s): Alessia Finotti , Nicoletta Bianchi , Enrica Fabbri , Monica Borgatti , Giulia Breveglieri , Jessica Gasparello , Roberto Gambari
      Rapamycin, an inhibitor of mTOR activity, is a potent inducer of erythroid differentiation and fetal hemoglobin production in β-thalassemic patients. Mithramycin (MTH) was studied to see if this inducer of K562 differentiation also operates through inhibition of mTOR. We can conclude from the study that the mTOR pathway is among the major transcript classes affected by mithramycin-treatment in K562 cells and a sharp decrease of raptor protein production and p70S6 kinase is detectable in mithramycin treated K562 cells. The promoter sequence of the raptor gene contains several Sp1 binding sites which may explain its mechanism of action. We hypothesize that the G+C-selective DNA-binding drug mithramycin is able to interact with these sequences and to inhibit the binding of Sp1 to the raptor promoter due to the following results: (a) MTH strongly inhibits the interactions between Sp1 and Sp1-binding sites of the raptor promoter (studied by electrophoretic mobility shift assays, EMSA); (b) MTH strongly reduces the recruitment of Sp1 transcription factor to the raptor promoter in intact K562 cells (studied by chromatin immunoprecipitation experiments, ChIP); (c) Sp1 decoy oligonucleotides are able to specifically inhibit raptor mRNA accumulation in K562 cells. In conclusion, raptor gene expression is involved in mithramycin-mediated induction of erythroid differentiation of K562 cells and one of its mechanism of action is the inhibition of Sp1 binding to the raptor promoter.
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      PubDate: 2014-12-07T02:49:27Z
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