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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]
  • 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
       
  • Does vitamin D supplementation alter plasma adipokines concentrations'
           A systematic review and meta-analysis of randomized controlled trials
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107
      Author(s): Madalina Dinca, Maria-Corina Serban, Amirhossein Sahebkar, Dimitri P. Mikhailidis, Peter P. Toth, Seth S. Martin, Michael J. Blaha, Matthias Blüher, Camelia Gurban, Peter Penson, Erin D. Michos, Adrian V. Hernandez, Steven R. Jones, Maciej Banach
      We aimed to elucidate the role of vitamin D supplementation on adipokines through a systematic review and a meta-analysis of randomized placebo-controlled trials (RCTs). The search included PUBMED, Scopus, Web of Science and Google Scholar through July 1st, 2015. Finally we identified 9 RCTs and 484 participants. Meta-analysis of data from 7 studies did not find a significant change in plasma adiponectin concentrations following vitamin D supplementation (mean difference [MD]: 4.45%, 95%CI: −3.04, 11.93, p =0.244; Q =2.18, I2 =0%). In meta-regression, changes in plasma adiponectin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: 0.25; 95%CI: −0.69, 1.19; p =0.603) and changes in serum 25-hydroxy vitamin D [25(OH)D] levels (slope: −0.02; 95%CI: −0.15, 0.12; p =0.780). Meta-analysis of data from 6 studies did not find a significant change in plasma leptin concentrations following vitamin D supplementation (MD: −4.51%, 95%CI: −25.13, 16.11, p =0.668; Q =6.41, I2 =21.97%). Sensitivity analysis showed that this effect size is sensitive to one of the studies; removing it resulted in a significant reduction in plasma leptin levels (MD: −12.81%, 95%CI: −24.33, −1.30, p =0.029). In meta-regression, changes in plasma leptin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: −1.93; 95%CI: −4.08, 0.23; p =0.080). However, changes in serum 25(OH)D were found to be significantly associated with changes in plasma leptin levels following vitamin D supplementation (slope: 1.05; 95%CI: 0.08, 2.02; p =0.033). In conclusion, current data did not indicate a significant effect of vitamin D supplementation on adiponectin and leptin levels.
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      PubDate: 2016-05-14T21:24:18Z
       
  • 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
       
  • Editorial Board
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107




      PubDate: 2016-05-14T21:24:18Z
       
  • A pharmacological assessment of agonists and modulators at
           α4β2γ2 and α4β2δ GABAA receptors: The
           challenge in comparing apples with oranges
    • Abstract: Publication date: Available online 10 May 2016
      Source:Pharmacological Research
      Author(s): Philip K. Ahring, Line Haunstrup Bang, Marianne Lerbech Jensen, Dorte Strøbæk, Leonny Y. Hartiadi, Mary Chebib, Nathan Absalom
      Extrasynaptically located γ-aminobutyric acid (GABA) receptors type A are often characterized by the presence of a δ subunit in the receptor complex. δ-containing receptors respond to low ambient concentrations of GABA, or respond to spillover of GABA from the synapse, and give rise to tonic inhibitory currents. In certain brain regions, e.g. thalamocortical neurons, tonic inhibition is estimated to represent the majority of total GABA-mediated inhibition, which has raised substantial interest in extrasynaptic receptors as potential drug targets. Thalamocortical neurons typically express α4β2/3δ receptors, however, these have proven difficult to study in recombinant in vitro expression systems due to the inherently low current levels elicited in response to GABA. In this study, we sought to characterize a range of agonists and positive allosteric modulators at α4β2δ and α4β2γ2 receptors. All tested agonists (GABA, THIP, muscimol, and taurine) displayed between 8 and 22 fold increase in potency at the α4β2δ receptor. In contrast, modulatory potencies of steroids (allopregnanolone, THDOC and alfaxalone), anesthetics (etomidate, pentobarbital) and Delta-Selective agents 1 and 2 (DS1 and DS2) were similar at α4β2δ and α4β2γ2 receptors. When evaluating modulatory efficacies, the neurosteroids and anesthetics displayed highest efficacy at α4β2γ2 receptors whereas DS1 and in particular DS2 had highest efficacy at α4β2δ receptors. Overall, several key messages emerged: i) none of the tested compounds displayed significant selectivity and a great need for identifying new δ-selective compounds remains; ii) α4β2δ and α4β2γ2 receptors have such divergent intrinsic activation properties that valid comparisons of modulator efficacies are at best challenging.
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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
       
  • Estimating genotype and allele frequencies of the CYP2D6 gene
    • Abstract: Publication date: Available online 11 May 2016
      Source:Pharmacological Research
      Author(s): M. Acuña, Y.L. Eaton



      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.
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      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.
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      PubDate: 2016-05-14T21:24:18Z
       
  • ABCB1 C3435T gene polymorphism as a potential biomarker of clinical
           outcomes in HER2-positive breast cancer patients
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Adela Madrid-Paredes, Marisa Cañadas-Garre, Antonio Sánchez-Pozo, Ana María Segura-Pérez, Clara Chamorro-Santos, Esther Vergara-Alcaide, Lucía Castillo-Portellano, Miguel Ángel Calleja-Hernández
      HER2-positive breast cancer patients treated with trastuzumab schemes have good initial clinical outcomes. Despite this beneficial effect, many patients experiment resistance to these drugs. Several gene polymorphisms in ABCB1, HER2, and CCND1 have been proposed as potential predictors of clinical outcomes of trastuzumab schemes. The aim of this study was to evaluate the association between 4 gene polymorphisms potentially responsible for bad prognosis (HER2-Ile655Val, CCND1-A870G and ABCB1C1236T, C3435T) and clinical outcomes in HER2-positive BC patients. A retrospective cohorts study was performed. Eighty-four HER2-positive BC patients treated with trastuzumab schemes were included. The four gene polymorphisms were analyzed by PCR Real-Time with Taqman® probes. Genotypes were investigated for their association with tumor response, survival and resistance. Patients with CC genotype of ABCB1-C3435T presented higher risk of resistance to chemotherapy/trastuzumab schemes, compared to those carrying the T-allele (RR: 2.71; CI95%:1.29–5.68; p=0.013888), progression (RR: 1.89; p=0.017964); and exitus (RR: 2.09; p=0.03276). Multivariate logistic regression analysis considering clinical variables and ABCB1-C3435T revealed that the only independent factor associated to resistance to therapy was ABCB1-C3435T gene polymorphism (ORCT/CC: 0.25; p=0.0123; ORTT/CC: 0.09; p=0.0348. The protective effect of ABCB1-C3435T T-allele was confirmed in the multivariate Cox regression analysis for PFS (HRCT/CC: 0.41; p=0.00806; HRTT/CC: 0.22; p=0.01982) and OS (HRCT/CC: 0.49; p=0.0555; HRTT/CC: 0.12; p=0.0398). ABCB1-C1236T, CCND1-A870G and HER2-Ile655Val polymorphisms were not associated to resistance, PFS or OS (p>0.05). The A-allele for CCND1-rs9344 was associated with higher response rates (RR: 3.44; uncorrected p-value: 0.03816) in the bivariate analysis, but no statically association was found after Bonferroni correction (p=0.15264). ABCB1-C3435T, ABCB1-C1236T and HER2-Ile655Val gene polymorphisms were not associated with response. Although this study demonstrates a prognostic value of ABCB1-C3435T gene polymorphism to predict clinical outcomes, further studies with a larger sample will be necessary to validate this result.
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      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.
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      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.
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      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.
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      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.
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      PubDate: 2016-05-08T20:52:32Z
       
  • Pharmacology in Estonia, Latvia and Lithuania: from historical roots to
           nowadays achievements
    • Abstract: Publication date: Available online 7 May 2016
      Source:Pharmacological Research
      Author(s): Baiba Jansone, Malle Kuum, Romaldas Maciulaitis
      This Info article offers a overview on the main historical facts and the current perspectives of the scientific and educational competence in field of pharmacology in three European countries on Baltic sea East coast: Estonia, Latvia and Lithuania. The research areas have changed constantly due to economical and political reasons during the last 200 years and today do cover quite different pharmacological areas in each of Baltic countries and are recognized internationally. Today the main topics of studies in Estonia are the pharmacology of neurodegenerative diseases, mood disorders and brain plasticity; the role of mitochondria in neurodegenerative diseases, and the epigenetics of drug dependence. In Latvia, the primary research areas include molecular, neuropharmacology, particularly search for novel medicines capable to halt neurodegenerative diseases as well as cardiovascular pharmacology. In Lithuania the main focus is on clinical pharmacology, rational use of drugs, pharmacoepidemiology and pharmacoeconomy, in experimental pharmacology on regenerative medicine and nephropharmacology. All three countries have theier own active Societies of Pharmacology.


      PubDate: 2016-05-08T20:52:32Z
       
  • Label-free Technologies and Pharmacology
    • Abstract: Publication date: Available online 4 May 2016
      Source:Pharmacological Research
      Author(s): Ye Fang

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      PubDate: 2016-05-05T20:25:00Z
       
  • Dioscin reduces ovariectomy-induced bone loss by enhancing
           osteoblastogenesis and inhibiting osteoclastogenesis
    • Abstract: Publication date: Available online 4 May 2016
      Source:Pharmacological Research
      Author(s): Xufeng Tao, Yan Qi, Lina Xu, Lianhong Yin, Xu Han, Youwei Xu, Changyuan Wang, Huijun Sun, Jinyong Peng
      Our previous studies showed that dioscin can promote osteoblasts proliferation and differentiation in vitro, but its anti-osteoporosis effect in vivo and the underlying mechanisms remain unclear. In the present work, the results showed that dioscin significantly increased the viability of MC3T3-E1 cells, ALP level and alizarin red S staining area, markedly decreased the numbers of RANKL-induced TRAP-positive multinucleated cells and bone resorption pits formation, enhanced the levels of some osteogenic markers including COL1A2, ALP and OC, which suggested that dioscin clearly promoted osteoblasts proliferation and suppressed osteoclasts formation. In vivo experiments demonstrated that dioscin obviously reduced OVX-induced body weight increase, and improved the biochemical indexes including ALP, StrACP, OC, DPD/Cr, HOP/Cr, BMD, biomechanics and microarchitecture. Moreover, H&E, TB, TRAP staining, and fluorescent double labeling tests indicated that dioscin enhanced osteoblastogenesis and inhibited osteoclastogenesis. Further researches demonstrated that dioscin promoted osteoblastogenesis through up-regulating OPG/RANKL ratio, and inhibited osteoclastogenesis through down-regulating the levels of RANKL induced TRAF6 and the downstream signal molecules including MAPKs, Akt, NF-κB, AP-1, cathepsin K and NFATc1. In addition, dioscin also inhibited TLR4/MyD88 pathway to decrease the levels of TRAF6 and the related proteins. These findings provide new insights to elucidate the effects of dioscin against OVX-induced bone loss, which should be developed as a potential candidate for treating postmenopausal osteoporosis in the future.
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      PubDate: 2016-05-05T20:25:00Z
       
  • Clinical research in neonates and infants: Challenges and perspectives
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Raffaele Coppini, Sinno H.P. Simons, Alessandro Mugelli, Karel Allegaert
      To date, up to 65% of drugs used in neonates and infants are off-label or unlicensed, as they were implemented in clinical care without the usual regulatory phases of pharmacological drug development. Pharmacotherapy in this age group is still mainly based on the individual clinical expertise of specialized pediatricians. Pharmacological trials involving neonates are indeed more difficult to perform: appropriate dosing is hampered by the rapid physiological changes occurring at this stage of development, and the selection of proper end-points and biomarkers is complicated by the limited knowledge of the pathophysiology of the specific diseases of infancy. Moreover, there are many ethical challenges in planning and conducting drug studies in pediatric patients (especially in newborns and infants). In the current review, we address some challenges and discuss possible perspectives to stimulate scientific and clinical pharmacological research in neonates and infants. We hereby aim to illustrate the add on value of the regulatory framework for model-based neonatal medicinal development currently used in Europe and the United States. We provide several examples of successful recent pharmacological trials performed in neonates and infants. In these examples, success was ensured by the implementation of specific pharmacokinetic assessments, thanks to accurate drug dosing achieved with a combination of dose validation, population pharmacokinetics and mathematical models of drug clearance and distribution; moreover, age-specific pharmacodynamics was considered via appropriate evaluations of drug efficacy with end-points adapted to the peculiar pathophysiology of diseases in this age group. These “pharmacological” challenges add to the ethical challenges that are always present in planning and conducting clinical studies in neonates and infants and support the opinion that clinical research in pediatrics should be evaluated by ad hoc ethical committees with specific expertise.


      PubDate: 2016-05-05T20:25:00Z
       
  • Circulating microRNAs in Huntingtońs Disease: emerging mediators in
           metabolic impairment
    • Abstract: Publication date: Available online 4 May 2016
      Source:Pharmacological Research
      Author(s): C. Díez-Planelles, P. Sánchez-Lozano, M.C. Crespo-Lorenzo, J. Gil-Zamorano, R. Ribacoba, N. González, E. Suárez, A. Martínez-Descals, P. Martínez-Camblor, V. Álvarez, R. Martín-Hernández, I. Huerta-Ruíz, I. González-García, J.M. Cosgaya, F. Visioli, A. Dávalos, E. Iglesias-Gutiérrez, C. Tomás-Zapico
      Huntingtońs disease (HD) is a hereditary neurodegenerative disease, with peripheral consequences that negatively contribute to quality of life. Circulating microRNAs (cmiRNAs) are being explored for their roles in intercellular communication and gene expression regulation, which allows gaining insight into the regulation of crosstalk between neuronal and peripheral tissues. Here, we explore the cmiRNA profile of plasma samples from fifteen symptomatic patients, with 40-45CAG repeats in the HTT gene, and seven healthy matched controls. Isolated miRNAs from plasma samples were run against human miRNome panels, which have sequences for 752 human mature miRNAs. We found that 168cmiRNAs are altered in symptomatic patients. Considering Bonferronís correction, miR-877-5p, miR-223-3p, miR-223-5p, miR-30d-5p, miR-128, miR-22-5p, miR-222-3p, miR-338-3p, miR-130b-3p, miR-425-5p, miR-628-3p, miR-361-5p, miR-942 are significantly increased in HD patients as compared with controls. Moreover, after patient́s organization according to approved HD scales, miR-122-5p is significantly decreased in HD patients with Unified Huntingtońs Disease Rating Scale>24, whereas an increase in miR-100-5p levels and a decrease in miR-641 and miR-330-3p levels were recorded when patients were rearranged by Total Functional Capacity. These results suggest that cmiRNA profile could be further modified by disease progression, making cmiRNAs useful as monitoring biomarkers. Analysis of target genes indicated a general overexpression of cmiRNAs implicated in metabolism regulation. Profiling cmiRNA of HD subjects opens the possibility of personalized therapies for different groups of HD patients, based on disease modifiers: regulation of altered pathways might contribute to not only alleviate disease symptoms, but also influence HD progression.
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      PubDate: 2016-05-05T20:25:00Z
       
  • 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.
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      PubDate: 2016-05-05T20:25:00Z
       
  • ApoA-IMilano phospholipid complex (ETC-216) infusion in human volunteers.
           Insights into the phenotypic characteristics of ApoA-IMilano carriers
    • Abstract: Publication date: Available online 4 May 2016
      Source:Pharmacological Research
      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: 2016-05-05T20:25:00Z
       
  • Dissociating the role of endocannabinoids in the pleasurable and
           motivational properties of social play behaviour in rats
    • Abstract: Publication date: Available online 3 May 2016
      Source:Pharmacological Research
      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: 2016-05-05T20:25:00Z
       
  • Label-free analysis of GPCR-stimulation: The critical impact of cell
           adhesion
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): S. Lieb, S. Michaelis, N. Plank, G. Bernhardt, A. Buschauer, J. Wegener
      Label-free cell-based assays have been attracting growing attention in drug research. Optical approaches based on evanescent electric fields (e.g. EPIC, RWG/DMR, SPR) and electrochemical impedance analysis (ECIS, xCELLigence) are by far the most widespread techniques for such purposes. We compared three label-free approaches (ECIS, RWG/DMR and SPR) with respect to the activation of the human histamine H1 receptor (H1R) expressed by U-373 MG glioblastoma and genetically engineered HEK 293T cells. HEK 293T cells were either expressing the hH1R alone or in combination with the adhesion protein hMSR1. The β2-adrenergic receptor (β2-AR) expressed by bovine aortic endothelial cells (BAEC) served as a second cell model. Reduced cell adhesion to the surface of the sensing devices affected both, the optical and the impedance-based readout, but became much more obvious in case of RWG- or SPR-based assays. By contrast, the co-expression of hH1R and hMSR1 in HEK 293T cells strongly enhanced the signal compared to hH1R expression alone. As the sensitivity of the optical readouts is confined to a distance of 100–200nm from the surface, depending on the wavelength of the incident light, this observation is in accordance with tighter adhesion of the co-transfectants, inducing a shorter distance between the cell membrane and the substrate. Combining ECIS and SPR, allowing for simultaneous registration of both signals for a single cell population, provided a direct correlation of both readouts, when H1R or β2-AR stimulation was investigated for the same cell populations. Cell adhesion was found to have a critical impact on the results of label-free cell monitoring, in particular when techniques based on evanescent electric fields are applied.
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      PubDate: 2016-05-05T20:25:00Z
       
  • Tumor suppressive actions of the nuclear receptor corepressor 1
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Olaia Martínez-Iglesias, Elvira Alonso-Merino, Ana Aranda
      Nuclear Receptor Corepressor 1 (NCoR) is an important transcriptional regulator that interacts with nuclear receptors and other transcription factors. Recent results have shown the presence of inactivating mutations or deletions of the NCoR gene in human tumors. NCoR has a strong tumor suppressor activity, inhibiting invasion, metastasis formation and tumor growth in xenograft mouse models. These changes are associated to transcriptional inhibition of genes linked to bad prognosis and increased metastasis in cancer patients. NCoR loss causes a long-term repression of NCoR gene transcription, suggesting that NCoR deficiency in the cancer cell could be propagated playing a role in tumor progression in the absence of NCoR gene mutations. The thyroid hormone receptor TRβ increases NCoR expression and this induction is essential in mediating the anti-metastatic and tumor suppressive actions of the receptor. Since metastasis is the main cause of cancer-related deaths, these results define NCoR as a potential target for cancer therapy.
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      PubDate: 2016-05-05T20:25:00Z
       
  • Notch in fibrosis and as a target of anti-fibrotic therapy
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Biao Hu, Sem H. Phan
      The Notch pathway represents a highly conserved signaling network with essential roles in regulation of key cellular processes and functions, many of which are critical for development. Accumulating evidence indicates that it is also essential for fibrosis and thus the pathogenesis of chronic fibroproliferative diseases in diverse organs and tissues. Different effects of Notch activation are observed depending on cellular and tissue context as well as in both physiologic and pathologic states. Close interactions of Notch signaling pathway with other signaling pathways have been identified. In this review, current knowledge on the role of the Notch signaling with special focus on fibrosis and its potential as a therapeutic target is summarized.
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      PubDate: 2016-05-05T20:25:00Z
       
  • Modulation of endothelial function by Toll like receptors
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Beatriz Salvador, Alicia Arranz, Sara Francisco, Laura Córdoba, Carmen Punzón, Miguel Ángel Llamas, Manuel Fresno
      Endothelial cells (EC) are able to actively control vascular permeability, coagulation, blood pressure and angiogenesis. Most recently, a role for endothelial cells in the immune response has been described. Therefore, the endothelium has a dual role controlling homeostasis but also being the first line for host defence and tissue damage repair thanks to its ability to mount an inflammatory response. Endothelial cells have been shown to express pattern-recognition receptors (PRR) including Toll-like receptors (TLR) that are activated in response to stimuli within the bloodstream including pathogens and damage signals. TLRs are strategic mediators of the immune response in endothelial cells but they also regulate the angiogenic process critical for tissue repair. Nevertheless, endothelial activation and angiogenesis can contribute to some pathologies. Thus, inappropriate endothelial activation, also known as endothelial dysfunction, through TLRs contributes to tissue damage during autoimmune and inflammatory diseases such as atherosclerosis, hypertension, ischemia and diabetes associated cardiovascular diseases. Also TLR induced angiogenesis is required for the growth of some tumors, atherosclerosis and rheumatoid arthritis, among others. In this review we discuss the importance of various TLRs in modulating the activation of endothelial cells and their importance in immunity to infection and vascular disease as well as their potential as therapeutic targets.
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      PubDate: 2016-04-30T20:15:04Z
       
  • 2-pentadecyl-2-oxazoline: Identification in coffee, synthesis and activity
           in a rat model of carrageenan-induced hindpaw inflammation
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Daniela Impellizzeri, Marika Cordaro, Giuseppe Bruschetta, Rosalia Crupi, Jennifer Pascali, Daniele Alfonsi, Gabriele Marcolongo, Salvatore Cuzzocrea
      N-acylethanolamines (NAEs) comprise a family of bioactive lipid molecules present in animal and plant tissues, with N-palmitoylethanolamine (PEA) having received much attention owing to its anti-inflammatory, analgesic and neuroprotective activities. 2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline of PEA, reportedly modulates activity of N-acylethanolamine-hydrolyzing acid amidase (NAAA), which catabolizes PEA. Because PEA is produced on demand and exerts pleiotropic effects on non-neuronal cells implicated in neuroinflammation, modulating the specific amidases for NAEs (NAAA in particular) could be a way to preserve PEA role in maintaining cellular homeostasis through its rapid on-demand synthesis and equally rapid degradation. This study provides the first description of PEA-OXA in both green and roasted coffee beans and Moka infusions, and its synthesis. In an established model of carrageenan (CAR)-induced rat paw inflammation, PEA-OXA was orally active in limiting histological damage and thermal hyperalgesia 6h after CAR intraplantar injection in the right hindpaw and the accumulation of infiltrating inflammatory cells. PEA-OXA appeared to be more potent compared to ultramicronized PEA given orally at the same dose (10mg/kg). PEA-OXA markedly reduced also the increase in hindpaw myeloperoxidase activity, an index of polymorphonuclear cell accumulation in inflammatory tissues. NAAA modulators like PEA-OXA may serve to maximize availability of NAEs (e.g. PEA) while providing for recycling of the NAE components for further resynthesis.
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      PubDate: 2016-04-30T20:15:04Z
       
  • Gender difference in prescription opioid abuse: A focus on oxycodone and
           hydrocodone
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Manuela Graziani, Robert Nisticò
      Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women’s data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects.
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      PubDate: 2016-04-30T20:15:04Z
       
  • What are they waiting for'—Tethered agonism in G protein-coupled
           receptors
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Torsten Schöneberg, Gunnar Kleinau, Antje Brüser
      In classical pharmacology agonists bind to their respective receptors by specific interaction and induce structural changes followed by cellular responses. However, some G protein-coupled receptor (GPCRs), such as rhodopsin and protease-activated receptors (PARs), have their agonists already covalently bound and are parts of the receptor proteins, respectively. Recent studies add adhesion GPCRs and glycoprotein hormone receptors (GPHRs) to the group of GPCRs activated by integral agonists. In contrast to rhodopsin and PARs, adhesion GPCRs and GPHRs exhibit large ectodomains (ECDs) which bind a number of different proteins and other extracellular molecules. It seems that these large size ECDs are required to integrate a multitude of extracellular signals, such as protein ligand binding, cell-cell contacts and even mechanical forces, into uniform intracellular signals. Upon extracellular ligand binding, the intramolecular agonist of those receptors is exposed or isomerizes and induces structural changes in the 7-transmembrane helix domain triggering G-protein activation. The existence of activating structures integrated in receptor molecules challenges our current pharmacological definition of an agonist. We summarized and discussed the specifics of tethered agonist pharmacology which add a number of new features of the already broad signaling abilities of GPCRs and may find useful applications in designer GPCRs.
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      PubDate: 2016-04-26T19:29:02Z
       
  • Label-free cell phenotypic profiling and pathway deconvolution of
           neurotensin receptor-1
    • Abstract: Publication date: Available online 23 April 2016
      Source:Pharmacological Research
      Author(s): Tao Hou, Liying Shi, Jixia Wang, Lai Wei, Lala Qu, Xiuli Zhang, Xinmiao Liang
      Neurotensin (NT), an endogenous peptide found in the central nervous system and in peripheral tissues, contributes to the pathophysiology of neurodegenerative and psychiatric diseases, cancer, inflammation, and immunomodulatory disease. NT exerts its physiological effects predominantly through its cognate high-affinity neurotensin receptor-1 (NTS1). NTS1 emerges as a druggable target; however, there are limited numbers of NTS1 active compounds reported to date. Here we reported a label-free cell phenotypic profiling model for screening NTS1 ligands and differentiating their biased agonism. Resonant waveguide grating enabled dynamic mass redistribution (DMR) assay was first optimized against cell confluency and then used to characterize the endogenous NTS1 in HT29 cell using known agonists and antagonists. Pathway modulators were also used to deconvolute the signaling pathways of endogenous NTS1. Results showed that the NTS1 DMR assay is robust for screening and can differentiate biased agonism; and the activation of NTS1 in HT29 triggers multiple pathways including Gq signaling and epidermal growth factor receptor transactivation. This study highlighted the power of label-free DMR assay to characterize receptor signaling and pharmacology of distinct classes of ligands for NTS1, G protein-coupled receptors in general.
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      PubDate: 2016-04-26T19:29:02Z
       
  • Inhibiting angiotensin-converting enzyme promotes renal repair by
           modulating progenitor cell activation
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Paola Rizzo, Rubina Novelli, Ariela Benigni, Giuseppe Remuzzi
      Independently of the initial insult, activation and accumulation of parietal progenitor cells within the Bowman’s space is a peculiar feature of proliferative chronic kidney diseases. Clinical and experimental studies demonstrated that, in the presence of extensive renal damage, progenitor cells proliferate excessively in the failed attempt to replace the injured podocytes, contributing to the development of crescentic lesions. Inhibiting angiotensin-converting enzyme (ACE) halts crescent formation and promotes the restoration of normal glomerular architecture by limiting progenitor cell proliferation and migration towards the glomerular tuft. Among the mediators involved in the dysregulated response of renal precursors, the angiotensin II (ang II)/ang II type-1 (AT1) receptor/CXCR4 pathway have been demonstrated to be crucial in proliferative diseases. Understanding the mechanisms underlying the formation of crescentic lesions could be instrumental to developing new therapies, which can be more effective and more targeted to molecular mediators than the currently used cytotoxic agents.
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      PubDate: 2016-04-26T19:29:02Z
       
  • Osteopontin plays a key role in vascular smooth muscle cell proliferation
           via EGFR-mediated activation of AP-1 and C/EBPβ pathways
    • Abstract: Publication date: June 2016
      Source:Pharmacological Research, Volume 108
      Author(s): Seung Jin Lee, Seung Eun Baek, Min A Jang, Chi Dae Kim
      Osteopontin (OPN) is known as an active player in the progression of vascular remodeling diseases, however, the precise role in the proliferation of vascular smooth muscle cells (VSMC) is unclear. Thus, this study investigated the role of OPN in VSMC proliferation induced by 4-hydroxynonenal (HNE), and identified the intracellular signaling pathways involved in 4-HNE-induced OPN production. In VSMC primary cultured from rat thoracic aorta as well as in VSMC in the media of aorta, HNE enhanced OPN expression in concentration-dependent manners. Both the proliferation of cultured VSMC and PCNA positive cells in aortic tissues were also increased by HNE, which were attenuated in OPN-deficient cells and aortic tissues isolated from OPN-deficient mice, indicating a pivotal role of OPN in HNE-induced VSMC proliferation. In the promoter assay, HNE increased OPN promoter activity, which was attenuated when the regions harboring AP-1 and C/EBPβ binding sites were mutated. The increased bindings of AP-1 and C/EBPβ to the OPN promoter were also demonstrated by ChIP analysis. In addition, the increases in both OPN expression and the activities of AP-1 and C/EBPβ by HNE were attenuated by AG1478, an EGFR antagonist. Based on these results, it was suggested that HNE induced OPN expression in VSMC via signaling pathways involving AP-1 and C/EBPβ, leading to increases in VSMC proliferation and subsequent vascular remodeling.
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      PubDate: 2016-04-26T19:29:02Z
       
  • Pharmacology of the cell/matrix form of adhesion
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107
      Author(s): Jacopo Meldolesi
      Cell adhesions are heterogeneous processes including two main forms, CAM and cell/matrix forms. Both these forms induce the interaction among cells and with the extracellular matrix, and the generation of intracellular signals. The signaling of the two adhesion forms include, at the cell surface, involvement of distinct integrins, necessary for intracellular cascade activation. I will focus on the cell/integrin form based on two specific integrins, α5β1 (the most important) and αvβ3, activated by the preferential binding of fibronectin, a unique extracellular matrix protein. Such binding induces local assembly of stratified adhesion complexes containing protein kinases, that trigger the intracellular signaling cascades (Akt, ERK and others); proteins that sustain mechanical processes; and proteins associated with the cytoskeleton. In view of its role in several diseases, from cancers to the eye macular-degeneration; from brain neurodegeneration to fibroses, the pharmacological interest for the cell/integrin adhesion has grown, and presumably will further grow in the near future. The agents identified and developed for therapy include antibodies, many peptides and chemical drugs against α5β1 integrin; drugs against fibronectin and metalloproteinases 2/9, responsible of the latter enzyme proteolysis; anti-kinase and anti-cascade drugs, some of which targeted to the activation of transcription factors and/or their transfer to the nucleus, with repression or activation of gene expression. A new perspective, based on the investigation of both animal models and human patients, includes factors active on the cell/matrix and CAM adhesions, considered separately or coordinately in distinct therapeutic approaches, integrated or not with classical chemotherapic treatments.
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      PubDate: 2016-04-22T18:25:01Z
       
  • Pharmacological treats for SUMO addicts
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107
      Author(s): Marco P. Licciardello, Stefan Kubicek
      Non-oncogene addiction exploits cancer vulnerabilities resulting from altered cellular signaling pathways in response to oncogenic mutations that are not directly druggable. In this perspective, we address recent findings showing how the SUMOylation cascade provides a synthetic lethal target in the context of different malignant transformations. Functional genomics screens have revealed that the activation of oncogenes such as NOTCH1, MYC or KRAS generates a cancer-specific dependency on SUMOylation. Pharmacological targeting of the SUMOylation cascade induces cancer cell death in these settings, suggesting potential therapeutic applications in oncology. However, the physicochemical properties of the few currently available SUMOylation inhibitors preclude clear-cut investigations and clinical testing. We therefore encourage the development of better chemical probes targeting this multifaceted post-translational modification. Such optimized molecules would enable proof of concept studies to evaluate the therapeutic potential of non-oncogene addiction to SUMO.
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      PubDate: 2016-04-14T16:59:24Z
       
  • Microenvironment and autophagy cross-talk: Implications in cancer therapy
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107
      Author(s): Luciana R. Gomes, Alexandre T. Vessoni, Carlos F.M. Menck
      There are many ongoing clinical trials to validate tumour microenvironment or autophagic pathway components as targets for anticancer therapies. Different components of the tumour microenvironment play important roles in tumour cell responses, directly affecting malignant transformation, drug resistance and metastasis. Autophagy is also related to chemotherapy responses by inducing tumour cell death or survival. Thus, the autophagy pathway may act as oncosuppressor, in addition to protecting cells from chemotherapy. The cross-talk between the microenvironment and autophagy is very complex and poorly understood. In a recent study using a three-dimensional (3D) cell culture model, the well-documented chemotherapy-mediated activation of autophagy was impaired in breast cancer cells, suggesting a context-dependent outcome for autophagy modulators, under the control of the p53 protein. A deeper understanding of this microenvironment/autophagy interplay may provide important clues for identifying differences in the tumour cell signalling network from in vitro basic research studies to the actual clinical context. In this work, we summarize the role of the microenvironment and autophagy in physiological and tumourigenic conditions, their interactions, and the challenges related to the use of drugs that target these pathways in cancer treatment protocols, emphasizing the potential use of 3D cell culture models in preclinical studies.
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      PubDate: 2016-04-10T16:47:33Z
       
  • Effect of pentoxifylline on renal outcomes in chronic kidney disease
           patients: A systematic review and meta-analysis
    • Abstract: Publication date: May 2016
      Source:Pharmacological Research, Volume 107
      Author(s): Christian Leporini, Anna Pisano, Emilio Russo, Graziella D’Arrigo, Giovambattista de Sarro, Giuseppe Coppolino, Davide Bolignano
      Chronic kidney disease (CKD) represents an important health problem worldwide and the search for new therapeutic approaches for retarding CKD progression is a timely issue. Recent evidence suggest that the anti-inflammatory and hemorrheologic drug Pentoxifylline (PTX), may produce favorable effects on kidney function. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to ascertain whether PTX derivatives, alone or in combination to other treatments, may be useful in slowing down disease progression in patients with diabetic or non-diabetic CKD. We found 26 studies (1518 subjects) matching our search criteria. Information on the effects of PTX on hard renal outcomes (doubling of serum creatinine or need for chronic dialysis) were lacking in all the reviewed trials. Conversely, PTX was effective in reducing proteinuria compared to control, a benefit that was more evident in patients with type-1 diabetes mellitus, higher proteinuria at baseline and early renal impairment. An improvement in renal function (eGFR/creatinine clearance) was observed particularly in patients with more advanced CKD stage and in studies with longer follow-up. Conversely, cumulative analyses did not reveal any evident reduction in urinary albumin excretion, even in diabetic patients. The use of PTX was relatively safe as most trials recorded only minor gastrointestinal adverse effects. Although these findings point at some reno-protective effects of PTX, there is no conclusive evidence proving the usefulness of this agent for improving renal outcomes in subjects with chronic kidney disease of various etiology. Future trials adequately powered and designed on hard clinical end-points are needed.
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      PubDate: 2016-04-10T16:47:33Z
       
  • CurcuminDownregulates Human Tumor Necrosis Factor-α Levels:A
           systematic review and meta-analysis ofrandomized controlled trials
    • Abstract: Publication date: Available online 26 March 2016
      Source:Pharmacological Research
      Author(s): Amirhossein Sahebkar, Arrigo F.G. Cicero, Luis E. Simental-Mendía, Bharat B. Aggarwal, Subash C. Gupta
      BACKGROUND Tumor necrosis factor-α (TNF-α) is a key inflammatory mediator and its reduction is a therapeutic target in several inflammatory diseases. Curcumin, a bioactive polyphenol from turmeric, has been shown in several preclinical studies to block TNF-α effectively. However, clinical evidence has not been fully conclusive. OBJECTIVE The aim of the present meta-analysis was to evaluate the efficacy of curcumin supplementation on circulating levels of TNF-α in randomized controlled trials (RCTs). METHODS The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to September 21, 2015, to identify RCTs investigating the impact of curcumin on circulating TNF-α concentration. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. RESULTS Eight RCTs comprising nine treatment arms were finally selected for the meta-analysis. There was a significant reduction of circulating TNF-α concentrations following curcumin supplementation (WMD: −4.69pg/mL, 95% CI: −7.10, −2.28, p <0.001). This effect size was robust in sensitivity analysis. Meta-regression did not suggest any significant association between the circulating TNF-α-lowering effects of curcumin with either dose or duration (slope: 0.197; 95% CI: −1.73, 2.12; p =0.841) of treatment. CONCLUSION This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating TNF-α concentration.
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      PubDate: 2016-03-28T15:08:08Z
       
  • Off-Target Drug Effects Resulting in Altered Gene Expression Events with
           Epigenetic and “Quasi-Epigenetic” Origins
    • Abstract: Publication date: Available online 26 March 2016
      Source:Pharmacological Research
      Author(s): Stephen J. Anderson, Kristina M. Feye, Garrett R. Schmidt-McCormack, Emir Malovic, Gregory S.A. Mlynarczyk, Patricia Izbicki, Larissa F. Arnold, Matthew A. Jefferson, Bierlein M. de la Rosa, Rita F. Wehrman, KC Luna, Hilary Z. Hu, Naveen C. Kondru, Michael D. Kleinhenz, Joe S. Smith, Sireesha Manne, Marson R. Putra, Shivani Choudhary, Nyzil Massey, Diou Luo, Carrie A. Berg, Sreemoyee Acharya, Shaunik Sharma, Sri Harsha Kanuri, Jennifer K. Lange, Steve A. Carlson
      This review synthesizes examples of pharmacological agents that have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include “quasi-epigenetic” mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of “pharmacoepigenetic” mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.
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      PubDate: 2016-03-28T15:08:08Z
       
  • Bioresorbable vascular scaffolds: Biodegradation, drug delivery and
           vascular remodeling
    • Abstract: Publication date: Available online 18 March 2016
      Source:Pharmacological Research
      Author(s): Belay Tesfamariam
      The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release over time, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis.
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      PubDate: 2016-03-20T13:09:50Z
       
  • Pharmacological targeting of redox regulation systems as new therapeutic
           approach for psychiatric disorders: a literature overview
    • Abstract: Publication date: Available online 16 March 2016
      Source:Pharmacological Research
      Author(s): Stefania Schiavone, Luigia Trabace
      Redox dysregulation occurs following a disequilibrium between reactive oxygen species (ROS) producing and degrading systems, i.e. mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and nitric oxide synthase (NOS) on one hand and the principal antioxidant system, the glutathione, on the other hand. Increasing recent evidence points towards a pathogenetic role of an altered redox state in the development of several mental disorders, such as anxiety, bipolar disorders, depression, psychosis, autism and post-traumatic stress disorders (PTSD). In this regard, pharmacological targeting of the redox state regulating systems in the brain has been proposed as an innovative and promising therapeutic approach for the treatment of these mental diseases. This review will summarize current knowledge obtained from both pre-clinical and clinical studies in order to descant “lights and shadows” of targeting pharmacologically both the producing and degrading reactive oxygen species (ROS) systems in psychiatric disorders.
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      PubDate: 2016-03-20T13:09:50Z
       
  • Cyclin-dependent protein kinase inhibitors including palbociclib as
           anticancer drugs
    • Abstract: Publication date: Available online 16 March 2016
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Then CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factors, which in turn lead to the generation of several proteins required for cell cycle progression. As a result, cells pass through the G1-restriction point and are committed to complete cell division. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S, G2, and M-phase progression. Increased cyclin or CDK expression or decreased levels of endogenous CDK inhibitors such as INK4 or CIP/KIP have been observed in various cancers. In contrast to the mutational activation of EGFR, Kit, or B-Raf in the pathogenesis of malignancies, mutations in the CDKs that cause cancers are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Abemaciclib (LY2835219), ribociclib (Lee011), and palbociclib (Ibrance® or PD0332991) target CDK4/6 with IC50 values in the low nanomolar range. Palbociclib and other CDK inhibitors bind in the cleft between the small and large lobes of the CDKs and inhibit the binding of ATP. Like ATP, palbociclib forms hydrogen bonds with residues in the hinge segment of the cleft. Like the adenine base of ATP, palbociclib interacts with catalytic spine residues CS6 and CS7. CDK antagonists are in clinical trials for the treatment of a variety of malignancies. Significantly, palbociclib has been approved by the FDA for the treatment of hormone-receptor positive/human epidermal growth factor receptor-2 negative breast cancer in conjunction with letrozole as a first-line therapy and with fulvestrant as a second-line treatment. As inhibitors of the cell cycle, it is not surprising that one of their most common toxicities is myelosuppression with decreased neutrophil production.
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      PubDate: 2016-03-20T13:09:50Z
       
  • Targeting Mutant NRAS Signaling Pathways in Melanoma
    • Abstract: Publication date: Available online 15 March 2016
      Source:Pharmacological Research
      Author(s): Ha Linh Vu, Andrew E. Aplin

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      PubDate: 2016-03-16T12:47:40Z
       
  • ROSUVASTATIN: BEYOND THE CHOLESTEROL-LOWERING EFFECT
    • Abstract: Publication date: Available online 2 March 2016
      Source:Pharmacological Research
      Author(s): Francesca Cortese, Michele Gesualdo, Anna Maria Cortese, Santa Carbonara, Fiorella Devito, Annapaola Zito, Gabriella Ricci, Pietro Scicchitano, Marco Matteo Ciccone
      Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a liver enzyme responsible of the rate-limiting step in cholesterol synthesis. When compared to other molecules of the same class, it shows high efficacy in the improvement of lipid profile, and, thanks to its non-cholesterol-lowering actions (anti-inflammatory, antioxidant and antithrombotic), represents a crucial tool for cardiovascular primary and secondary prevention. Moreover, recent data highlight rosuvastatin beneficial effects in several other fields. In this manuscript we analyzed literature sources in order to better define rosuvastatin features and discuss some critical issues.
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      PubDate: 2016-03-06T07:52:52Z
       
  • E-Syts; the extended story
    • Abstract: Publication date: Available online 27 February 2016
      Source:Pharmacological Research
      Author(s): Chelsea Herdman, Tom Moss
      The Extended-Synaptotagmin (E-Syt) membrane proteins were only recently discovered, but have already been implicated in a range of interrelated cellular functions, including calcium and receptor signaling, and membrane lipid transport. However, despite their evolutionary conservation and detailed studies of their molecular actions, we still have little idea of how and when these proteins are required in cellular and organism physiology. Here we review our present understanding of the E-Syts and discuss the molecular functions and in vivo requirements for these proteins.
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      PubDate: 2016-02-29T07:41:40Z
       
  • Sniping the Scout: Targeting the key molecules in dendritic cell functions
           for treatment of autoimmune diseases
    • Abstract: Publication date: Available online 27 February 2016
      Source:Pharmacological Research
      Author(s): Xing Li, Yanping Han, Erwei Sun
      Dendritic cells (DCs) are a power tool for manipulating immune system. They play important roles in the induction of immunity as well as inducing intrathymic and peripheral tolerance. After generated from stem cells in the bone marrow, DCs traffic to the peripheral tissues, where they capture and process antigens, express lymphocyte co-stimulators, migrate to the secondary lymph organs and present the processed antigen to naive T cells to either activate or tolerize them. These processes are modulated subtly and influenced by various factors. Aberrant regulation of the processes may cause autoimmunity. Investigation into the biology of DCs and the molecules and mechanisms that regulate them helps us understanding the pathogenesis of autoimmune diseases and reveals numerous steps for pharmacological manipulation. In this review, we made a sketch line of the critical events of DC biology that are potential pharmacologic targets for the treatment of autoimmune diseases.


      PubDate: 2016-02-29T07:41:40Z
       
 
 
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