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Journal Cover Pharmacological Research
  [SJR: 1.693]   [H-I: 84]   [3 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2970 journals]
  • Targeting the cannabinoid CB2 receptor to attenuate the progression of
           motor deficits in LRRK2-transgenic mice
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Cristina Palomo-Garo, Yolanda Gómez-Gálvez, Concepción García, Javier Fernández-Ruiz
      Most of cases of Parkinson’s disease (PD) have a sporadic origin, with their causes mostly unknown, although overexposure to some environmental factors has been found to occur in some cases. Other forms of parkinsonism are the consequence of dominant or recessive mutations in specific genes, e.g. α-synuclein, parkin and, more recently, leucine-rich repeat kinase 2 (LRRK2), whose G2019S mutation represents the most prevalent form of late-onset, autosomal dominant familial PD. A transgenic mouse model expressing the G2019S mutation of LRRK2 is already available and apparently may represent a valuable experimental model for investigating PD pathogenesis and novel treatments. We designed a long-term study with these animals aimed at: (i) elucidating the changes experienced by the endocannabinoid signaling system in the basal ganglia during the progression of the disease in these mice, paying emphasis in the CB2 receptor, which has emerged as a promising target in PD, and (ii) evaluating the potential of compounds selectively activating this CB2 receptor, as disease-modifying agents in these mice. Our results unequivocally demonstrate that LRRK2 transgenic mice develop motor impairment consisting of small anomalies in rotarod performance (presumably reflecting a deficit in motor coordination and dystonia) and a strong deficiency in the hanging-wire test (reflecting muscle weakness), rather than hypokinesia which was difficult to be demonstrated in the actimeter. These behavioral responses occurred in absence of any evidence of reactive gliosis and neuronal losses, as well as synaptic deterioration in the basal ganglia, except an apparent impairment in autophagy reflected by elevated LAMP-1 immunolabelling in the striatum and substantia nigra. Furthermore, there were no changes in the status of the CB2 receptor, as well as in other elements of the endocannabinoid signaling, in the basal ganglia, but, paradoxically, the selective activation of this receptor partially reversed the deficits in the hanging-wire test of LRRK2 transgenic mice. This was accompanied by normalization in LAMP-1 immunolabelling in the basal ganglia, although it is possible that other CNS structures, remaining to be identified, are involved in the behavioral improvement. In summary, our data support the interest of the CB2 receptor as a potential pharmacological target in LRRK2 transgenic mice, although the neuronal substrates underlying these benefits might be not completely related to the basal ganglia and to the presumed parkinsonian features of these mice.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Where’s my entourage? The curious case of 2-oleoylglycerol,
           2-linolenoylglycerol, and 2-palmitoylglycerol
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Natalia Murataeva, Amey Dhopeshwarkar, Danielle Yin, José Mitjavila, Heather Bradshaw, Alex Straiker, Ken Mackie
      2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid in the brain and an agonist at two cannabinoid receptors (CB1 and CB2). The synthesis, degradation and signaling of 2-AG have been investigated in detail but its relationship to other endogenous monoacylglycerols has not been fully explored. Three congeners that have been isolated from the CNS are 2-linoleoylglycerol (2-LG), 2-oleoylglycerol (2-OG), and 2-palmitoylglycerol (2-PG). These lipids do not orthosterically bind to cannabinoid receptors but are reported to potentiate the activity of 2-AG, possibly through inhibition of 2-AG degradation. This phenomenon has been dubbed the ‘entourage effect’ and has been proposed to regulate synaptic activity of 2-AG. To clarify the activity of these congeners of 2-AG we tested them in neuronal and cell-based signaling assays. The signaling profile for these compounds is inconsistent with an entourage effect. None of the compounds inhibited neurotransmission via CB1 in autaptic neurons. Interestingly, each failed to potentiate 2-AG-mediated depolarization-induced suppression of excitation (DSE), behaving instead as antagonists. Examining other signaling pathways we found that 2-OG interferes with agonist-induced CB1 internalization while 2-PG modestly internalizes CB1 receptors. However in tests of pERK, cAMP and arrestin recruitment, none of the acylglycerols altered CB1 signaling. Our results suggest 1) that these compounds do not serve as entourage compounds under the conditions examined, and 2) that they may instead serve as functional antagonists. Our results suggest that the relationship between 2-AG and its congeners is more nuanced than previously appreciated.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and
           the CB1 cannabinoid receptor on the endogenous cannabinoid-related
           lipidome in eight regions of the mouse brain
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Emma Leishman, Ben Cornett, Karl Spork, Alex Straiker, Ken Mackie, Heather B. Bradshaw
      Background and purpose The enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) hydrolyze endogenous cannabinoids (eCBs), N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), respectively. These enzymes also metabolize eCB analogs such as lipoamines and 2-acyl glycerols, most of which are not ligands at CB1. To test the hypothesis that deleting eCB hydrolyzing enzymes and CB1 shifts lipid metabolism more broadly and impacts more families of eCB structural analogs, targeted lipidomics analyses were performed on FAAH KO, MAGL KO, and CB1 KO mice and compared to WT controls in 8 brain regions. Experimental approach Methanolic extracts of discrete brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus) were partially purified on C-18 solid-phase extraction columns. Over 70 lipids per sample were then analyzed with HPLC/MS/MS. Key results AEA and 2-AG were unaffected throughout the brain in CB1 KO mice; however, there was an increase in the arachidonic acid (AA) metabolite, PGE2 in the majority of brain areas. By contrast, PGE2 and AA levels were significantly reduced throughout the brain in the MAGL KO corresponding to significant increases in 2-AG. No changes in AA or PGE2 were seen throughout in the FAAH KO brain, despite significant increases in AEA, suggesting AA liberated by FAAH does not contribute to steady state levels of AA or PGE2. Changes in the lipidome were not confined to the AA derivatives and showed regional variation in each of the eCB KO models. Conclusions and implications AEA and 2-AG hydrolyzing enzymes and the CB1 receptor link the eCB system to broader lipid signaling networks in contrasting ways, potentially altering neurotransmission and behavior independently of cannabinoid receptor signaling.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Estimating genotype and allele frequencies of the CYP2D6 gene
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): M. Acuña, Y.L. Eaton



      PubDate: 2016-06-18T18:56:10Z
       
  • Reply to the commentary: Estimating genotype and allele frequencies of the
           CYP2D6 gene
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Nelson M. Varela, Luis A. Quiñones



      PubDate: 2016-06-18T18:56:10Z
       
  • Dissociating the role of endocannabinoids in the pleasurable and
           motivational properties of social play behaviour in rats
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): E.J. Marijke Achterberg, Maaike M.H. van Swieten, Nina V. Driel, Viviana Trezza, Louk J.M.J. Vanderschuren
      Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Preconditioning is hormesis part II: How the conditioning dose mediates
           protection: Dose optimization within temporal and mechanistic frameworks
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Edward J. Calabrese
      In Part I, hormetic doses of a variety of agents stimulated adaptive responses that conditioned and protected cells against the subsequent toxicity resulting from a second, higher dose (called a challenging dose) of the same or different agents. Herein (Part II), the optimal conditioning (hormetic) doses of many agents are documented, cellular mechanisms and temporal profiles are examined from which the conditioning (hormetic) responses are elicited, and the optimal conditioning doses are compared to the levels at which optimal protection occurs in response to the toxic challenge dose. Entry criteria for study evaluation required a conditioning mechanism-induced endpoint response, an hormetic/biphasic dose response for the protective response following the challenging dose, and a mechanistic assessment of how the conditioning dose afforded protection against a toxic challenging dose. The conditioning dose that demonstrated the largest increase in a mechanism-related conditioning (hormetic) response (i.e., prior to administration of the challenging dose) was the same dose that was optimally protective following the challenging dose. Specific receptor antagonists and/or inhibitors of cell signaling pathways which blocked the induction of conditioning (hormetic) effects during the conditioning period abolished the protective effects following the application of a challenge dose, thus identifying a specific and essential component of the hormetic mechanism. Conditioning responses often had sufficient doses to assess the nature of the dose response. In each of the cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose. Furthermore, based on optimal dosage, temporal relationships and the known mediating actions of receptor-based and/or cell signaling-based mechanisms, the protective effects were shown to be directly linked to the actions of the conditioning (hormetic) doses. These findings indicate that the biological/biomedical effects induced by conditioning represent a specific type of hormetic dose response and thereby contribute significantly to a generalization of the hormetic concept.
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      PubDate: 2016-06-18T18:56:10Z
       
  • l-Asparaginase as morpheein: A potential drug target
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Archana Vimal, Awanish Kumar



      PubDate: 2016-06-18T18:56:10Z
       
  • Editorial Board
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110




      PubDate: 2016-06-18T18:56:10Z
       
  • Preconditioning is hormesis part I: Documentation, dose-response features
           and mechanistic foundations
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Edward J. Calabrese
      This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30–60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning induced early (1–3h) and delayed (12–72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Biological characterization of PM226, a chromenoisoxazole, as a selective
           CB2 receptor agonist with neuroprotective profile
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): M. Gómez-Cañas, P. Morales, L. García-Toscano, C. Navarrete, E. Muñoz, N. Jagerovic, J. Fernández-Ruiz, M. García-Arencibia, M.R. Pazos
      Cannabinoids have emerged as promising neuroprotective agents due to their capability to activate specific targets, which are involved in the control of neuronal homeostasis and survival. Specifically, those ligands that selectively target and activate the CB2 receptor may be useful for their anti-inflammatory and neuroprotective properties in various neurological disorders, with the advantage of being devoid of psychotropic effects associated with the activation of CB1 receptors. The aim of this work has been to investigate the neuroprotective properties of 7-(1,1-dimethylheptyl)-4,4-dimethyl-9-methoxychromeno[3,4-d]isoxazole (PM226), a compound derived from a series of chromeno-isoxazoles and −pyrazoles, which seems to have a promising profile related to the CB2 receptor. The compound binds selectively to this receptor with an affinity in the nanomolar range (K i =12.8±2.4nM). It has negligible affinity for the CB1 receptor (K i >40000nM) and no activity at the GPR55. PM226 was also evaluated in GTPγS binding assays specific to the CB2 receptor showing agonist activity (EC50 =38.67±6.70nM). In silico analysis of PM226 indicated that it has a good pharmacokinetic profile and a predicted ability to cross the blood-brain barrier. Next, PM226 was investigated in an in vitro model to explore its anti-inflammatory/neuroprotective properties. Conditioned media were collected from LPS-stimulated cultures of BV2 microglial cell line in the absence or presence of different doses of PM226, and then media were added to cultured M213-2O neuronal cells to record their influence on cell viability evaluated using MTT assays. As expected, cell viability was significantly reduced by the exposure to these conditioned media, while the addition of PM226 attenuated this reduction in a dose-dependent manner. This effect was reversed by co-incubating with the CB2 antagonist SR144528, thus confirming the involvement of CB2 receptors, whereas the addition of PM226 to neuronal cultures instead cultured BV2 cells was not effective. PM226 has also been studied in an in vivo model of mitochondrial damage generated by intrastriatal application of malonate in rats. MRI analysis showed that PM226 administration decreased the volume of the striatal lesion caused by malonate, effect that was confirmed after the histopathological evaluation (Nissl staining, Iba-1 immunostaining and TUNEL assay) of striatal sections derived from malonate-lesioned rats in the absence or presence of PM226. Again, the beneficial effects of PM226 were dependent on the activation of CB2 receptors as they were reversed by blocking these receptors with AM630. Overall, PM226 has shown to have a promising neuroprotective profile derived from its ability to selectively activate CB2 receptor, so that it could be a useful disease-modifying agent in those neurodegenerative pathologies in which the activation of these receptors may have therapeutic value.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Tangeretin, a citrus pentamethoxyflavone, antagonizes ABCB1-mediated
           multidrug resistance by inhibiting its transport function
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Sen-Ling Feng, Zhong-Wen Yuan, Xiao-Jun Yao, Wen-Zhe Ma, Liang Liu, Zhong-Qiu Liu, Ying Xie
      Multidrug resistance (MDR) and tumor metastasis are the main causes of chemotherapeutic treatment failure and mortality in cancer patients. In this study, at achievable nontoxic plasma concentrations, citrus flavonoid tangeretin has been shown to reverse ABCB1-mediated cancer resistance to a variety of chemotherapeutic agents effectively. Co-treatment of cells with tangeretin and paclitaxel activated apoptosis as well as arrested cell cycle at G2/M-phase. Tangeretin profoundly inhibited the ABCB1 transporter activity since it significantly increased the intracellular accumulation of doxorubicin, and flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the expression of ABCB1. Moreover, it stimulated the ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. The molecular docking results indicated a favorable binding of tangeretin with the transmemberane region site 1 of homology modeled ABCB1 transporter. The overall results demonstrated that tangeretin could sensitize ABCB1-overexpressing cancer cells to chemotherapeutical agents by directly inhibiting ABCB1 transporter function, which encouraged further animal and clinical studies in the treatment of resistant cancers.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Antischistosomal activity of artemisinin derivatives in vivo and in
           patients
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Mohamed E.M. Saeed, Sanjeev Krishna, Henry Johannes Greten, Peter G. Kremsner, Thomas Efferth
      Schistosomiasis is a helminthic disease affecting more than 200 million people in the tropics as well as returning travellers. Treatment mainly relies on a single drug, praziquantel. Praziquantel cannot kill developing schistosomula resulting in frequent treatment failures and re-infections. Monotherapy also favors the selection for resistance. New drugs are therefore urgently needed. The activity of the semi-synthetic artemisinin derivatives artemether, artesunate and arteether is not restricted to malaria. We reviewed their anti-schistosomal activity in vivo and in patients by searching the PubMed database for publications since 1983 with the search terms “artemisinin” and “Schistosoma”. Reports on in vivo studies in animals and clinical trials in human beings were selected. S. mansoni, S. japonicum, and S. haematobium have been tested in mice, rabbits, hamsters, and dogs. These artemisinin derivatives strongly reduced total worm rates with stronger reduction rates for female worms than for males. The drugs also reduced egg burden and egg-caused granulomata in the host liver. Artemisinin-type drugs induced oxidative and metabolic stress leading to morphological damage and decreased fertility of the parasites. Although artemether and artesunate have been investigated in numerous clinical trials, the poor quality of many has led to inconsistent results and has not provided convincing evidence on the therapeutic value against schistosomiasis. Despite these methodological concerns, clinical trials may indicate anti-schistosomal activity in patients. Convincing clinical trials providing unambiguous evidence are now needed. Furthermore, suitable treatment protocols for combination therapy to prevent/treat praziquantel-resistant Schistosoma strains should be investigated.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Berberine ameliorates chronic relapsing dextran sulfate sodium-induced
           colitis in C57BL/6 mice by suppressing Th17 responses
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Yan-hong Li, Hai-tao Xiao, Dong-dong Hu, Sarwat Fatima, Cheng-yuan Lin, Huai-xue Mu, Nikki P. Lee, Zhao-xiang Bian
      Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC–MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4 + cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4 + cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4 + cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Corrigendum to “Characterization of the CYP2D6 drug metabolizing
           phenotypes of the Chilean mestizo population through polymorphism
           analyses” [Pharm. Res. 101 (November) (2015) 124–129]
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Nelson Varela, Luis A. Quiñones, Jana Stojanova, Joselyn Garay, Dante Cáceres, Silvia Cespedes, Jaime Sasso, Carla Miranda



      PubDate: 2016-06-18T18:56:10Z
       
  • Corrigendum to “Identification of cromolyn sodium as an
           anti-fibrotic agent targeting both hepatocytes and hepatic stellate
           cells” [Pharmacol. Res. 102 (2015) 176–183]
    • Abstract: Publication date: August 2016
      Source:Pharmacological Research, Volume 110
      Author(s): Joon-Seok Choi, Jun Ki Kim, Yoon Jung Yang, Yeseul Kim, Pilhan Kim, Sang Gyu Park, Eun-Young Cho, Dae Ho Lee, Jin Woo Choi



      PubDate: 2016-06-18T18:56:10Z
       
  • Editorial Board
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109




      PubDate: 2016-06-18T18:56:10Z
       
  • Introductory letter from the Guest Editors
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Juan José Poderoso, Gabriela Beatriz Acosta



      PubDate: 2016-06-18T18:56:10Z
       
  • Letter from the President of the Argentinian Society of Pharmacology
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Sergio F. Sánchez Bruni



      PubDate: 2016-06-18T18:56:10Z
       
  • Argentinean Society of Experimental Pharmacology: Brief history and main
           scientific contributions to the discipline
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Sergio F. Sánchez Bruni, Gabriela B. Acosta
      Argentina Biomedical Science has been historically strong. The development of Human and Veterinary Pharmacology in our country as a pivotal discipline has been acknowledged worldwide because of the quality of its contributions. Argentinean Society of Experimental Pharmacology (SAFE) is a non- profit association whose research fields include Experimental and Clinical Pharmacology. SAFE main goals are described as follow (a) To meet active researchers for studying concerns regarding Experimental and Clinical Pharmacology (b) To launch an initiative for development of the discipline in mainly our country and other collaborative countries worldwide (c) To spread the pharmacological know-how obtained from different research teams (d) To strengthen relations between pharmacologists (e) To facilitate the presentation and discussion of scientific papers. This current article shows the SAFE’s more important scientific contribution to pharmacology through its former research scientists to the present.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Daniel P. Cardinali, Diego A. Golombek, Ruth E. Rosenstein, Luis I. Brusco, Daniel E. Vigo
      The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Role of thioredoxin-1 in ischemic preconditioning, postconditioning and
           aged ischemic hearts
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Veronica D’Annunzio, Virginia Perez, Alberto Boveris, Ricardo J. Gelpi, Juan J. Poderoso
      Thioredoxin is one of the most important cellular antioxidant systems known to date, and is responsible of maintaining the reduced state of the intracellular space. Trx-1 is a small cytosolic protein whose transcription is induced by stress. Therefore it is possible that this antioxidant plays a protective role against the oxidative stress caused by an increase of reactive oxygen species concentration, as occurs during the reperfusion after an ischemic episode. However, in addition to its antioxidant properties, it is able to activate other cytoplasmic and nuclear mediators that confer cardioprotection. It is remarkable that Trx-1 also participates in myocardial protection mechanisms such as ischemic preconditioning and postconditioning, activating proteins related to cellular survival. In this sense, it has been shown that Trx-1 inhibition abolished the preconditioning cardioprotective effect, evidenced through apoptosis and infarct size. Furthermore, ischemic postconditioning preserves Trx-1 content at reperfusion, after ischemia. However, comorbidities such as aging can modify this powerful cellular defense leading to decrease cardioprotection. Even ischemic preconditioning and postconditioning protocols performed in aged animal models failed to decrease infarct size. Therefore, the lack of success of antioxidants therapies to treat ischemic heart disease could be solved, at least in part, avoiding the damage of Trx system.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Physiological and pathophysiological factors affecting the expression and
           activity of the drug transporter MRP2 in intestine. Impact on its function
           as membrane barrier
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Maite R. Arana, Guillermo N. Tocchetti, Juan P. Rigalli, Aldo D. Mottino, Silvina S.M. Villanueva
      The gastrointestinal epithelium functions as a selective barrier to absorb nutrients, electrolytes and water, but at the same time restricts the passage into the systemic circulation of intraluminal potentially toxic compounds. This epithelium maintains its selective barrier function through the presence of very selective and complex intercellular junctions and the ability of the absorptive cells to reject those compounds. Accordingly, the enterocytes metabolize orally incorporated xenobiotics and secrete the hydrophilic metabolites back into the intestinal lumen through specific transporters localized apically. In the recent decades, there has been increasing recognition of the existence of the intestinal cellular barrier. In the present review we focus on the role of the multidrug resistance-associated protein 2 (MRP2, ABCC2) in the apical membrane of the enterocytes, as an important component of this intestinal barrier, as well as on its regulation. We provide a detailed compilation of significant contributions demonstrating that MRP2 expression and function vary under relevant physiological and pathophysiological conditions. Because MRP2 activity modulates the availability and pharmacokinetics of many therapeutic drugs administered orally, their therapeutic efficacy and safety may vary as well.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Glyco-nano-oncology: Novel therapeutic opportunities by combining small
           and sweet
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Pablo F. Hockl, Alejandro Wolosiuk, Juan M. Pérez-Sáez, Andrea V. Bordoni, Diego O. Croci, Yamili Toum-Terrones, Galo J.A.A. Soler-Illia, Gabriel A. Rabinovich
      Recent efforts toward defining the molecular features of the tumor microenvironment have revealed dramatic changes in the expression of glycan-related genes including glycosyltransferases and glycosidases. These changes affect glycosylation of proteins and lipids not only in cancer cells themselves, but also in cancer associated-stromal, endothelial and immune cells. These glycan alterations including increased frequency of β1,6-branched N-glycans and bisecting N-glycans, overexpression of tumor-associated mucins, preferred expression of T, Tn and sialyl-Tn antigen and altered surface sialylation, may contribute to tumor progression by masking or unmasking specific ligands for endogenous lectins, including members of the C-type lectin, siglec and galectin families. Differential expression of glycans or glycan-binding proteins could be capitalized for the identification of novel biomarkers and might provide novel opportunities for therapeutic intervention. This review focuses on the biological relevance of lectin-glycan interactions in the tumor microenvironment (mainly illustrated by the immunosuppressive and pro-angiogenic activities of galectin-1) and the design of functionalized nanoparticles for pharmacological delivery of multimeric glycans, lectins or selective inhibitors of lectin-glycan interactions with antitumor activity.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Thyroid hormones and their membrane receptors as therapeutic targets for T
           cell lymphomas
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Graciela A. Cremaschi, Florencia Cayrol, Helena Andrea Sterle, María Celeste Díaz Flaqué, María Laura Barreiro Arcos
      Thyroid hormones (THs) are important regulators of metabolism, differentiation and cell proliferation. They can modify the physiology of human and murine T cell lymphomas (TCL). These effects involve genomic mechanisms, mediated by specific nuclear receptors (TR), as well as nongenomic mechanisms, that lead to the activation of different signaling pathways through the activation of a membrane receptor, the integrin αvβ3. Therefore, THs are able to induce the survival and growth of TCL. Specifically, the signaling induced by THs through the integrin αvβ3 activates proliferative and angiogenic programs, mediated by the regulation of the vascular endothelial growth factor (VEGF). The genomic or pharmacologic inhibition of integrin αvβ3 reduces the production of VEGF and induces cell death both in vitro and in xenograft models of human TCL. Here we review the mechanisms involved in the modulation of the physiology of TCL induced by THs, the analysis of the interaction between genomic and nongenomic actions of THs and their contribution to T cell lymphomagenesis. These actions of THs suggest a novel mechanism for the endocrine modulation of the physiopathology of TCL and they provide a potential molecular target for its treatment.
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      PubDate: 2016-06-18T18:56:10Z
       
  • Long-term effects of early life stress exposure: Role of epigenetic
           mechanisms
    • Abstract: Publication date: July 2016
      Source:Pharmacological Research, Volume 109
      Author(s): Dafne M. Silberman, Gabriela B. Acosta, María A. Zorrilla Zubilete
      Stress is an adaptive response to demands of the environment and thus essential for survival. Exposure to stress during the first years of life has been shown to have profound effects on the growth and development of an adult individual. There are evidences demonstrating that stressful experiences during gestation or in early life can lead to enhanced susceptibility to mental disorders. Early-life stress triggers hypothalamic-pituitary-adrenocortical (HPA) axis activation and the associated neurochemical reactions following glucocorticoid release are accompanied by a rapid physiological response. An excessive response may affect the developing brain resulting in neurobehavioral and neurochemical changes later in life. This article reviews the data from experimental studies aimed to investigate hormonal, functional, molecular and epigenetic mechanisms involved in the stress response during early-life programming. We think these studies might prove useful for the identification of novel pharmacological targets for more effective treatments of mental disorders.
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      PubDate: 2016-06-18T18:56:10Z
       
  • ApoA-IMilano phospholipid complex (ETC-216) infusion in human volunteers.
           Insights into the phenotypic characteristics of ApoA-IMilano carriers
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Charles L. Bisgaier, Rose Ackermann, Thomas Rea, Wendi V. Rodrigueza, Daniel Hartman
      Epidemiological studies support an inverse correlation between HDL-C and cardiovascular disease. However, low HDL-C levels do not always segregate with premature disease. These include, LCAT deficiency and the apolipoproteinA-IMilano (AIM) variant. AIM has a cysteine for arginine at position 173 in the otherwise cysteine free protein permitting AIM homodimerization and apoA-II heterodimerization. We relate the biochemical characteristics of low HDL-C phenotype AIM carriers to lipoprotein changes in humans administered recombinant dimeric AIM/palmitoyl-oleoyl phosphatidyl choline (ETC-216). Pharmacokinetic analysis of infused ETC-216 suggest a slow distribution of AIM into peripheral tissue and an extremely long terminal half-life in plasma. Following ETC-216 administration to normal human volunteers, an initial dose-dependent HDL-C elevation was observed. Thereafter, subjects transiently acquired a lipoprotein profile similar to that of AIM carriers, including reduced HDL-C and mild hypertriglyceridemia. The time-dependent changes in plasma lipids/lipoproteins may support an increased tissue cholesterol removing capacity of ETC-216. These findings provide mechanistic insight into the rapid removal of atheromatous plaques observed in humans, possibly linked to enhanced cholesterol removal capacity of ETC-216.


      PubDate: 2016-06-14T04:04:18Z
       
  • PPARγ Signaling and Emerging Opportunities for Improved Therapeutics
    • Abstract: Publication date: Available online 4 June 2016
      Source:Pharmacological Research
      Author(s): Shuibang Wang, Edward J. Dougherty, Robert L. Danner
      Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARγ are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPARγ signaling and to develop safer and more effective PPARγ-directed therapeutics. In addition to PPARγ itself, many PPARγ ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPARγ responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPARγ genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPARγ co-activator-1α, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPARγ-dependent transcription. Therefore in endothelium, GPR40 and PPARγ function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPARγ. Thus the role of GPR40 in PPARγ signaling may have important implications for drug development. Ligands that strongly activate PPARγ, but do not bind to or activate GPR40 may be safer than currently approved PPARγ agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPARγ, but not ERK1/2, avoiding its harmful effects on PPARγ signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.
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      PubDate: 2016-06-08T02:47:07Z
       
  • The unusual pharmacokinetics of meldomium: implications for doping
    • Abstract: Publication date: Available online 2 June 2016
      Source:Pharmacological Research
      Author(s): Edgars Liepinsh, Maija Dambrova

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      PubDate: 2016-06-03T01:39:31Z
       
  • Loganin possesses neuroprotective properties, restores SMN protein and
           activates protein synthesis positive regulator Akt/mTOR in experimental
           models of spinal muscular atrophy
    • Abstract: Publication date: Available online 27 May 2016
      Source:Pharmacological Research
      Author(s): Yu-Ting Tseng, Cheng-Sheng Chen, Yuh-Jyh Jong, Fang-Rong Chang, Yi-Ching Lo
      Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.
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      PubDate: 2016-05-29T00:53:10Z
       
  • Skp1: Implications in cancer and SCF-oriented anti-cancer drug discovery
    • Abstract: Publication date: Available online 26 May 2016
      Source:Pharmacological Research
      Author(s): Muzammal Hussain, Yongzhi Lu, Yong-Qiang Liu, Kai Su, Jiancun Zhang, Jinsong Liu, Guang-Biao Zhou
      In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into seven groups (CRL1-7) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1)-Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology. Currently, there is growing interest in developing SCF-targeting anti-cancer therapies for clinical application. Indeed, the research in this field has seen some progress in the form of cullin neddylation- and Skp2-inhibitors. However, it still remains an underdeveloped area and needs to design new strategies for developing improved form of therapy. In this review, we venture a novel strategy that rational pharmacological targeting of Skp1, a central regulator of SCF complexes, may provide a novel avenue for SCF-oriented anti-cancer therapy, expected: (i) to simultaneously address the critical roles that multiple SCF oncogenic complexes play in cancer biology, (ii) to selectively target cancer cells with minimal normal cell toxicity, and (iii) to offer multiple chemical series, via therapeutic interventions at the Skp1 binding interfaces in SCF complex, thereby maximizing chances of success for drug discovery. In addition, we also discuss the challenges that might be posed regarding rational pharmacological interventions against Skp1.
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      PubDate: 2016-05-29T00:53:10Z
       
  • Increase of neurofilament-H protein in sensory neurons in antiretroviral
           neuropathy: evidence for a neuroprotective response mediated by the
           RNA-binding protein HuD
    • Abstract: Publication date: Available online 26 May 2016
      Source:Pharmacological Research
      Author(s): M.D. Sanna, D. Peroni, T. Mello, C. Ghelardini, A. Quattrone, N. Galeotti
      Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, antiretroviral toxic neuropathy has become a common peripheral neuropathy among HIV/AIDS patients leading to discontinuation of antiretroviral therapy, for which the underlying pathogenesis is uncertain. This study examines the role of neurofilament (NF) proteins in the spinal dorsal horn, DRG and sciatic nerve after NRTI neurotoxicity in mice treated with zalcitabine (2′,3′-dideoxycitidine; ddC). ddC administration up-regulated NF-M and pNF-H proteins with no effect on NF-L. The increase of pNF-H levels was counteracted by the silencing of HuD, an RNA binding protein involved in neuronal development and differentiation. Sciatic nerve sections of ddC exposed mice showed an increased axonal caliber, concomitantly to a pNF-H up-regulation. Both events were prevented by HuD silencing. pNF-H and HuD colocalize in DRG and spinal dorsal horn axons. However, the capability of HuD to bind NF mRNA was not demonstrated, indicating the presence of an indirect mechanism of control of NF expression by HuD. RNA immunoprecipitation experiments showed the capability of HuD to bind the BDNF mRNA and the administration of an anti-BDNF antibody prevented pNF-H increase. These data indicate the presence of a HuD − BDNF − NF-H pathway activated as a regenerative response to the axonal damage induced by ddC treatment to counteract the antiretroviral neurotoxicity. Since analgesics clinically used to treat neuropathic pain are ineffective on antiretroviral neuropathy, a neuroregenerative strategy might represent a new therapeutic opportunity to counteract neurotoxicity and avoid discontinuation or abandon of NRTI therapy.
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      PubDate: 2016-05-29T00:53:10Z
       
  • Combined therapy using bevacizumab and turmeric ethanolic extract (with
           absorbable curcumin) exhibited beneficial efficacy in colon cancer mice
    • Abstract: Publication date: Available online 27 May 2016
      Source:Pharmacological Research
      Author(s): Grace Gar-Lee Yue, Hin-Fai Kwok, Julia Kin-Ming Lee, Lei Jiang, Eric Chun-Wai Wong, Si Gao, Hing-Lok Wong, Lin Li, Kar-Man Chan, Ping-Chung Leung, Kwok-Pui Fung, Zhong Zuo, Clara Bik-San Lau
      Turmeric is commonly used as a medicinal herb and dietary supplement. Its active ingredient, curcumin, has been shown to possess antitumor effects in colorectal cancer patients. However, poor absorption of curcumin in intestine impedes its wide clinical application. Our previous findings showed that the presence of turmerones increased the accumulation of curcumin inside colonic cells. Hence, we hypothesized that curcumin with turmerones or present in turmeric ethanolic extract would augment its anti-tumor activities in tumor-bearing mice. The pharmacokinetics of curcumin in different preparations (containing same amount of curcumin) were studied in mice. The anti-tumor efficacies of curcumin or turmeric extract (with absorbable curcumin) in combination with bevacizumab were further investigated in HT29 colon tumor-bearing mice. Pharmacokinetic results showed that the plasma curcumin level of turmeric extract-fed mice was the highest, suggesting turmeric extract had the best bioavailability of curcumin. Besides, combined turmeric extract plus bevacizumab treatment significantly inhibited the tumor growth. Such inhibitory effects were stronger than those of curcumin plus bevacizumab or bevacizumab alone and were comparable with those of 5-fluorouracil+leucovorin+oxaliplatin (FOLFOX) plus bevacizumab. Notably, there was no observable side effect induced by turmeric extract treatment while significant side effects were found in FOLFOX-treated mice. In conclusion, combination of turmeric extract with bevacizumab possessed potent anti-tumor effects without observable side effects, strongly suggesting the adjuvant use of turmeric extract in colorectal cancer therapy. Our current findings warrant the confirmation regarding the benefits arising from the combined use of bevacizumab and turmeric in colorectal cancer patients in the near future.
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      PubDate: 2016-05-29T00:53:10Z
       
  • The membrane tethered Matrix Metalloproteinase MT1-MMP at the forefront of
           melanoma cell invasion and metastasis.
    • Abstract: Publication date: Available online 21 May 2016
      Source:Pharmacological Research
      Author(s): Varsha Thakur, Barbara Bedogni
      The Extracellular Matrix (ECM) plays an important role in normal physiological development and functioning of cells, tissues and organs [1]. Under normal physiological conditions degradation of the ECM is a finely regulated process, and altered homeostasis of ECM degradation (excessive or insufficient) is associated with many diseases [2–5] such as cancer, fibrosis, arthritis, nephritis, encephalomyelitis and chronic ulcers. The remodeling of the ECM is carried out by a family of enzymes known as matrix metalloproteinases (MMP). MMPs constitute a large group of multidomain, zinc dependent endopeptidases capable of hydrolyzing all protein components of the ECM [6]. Additional functions of MMPs have also been identified. MMPs, and in particular MT1-MMP, the prototypic membrane-tethered matrix metalloproteinase, are no longer only ECM remodeling enzymes but rather regulators of several cellular functions including growth, migration, invasion and gene expression. Here we will focus on the role of the membrane bound MT1-MMP in melanoma growth, invasion and metastasis. MT1-MMP has in fact emerged as a multifaceted protease capable of influencing melanoma metastasis by canonical means, i.e. ECM degradation, but also via regulation of genes involved in several pro-tumorigenic functions including tumor cell growth and motility.
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      PubDate: 2016-05-24T07:06:49Z
       
  • Long non-coding RNAs as novel therapeutic targets in cancer
    • Abstract: Publication date: Available online 19 May 2016
      Source:Pharmacological Research
      Author(s): Giovanni Lavorgna, Riccardo Vago, Mohamad Sarmini, Francesco Montorsi, Andrea Salonia, Matteo Bellone
      Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity.
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      PubDate: 2016-05-24T07:06:49Z
       
  • Drug interaction study of natural steroids from herbs specifically toward
           human UDP-glucuronosyltransferase (UGT) 1A4 and their quantitative
           structure activity relationship (QSAR) analysis for prediction
    • Abstract: Publication date: Available online 18 May 2016
      Source:Pharmacological Research
      Author(s): Min Xu, Peipei Dong, Xiangge Tian, Chao Wang, Xiaokui Huo, Baojing Zhang, Lijun Wu, Sa Deng, Xiaochi Ma
      The wide application of herbal medicines and foods containing steroids has resulted in the high risk of herb-drug interactions (HDIs). The present study aims to evaluate the inhibition potential of 43 natural steroids from herb medicines toward human UDP- glucuronosyltransferases (UGTs). A remarkable structure-dependent inhibition toward UGT1A4 was observed in vitro. Some natural steroids such as gitogenin, tigogenin, and solasodine were found to be the novel selective inhibitors of UGT1A4, and did not inhibit the activities of major human CYP isoforms. To clarify the possibility of the in vivo interaction of common steroids and clinical drugs, the kinetic inhibition type and related kinetic parameters (Ki) were measured. The target compounds 2-6 and 15, competitively inhibited the UGT1A4-catalyzed trifluoperazine glucuronidation reaction, with Ki values of 0.6, 0.18, 1.1, 0.7, 0.8, and 12.3μM, respectively. And this inhibition of steroids towards UGT1A4 was also verified in human primary hepatocytes. Furthermore, a quantitative structure-activity relationship (QSAR) of steroids with inhibitory effects toward human UGT1A4 isoform was established using the computational methods. Our findings elucidate the potential for in vivo HDI effects of steroids in herbal medicine and foods, with the clinical drugs eliminated by UGT1A4, and reveal the vital pharamcophoric requirement of natural steroids for UGT1A4 inhibition activity.
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      PubDate: 2016-05-19T06:22:10Z
       
  • Contrast Agents in Diagnostic Imaging: present and future
    • Abstract: Publication date: Available online 9 May 2016
      Source:Pharmacological Research
      Author(s): Luca Caschera, Angelo Lazzara, Lorenzo Piergallini, Domenico Ricci, Bruno Tuscano, Angelo Vanzulli
      Specific contrast agents have been developed for x ray examinations (mainly CT), sonography and Magnetic Resonance Imaging. Most of them are extracellular agents which create different enhancement on basis of different vascularization or on basis of different interstitial network in tissues, but some can be targeted to a particular cell line (e.g. hepatocyte).
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      PubDate: 2016-05-14T21:24:18Z
       
  • Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug
           interaction between pazopanib and cisplatin
    • Abstract: Publication date: Available online 10 May 2016
      Source:Pharmacological Research
      Author(s): C. Sauzay, M. White-Koning, I. Hennebelle, T. Deluche, C. Delmas, D.C. Imbs, E. Chatelut, F. Thomas
      We hypothesized that pazopanib is an inhibitor of cisplatin renal transporters OCT2, MATE1 and MATE2-K based on previous studies demonstrating an interaction between tyrosine kinase inhibitors and these transporters. Because several combinations of targeted therapies and cytotoxics are currently in development for cancer treatment, such an interaction is worth investigating. Experiments on HEK293 cells stably transfected to express OCT2, MATE1, MATE2-K or an empty vector (EV) were conducted. The inhibitory effect of pazopanib on these transporters was measured using the uptake of fluorescent substrate ASP+ and cisplatin in the different cell lines. The effect of pazopanib on cisplatin-induced cytotoxicity was also evaluated. A decrease of ASP+ uptake was observed in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines after addition of pazopanib at increasing concentrations. Pazopanib inhibited cisplatin specific uptake in OCT2-HEK, MATE1-HEK and MATE2K-HEK lines. Cytotoxicity experiments showed that co-incubation of cisplatin with pazopanib multiplied up to 2.7, 2.4 and 1.6 times the EC50 values of cisplatin in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines respectively, reaching about the same values as in EV-HEK cells. To conclude, pazopanib inhibits OCT2, MATE1 and MATE2-K, which are involved in cisplatin secretion into urine. The combination of these two drugs may lead to an interaction and increase the cisplatin-induced systemic toxicity. Given the wide variability of plasma pazopanib concentrations observed in vivo, the interaction may occur in a clinical setting, particularly in overexposed patients. The existence of a drug-drug interaction should be investigated when pazopanib is associated with a substrate of these transporters.
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      PubDate: 2016-05-14T21:24:18Z
       
  • G protein-coupled receptor kinases as regulators of dopamine receptor
           functions
    • Abstract: Publication date: Available online 10 May 2016
      Source:Pharmacological Research
      Author(s): Eugenia V. Gurevich, Raul R. Gainetdinov, Vsevolod V. Gurevich
      Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non-visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA-induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson’s disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affect psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain ▯o Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
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      PubDate: 2016-05-14T21:24:18Z
       
  • Preventing epileptogenesis: A realistic goal'
    • Abstract: Publication date: Available online 10 May 2016
      Source:Pharmacological Research
      Author(s): Gaetano Terrone, Alberto Pauletti, Rosaria Pascente, Annamaria Vezzani
      The definition of the pathologic process of epileptogenesis has considerably changed over the past few years due to a better knowledge of the dynamics of the associated molecular modifications and to clinical and experimental evidence of progression of the epileptic condition beyond the occurrence of the first seizures. Interference with this chronic process may lead to the development of novel preventive therapies which are still lacking. Notably, epileptogenesis is often associated with comorbid behaviors which are now considered primary outcome measures for novel therapeutics. Anti-epileptogenic interventions may improve not only seizure onset and their frequency and severity but also comorbidities and cell loss, and when applied after the onset of the disease may provide disease-modifying effects by favorably modifying the disease course. In the preclinical arena, several novel targets for anti-epileptogenic and disease-modifying interventions are being characterized and validated in rodent models of epileptogenesis. To move proof-of-concept anti-epileptogenesis studies to validation in preclinical trials and eventually to clinical translation is a challenging task which would be greatly facilitated by the development of non invasive biomarkers of epileptogenesis. Biomarker discovery together with testing potential novel drugs would provide a major advance in the treatment of human epilepsy beyond the pure symptomatic control of seizures.
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      PubDate: 2016-05-14T21:24:18Z
       
  • Imperatorin exerts antiallergic effects in Th2-mediated allergic asthma
           via induction of IL-10-producing regulatory T cells by modulating the
           function of dendritic cells
    • Abstract: Publication date: Available online 13 May 2016
      Source:Pharmacological Research
      Author(s): Chu-Lun Lin, George Hsiao, Ching-Chiung Wang, Yueh-Lun Lee
      Imperatorin is a furanocoumarin compound which exists in many medicinal herbs and possesses various biological activities. Herein, we investigated the antiallergic effects of imperatorin in asthmatic mice and explored the immunomodulatory actions of imperatorin on immune cells. We used a murine model of ovalbumin (OVA)-induced asthma to evaluate the therapeutic potential of imperatorin. Additionally, bone marrow-derived dendritic cells (DCs; BMDCs) were used to clarify whether imperatorin exerts an antiallergic effect through altering the ability of DCs to regulate T cells. Oral administration of imperatorin to OVA-sensitized and −challenged mice decreased serum OVA-specific immunoglobulin E (IgE) production, attenuated the airway hyperresponsiveness (AHR), and alleviated airway inflammation in a dose-dependent manner. Notably, secretions of Th2 cytokines and chemokines were reduced, and numbers of interleukin (IL)-10-producing regulatory T cells (Tregs) increased in imperatorin-treated mice. Imperatorin inhibited proinflammatory cytokines and IL-12 production but enhanced IL-10 secretion by lipopolysaccharide (LPS)-stimulated BMDCs. Compared to fully mature DCs, imperatorin-treated DCs expressed high levels of the inducible costimulatory ligand (ICOSL) and Jagged1 molecules, and had the regulatory capacity to promote the generation of IL-10-producing CD4+ T cells in vitro. Additionally, imperatorin directly suppressed activated CD4+ T-cell proliferation and cytokine production. Imperatorin may possess therapeutic potential against Th2-mediated allergic asthma not only via stimulating DC induction of Tregs but also via direct inhibition of Th2 cell activation. These findings provide new insights into how imperatorin affects the Th2 immune response and the development of imperatorin as a Treg-type immunomodulatory agent to treat allergic asthma.
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      PubDate: 2016-05-14T21:24:18Z
       
  • Verapamil and ethacrynic acid are associated with neuronal acidification
           in hippocampal CA3-neurons (slice preparation, guinea pig): contribution
           to their anti-seizure potency'
    • Abstract: Publication date: Available online 11 May 2016
      Source:Pharmacological Research
      Author(s): Udo Bonnet, Martin Wiemann



      PubDate: 2016-05-14T21:24:18Z
       
  • The Expanding GRK Interactome: Implications in Cardiovascular Disease and
           Potential for Therapeutic Development
    • Abstract: Publication date: Available online 12 May 2016
      Source:Pharmacological Research
      Author(s): Jonathan Hullmann, Christopher J. Traynham, Ryan C. Coleman, Walter J. Koch
      Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are “turned off” by GPCR kinases (GRKs) in a process known as “desensitization”. GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20 years, both GRK2 and GRK5 have been demonstrated to be critical mediators of the molecular alterations that occur in the failing heart. In the present review, we will highlight recent findings that further characterize “non-canonical” GRK signaling observed in HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, microRNAs, gene therapy) that may have potential in combating the deleterious effects of GRKs in HF.
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      PubDate: 2016-05-14T21:24:18Z
       
  • Segetoside I, a plant-derived bisdesmosidic saponin, induces apoptosis in
           human hepatoma cells in vitro and inhibits tumor growth in vivo.
    • Abstract: Publication date: Available online 12 May 2016
      Source:Pharmacological Research
      Author(s): Caleb Kesse Firempong, Hui Yun Zhang, Yan Wang, Jingjing Chen, Xia Cao, Wenwen Deng, Jie Zhou, Qiang Wang, Shan-Shan Tong, Jiangnan Yu, Ximing Xu
      Segetoside I is a plant-derived bisdesmosidic saponin from Vaccaria segetalis (Neck) with reported anticancer-related activities. This development has raised an interest in the therapeutic potential of segetoside I. Here, we report the in vitro and in vivo antitumor activities of segetoside I against some selected cancer cell lines (HepG2, human hepatoma; H22, mouse hepatoma; MCF-7, breast cancer; U251, gliocoma; BGC, HGC & SGC, gastric cancinoma; Lovo-1,colon cancer). MTT bioassay analysis showed that HepG2 cells were the most sensitive to segetoside I compared with the other cancer cell lines, with lower toxicity in healthy mouse embryonic fibroblast cells. Segetoside I pretreatment of HepG2 resulted in apoptotic induction, dose-dependent DNA fragmentation, inhibition of cell migration, up-regulation of Bax and down-regulation of Bcl-2, which indicated that an apoptotic signaling event could have been initiated. The segetoside I also suppressed hepato-tumour growth in mice with virtually no cytotoxicity and prolonged animal survival, making it a strong oncology drug agent. These findings showed that segetoside I exhibited its antitumor activity via apoptotic induction and significantly support the possible application of the antitumor agent as a potential chemotherapeutic candidate worthy of further investigations.
      Graphical abstract image

      PubDate: 2016-05-14T21:24:18Z
       
  • Oral Delivery of Insulin via Polyethylene Imine-based Nanoparticles for
           Colonic Release Allows Glycemic Control in Diabetic Rats
    • Abstract: Publication date: Available online 12 May 2016
      Source:Pharmacological Research
      Author(s): Lucia Salvioni, Luisa Fiandra, Maria Dorly Del Curto, Serena Mazzucchelli, Raffaele Allevi, Marta Truffi, Luca Sorrentino, Benedetta Santini, Matteo Cerea, Luca Palugan, Fabio Corsi, Miriam Colombo
      In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Only the nanoformulation loaded into the three-layer pellets was able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption.
      Graphical abstract image

      PubDate: 2016-05-14T21:24:18Z
       
  • Implications of MDSCs-targeting in lung cancer chemo-immunotherapeutics
    • Abstract: Publication date: Available online 6 May 2016
      Source:Pharmacological Research
      Author(s): Dickson Adah, Muzammal Hussain, Limei Qin, Li Qin, Jiancun Zhang, Xiaoping Chen
      Despite advances in chemotherapy and immunotherapy, advanced lung cancer remains an incurable disease. Novel trends in anticancer therapeutics focus on harnessing the therapeutically-targeted tumor-related immune suppression. In this respect, myeloid-derived suppressor cells (MDSCs) have captured considerable attention in the last few years, as they are vividly implicated in tumor immune escape mechanisms. In this review, we specifically discuss the multifaceted roles of MDSCs in lung tumor microenvironment, encompassing lung tumor growth and progression via suppression of anti-tumor immunity, association with worse prognosis, and hampering the efficacy of lung cancer chemotherapy and immunotherapy. In addition, we also discuss that therapeutic manipulation of MDSCs-targeting, either alone or in combination with chemo- and/or immune-therapeutic regimens, may not only have tumor growth inhibition, anti-angiogenesis and anti-metastasis effects, but may also have the potential to enhance the efficacy of lung cancer chemotherapy and immunotherapy.
      Graphical abstract image

      PubDate: 2016-05-08T20:52:32Z
       
  • The Effects of a Nutraceutical Combination on Plasma Lipids and Glucose: a
           Systematic Review and Meta-Analysis of Randomized Controlled Trials.
    • Abstract: Publication date: Available online 6 May 2016
      Source:Pharmacological Research
      Author(s): Matteo Pirro, Massimo Raffaele Mannarino, Vanessa Bianconi, Luis E. Simental-Mendía, Francesco Bagaglia, Elmo Mannarino, Amirhossein Sahebkar
      Dyslipidemia and hyperglycemia are associated with an increased risk of ischemic cardiovascular disease. Positive effects of a nutraceutical combination comprising red yeast rice, berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid (NComb) on plasma lipid and glucose levels have been reported in some but not all clinical trials. To address this inconsistency, we tried to estimate the size of lipid- and glucose-lowering effects of NComb through a systematic review and meta-analysis of randomized controlled trials. A systematic literature search in PubMed-Medline, SCOPUS and Google Scholar databases was conducted to identify randomized controlled trials investigating the effects of NComb on plasma lipids and glucose levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid and glucose levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma lipid and glucose levels. Fourteen trials (1670 subjects in the NComb arm and 1489 subjects in the control arm) met the eligibility criteria for lipid analysis and 10 trials (1014 subjects in the NComb arm and 962 subjects in the control arm) for glucose analysis. Overall, WMDs were significant for the impact of NComb supplementation on plasma levels of total cholesterol (-26.15mg/dL, p<0.001), LDL-cholesterol (-23.85mg/dL, p<0.001), HDL-cholesterol (2.53mg/dL, p<0.001), triglycerides (-13.83mg/dL, p<0.001) and glucose (-2.59mg/dL, p=0.010). NComb-induced amelioration of lipid profile was not affected by duration of supplementation nor by baseline lipid levels; conversely, a greater glucose-lowering effect of NComb was found with higher baseline glucose levels and longer durations of supplementation. In conclusion, the present results suggest that NComb supplementation is associated with improvement of lipid and glucose profile. Short-term beneficial effects of NComb supplementation appear to be maintained in the long term.
      Graphical abstract image

      PubDate: 2016-05-08T20:52:32Z
       
  • Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral
           efavirenz
    • Abstract: Publication date: Available online 6 May 2016
      Source:Pharmacological Research
      Author(s): Dhwanil A. Dalwadi, Seongcheol Kim, Shahnawaz M. Amdani, Zhenglan Chen, Ren-Qi Huang, John A. Schetz
      Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-
      DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.
      Graphical abstract image

      PubDate: 2016-05-08T20:52:32Z
       
  • A Cell-Based Quantitative High-Throughput Image Screening Identified Novel
           Autophagy Modulators
    • Abstract: Publication date: Available online 7 May 2016
      Source:Pharmacological Research
      Author(s): Yuan Li, Steven McGreal, Jean Zhao, Ruili Huang, Yan Zhou, Hua Zhong, Menghang Xia, Wen-Xing Ding
      Macroautophagy is a major cellular degradation pathway for long-lived proteins and cellular organelles to maintain cellular homeostasis. Reduced autophagy has been implicated in neurodegenerative diseases, metabolic syndrome, and tumorigenesis. In contrast, increased autophagy has been shown to protect against tissue injury and aging. Here we employed a cell-based quantitative high-throughput image screening (qHTS) for autophagy modulators using mouse embryonic fibroblasts (MEFs) that are stably expressing GFP-LC3. The library of pharmacologically active compounds (LOPAC) was used to screen for the autophagy modulators in compound alone or combination with the lysosome inhibitor chloroquine. The GFP-LC3 puncta were then quantified to measure autophagic flux. The primary screening revealed 173 compounds with efficacy more than 40%. These compounds were cherry-picked and re-tested at multiple different concentrations using the same assay. A number of novel autophagy inducers, inhibitors, and modulators with dual-effects on autophagy were identified from the cherry-pick screening. Interestingly, we found a group of compounds that induce autophagy are related to dopamine receptors and are commonly used as clinical psychiatric drugs. Among them, indatraline hydrochloride (IND), a dopamine inhibitor, and chlorpromazine hydrochloride (CPZ) and fluphenazine dihydrochloride (FPZ), two dopamine receptor antagonists, were further evaluated. We found that FPZ-induced autophagy through mTOR inhibition but IND and CPZ induced autophagy in an mTOR-independent manner. Our data suggest that image-based autophagic flux qHTS can efficiently identify autophagy inducers and inhibitors.
      Graphical abstract image

      PubDate: 2016-05-08T20:52:32Z
       
  • Comparison of Two Endogenous Delivery Agents in Cancer Therapy: Exosomes
           and Ferritin
    • Abstract: Publication date: Available online 5 May 2016
      Source:Pharmacological Research
      Author(s): Le Li, Lianbing Zhang, Mato Knez
      Exosomes and ferritin: Two biomacromolecules from our human bodies both draw increasing interest for advanced drug delivery due to their endogenous origin and their morphology, the cage-like structures. They possess perfect naturally designed structures for loading and shielding of cargo. Their intrinsic biological functions enable a natural delivery of the load and specific targeting. More and more evidences point towards the evolution of a new era of drug delivery strategies with exosomes and ferritin, even for potential personalized therapy. This review focuses on the advantages as well as limits of exosomes and ferritin as endogenous carriers for cancer therapy. We compare their structure-specific cargo loading and their intrinsic cancer-related biological functions. Remaining challenges and promising perspectives for future development to use these two endogenous agents are discussed.
      Graphical abstract image

      PubDate: 2016-05-05T20:25:00Z
       
 
 
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