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Publisher: Elsevier   (Total: 2969 journals)

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Journal Cover Pharmacological Research
  [SJR: 1.693]   [H-I: 84]   [2 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2969 journals]
  • Enzyme-responsive multistage vector for drug delivery to tumor tissue
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Yu Mi, Joy Wolfram, Chaofeng Mu, Xuewu Liu, Elvin Blanco, Haifa Shen, Mauro Ferrari
      Various nanodelivery systems have been designed to release therapeutic agents upon contact with specific enzymes. However, enzyme-triggered release typically takes place in the tissue interstitium, thereby resulting in the extracellular delivery of drugs. Here, we have designed an enzyme-stimulated multistage vector (ESMSV), which enables stimulus-triggered release of drug-encapsulated nanoparticles from a microparticle. Specifically, polymeric nanoparticles with a surface matrix metalloproteinase-2 (MMP2) peptide substrate were conjugated to the surface of porous silicon microparticles. In the presence of MMP2, the polymeric nanoparticles were released into the tumor interstitium. This platform can be used to attain triggered drug release, while simultaneously facilitating the cellular internalization of drugs. The results indicate that nanoparticle release was MMP2-specific and resulted in improved intracellular uptake of hydrophobic agents in the presence of MMP2. Furthermore, in a mouse model of melanoma lung metastasis, systemic delivery of ESMSVs caused a substantial increase in intracellular accumulation of agents in cancer cells in comparison to delivery with non-stimulus-responsive particles.
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      PubDate: 2016-08-23T08:51:54Z
       
  • The hypophagic factor oleoylethanolamide differentially increases c-fos
           expression in appetite regulating centres in the brain of wild type and
           histamine deficient mice
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Hayato Umehara, Roberta Fabbri, Gustavo Provensi, M. Beatrice Passani
      Histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMN) establish connections with virtually all brain areas. Recent evidence suggests that feeding-related motivation is correlated with the activation of a subpopulation of histamine neurons in the ventral TMN that project to hypothalamic and subcortical areas controlling feeding behaviour. Oleoylethanolamide (OEA) is a hypophagic lipid-amide released by the small intestine in response to daily fat intake that indirectly activates hypothalamic oxytocin-neurons in the paraventricular (PVN) and supraoptic (SON) nuclei. We recently showed that OEA requires the integrity of neuronal histamine to fully display its hypophagic effect. Here we aimed to investigate if differences exist in OEA-induced c-Fos expression in several brain regions of fasted, histidine decarboxylase (HDC)-KO mice that do not synthesize histamine, and wild type (WT) littermates. All the brain regions examined receive histaminergic innervation and are involved in different aspects of feeding behaviour. We found that OEA increased c-Fos expression in the SON, arcuate nucleus (ARC) and the amygdala of WT mice, but not HDC-KO mice, whereas neither genotype nor treatment differences were observed in the lateral and dorsomedial hypothalamus. Furthermore, oxytocin-immunostaining was markedly increased in the neurohypophysis of WT and not in HDC-KO mice. Of note, OEA increased c-Fos expression in the nucleus of solitary tract of both genotypes. Our findings suggest that the TMN serves as a relay station to elaborate peripheral signals that control homeostatic and adaptive behavioural responses.
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      PubDate: 2016-08-23T08:51:54Z
       
  • The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing
           activity through 5-HT1A, D2 and TAAR1 receptors
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Danilo De Gregorio, Luca Posa, Rafael Ochoa-Sanchez, Ryan McLaughlin, Sabatino Maione, Stefano Comai, Gabriella Gobbi
      d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5–20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT2A and D2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30–120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.
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      PubDate: 2016-08-23T08:51:54Z
       
  • The novel cannabinoid antagonist SM-11 reduces hedonic aspect of food
           intake through a dopamine-dependent mechanism
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): G.R. Fois, L. Fattore, G. Murineddu, A. Salis, G. Pintore, B. Asproni, G.A. Pinna, M. Diana
      Cannabinoids, endogenous and exogenously administered, are known to positively regulate food intake and energy balance. Since CB1 receptor antagonists reduce food intake and antagonize overweight, we developed a new CB1 receptor antagonist in an attempt to identify a compound with potential application in overeating disorders. The newly developed SM-11 compound dose-dependently decreases food intake in rats by 15–20%. Moreover, SM-11 reduces self-administration of palatable food in both food restricted and ad libitum fed rats, suggesting an action on the hedonic component of food intake. Thus, we next tested the effect of SM-11 on the stimulating properties of the CB1 receptor agonist WIN55,212-2 (WIN) on the electrophysiological activity of Nucleus Accumbens-projecting dopaminergic neurons of the ventral tegmental area (VTA). SM-11 fully and readily antagonized the WIN-induced increments in single spiking and burst firing of antidromically-identified dopamine neurons. When administered to naïve (no WIN-pretreated) rats, SM-11 did not alter basal neuronal activity, thereby suggesting a pure antagonistic profile. SM-11 thus appears as a promising candidate in the search of potential anti-obesity medications.
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      PubDate: 2016-08-23T08:51:54Z
       
  • Screening of a composite library of clinically used drugs and
           well-characterized pharmacological compounds for cystathionine
           β-synthase inhibition identifies benserazide as a drug potentially
           suitable for repurposing for the experimental therapy of colon cancer
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Nadiya Druzhyna, Bartosz Szczesny, Gabor Olah, Katalin Módis, Antonia Asimakopoulou, Athanasia Pavlidou, Petra Szoleczky, Domokos Gerö, Kazunori Yanagi, Gabor Törö, Isabel López-García, Vassilios Myrianthopoulos, Emmanuel Mikros, John R. Zatarain, Celia Chao, Andreas Papapetropoulos, Mark R. Hellmich, Csaba Szabo
      Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the ‘Killer Plates’ collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H2S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H2S production) and were assessed for their ability to quench the H2S signal produced by the H2S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H2S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC50: ∼60μM), tannic acid (IC50: ∼40μM) and benserazide (IC50: ∼30μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC50: ∼3μM) and NSC67078 (IC50: ∼1μM), while aurintricarboxylic acid (IC50: ∼3μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC50: ∼1μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC50 of ∼6μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC50: ∼6μM), tannic acid (IC50: ∼20μM), benserazide (IC50: ∼20μM), and NSC67078 (IC50: ∼0.3μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC50: ∼300μM). In contrast, although a CBS inhibitor in the cell-free assay, aurintricarboxylic acid failed to inhibit HCT116 proliferation at lower concentrations, and stimulated cell proliferation at 300μM. Copper-containing compounds present in the libraries, were also found to be potent inhibitors of recombinant CBS; however this activity was due to the CBS inhibitory effect of copper ions themselves. However, copper ions, up to 300μM, did not inhibit HCT116 cell proliferation. Benserazide was only a weak inhibitor of the activity of the other H2S-generating enzymes CSE and 3-MST activity (16% and 35% inhibition at 100μM, respectively) in vitro. Benserazide suppressed HCT116 mitochondrial function and inhibited proliferation of the high CBS-expressing colon cancer cell line HT29, but not the low CBS-expressing line, LoVo. The major benserazide metabolite 2,3,4-trihydroxybenzylhydrazine also inhibited CBS activity and suppressed HCT116 cell proliferation in vitro. In an in vivo study of nude mice bearing human colon cancer cell xenografts, benserazide (50mg/kg/days.q.) prevented tumor growth. In silico docking simulations showed that benserazide binds in the active site of the enzyme and reacts with the PLP cofactor by forming reversible but kinetically stable Schiff base-like adducts with the formyl moiety of pyridoxal. We conclude that benserazide inhibits CBS activity and suppresses colon cancer cell proliferation and bioenergetics in vitro, and tumor growth in vivo. Further pharmacokinetic, pharmacodynamic and preclinical animal studies are necessary to evaluate the potential of repurposing benserazide for the treatment of colorectal cancers.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Integrins in glioblastoma: Still an attractive target'
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Mayra Paolillo, Massimo Serra, Sergio Schinelli
      Integrin-mediated signaling pathways have been found to promote the invasiveness and survival of glioma cells by modifying the brain microenvironment to support the formation of the tumoral niche. A variety of cells in the niche express integrin receptors, including tumor-associated macrophages, fibroblasts, endothelial cells and pericytes. In particular, RGD-binding integrins have been demonstrated to have an important role in the epithelial-mesenchymal transition process, considered the first step in the infiltration of tissue by cancer cells and molecular markers of which have been found in glioma cells. In simultaneous research, Small Molecule Integrin Antagonists (SMIA) yielded initially promising results in in vitro and in vivo studies, leading to clinical trials to test their safety and efficacy in combination with other anticancer drugs in the treatment of several tumor types. The initially high expectations, especially because of their antiangiogenic activity, which appeared to be a winning strategy against GBM, were not confirmed and this cast serious doubts on the real benefits to be gained from the use of SMIA for the treatment of cancer in humans. In this review, we provide an overview of recent findings concerning the functional roles of integrins, especially RGD-binding integrins, in the processes related to glioma cells survival and brain tissue infiltration. These findings disclose a new scenario in which recently developed SMIA might become useful tools to hinder glioblastoma cell dissemination.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in
           the periaqueductal grey
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Manish K. Madasu, Bright N. Okine, Weredeselam M. Olango, Kieran Rea, Róisín Lenihan, Michelle Roche, David P. Finn
      Negative affective state has a significant impact on pain, and genetic background is an important moderating influence on this interaction. The Wistar–Kyoto (WKY) inbred rat strain exhibits a stress-hyperresponsive, anxiety/depressive-like phenotype and also displays a hyperalgesic response to noxious stimuli. Transient receptor potential subfamily V member 1 (TRPV1) within the midbrain periaqueductal grey (PAG) plays a key role in regulating both aversive and nociceptive behaviour. In the present study, we investigated the role of TRPV1 in the sub-columns of the PAG in formalin-evoked nociceptive behaviour in WKY versus Sprague-Dawley (SD) rats. TRPV1 mRNA expression was significantly lower in the dorsolateral (DL) PAG and higher in the lateral (L) PAG of WKY rats, compared with SD counterparts. There were no significant differences in TRPV1 mRNA expression in the ventrolateral (VL) PAG between the two strains. TRPV1 mRNA expression significantly decreased in the DLPAG and increased in the VLPAG of SD, but not WKY rats upon intra-plantar formalin administration. Intra-DLPAG administration of either the TRPV1 agonist capsaicin, or the TRPV1 antagonist 5′-Iodoresiniferatoxin (5′-IRTX), significantly increased formalin-evoked nociceptive behaviour in SD rats, but not in WKY rats. The effects of capsaicin were likely due to TRPV1 desensitisation, given their similarity to the effects of 5′-IRTX. Intra-VLPAG administration of capsaicin or 5′-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, and similar effects were seen with 5′-IRTX in WKY rats. Intra-LPAG administration of 5′-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, but not in WKY rats. These results indicate that modulation of inflammatory pain by TRPV1 in the PAG occurs in a sub-column-specific manner. The data also provide evidence for differences in the expression of TRPV1, and differences in the effects of pharmacological modulation of TRPV1 in specific PAG sub-columns, between WKY and SD rats, suggesting that TRPV1 expression and/or functionality in the PAG plays a role in hyper-responsivity to noxious stimuli in a genetic background prone to negative affect.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Gene polymorphisms as predictors of response to biological therapies in
           psoriasis patients
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Teresa María Linares-Pineda, Marisa Cañadas-Garre, Antonio Sánchez-Pozo, Miguel Ángel Calleja-Hernández
      Psoriasis is a chronic inflammatory autoimmune skin disease, characterized by the formation of erythematous scaly plaques on the skin and joints. The therapies for psoriasis are mainly symptomatic and sometimes with poor response. Response among patients is very variable, especially with biological drugs (adalimumab, etarnecept, infliximab and ustekimumab). This variability may be partly explained by the effect of different genetic backgrounds. This has prompted the investigation of many genes, such as FCGR3A, HLA, IL17F, IL23R, PDE3A-SLCO1C1, TNFα and other associated genes, as potential candidates to predict response to the different biological drugs used for the treatment of psoriasis. In this article, we will review the influence of gene polymorphisms investigated to date on response to biological drugs in psoriasis patients.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Novel, selective EPO receptor ligands lacking erythropoietic activity
           reduce infarct size in acute myocardial infarction in rats
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Krisztina Kiss, Csaba Csonka, János Pálóczi, Judit Pipis, Anikó Görbe, Gabriella F. Kocsis, Zsolt Murlasits, Márta Sárközy, Gergő Szűcs, Christopher P. Holmes, Yijun Pan, Ashok Bhandari, Tamás Csont, Mehrdad Shamloo, Kathryn W. Woodburn, Péter Ferdinandy, Péter Bencsik
      Erythropoietin (EPO) has been shown to protect the heart against acute myocardial infarction in pre-clinical studies, however, EPO failed to reduce infarct size in clinical trials and showed significant safety problems. Here, we investigated cardioprotective effects of two selective non-erythropoietic EPO receptor ligand dimeric peptides (AF41676 and AF43136) lacking erythropoietic activity, EPO, and the prolonged half-life EPO analogue, darbepoetin in acute myocardial infarction (AMI) in rats. In a pilot study, EPO at 100U/mL significantly decreased cell death compared to vehicle (33.8±2.3% vs. 40.3±1.5%, p<0.05) in rat neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. In further studies (studies 1–4), in vivo AMI was induced by 30min coronary occlusion and 120min reperfusion in male Wistar rats. Test compounds and positive controls for model validation (B-type natriuretic peptide, BNP or cyclosporine A, CsA) were administered iv. before the onset of reperfusion. Infarct size (IS) was measured by standard TTC staining. In study 1, 5000U/kg EPO reduced infarct size significantly compared to vehicle (45.3±4.8% vs. 59.8±4.5%, p<0.05). In study 2, darbepoetin showed a U-shaped dose-response curve with maximal infarct size-reducing effect at 5μg/kg compared to the vehicle (44.4±5.7% vs. 65.9±2.7%, p<0.01). In study 3, AF41676 showed a U-shaped dose-response curve, where 3mg/kg was the most effective dose compared to the vehicle (24.1±3.9% vs. 44.3±2.5%, p<0.001). The positive control BNP significantly decreased infarct size in studies 1–3 by approximately 35%. In study 4, AF43136 at 10mg/kg decreased infarct size, similarly to the positive control CsA compared to the appropriate vehicle (39.4±5.9% vs. 58.1±5.4% and 45.9±2.4% vs. 63.8±4.1%, p<0.05, respectively). This is the first demonstration that selective, non-erythropoietic EPO receptor ligand dimeric peptides AF41676 and AF43136 administered before reperfusion are able to reduce infarct size in a rat model of AMI. Therefore, non-erythropoietic EPO receptor peptide ligands may be promising cardioprotective agents.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Hydrogen sulfide compensates nitric oxide deficiency in murine corpus
           cavernosum
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Günay Yetik-Anacak, Aycan Dikmen, Ciro Coletta, Emma Mitidieri, Mehmet Dereli, Erminia Donnarumma, Roberta d'Emmanuele di Villa Bianca, Raffaella Sorrentino
      Erectile dysfunction (ED) is considered as a marker for cardiovascular diseases. Nitric oxide (NO) deficiency is the major cause of erectile dysfunction (ED). The role of hydrogen sulfide (H2S) in erection has recently been recognized and is receiving attention as a pharmacological target. Several studies have focused on the effect of H2S on NO-dependent relaxation, but the role of NO on H2S in penile tissue has not been studied yet. Unlike NO, H2S is mainly synthesized from smooth muscle cells rather than endothelial cells. We hypothesized that H2S may compensate for the decreased NO bioavailability and may be beneficial in severe ED where endothelial dysfunction is present. Thus we studied the effect of NO deficiency on H2S formation and vasorelaxation induced by l-cysteine, which is the substrate of the H2S producing enzymes in mice corpus cavernosum (MCC). NO deficiency induced by Nω-Nitro-l-arginine (L-NNA) was confirmed by the inhibition of acetylcholine-induced relaxation. l-cysteine, the substrate for the endogenous H2S production, caused a concentration-dependent relaxation that was reduced by CBS/CSE inhibitor aminooxyacetic acid (AOAA) in MCC strips. L-NNA caused a significant increase in l-cysteine-induced relaxation, and this effect was reversed by AOAA. On the contrary, no change in relaxation to NaHS (exogenous H2S donor) in MCC was observed. L-NNA increased H2S formation stimulated by l-cysteine in wild type MCC but not in CSE−/− mice. In parallel, the expression of both cysthationine γ lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST) was increased, whereas cysthationine-β synthase (CBS) was decreased in eNOS−/− MCC. We conclude that H2S plays a compensatory role in the absence of NO by enhancing the relaxation induced by endogenous H2S through CSE and 3-MPST in MCC, without altering downstream mechanisms. We suggest that H2S-targeting drugs may provide the maintenance of compensatory treatment in ED patients. This may be more relevant in ED with severe endothelial dysfunction, as H2S is mainly derived from smooth muscle.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Timing and crosstalk of glucocorticoid signaling with cytokines,
           neurotransmitters and growth factors
    • Abstract: Publication date: November 2016
      Source:Pharmacological Research, Volume 113, Part A
      Author(s): Margarita Arango-Lievano, Freddy Jeanneteau
      Glucocorticoid actions are tailored to the organs and cells responding thanks to complex integration with ongoing signaling mediated by cytokines, hormones, neurotransmitters, and growth factors. Disruption of: (1) the amount of signaling molecules available locally; (2) the timing with other signaling pathways; (3) the post-translational modifications on glucocorticoid receptors; and (4) the receptors-interacting proteins within cellular organelles and functional compartments, can modify the sensitivity and efficacy of glucocorticoid responses with implications in physiology, diseases and treatments. Tissue sensitivity to glucocorticoids is sustained by multiple systems that do not operate in isolation. We take the example of the interplay between the glucocorticoid and brain-derived neurotrophic factor signaling pathways to deconstruct context-dependent glucocorticoid responses that play key roles in physiology, diseases and therapies.
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      PubDate: 2016-08-18T08:47:32Z
       
  • Activation of delta-opioid receptor contributes to the antinociceptive
           effect of oxycodone in mice
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Pao-Pao Yang, Geng-Chang Yeh, Teng-Kuang Yeh, Jinghua Xi, Horace H. Loh, Ping-Yee Law, Pao-Luh Tao
      Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors. In this study, using male mu-opioid receptor knock-out (MOR-KO) mice, we examined whether delta-opioid receptor was involved in oxycodone antinociception. Systemic subcutaneous (s.c.) administration of oxycodone (above 40mg/kg) could induce a small but significant antinociceptive effect in MOR-KO mice by the tail flick test. Delta-opioid receptor antagonist (naltrindole, 10mg/kg or 20mg/kg, i.p.) could block this effect. When oxycodone was injected directly into the brain of MOR-KO mice by intracerebroventricular (i.c.v.) route, oxycodone at doses of 50nmol or higher could induce similar level of antinociceptive responses to those observed in wild type mice at the same doses by i.c.v. Delta-opioid receptor antagonists (naltrindole at 10nmol or ICI 154,129 at 20μg) completely blocked the supraspinal antinociceptive effect of oxycodone in MOR-KO mice. Such oxycodone antinociceptive responses were probably not due to its active metabolites oxymorphone because (a) the relative low level of oxymorphone was found in the brain after systemically or centrally oxycodone injection using LC/MS/MS analysis; (b) oxymorphone at a dose that mimics the level detected in the mice brain did not show any significant antinocieption effect; (c) oxycodone exhibits equal potency as oxymorphone albeit being a partial agonist in regulating [Ca2+]I transients in a clonal cell line expressing high level of mu-opioid receptor. These data suggest that oxycodone by itself can activate both the mu- and delta-opioid receptors and that delta-opioid receptors may contribute to the central antinociceptive effect of oxycodone in mice.
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      PubDate: 2016-08-13T08:43:12Z
       
  • Protection of neonatal rat cardiac myocytes against radiation-induced
           damage with agonists of growth hormone-releasing hormone
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Laura Kiscsatári, Zoltán Varga, Andrew V. Schally, Renáta Gáspár, Csilla Terézia Nagy, Zoltán Giricz, Péter Ferdinandy, Gabriella Fábián, Zsuzsanna Kahán, Anikó Görbe
      Despite the great clinical significance of radiation-induced cardiac damage, experimental investigation of its mechanisms is an unmet need in medicine. Beneficial effects of growth hormone-releasing hormone (GHRH) agonists in regeneration of the heart have been demonstrated. The aim of this study was the evaluation of the potential of modern GHRH agonistic analogs in prevention of radiation damage in an in vitro cardiac myocyte-based model. Cultures of cardiac myocytes isolated from newborn rats (NRVM) were exposed to a radiation dose of 10Gy. The effects of the agonistic analogs, JI-34 and MR-356, of human GHRH on cell viability, proliferation, their mechanism of action and the protein expression of the GHRH/SV1 receptors were studied. JI-34 and MR-356, had no effect on cell viability or proliferation in unirradiated cultures. However, in irradiated cells JI-34 showed protective effects on cell viability at concentrations of 10 and 100nM, and MR-356 at 500nM; but no such protective effect was detected on cell proliferation. Both agonistic analogs decreased radiation-induced ROS level and JI-34 interfered with the activation of SAFE/RISK pathways. Using Western blot analysis, a 52kDa protein isoform of GHRHR was detected in the samples in both irradiated and unirradiated cells. Since GHRH agonistic analogs, JI-34 and MR-356 alleviated radiation-induced damage of cardiac myocytes, they should be tested in vivo as potential protective agents against radiogenic heart damage.
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      PubDate: 2016-08-13T08:43:12Z
       
  • Tumor deconstruction as a tool for advanced drug screening and
           repositioning
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Rutika R. Naik, Ting Luo, Mohammad Kohandel, Sharmila A. Bapat
      A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof‐of‐principle for cytotoxicity (POC). However, this end-point lacks any assessment of drug resistance of the residual tumor and its capability to establish refractory and/or recurrent disease, which would represent more appropriate indicators of therapeutic failure. We have recently developed a flow cytometry-based approach for the analyses of intra-tumor cellular heterogeneity across stem cell hierarchies, genetic instability and differential cell cycling fractions, which can potentially be predictive of refractory disease and tumor relapse. Iterating this approach after initial POC screening in the drug discovery pipeline would have a great impact in terms of precision of drug evaluation, design of optimal drug combinations and/or drug repositioning. In this perspective, we highlight how through embracing of a comprehensive, informative and analytical assessment of the cellular content of residual tumors, the fidelity and statistical robustness of preclinical drug discovery can be greatly improved.
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      PubDate: 2016-08-08T07:43:04Z
       
  • Nitric oxide-induced oxidative stress impairs pacemaker function of murine
           interstitial cells of Cajal during inflammation
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Noriyuki Kaji, Kazuhide Horiguchi, Satoshi Iino, Shinsuke Nakayama, Tomohiko Ohwada, Yuko Otani, Firman, Takahisa Murata, Kenton M. Sanders, Hiroshi Ozaki, Masatoshi Hori
      The pacemaker function of interstitial cells of Cajal (ICC) is impaired during intestinal inflammation. The aim of this study is to clarify the pathophysiological mechanisms of ICC dysfunction during inflammatory condition by using intestinal cell clusters. Cell clusters were prepared from smooth muscle layer of murine jejunum and treated with interferon-gamma and lipopolysaccharide (IFN-γ+LPS) for 24h to induce inflammation. Pacemaker function of ICC was monitored by measuring cytosolic Ca2+ oscillation in the presence of nifedipine. Treatment with IFN-γ+LPS impaired the pacemaker activity of ICC with increasing mRNA level of interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 in cell clusters; however, treatment with these cytokines individually had little effect on pacemaker activity of ICC. Treatment with IFN-γ+LPS also induced the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and resident macrophages, but not in ICC. Pretreatment with NOS inhibitor, L-NAME or iNOS inhibitor, 1400W ameliorated IFN-γ+LPS-induced pacemaker dysfunction of ICC. Pretreatment with guanylate cyclase inhibitor, ODQ did not, but antioxidant, apocynin, to suppress NO-induced oxidative stress, significantly suppressed the impairment of ICC function induced by IFN-γ+LPS. Treatment with IFN-γ+LPS also decreased c-Kit-positive ICC, which was prevented by pretreatment with L-NAME. However, apoptotic ICC were not detected in IFN-γ+LPS-treated clusters, suggesting IFN-γ+LPS stimulation just changed the phenotype of ICC but not induced cell death. Moreover, ultrastructure of ICC was not disturbed by IFN-γ+LPS. In conclusion, ICC dysfunction during inflammation is induced by NO-induced oxidative stress rather than NO/cGMP signaling. NO-induced oxidative stress might be the main factor to induce phenotypic changes of ICC.
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      PubDate: 2016-08-08T07:43:04Z
       
  • Impact of statin therapy on plasma resistin and visfatin concentrations: A
           systematic review and meta-analysis of controlled clinical trials
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Amirhossein Sahebkar, Paolo Giorgini, Valeria Ludovici, Claudio Pedone, Gianna Ferretti, Tiziana Bacchetti, Davide Grassi, Paolo Di Giosia, Claudio Ferri
      The beneficial effects of statin therapy in reducing cardiovascular morbidity and mortality is not merely explained by the lipid-modulating effects. Although adipokines levels have been associated with cardiometabolic disorders, a few studies have explored the effect of statin on resistin and visfatin. We aimed to evaluate the impact of statin therapy on levels of resistin and visfatin through a meta-analysis of published studies. A systematic literature search in Medline and SCOPUS databases was conducted up to January 2015 to identify controlled trials assessing changes in plasma concentrations of visfatin and resistin during treatment with statins. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. 12 eligible studies with 14 treatment arms were included. Overall, 844 participants were studied. No significant change in plasma resistin concentrations was observed following statin therapy (WMD: −0.11ng/mL, CI: −1.94,1.73, p =0.909). This effect was robust and not affected by statin type, treatment duration and LDL-cholesterol concentrations. With respect to visfatin concentrations, there was a marginally significant reduction following statin therapy (WMD: −2.40ng/mL, CI: −4.79,−0.002, p =0.050). However, this effect size was weak and sensitive to three of the trials included in the analysis. This meta-analysis did not suggest any effect of statin therapy on plasma resistin levels, while a slight reduction in visfatin levels was found. The effect of statins on visfatin levels may represent a novel pleiotropic characteristic of these drugs.
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      PubDate: 2016-08-08T07:43:04Z
       
  • mTOR-Independent autophagy inducer trehalose rescues against insulin
           resistance-induced myocardial contractile anomalies: Role of p38 MAPK and
           Foxo1
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Qiurong Wang, Jun Ren
      Insulin resistance is associated with cardiovascular diseases although the precise mechanisms remain elusive. Akt2, a critical member of the Akt family, plays an essential role in insulin signaling. This study was designed to examine the effect of trehalose, an mTOR-independent autophagy inducer, on myocardial function in an Akt2 knockout-induced insulin resistance model. Adult WT and Akt2 knockout (Akt2−/−) mice were administered trehalose (1mg/g/day, i.p.) for two days and were then given 2% trehalose in drinking water for two more months. Echocardiographic and myocardial mechanics, intracellular Ca2+ properties, glucose tolerance, and autophagy were assessed. Apoptosis and ER stress were evaluated using TUNEL staining, Caspase 3 assay and Western blot. Autophagy and autophagy flux were examined with a focus on p38 mitogen activated protein kinase (MAPK), Forkhead box O (Foxo1) and Akt. Akt2 ablation impaired glucose tolerance, myocardial geometry and function accompanied with pronounced apoptosis, ER stress and dampened autophagy, the effects of which were ameliorated by trehalose treatment. Inhibition of lysosomal activity using bafilomycin A1 negated trehalose–induced induction of autophagy (LC3B-II and p62). Moreover, phosphorylation of p38 MAPK and Foxo1 were upregulated in Akt2−/− mice, the effect of which was attenuated by trehalose. Phosphorylation of Akt was suppressed in Akt2−/− mice and was unaffected by trehalose. In vitro findings revealed that the p38 MAPK activator anisomycin and the Foxo1 inhibitor (through phosphorylation) AS1842856 effectively masked trehalose-offered beneficial cardiomyocyte contractile response against Akt2 ablation. These data suggest that trehalose may rescue against insulin resistance-induced myocardial contractile defect and apoptosis, via autophagy associated with dephosphorylation of p38 MAPK and Foxo1 without affecting phosphorylation of Akt.
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      PubDate: 2016-08-04T07:03:48Z
       
  • A PRISMA-compliant systematic review and meta-analysis of randomized
           controlled trials investigating the effects of statin therapy on plasma
           lipid concentrations in HIV-infected patients
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Maciej Banach, Madalina Dinca, Sorin Ursoniu, Maria-Corina Serban, George Howard, Dimitri P. Mikhailidis, Stephen Nicholls, Gregory Y.H. Lip, Stephen Glasser, Seth S. Martin, Paul Muntner, Jacek Rysz, Peter P. Toth, Amirhossein Sahebkar
      Statin therapy may lower plasma lipid concentrations, but the evidence in HIV-infected patients is still unclear. Therefore, we aimed to investigate the impact of statin therapy on plasma lipid concentrations through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included PUBMED, SCOPUS, Web of Science and Google Scholar up to October 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). Two investigators independently reviewed the title or abstract, further reviewed the full-texts and extracted information on study characteristics and study outcomes. Meta-analysis of 12 RCTs with 697 participants suggested significant reductions in plasma concentrations of low density lipoprotein (LDL) cholesterol (WMD: −0.72mmol/L [−27.8mg/dL], 95%CI: −1.04, −0.39, p <0.001; I2 =85.7%), total cholesterol (WMD: −1.03mmol/L [-39.8mg/dL], 95%CI: −1.42, −0.64, p <0.001; I2 =94.7%) and non-high density lipoprotein cholesterol (non-HDL-C) (WMD: −0.81mmol/L [−31.3mg/dl], 95%CI: −1.32, −0.30, p =0.002; I2 =76.5%), and elevations in HDL-C (WMD: 0.072mmol/L [2.8mg/dL], 95%CI: 0.053, 0.092, p <0.001; I2 =0%) following treatment with statins (mostly of moderate-intensity). No significant alteration in plasma triglycerides (TG) concentrations was found (WMD: −0.16mmol/L [−14.2mg/dL], 95%CI: −0.61, 0.29, p =0.475; I2 =90.2%). All these effects were robust in sensitivity analysis, suggesting that the computed effect is not driven by any single study. In subgroup analysis, no significant difference was found among different statins in terms of changing plasma concentrations of LDL-C, HDL-C and TG. However, atorvastatin was found to be more efficacious in reducing plasma total cholesterol concentrations (p <0.001). In conclusion, the meta-analysis suggested significant reductions in plasma concentrations of LDL-C, total cholesterol and non-HDL-C, and elevations in HDL-C, but no significant alteration in plasma TG following treatment with statins.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Antioxidants as therapeutics in the intensive care unit: Have we ticked
           the redox boxes'
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Nikos V. Margaritelis
      Critically ill patients are under oxidative stress and antioxidant administration reasonably emerged as a promising approach to combat the aberrant redox homeostasis in this patient cohort. However, the results of the antioxidant treatments in the intensive care unit are conflicting and inconclusive. The main objective of the present review is to highlight some inherent, yet widely overlooked redox-related issues about the equivocal effectiveness of antioxidants in the intensive care unit, beyond methodological considerations. In particular, the discrepancy in the literature partially stems from: (1) the largely unspecified role of reactive species in disease onset and progression, (2) our fragmentary understanding on the interplay between inflammation and oxidative stress, (3) the complex spatiotemporal specificity of in vivo redox biology, (4) the pleiotropic effects of antioxidants and (5) the divergent effects of antioxidants according to the temporal administration pattern. In addition, two novel and sophisticated practices with promising pre-clinical results are presented: (1) the selective neutralization of reactive species in key organelles after they are formed (i.e., in mitochondria) and (2) the targeted complete inhibition of dominant reactive species sources (i.e., NADPH oxidases). Finally, the reductive potential of NADPH as a key pharmacological target for redox therapies is rationalized. In light of the above, the recontextualization of knowledge from basic redox biology to translational medicine seems imperative to perform more realistic in vivo studies in the fast-growing field of critical care pharmacology.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Ultramicronized palmitoylethanolamide (PEA-um®) in the treatment of
           idiopathic pulmonary fibrosis
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Rosanna Di Paola, Daniela Impellizzeri, Roberta Fusco, Marika Cordaro, Rosalba Siracusa, Rosalia Crupi, Emanuela Esposito, Salvatore Cuzzocrea
      Pulmonary fibrosis is a chronic condition characterized by progressive scarring of lung parenchyma. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (PEA-um®), an endogenous fatty acid amide, in mice subjected to idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis was induced in male mice by a single intratracheal administration of saline with bleomycin sulphate (1mg/kg body weight) in a volume of 100μL. PEA-um® was injected intraperitoneally at 1, 3 or 10mg/kg 1h after bleomycin instillation and daily thereafter. Animals were sacrificed after 7 and 21days by pentobarbitone overdose. One cohort of mice was sacrificed after seven days of bleomycin administration, followed by bronchoalveloar lavage and determination of myeloperoxidase activity, lung edema and histopathology features. In the 21-day cohort, mortality was assessed daily, and surviving mice were sacrificed followed by the above analyses together with immunohistochemical localization of CD8, tumor necrosis factor-α, CD4, interleukin-1β, transforming growth factor-β, inducible nitric oxide synthase and basic fibroblast growth factor. Compared to bleomycin-treated mice, animals that received also PEA-um® (3 or 10mg/kg) had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21days. PEA-um® (1mg/kg) did not significantly inhibit the inflammation response and lung fibrosis. This study demonstrates that PEA-um® (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis.
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      PubDate: 2016-08-04T07:03:48Z
       
  • TGR5 activation suppressed S1P/S1P2 signaling and resisted high
           glucose-induced fibrosis in glomerular mesangial cells
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Zhiying Yang, Fengxiao Xiong, Yu Wang, Wenyan Gong, Junying Huang, Cheng Chen, Peiqing Liu, Heqing Huang
      Glucose and lipid metabolism disorders and chronic inflammation in the kidney tissues are largely responsible for causative pathological mechanism of renal fibrosis in diabetic nephropathy (DN). As our previous findings confirmed that, sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling activation promoted renal fibrosis in diabetes. Numerous studies have demonstrated that the G protein-coupled bile acid receptor TGR5 exhibits effective regulation of glucose and lipid metabolism and anti-inflammatory effects. TGR5 is highly expressed in kidney tissues, whether it attenuates the inflammation and renal fibrosis by inhibiting the S1P/S1P2 signaling pathway would be a new insight into the molecular mechanism of DN. Here we investigated the effects of TGR5 on diabetic renal fibrosis, and the underlying mechanism would be also discussed. We found that TGR5 activation significantly decreased the expression of intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta 1 (TGF-β1), as well as fibronectin (FN) induced by high glucose in glomerular mesangial cells (GMCs), which were pathological features of DN. S1P2 overexpression induced by high glucose was diminished after activation of TGR5, and AP-1 activity, including the phosphorylation of c-Jun/c-Fos and AP-1 transcription activity, was attenuated. As a G protein-coupled receptor, S1P2 interacted with TGR5 in GMCs. Furthermore, INT-777 lowered S1P2 expression and promoted S1P2 internalization. Taken together, TGR5 activation reduced ICAM-1, TGF-β1 and FN expressions induced by high glucose in GMCs, the mechanism might be through suppressing S1P/S1P2 signaling, thus ameliorating diabetic nephropathy.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Pharmacological characterization of CRTh2 antagonist LAS191859: Long
           receptor residence time translates into long-lasting in vivo efficacy
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Marta Calbet, Miriam Andrés, Clara Armengol, Mónica Bravo, Peter Eichhorn, Rosa López, Vicente García-González, Richard Roberts, Montserrat Miralpeix
      The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.
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      PubDate: 2016-08-04T07:03:48Z
       
  • The role of epsilon PKC in acute and chronic diseases: Possible
           pharmacological implications of its modulators
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Barbara Capuani, Francesca Pacifici, Donatella Pastore, Raffaele Palmirotta, Giulia Donadel, Roberto Arriga, Alfonso Bellia, Nicola Di Daniele, Paola Rogliani, Pasquale Abete, Paolo Sbraccia, Fiorella Guadagni, Davide Lauro, David Della-Morte
      Epsilon Protein kinase C (εPCK) is a particular kinase that, when activated, is able to protect against different stress injuries and therefore has been proposed to be a potential molecular target against acute and chronic diseases. Particular attention has been focused on εPCK for its involvement in the protective mechanism of Ischemic Preconditioning (IPC), a powerful endogenous mechanism characterized by subthreshold ischemic insults able to protect organs against ischemic injury. Therefore, in the past decades several εPCK modulators have been tested with the object to emulate εPCK mediate protection. Among these the most promising, so far, has been the ΨεRACK peptide, a homologous of RACK receptor for εPKC, that when administrated can mimic its effect in the cells. However, results from studies on εPCK indicate controversial role of this kinase in different organs and diseases, such as myocardial infarct, stroke, diabetes and cancer. Therefore, in this review we provide a discussion on the function of εPCK in acute and chronic diseases and how the different activators and inhibitors have been used to modulate its activity. A better understanding of its function is still needed to definitively target εPCK as novel therapeutic strategy.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Immunotherapy: A promising approach to reverse sepsis-induced
           immunosuppression
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Naeem K. Patil, Julia K. Bohannon, Edward R. Sherwood
      Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection (Third International Consensus definition for Sepsis and septic shock). Despite decades of research, sepsis remains the leading cause of death in intensive care units. More than 40 clinical trials, most of which have targeted the sepsis-associated pro-inflammatory response, have failed. Thus, antibiotics and fluid resuscitation remain the mainstays of supportive care and there is intense need to discover and develop novel, targeted therapies to treat sepsis. Both pre-clinical and clinical studies over the past decade demonstrate unequivocally that sepsis not only causes hyper-inflammation, but also leads to simultaneous adaptive immune system dysfunction and impaired antimicrobial immunity. Evidences for immunosuppression include immune cell depletion (T cells most affected), compromised T cell effector functions, T cell exhaustion, impaired antigen presentation, increased susceptibility to opportunistic nosocomial infections, dysregulated cytokine secretion, and reactivation of latent viruses. Therefore, targeting immunosuppression provides a logical approach to treat protracted sepsis. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7, anti-programmed cell death 1 antibody (anti-PD-1), anti-programmed cell death 1 ligand antibody (anti-PD-L1), and others have demonstrated reversal of T cell dysfunction and improved survival. Therefore, identifying immunosuppressed patients with the help of specific biomarkers and administering specific immunomodulators holds significant potential for sepsis therapy in the future. This review focusses on T cell dysfunction during sepsis and discusses the potential immunotherapeutic agents to boost T cell function during sepsis and improve host resistance to infection.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Pharmacokinetics interactions of monoclonal antibodies
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Nicola Ferri, Stefano Bellosta, Ludovico Baldessin, Donatella Boccia, Giorgi Racagni, Alberto Corsini
      The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate’s inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the “inhibitory” effect of IL-6 on CYP substrates, resulting in a “normalization” of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction.
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      PubDate: 2016-08-04T07:03:48Z
       
  • HMGB1 as biomarker and drug target
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Emilie Venereau, Federica De Leo, Rosanna Mezzapelle, Giorgia Careccia, Giovanna Musco, Marco E. Bianchi
      High Mobility Group Box 1 protein was discovered as a nuclear protein, but it has a “second life” outside the cell where it acts as a damage-associated molecular pattern. HMGB1 is passively released or actively secreted in a number of diseases, including trauma, chronic inflammatory disorders, autoimmune diseases and cancer. Extracellular HMGB1 triggers and sustains the inflammatory response by inducing cytokine release and by recruiting leucocytes. These characteristics make extracellular HMGB1 a key molecular target in multiple diseases. A number of strategies have been used to prevent HMGB1 release or to inhibit its activities. Current pharmacological strategies include antibodies, peptides, decoy receptors and small molecules. Noteworthy, salicylic acid, a metabolite of aspirin, has been recently found to inhibit HMGB1. HMGB1 undergoes extensive post-translational modifications, in particular acetylation and oxidation, which modulate its functions. Notably, high levels of serum HMGB1, in particular of the hyper-acetylated and disulfide isoforms, are sensitive disease biomarkers and are associated with different disease stages. In the future, the development of isoform-specific HMGB1 inhibitors may potentiate and fine-tune the pharmacological control of inflammation. We review here the current therapeutic strategies targeting HMGB1, in particular the emerging and relatively unexplored small molecules-based approach.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Adverse vascular remodelling is more sensitive than endothelial
           dysfunction to hyperglycaemia in diabetic rat mesenteric arteries
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Nicola Kahlberg, Cheng Xue Qin, Jarryd Anthonisz, Edwina Jap, Hooi Hooi Ng, Maria Jelinic, Laura J. Parry, Barbara K. Kemp-Harper, Rebecca H. Ritchie, Chen Huei Leo
      Increased vascular stiffness and reduced endothelial nitric oxide (NO) bioavailability are characteristic of diabetes. Whether these are evident at a more moderate levels of hyperglycaemia has not been investigated. The objectives of this study were to examine the association between the level of glycaemia and resistance vasculature phenotype, incorporating both arterial stiffness and endothelial function. Diabetes was induced in male Sprague Dawley rats with streptozotocin (STZ; 55mg/kg i.v.) and followed for 8 weeks. One week post STZ, diabetic rats were allocated to either moderate (∼20mM blood glucose, 6–7U/insulins.c. daily) or severe hyperglycaemia (∼30mM blood glucose, 1–2U/insulins.c. daily as required). At study end, rats were anesthetized, and the mesenteric arcade was collected. Passive mechanical wall properties were assessed by pressure myography. Responses to the endothelium-dependent vasodilator acetylcholine (ACh) were assessed using wire myography. Our results demonstrated for the first time that mesenteric arteries from both moderate and severely hyperglycaemic diabetic rats exhibited outward hypertrophic remodelling and increased axial stiffness compared to arteries from non-diabetic rats. Secondly, mesenteric arteries from severely (∼30mM blood glucose), but not moderately hyperglycaemic (∼20mM blood glucose) rats exhibit a significant reduction to ACh sensitivity compared to their non-diabetic counterparts. This endothelial dysfunction was associated with significant reduction in endothelium-derived hyperpolarisation and endothelium-dependent NO-mediated relaxation. Interestingly, endothelium-derived nitroxyl (HNO)-mediated relaxation was intact. Therefore, moderate hyperglycaemia is sufficient to induce adverse structural changes in the mesenteric vasculature, but more severe hyperglycaemia is essential to cause endothelial dysfunction.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Effect of curcumin on circulating interleukin-6 concentrations: A
           systematic review and meta-analysis of randomized controlled trials
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Giuseppe Derosa, Pamela Maffioli, Luis E. Simental-Mendía, Simona Bo, Amirhossein Sahebkar
      The aim of this meta-analysis was to evaluate the efficacy of curcuminoids supplementation on circulating concentrations of IL-6 in randomized controlled trials (RCTs). The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to November 01, 2015, to identify RCTs investigating the impact of curcuminoids on circulating IL-6 concentrations. Nine RCTs comprising 10 treatment arms were found to be eligible for the meta-analysis. There was a significant reduction of circulating IL-6 concentrations following curcuminoids supplementation (WMD: −0.60pg/mL, 95% CI: −1.06, −0.14, p =0.011). Meta-regression did not suggest any significant association between the circulating IL-6 lowering effects of curcuminoids with either dose or duration of treatment. There was a significant association between the IL-6-lowering activity of curcumin and baseline IL-6 concentration (slope: −0.51; 95% CI: −0.80, −0.23; p=0.005). This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating IL-6 concentrations. This effect appears to be more evident in patients with higher degrees of systemic inflammation.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Friend or foe' Telomerase as a pharmacological target in cancer and
           cardiovascular disease
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Karima Ait-Aissa, Johnathan D. Ebben, Andrew O. Kadlec, Andreas M. Beyer
      Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Genetic and clinical biomarkers of tocilizumab response in patients with
           rheumatoid arthritis
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Mar Maldonado-Montoro, Marisa Cañadas-Garre, Alfonso González-Utrilla, José Cristian Plaza-Plaza, Miguel Ángel Calleja-Hernández
      The aim of this study was to investigate the influence of clinical and genetic factors on response to tocilizumab (TCZ) response, remission, low disease activity (LDA) and DAS28 improvement. A retrospective cohort study in 79 RA patients treated with TCZ during 6/18 months of therapy was conducted. CD69(rs11052877), GALNT18(rs4910008), CLEC2D(rs1560011), KCNMB1(rs703505), ENOX1(rs9594987), rs10108210, and rs703297 gene polymorphisms, identified in a recent GWAS as putative predictors of TCZ response, were analysed. Variables independently associated to satisfactory EULAR response at 6 months were GALNT18-CC genotype (ORCC/T-:12.8; CI95%:1.5,108.7; p=0.02), CD69 gene polymorphism (ORAA/GG:17.2; CI95%:2.5,119.6; p=0.004) and lower number of previous biological therapy, BT (OR: 0.45; CI95%:0.3, 0.7; p=0.001). The factors independently associated to higher remission were lower number of previous BT (OR:0.56; CI95%:0.38, 0.82; p=0.003), and GALNT18 CC genotype (ORCT/CC:0.09; CI95%:0.02,0.45;p=0.004; ORTT/CC:0.14; CI95%:0.02,0.79; p=0.026). The A-allele of CD69 (ORA_/GG:6.68;CI95%:1.68,26.51;p=0.007) and lower number of previous BT (OR:0.50; CI95%:0.32,0.77; p=0.002) were independent factors capable to predict higher LDA rates at 6 months. Independent factors associated to higher improvement in DAS28 at 6 months were CD69-AA genotype (B=−0.56; CI95%:-1.09, −0.03; p=0.039), GALNT18-CC genotype (B=−0.88;CI95%:-1.49, −0.27; p=0.005), subcutaneous administration (B=1.03; CI95%:0.44,1.62; p=0.001) and higher baseline DAS28 (B=0.82; CI95%:0.59, 1.05; p=4.9×10−10). Lower number of previous BT was the only independent predictor of satisfactory EULAR response (OR:0.60; CI95%:0.34,0.88; p=0.010) and higher remission (OR:0.65; CI95%:0.46,0.93; p=0.018) at 18 months. The C-allele of GALNT18 (ORC-/TT:4.60; CI95%:1.16, 18.27; p=0.03) and lower number of previous BT (OR:0.47; CI95%:0.29,0.74; p=0.001) were independent factors capable to predict higher LDA rates at 18 months. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates in patients carrying the GALNT18 C-allele or the CD69 A-allele, particularly when lower number of BT were previously administered.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Therapeutic potential of targeting TBK1 in autoimmune diseases and
           interferonopathies
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Maroof Hasan, Nan Yan
      The serine/threonine protein kinase, TBK1, plays a crucial role as the hub for many innate immune signaling pathways that lead to the induction of type I interferon (IFN) and interferon-stimulated genes (ISGs). Due to its key function in maintaining homeostasis of the immune system, cell survival and proliferation, TBK1 activity is tightly regulated. Dysregulation of TBK1 activity is often associated with autoimmune diseases and cancer, implicating the potential therapeutic benefit for targeting TBK1. Tremendous effort from both academic institutions and private sectors during the past few years has led to the development of many potent and selective TBK1 inhibitors, many of which have shown great promise in disease models in vivo. This review summarizes recent advance on the pharmacological inhibition of TBK1 and its potential for treating autoimmune diseases and interferonopathies.


      PubDate: 2016-08-04T07:03:48Z
       
  • Fibrate therapy and flow-mediated dilation: A systematic review and
           meta-analysis of randomized placebo-controlled trials
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Amirhossein Sahebkar, Renato Giua, Claudio Pedone, Kausik K. Ray, Antonio J. Vallejo-Vaz, Luisa Costanzo
      Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of fibrates on endothelial function as estimated by FMD. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p<0.001) and the result was confirmed in both subgroups with treatment durations ≤8 weeks (WMD: 1.35%, 95% CI: 0.85, 1.86, p<0.001) and >8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p<0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with fibrates. The results of this meta-analysis suggest that fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Palmitoylation in Alzheimer’s disease and other neurodegenerative
           diseases
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Eunsil Cho, Mikyoung Park
      Posttranslational modifications of proteins are important regulatory processes endowing the proteins functional complexity. Over the last decade, numerous studies have shed light on the roles of palmitoylation, one of the most common lipid modifications, in various aspects of neuronal functions. Major players regulating palmitoylation are the enzymes that mediate palmitoylation and depalmitoylation which are palmitoyl acyltransferases (PATs) and protein thioesterases, respectively. In this review, we will provide and discuss current understandings on palmitoyation/depalmitoylation control mediated by PATs and/or protein thioesterases for neuronal functions in general and also for Alzheimer’s disease in particular, and other neurodegenerative diseases such as Huntington’s disease, schizophrenia and intellectual disability.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Perspective: Targeting the JAK/STAT pathway to fight age-related
           dysfunction
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Ming Xu, Tamar Tchkonia, James L. Kirkland
      Senescent cells accumulate in a variety of tissues with aging. They can develop a senescence-associated secretory phenotype (SASP) that entails secretion of inflammatory cytokines, chemokines, proteases, and growth factors. These SASP components can alter the microenvironment within tissues and affect the function of neighboring cells, which can eventually lead to local and systemic dysfunction. The JAK pathway is more highly activate in senescent than non-senescent cells. Inhibition of the JAK pathway suppresses the SASP in senescent cells and alleviates age-related tissue dysfunction. Targeting senescent cells could be a promising way to improve healthspan in aged population.
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      PubDate: 2016-08-04T07:03:48Z
       
  • A systematic review and meta-analysis of randomized controlled trials on
           the effects of magnesium supplementation on insulin sensitivity and
           glucose control
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Luis E. Simental-Mendía, Amirhossein Sahebkar, Martha Rodríguez-Morán, Fernando Guerrero-Romero
      A systematic review and meta-analysis was conducted to evaluate the effect of oral magnesium supplementation on insulin sensitivity and glucose control in both diabetic and non-diabetic individuals. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (from inception to November 25, 2015) to identify RCTs evaluating the effect of magnesium on insulin sensitivity and glucose control. A random-effects model and generic inverse variance method were used to compensate for the heterogeneity of studies. Publication bias, sensitivity analysis, and meta-regression assessments were conducted using standard methods. The impact of magnesium supplementation on plasma concentrations of glucose, glycated hemoglobin (HbA1c), insulin, and HOMA-IR index was assessed in 22, 14, 12 and 10 treatment arms, respectively. A significant effect of magnesium supplementation was observed on HOMA-IR index (WMD: −0.67, 95% CI: −1.20, −0.14, p =0.013) but not on plasma glucose (WMD: −0.20mmol/L, 95% CI: −0.45, 0.05, p =0.119), HbA1c (WMD: 0.018mmol/L, 95% CI: −0.10, 0.13, p =0.756), and insulin (WMD: −2.22mmol/L, 95% CI: −9.62, 5.17, p =0.556). A subgroup analysis comparing magnesium supplementation durations of <4 months versus ≥4 months, exhibited a significant difference for fasting glucose concentrations (p <0.001) and HOMA-IR (p =0.001) in favor of the latter subgroup. Magnesium supplementation for ≥4 months significantly improves the HOMA-IR index and fasting glucose, in both diabetic and non-diabetic subjects. The present findings suggest that magnesium may be a beneficial supplement in glucose metabolic disorders.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir
           intracellular accumulation and contributes to ganciclovir-induced
           neutropenia in renal transplant patients
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Pierre-André Billat, Tahani Ossman, Franck Saint-Marcoux, Marie Essig, Jean-Philippe Rerolle, Nassim Kamar, Lionel Rostaing, Hannah Kaminski, Gabin Fabre, Michal Otyepka, Jean-Baptiste Woillard, Pierre Marquet, Patrick Trouillas, Nicolas Picard
      Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=−0.68±0.28, p=0.029; replication cohort: β±SD=−0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (−61%; p<0.0001). The efflux process was almost abolished in cells expressing MRP4 rs11568658 variant protein. Molecular dynamic simulations of GCV membrane crossing showed a preferred location of the drug just beneath the polar head group region, which supports its interaction with efflux transporters.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Vemurafenib resistance increases melanoma invasiveness and modulates the
           tumor microenvironment by MMP-2 upregulation
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Silvana Sandri, Fernanda Faião-Flores, Manoela Tiago, Paula Comune Pennacchi, Renato Ramos Massaro, Débora Kristina Alves-Fernandes, Gustavo Noriz Berardinelli, Adriane Feijó Evangelista, Vinicius de Lima Vazquez, Rui Manuel Reis, Silvya Stuchi Maria-Engler
      The BRAFV600E mutation confers constitutive kinase activity and accounts for >90% of BRAF mutations in melanoma. This genetic alteration is a current therapeutic target; however, the antitumorigenic effects of the BRAFV600E inhibitor vemurafenib are short-lived and the majority of patients present tumor relapse in a short period after treatment. Characterization of vemurafenib resistance has been essential to the efficacy of next generation therapeutic strategies. Herein, we found that acute BRAF inhibition induced a decrease in active MMP-2, MT1-MMP and MMP-9, but did not modulate the metalloproteinase inhibitors TIMP-2 or RECK in naïve melanoma cells. In vemurafenib-resistant melanoma cells, we observed a lower growth rate and an increase in EGFR phosphorylation followed by the recovery of active MMP-2 expression, a mediator of cancer metastasis. Furthermore, we found a different profile of MMP inhibitor expression, characterized by TIMP-2 downregulation and RECK upregulation. In a 3D spheroid model, the invasion index of vemurafenib-resistant melanoma cells was more evident than in its non-resistant counterpart. We confirmed this pattern in a matrigel invasion assay and demonstrated that use of a matrix metalloproteinase inhibitor reduced the invasion of vemurafenib resistant melanoma cells but not drug naïve cells. Moreover, we did not observe a delimited group of cells invading the dermis in vemurafenib-resistant melanoma cells present in a reconstructed skin model. The same MMP-2 and RECK upregulation profile was found in this 3D skin model containing vemurafenib-resistant melanoma cells. Acute vemurafenib treatment induces the disorganization of collagen fibers and consequently, extracellular matrix remodeling, with this pattern observed even after the acquisition of resistance. Altogether, our data suggest that resistance to vemurafenib induces significant changes in the tumor microenvironment mainly by MMP-2 upregulation, with a corresponding increase in cell invasiveness.
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      PubDate: 2016-08-04T07:03:48Z
       
  • A pharmacological assessment of agonists and modulators at
           α4β2γ2 and α4β2δ GABAA receptors: The
           challenge in comparing apples with oranges
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Philip K. Ahring, Line H. Bang, Marianne L. 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: 2016-08-04T07:03:48Z
       
  • Selective GPR55 antagonism reduces chemoresistance in cancer cells
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Nagendra S. Singh, Michel Bernier, Irving W. Wainer
      G protein-coupled receptor 55 (GPR55) possesses pro-oncogenic activity and its function can be competitively inhibited with (R,R’)-4′-methoxy-1-naphthylfenoterol (MNF) through poorly defined signaling pathways. Here, the anti-tumorigenic effect of MNF was investigated in the human pancreatic cancer cell line, PANC-1, by focusing on the expression of known cancer biomarkers and the expression and function of multidrug resistance (MDR) exporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Incubation of PANC1 cells with MNF (1μM) for 24h significantly decreased EGF receptor, pyruvate kinase M2 (PKM2), and β-catenin protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1α and the phospho-active forms of PKM2 and β-catenin. Inhibition of GPR55 with either MNF or the GPR55 antagonist CID 16020046 lowered the amount of MDR proteins in total cellular extracts while diminishing the nuclear expression of Pgp and BCRP. There was significant nuclear accumulation of doxorubicin in PANC-1 cells treated with MNF and the pre-incubation with MNF increased the cytotoxicity of doxorubicin and gemcitabine in these cells. Potentiation of doxorubicin cytotoxicity by MNF was also observed in MDA-MB-231 breast cancer cells and U87MG glioblastoma cells, which express high levels of GPR55. The data suggest that inhibition of GPR55 activity produces antitumor effects via attenuation of the MEK/ERK and PI3K-AKT pathways leading to a reduction in the expression and function of MDR proteins.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Pharmacological effect of a new idebenone formulation in a model of
           carrageenan-induced inflammatory pain
    • Abstract: Publication date: September 2016
      Source:Pharmacological Research, Volume 111
      Author(s): Filomena Lauro, Sara Ilari, Luigino Antonio Giancotti, Cinzia Anna Ventura, Chiara Morabito, Micaela Gliozzi, Valentina Malafoglia, Ernesto Palma, Donatella Paolino, Vincenzo Mollace, Carolina Muscoli
      Considerable evidence demonstrated that the central role of reactive oxygen species and reactive nitrogen species (ROS and RNS) in the development of thermal hyperalgesia is associated to acute and chronic inflammation. Idebenone (IDE), a synthetic analogue of the endogenous cellular antioxidant coenzyme Q10 (CoQ10), is an active drug in the central nervous system which shows a protection in a variety of neurological disorders. Since it is lipophilic, poorly water soluble and highly bound to plasma proteins, different technological approaches have been explored to increase its solubility and new pharmaceutical properties. Therefore, it has been complexed with HP-β-cyclodextrins (HP) and its efficacy has been assessed in an animal model of carrageenan-induced thermal hyperalgesia. All male rats used for this study received a subplantar injection of carrageenan into the right hindpaw in the presence or absence of IDE alone and IDE/HP complex. We observed that IDE poorly reduced painful carrageenan effects whereas IDE/HP complex was able to prevent carrageenan-induced hyperalgesia and edema in a dose-dependent manner, reducing spinal MDA levels and protein nitration. Hence, our results demonstrated that when complexed with HP, idebenone exerts a potent analgesic and anti-inflammatory efficacy.
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      PubDate: 2016-08-04T07:03:48Z
       
  • Janus kinase (JAK) inhibitors in the treatment of inflammatory and
           neoplastic diseases
    • Abstract: Publication date: Available online 26 July 2016
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is found predominantly in hematopoietic cells. The Janus kinase family is regulated by numerous cytokines including interleukins, interferons, and hormones such as erythropoietin, thrombopoietin, and growth hormone. Ligand binding to cytokine and hormone receptors leads to the activation of associated Janus kinases, which then mediate the phosphorylation of the receptors. The SH2 domain of STATs (signal transducers and activators of transcription) binds to the receptor phosphotyrosines thereby promoting STAT phosphorylation by the Janus kinases and consequent activation. STAT dimers are translocated to the nucleus where they participate in the regulation of the expression of thousands of proteins. JAK-STAT dysregulation results in autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn disease. JAK-STAT dysregulation also plays a role in the pathogenesis of myelofibrosis, polycythemia vera, and other myeloproliferative illnesses. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and in a lower percentage of people with other neoplasms. JAK1/3 signaling participates in the pathogenesis of inflammatory afflictions while JAK1/2 signaling participates in the development of several malignancies including leukemias and lymphomas as well as myeloproliferative neoplasms. Tofacitinib is a pan-JAK inhibitor that is approved by the FDA for the treatment of rheumatoid arthritis and ruxolitinib is a JAK1/2 inhibitor that is approved for the treatment of polycythemia vera and myelofibrosis.
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      PubDate: 2016-07-30T06:04:17Z
       
  • Clarithromycin prevents human respiratory syncytial virus-induced airway
           epithelial responses by modulating activation of interferon regulatory
           factor-3
    • Abstract: Publication date: Available online 26 July 2016
      Source:Pharmacological Research
      Author(s): Keisuke Yamamoto, Soh Yamamoto, Noriko Ogasawara, Kenichi Takano, Tsukasa Shiraishi, Toyotaka Sato, Ryo Miyata, Takuya Kakuki, Ryuta Kamekura, Takashi Kojima, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota
      Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV) CAM treatment led to a significant reduction in poly I:C- and RSV-mediated IL-8, CCL5, IFN-β and −λ production. Furthermore, IFN-β promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role.
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      PubDate: 2016-07-30T06:04:17Z
       
  • Nanosystems based on siRNA silencing HuR expression counteract diabetic
           retinopathy in rat
    • Abstract: Publication date: Available online 27 July 2016
      Source:Pharmacological Research
      Author(s): Marialaura Amadio, Alessia Pascale, Sarha Cupri, Rosario Pignatello, Cecilia Osera, Velia D’Agata, Agata Grazia D’Amico, Gian Marco Leggio, Barbara Ruozi, Stefano Govoni, Filippo Drago, Claudio Bucolo
      We evaluated whether specifically and directly targeting human antigen R (HuR), a member of embryonic lethal abnormal vision (ELAV) proteins family, may represent a new potential therapeutic strategy to manage diabetic retinopathy. Nanosystems loaded with siRNA silencing HuR expression (lipoplexes), consisting of solid lipid nanoparticles (SLN) and liposomes (SUV) were prepared. Photon correlation spectroscopy analysis, Zeta potential measurement and atomic force microscopy (AFM) studies were carried out to characterize the complexation of siRNA with the lipid nanocarriers. Nanosystems were evaluated by using AFM and scanning electron microscopy. The lipoplexes were injected into the eye of streptozotocin (STZ)-induced diabetic rats. Retinal HuR and VEGF levels were detected by Western blot and ELISA, respectively. Retinal histology was also carried out. The results demonstrated that retinal HuR and VEGF are significantly increased in STZ-rats and are blunted by HuR siRNA treatment. Lipoplexes with a weak positive surface charge and with a 4:1N/P (cationic lipid nitrogen to siRNA phosphate) ratio exert a better transfection efficiency, significantly dumping retinal HuR and VEGF levels. In conclusion, we demonstrated that siRNA can be efficiently delivered into the rat retina using lipid-based nanocarriers, and some of the lipoplexes loaded with siRNA silencing HuR expression are potential candidates to manage retinal diseases.
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      PubDate: 2016-07-30T06:04:17Z
       
  • Strawberry tannins inhibit IL-8 secretion in a cell model of gastric
           inflammation
    • Abstract: Publication date: Available online 27 July 2016
      Source:Pharmacological Research
      Author(s): Marco Fumagalli, Enrico Sangiovanni, Urska Vrhovsek, Stefano Piazza, Elisa Colombo, Mattia Gasperotti, Fulvio Mattivi, Emma De Fabiani, Mario Dell’Agli
      In the present study we chemically profiled tannin-enriched extracts from strawberries and tested their biological properties in a cell model of gastric inflammation. The chemical and biological features of strawberry tannins after in vitro simulated gastric digestion were investigated as well. The anti-inflammatory activities of pure strawberry tannins were assayed to get mechanistic insights. Tannin-enriched extracts from strawberries inhibit IL-8 secretion in TNFα-treated human gastric epithelial cells by dampening the NF-κB signaling. In vitro simulated gastric digestion slightly affected the chemical composition and the biological properties of strawberry tannins. By using pure compounds, we found that casuarictin may act as a pure NF-κB inhibitor while agrimoniin inhibits IL-8 secretion also acting on other biological targets; in our system procyanidin B1 prevents the TNFα-induced effects without interfering with the NF-κB pathway. We conclude that strawberry tannins, even after in vitro simulated gastric digestion, exert anti-inflammatory activities at nutritionally relevant concentrations.
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      PubDate: 2016-07-30T06:04:17Z
       
  • 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
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      PubDate: 2016-05-24T07:06:49Z
       
 
 
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