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Travel Behaviour and Society     Full-text available via subscription  
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Video J. and Encyclopedia of GI Endoscopy     Open Access  
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Zoology     Hybrid Journal   (Followers: 6, SJR: 0.538, h-index: 28)

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Journal Cover Pharmacological Research     [SJR: 1.248]   [H-I: 76]
   [5 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2585 journals]
  • Irbesartan ameliorates diabetic cardiomyopathy by regulating protein
           kinase D and ER stress activation in a type 2 diabetes rat model
    • Abstract: Publication date: Available online 21 January 2015
      Source:Pharmacological Research
      Author(s): Xiangjuan Liu , Qun Xu , Xiaomeng Wang , Zhuo Zhao , Liping Zhang , Ling Zhong , Li Li , Weiqiang Kang , Yun Zhang , Zhiming Ge
      Recent studies demonstrate an important role of protein kinase D (PKD) in the cardiovascular system. However, the potential role of PKD in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. Irbesartan has beneficial effects against diabetes-induced heart damage, while the mechanisms were still poorly understood. Our present study was designed to investigate the effects of irbesartan in DCM and whether the cardioprotective effects of irbesartan were mediated by PKD and endoplasmic reticulum (ER) stress. We induced the type 2 diabetic rat model by high fat diet and low dose streptozotocin injection. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. 8-weeks administration of irbesartan (15, 30 and 45mg/kg/day) was used to evaluate the effect irbesartan in DCM. Diabetic rats revealed severe metabolic abnormalities, left ventricular dysfunction, myocardial fibrosis and apoptosis. PKD and ER stress were excessive activated in the myocardium of diabetic rats. Furthermore, cardiac fibrosis, apoptosis, diastolic dysfunction and ER stress were all significantly related to PKD activation in diabetic rats. Irbesartan treatment attenuated the activation of PKD and ER stress, which paralleled its cardioprotective effects. Our study suggests that irbesartan could ameliorate cardiac remodeling and dysfunction in type 2 diabetes, and these beneficial effects were associated with its ability to suppress the activation of PKD and ER stress.
      Graphical abstract image

      PubDate: 2015-01-23T20:43:56Z
       
  • Clinical evidence of statin therapy in non-dyslipidemic disorders
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Nicola Ferri , Alberto Corsini
      The clinical benefits of statins are strongly related to their low density lipoprotein cholesterol (LDL-C) lowering properties. However, considering that the pharmacological target of statins, the 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase, is one of the upstream enzyme of the mevalonate pathway, its inhibition may determine a substantial impoverishment of additional lipid moieties required for a proper cellular function. From this hypothesis, several experimental and clinical evidences have been reported indicating additional effects of statins beyond the LDL-C lowering, in particular anti-inflammatory and immunomodulatory effects. Thus statin therapy, indicated for hyperlipidemic patients for primary and secondary prevention of coronary heart disease (CHD) has begun to be considered effective in other diseases not necessarily linked to altered lipid profile. In the present review we summarized the current clinical evidence of the efficacy and safety profile of statins in a variety of diseases, such as rheumatoid arthritis, venous thromboembolism, liver diseases, polycystic ovary syndrome, and age-related macular degeneration. As discussed in the review, pending large, well designed, randomized trials, it is reasonable to conclude that there is no definitive evidence for the use of statins in the aforementioned diseases.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Cardiovascular effects of statins, beyond lipid-lowering properties
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Christos G. Mihos , Andres M. Pineda , Orlando Santana
      The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as ‘statins’, are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid-lowering properties, which include enhancement of endothelial function, anti-inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits.


      PubDate: 2015-01-14T20:41:24Z
       
  • Editorial Board
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88




      PubDate: 2015-01-14T20:41:24Z
       
  • Statin: New life for an old drug
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Maurizio Bifulco , Akira Endo



      PubDate: 2015-01-14T20:41:24Z
       
  • The pharmacology of statins
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Cesare R. Sirtori
      Statins, inhibitors of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme, are molecules of fungal origin. By inhibiting a key step in the sterol biosynthetic pathway statins are powerful cholesterol lowering medications and have provided outstanding contributions to the prevention of cardiovascular disease. Their detection in mycetes traces back to close to 40 years ago: there were, originally, widely opposing views on their therapeutic potential. From then on, intensive pharmaceutical development has led to the final availability in the clinic of seven statin molecules, characterized by differences in bioavailability, lipo/hydrophilicity, cytochrome P-450 mediated metabolism and cellular transport mechanisms. These differences are reflected in their relative power (mg LDL-cholesterol reduction per mg dose) and possibly in parenchymal or muscular toxicities. The impact of the antagonism of statins on a crucial step of intermediary metabolism leads, in fact, both to a reduction of cholesterol biosynthesis as well as to additional pharmacodynamic (so called “pleiotropic”) effects. In the face of an extraordinary clinical success, the emergence of some side effects, e.g. raised incidence of diabetes and cataracts as well as frequent muscular side effects, have led to increasing concern by physicians. However, also in view of the present relatively low cost of these drugs, their impact on daily therapy of vascular patients is unlikely to change.


      PubDate: 2015-01-14T20:41:24Z
       
  • Novel therapeutic approaches for diabetic nephropathy and retinopathy
    • Abstract: Publication date: Available online 29 October 2014
      Source:Pharmacological Research
      Author(s): Vera Usuelli , Ennio La Rocca
      Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Immunization in cancer patients: Where we stand
    • Abstract: Publication date: Available online 25 October 2014
      Source:Pharmacological Research
      Author(s): Christine Robin , Florence Beckerich , Catherine Cordonnier
      An increasing proportion of cancer patients benefit from new treatment strategies. However, infection remains a main cause of morbidity and mortality, either due to the underlying diseases, to treatment, or both. Although most opportunistic infections are sofar not routinely preventable by vaccines, community infections such as invasive pneumococcal disease and influenza may be avoided by vaccines in many instances. The immune response of cancer patients to vaccines is almost constantly depressed when compared to the one of healthy individuals of the same age range. However, they may, in many cases, reach seroprotection. This article addresses the rationale to develop and implement immunization programs in cancer patients, including patients with hematologic malignancies and recipients of stem cell transplantation, and the main specificities of this patient population regarding vaccines, and the potential approaches to improve the immune response. The Infectious Diseases Society of America has recently published guidelines for vaccination of the immunocompromised hosts. Although many questions remain to be clarified, oncologists and hematologists should be encouraged to implement these guidelines in their therapeutic programs and to develop prospective studies covering unsolved issues.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y)
           tetanus toxoid conjugate vaccine: Systematic review and meta-analysis
    • Abstract: Publication date: Available online 30 October 2014
      Source:Pharmacological Research
      Author(s): Paolo Pellegrino , Valentina Perrone , Sonia Radice , Annalisa Capuano , Emilio Clementi
      Meningococcal meningitis represents one of the leading cause of bacterial meningitis in developed countries. Among the thirteen described serogroups, only five are usually responsible of invasive infections making immunisation against multiple serogroups the best strategy to protect individuals from this disease. Herein we carried out a systematic review and meta-analysis, in accordance with the PRISMA statement, of the recently EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT). We included 15 randomised clinical trials, comparing MenACWY-TT and Men-PS (ten studies), MenACWY-TT and MenC-CRM197 (four studies) and MenACWY-TT and MenACWY-DT (one study). All studies included in the meta-analysis showed high immunogenicity for MenACWY-TT vaccines in all tested serogroups. Our results suggest that the MenACWY-TT vaccine is as immunogenic as the other commercial avaiable meningococcal vaccines.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Is narcolepsy a classical autoimmune disease'
    • Abstract: Publication date: Available online 29 October 2014
      Source:Pharmacological Research
      Author(s): María-Teresa Arango , Shaye Kivity , Yehuda Shoenfeld
      Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness. It is caused by the loss of orexin producing neurons in the lateral hypothalamus. Current evidences suggest an autoimmune mediated process causing the specific loss of orexin neurons. The high association of the disease with the HLA DQB1*06:02, as well as the link with environmental factors and are important clues supporting this theory. Recently, the association between the occurrence of the disease and vaccination campaign after the 2009 H1N1 pandemic highlighted the importance to increase the knowledge in the Pandora box of the vaccines. This review discusses the last finding regarding the pathogenesis of the disease and its relationship with the H1N1 vaccines.


      PubDate: 2015-01-14T20:41:24Z
       
  • Erratum to “Protection afforded by pre- or post-treatment with
           4-phenylbutyrate against liver injury induced by acetaminophen overdose in
           mice” [Pharmacol. Res. 87 (2014) 26–41]
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Daisuke Shimizu , Yoichi Ishitsuka , Keishi Miyata , Yoshiro Tomishima , Yuki Kondo , Mitsuru Irikura , Takao Iwawaki , Yuichi Oike , Tetsumi Irie



      PubDate: 2015-01-14T20:41:24Z
       
  • Indole-3-carbinol induces cMYC and IAP-family downmodulation and promotes
           apoptosis of Epstein–Barr virus (EBV)-positive but not of
           EBV-negative Burkitt's lymphoma cell lines
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Gema Perez-Chacon , Cristobal de los Rios , Juan M. Zapata
      Indole-3-carbinol (I3C) is a natural product found in broadly consumed plants of the Brassica genus, such as broccoli, cabbage, and cauliflower, which exhibits anti-tumor effects through poorly defined mechanisms. I3C can be orally administered and clinical trials have demonstrated that I3C and derivatives are safe in humans. In this study we show that I3C efficiently induces apoptosis in cell lines derived from EBV-positive Burkitt's lymphomas (virus latency I/II), while it does not have any cytotoxic activity against EBV-negative Burkitt's lymphomas and immortalized EBV-infected lymphoblastoid cell lines (virus latency III). The effect of I3C in EBV-positive Burkitt's lymphoma is very specific, since only I3C and its C6-methylated derivative, but not other 3-substituted indoles, have an effect on cell viability. I3C treatment caused apoptosis characterized by loss of mitochondria membrane potential and caspase activation. I3C alters the expression of proteins involved in the control of apoptosis and transcription regulation in EBV-positive Burkitt's lymphoma cell lines. Among those, cMYC, cIAP1/2 and XIAP downmodulation at mRNA and protein level precede apoptosis induction, thus suggesting a role in I3C cytotoxicity. We also showed that I3C and, more particularly, its condensation dimer 3,3′-diindolylmethane (DIM) prolonged survival and reduced tumor burden of mice xenotransplanted with EBV-positive Burkitt's lymphoma Daudi cells. In summary these results, together with previous reports from clinical trials indicating the lack of toxicity in humans of I3C and derivatives, support the use of these compounds as a new therapeutic approach for treating patients with endemic (EBV-positive) Burkitt's lymphoma.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • The effect of peroxynitrite decomposition catalyst MnTBAP on aldehyde
           dehydrogenase-2 nitration by organic nitrates: Role in nitrate tolerance
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Vincenzo Mollace , Carolina Muscoli , Concetta Dagostino , Luigino Antonio Giancotti , Micaela Gliozzi , Iolanda Sacco , Valeria Visalli , Santo Gratteri , Ernesto Palma , Natalia Malara , Vincenzo Musolino , Cristina Carresi , Saverio Muscoli , Cristiana Vitale , Daniela Salvemini , Francesco Romeo
      Bioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo. Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4h. This was expressed by attenuation of platelet aggregation induced by thrombin (40U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event in GTN tolerance, an effect counteracted both in vitro and in vivo by novel peroxynitrite decomposition catalyst.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Pharmacological activation of AMPK ameliorates perivascular
           adipose/endothelial dysfunction in a manner interdependent on AMPK and
           SIRT1
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Yan Sun , Jia Li , Na Xiao , Meng Wang , Junping Kou , Lianwen Qi , Fang Huang , Baolin Liu , Kang Liu
      Adipose and endothelial dysfunction is tightly associated with cardiovascular diseases in obesity and insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and SIRT1 activities implicated in adipocytokine expression and endothelial homeostasis under inflammatory conditions by using salicylate, metformin, AICA riboside (AICAR) and resveratrol as AMPK activating agents. We prepared conditioned medium (CM) by stimulating PVAT with palmitic acid (PA) and observed the effects of AMPK activating agents on adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of resveratrol and metformin in fructose-fed rats. We observed that PA stimulation induced inflammation and dysregulation of adipocytokine expression accompanied with reduced AMPK activity and SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory adipocytokines, and upregulated adiponectin and PPARγ expression in PVAT in an AMPK/SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with AMPK inhibitor compound C or SIRT1 inhibitor nicotinamide. Long-term fructose-feeding in rats induced dysregulation of adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by oral administration of resveratrol and metformin. Altogether, pharmacological activation of AMPK beneficially regulated adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/SIRT1-interdependent manner.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • The flavonoid quercetin induces acute vasodilator effects in healthy
           volunteers: Correlation with beta-glucuronidase activity
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Almudena Perez , Susana Gonzalez-Manzano , Rosario Jimenez , Rocío Perez-Abud , Jose M. Haro , Antonio Osuna , Celestino Santos-Buelga , Juan Duarte , Francisco Perez-Vizcaino
      Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). Design: double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26±5 years, 6 female) were given a capsule containing placebo, 200 or 400mg of quercetin in random order in three consecutive weeks. At 2h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1μM for 200 and 400mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Editorial Board
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89




      PubDate: 2015-01-14T20:41:24Z
       
  • Novel therapeutic strategies for ischemic heart disease
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Adam J. Perricone , Richard S. Vander Heide
      Despite significant advances in the physician's ability to initiate myocardial reperfusion and salvage heart tissue, ischemic heart disease remains one of the leading causes of death in the United States. Consequently, alternative therapeutic strategies have been intensively investigated, especially methods of enhancing the heart's resistance to ischemic cell death – so called “cardioprotective” interventions. However, although a great deal has been learned regarding the methods and mechanisms of cardioprotective interventions, an efficacious therapy has yet to be successfully implemented in the clinical arena. This review discusses the current understanding of cardioprotection in the context of ischemic heart disease pathophysiology, highlighting those elements of ischemic heart disease pathophysiology that have received less attention as potential targets of cardioprotective intervention.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • N6-isopentenyladenosine affects cytotoxic activity and cytokines
           production by IL-2 activated NK cells and exerts topical anti-inflammatory
           activity in mice
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89
      Author(s): Elena Ciaglia , Simona Pisanti , Paola Picardi , Chiara Laezza , Silvio Sosa , Aurelia Tubaro , Mario Vitale , Patrizia Gazzerro , Anna Maria Malfitano , Maurizio Bifulco
      N6-isopentenyladenosine (iPA) is a modified adenosine with an isopentenyl moiety derived from the mevalonate pathway which displays pleiotropic biological effects, including anti-tumor and anti-angiogenic activity. Previous evidence revealed a biphasic effect of iPA on phytohemagglutinin-stimulated lymphocytes, being pro-proliferative at low doses and anti-proliferative at high doses. Analogously, we have recently shown that low iPA concentrations (<1μM) increased the immune response of natural killer (NK) cells against cancer targets. In the present study, we evaluated the effect of iPA at high concentration (10μM) on IL-2-activated NK cells. iPA, inhibited NK cell proliferation and cytotoxicity against their conventional tumor target, human K562 cells. This inhibition was associated with decreased expression and functionality of NK cell activating receptors NKp44 and NKG2D as well as impaired cyto/chemokines secretion (RANTES, MIP-1α, TNF-α and IFN-γ). ERK/MAPK and STAT5 activation in IL-2-activated NK cells were inhibited by iPA. The results obtained in vitro were validated in vivo in the inflammatory murine model of croton oil-induced ear dermatitis. The topical application of iPA significantly reduced mouse ear oedema, thus suggesting anti-inflammatory properties of this molecule. These results show the ability of iPA to exert anti-inflammatory effects both in vitro and in vivo directly targeting NK cells, providing a novel pharmacological tool in those diseases characterized by a deregulated immune-response, such as cancer or inflammatory conditions.
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      PubDate: 2015-01-14T20:41:24Z
       
  • On pharmacologist and vaccines: Present and future challenges
    • Abstract: Publication date: Available online 10 November 2014
      Source:Pharmacological Research
      Author(s): Paolo Pellegrino , Annalisa Capuano , Sonia Radice



      PubDate: 2015-01-14T20:41:24Z
       
  • Ongoing pharmacovigilance on vaccines
    • Abstract: Publication date: Available online 10 November 2014
      Source:Pharmacological Research
      Author(s): Carmela Santuccio , Francesco Trotta , Patrizia Felicetti
      Vaccines have peculiar characteristics as well as their surveillance. Specific requirements, needs and challenges for the vaccine vigilance are discussed in the perspective to improve the whole system in order to guarantee a safer vaccine use and the keeping of the public confidence in vaccinations. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, the Italian experience is shortly described.
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      PubDate: 2015-01-14T20:41:24Z
       
  • EP2 and EP4 receptors mediate PGE2 induced relaxation in murine colonic
           circular muscle: Pharmacological characterization
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): M. Martinez-Cutillas , N. Mañé , D. Gallego , M. Jimenez , M.T. Martin
      Background Prostaglandin E2 (PGE2) is a regulator of gastrointestinal motility that might be involved in impaired motor function associated to gut inflammation. The aim of the present work is to pharmacologically characterize responses to exogenous and endogenous PGE2 in the mouse colon targeting EP2 and EP4 receptors. Methods Wild type (WT) and EP2 receptor knockout (EP2-KO) mice were used to characterize PGE2 and butaprost (EP2 receptor agonist) effects on smooth muscle resting membrane potential and myogenic contractility in circularly oriented colonic preparations. Results In WT animals, PGE2 and butaprost concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. Combination of both EP2 (PF-04418948 0.1μM) and EP4 receptor antagonists (L-161,982 10μM) was needed to block both electrical and mechanical PGE2 responses. Butaprost inhibitory responses (both electrical and mechanical) were totally abolished by PF-04418948 0.1μM. In EP2-KO mice, PGE2 (but not butaprost) concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. In EP2-KO mice, PGE2 inhibition of spontaneous contractility and hyperpolarization was fully antagonized by L-161,982 10μM. In WT animals, EP2 and EP4 receptor antagonists caused a smooth muscle depolarization and an increase in spontaneous mechanical activity. Conclusions PGE2 responses in murine circular colonic layer are mediated by post-junctional EP2 and EP4 receptors. PF-04418948 and L-161,982 are selective EP2 and EP4 receptor antagonists that inhibit PGE2 responses. These antagonists might be useful pharmacological tools to limit prostaglandin effects associated to dismotility in gut inflammatory processes.
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      PubDate: 2015-01-14T20:41:24Z
       
  • JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced
           peripheral neuropathy
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Iryna A. Khasabova , Xu Yao , Justin Paz , Cutler T. Lewandowski , Amy E. Lindberg , Lia Coicou , Natasha Burlakova , Don A. Simone , Virginia S. Seybold
      Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Histamine in the locus coeruleus promotes descending noradrenergic
           inhibition of neuropathic hypersensitivity
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Hong Wei , Cong-Yu Jin , Hanna Viisanen , Hao-Jun You , Antti Pertovaara
      Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1–10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Rutin has intestinal antiinflammatory effects in the CD4+ CD62L+ T cell
           transfer model of colitis
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Cristina Mascaraque , Carlos Aranda , Borja Ocón , María Jesús Monte , María Dolores Suárez , Antonio Zarzuelo , José Juan García Marín , Olga Martínez-Augustin , Fermín Sánchez de Medina
      Rutin, one of the most abundant flavonoids in nature, has been shown to exert intestinal antiinflammatory effects in experimental models of colitis. Our aim was to study the antiinflamatory effect of rutin in the CD4+ CD62L+ T cell transfer model of colitis, one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to Rag1−/− mice. Rutin was administered by gavage as a postreatment. Treatment with rutin improved colitis at the dose of 57mg/kg/day, while no effect was noted with 28.5mg/kg/day. Therapeutic benefit was evidenced by a reduced disease activity index, weight loss and damage score, plus a 36% lower colonic myeloperoxidase and a 54% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory cytokines (IFNγ and TNFα) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNγ, TNFα, CXCL1, S100A8 and IL-1β, was significantly reduced by more than 80% with rutin as assessed by RT-qPCR. Flavonoid treated mice exhibited decreased activation of splenic CD4+ cells (STAT4 phosphorylation and IFNγ expression) and reduced plasma cytokine levels. This effect was also apparent in mucosal lymphocytes based on reduced STAT4 phosphorylation. The protective effect was comparable to that of 3mg/kg/day budesonide. Rutin had no effect on splenocytes or murine T cells in vitro, while its aglycone, quercetin, exhibited a concentration dependent inhibition of proinflammatory cytokines, including IFNγ. Rutin but not quercetin showed vectorial basolateral to apical transport in IEC18 cells, associated with reduced biotransformation. We conclude that rutin exerts intestinal antiinflammatory activity in chronic, T lymphocyte dependent colitis via quercetin release and actions involving mucosal and lymph node T cells. Our results suggest that rutin may be useful in the management of inflammatory bowel disease in appropriate dosage conditions.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Fenofibrate and dipyridamole treatments in low-doses either alone or in
           combination blunted the development of nephropathy in diabetic rats
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Pitchai Balakumar , Rajavel Varatharajan , Ying Hui Nyo , Raja Renushia , Devarajan Raaginey , Ann Nah Oh , Shaikh Sohrab Akhtar , Mani Rupeshkumar , Karupiah Sundram , Sokkalingam A. Dhanaraj
      Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin–eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.
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      PubDate: 2015-01-14T20:41:24Z
       
  • A role for the sodium pump in H2O2-induced vasorelaxation in porcine
           isolated coronary arteries
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): P.S. Wong , M.J. Garle , S.P.H. Alexander , M.D. Randall , R.E. Roberts
      Hydrogen peroxide (H2O2) has been proposed to act as a factor for endothelium-derived hyperpolarization (EDH) and EDH may act as a ‘back up’ system to compensate the loss of the NO pathway. Here, the mechanism of action of H2O2 in porcine isolated coronary arteries (PCAs) was investigated. Distal PCAs were mounted in a wire myograph and pre-contracted with U46619 (1nM–50μM), a thromboxane A2-mimetic or KCl (60mM). Concentration–response curves to H2O2(1μM–1mM), bradykinin (0.01nM–1μM), sodium nitroprusside (SNP) (10nM–10μM), verapamil (1nM–10μM), KCl (0–20mM) or Ca2+-reintroduction (1μM–10mM) were constructed in the presence of various inhibitors. Activity of the Na+/K+-pump was measured through rubidium-uptake using atomic absorption spectrophotometry. H2O2 caused concentration-dependent vasorelaxations with a maximum relaxation (R max) of 100±16% (mean±SEM), pEC50 =4.18±0.20 (n =4) which were significantly inhibited by PEG-catalase at 0.1–1.0mM H2O2 (P <0.05). 10mM TEA significantly inhibited the relaxation up to 100μM H2O2 (P <0.05). 60mM K+ and 500nM ouabain significantly inhibited H2O2-induced vasorelaxation producing a relaxation of 40.8±8.5% (n =5) and 47.5±8.6% (n =6) respectively at 1mM H2O2 (P <0.0001). H2O2-induced vasorelaxation was unaffected by the removal of endothelium, inhibition of NO, cyclo-oxygenase, gap junctions, SKCa, IKCa, BKCa Kir, KV, KATP or cGMP. 100μM H2O2 had no effects on the KCl-induced vasorelaxation or Ca2+-reintroduction contraction. 1mM H2O2 inhibited both KCl-induced vasorelaxation and rubidium-uptake consistent with inhibition of the Na+/K+-pump activity. We have shown that the vascular actions of H2O2 are sensitive to ouabain and high concentrations of H2O2 are able to modulate the Na+/K+-pump. This may contribute towards its vascular actions.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Des-Arg9-bradykinin causes kinin B1 receptor mediated
           endothelium-independent contractions in endotoxin-treated porcine coronary
           arteries
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Amar S. More , Hye Min Kim , Gilson Khang , Tobias Hildebrandt , Christian Bernlöhr , Henri Doods , Paul M. Vanhoutte , Dongmei Wu
      This study examined responses of isolated pig coronary arteries after kinin B1 receptor induction by endotoxin. Des-Arg9-bradykinin (DBK) induced concentration-dependent, endothelium-independent contractions in lipopolysaccharide (LPS)-treated but not untreated arterial rings. The B1-receptor antagonist SSR240612, but not the B2-receptor antagonist HOE140, prevented the endothelium-independent contractions to DBK. The DBK-induced contractions were blocked by indomethacin (nonselective cyclooxygenase [COX] inhibitor), celecoxib (selective COX-2 inhibitor), and terbogrel (thromboxane-prostanoid [TP] receptor antagonist) but not valeryl salicylate (selective COX-1 inhibitor), AH6809 (an E prostanoid [EP] and PGD2 receptor [DP1] receptor antagonist), AL 8810 (a selective PGF2α [FP] receptor antagonist), or RO1138452 (a selective I prostanoid [IP] receptor antagonist). They were attenuated by N-(p-amylcinnamoyl) anthranilic acid (ACA), and by DETCA plus tiron but not by l-NAME. Quantitative RT-PCR revealed excessive up-regulations of mRNA expressions of B1 receptors, COX-2, and thromboxane A synthase 1 (TBXAS1) following LPS incubation, but not of B2 receptors or COX-1. The present data demonstrate that B1 receptors are coupled to COX-2 in causing endothelium-independent contractions in endotoxin-treated pig coronary arteries. Accordingly, kinin B1 receptor induction during inflammation may have a pathological significance in the vasculature, particular in coronary arteries with dysfunctional endothelial cells.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Identification of up- and down-regulated proteins in doxorubicin-resistant
           uterine cancer cells: Reticulocalbin-1 plays a key role in the development
           of doxorubicin-associated resistance
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Eugenie Wong Soon May , Szu-Ting Lin , Chi-Chen Lin , Jo-Fan Chang , Eric Hung , Yi-Wen Lo , Li-Hsun Lin , Ren-Yu Hu , Chi-Lun Feng , Dai-Ying Lin , Shine-Bei Wu , Wen-Chi Lee , Kevin W. Lyu , Hsiu-Chuan Chou , Hong-Lin Chan
      Drug resistance is a frequent cause of failure in cancer chemotherapy treatments. In this study, a pair of uterine sarcoma cancer lines, MES-SA, and doxorubicin-resistant partners, MES-SA/DxR-2μM cells and MES-SA/DxR-8μM cells, as a model system to investigate resistance-dependent proteome alterations and to identify potential therapeutic targets. We used two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to perform this research and the results revealed that doxorubicin-resistance altered the expression of 208 proteins in which 129 identified proteins showed dose-dependent manners in response to the levels of resistance. Further studies have used RNA interference, H2A.X phosphorylation assay, cell viability analysis, and analysis of apoptosis against reticulocalbin-1 (RCN1) proteins, to prove its potency on the formation of doxorubicin resistance as well as the attenuation of doxorubicin-associated DNA double strand breakage. To sum up, our results provide useful diagnostic markers and therapeutic candidates such as RCN1 for the treatment of doxorubicin-resistant uterine cancer.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Resveratrol and cardiovascular health – Promising therapeutic or
           hopeless illusion'
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Philip Chiu-Tsun Tang , Yam-Fung Ng , Susan Ho , Michael Gyda , Shun-Wan Chan
      Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenolic compound that exists in Polygonum cuspidatum, grapes, peanuts and berries, as well as their manufactured products, especially red wine. Resveratrol is a pharmacologically active compound that interacts with multiple targets in a variety of cardiovascular disease models to exert protective effects or induce a reduction in cardiovascular risks parameters. This review attempts to primarily serve to summarize the current research findings regarding the putative cardioprotective effects of resveratrol and the molecular pathways underlying these effects. One intent is to hopefully provide a relatively comprehensive resource for clues that may prompt ideas for additional mechanistic studies which might further elucidate and strengthen the role of the stilbene family of compounds in cardiovascular disease and cardioprotection. Model systems that incorporate a significant functional association with tissues outside of the cardiovascular system proper, such as adipose (cell culture, obesity models) and pancreatic (diabetes) tissues, were reviewed, and the molecular pathways and/or targets related to these models and influenced by resveratrol are discussed. Because the body of work encompassing the stilbenes and other phytochemicals in the context of longevity and the ability to presumably mitigate a plethora of afflictions is replete with conflicting information and controversy, especially so with respect to the human response, we tried to remain as neutral as possible in compiling and presenting the more current data with minimal commentary, permitting the reader free reign to extract the knowledge most helpful to their own investigations.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Erratum to “Muscarinic receptors stimulate cell proliferation in the
           human urothelium-derived cell line UROtsa” [Pharmacol. Res. 64
           (2011) 420–425]
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Nicola Arrighi , Serena Bodei , Alessandra Lucente , Martin C. Michel , Danilo Zani , Claudio Simeone , Sergio Cosciani Cunico , PierFranco Spano , Sandra Sigala



      PubDate: 2015-01-14T20:41:24Z
       
  • Editorial Board
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90




      PubDate: 2015-01-14T20:41:24Z
       
  • The resveratrol fiasco
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Francesco Visioli



      PubDate: 2015-01-14T20:41:24Z
       
  • Carbocysteine restores steroid sensitivity by targeting histone
           deacetylase 2 in a thiol/GSH-dependent manner
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Yun Song , Hao-Zhong Lu , Jian-Rong Xu , Xiao-Lin Wang , Wei Zhou , Li-Na Hou , Liang Zhu , Zhi-Hua Yu , Hong-Zhuan Chen , Yong-Yao Cui
      Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S-CMC), a mucolytic agent, in cellular and animal models of oxidative stress-mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress-induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Interaction of human organic anion transporter 2 (OAT2) and sodium
           taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Venkata V.V.R. Marada , Saskia Flörl , Annett Kühne , Judith Müller , Gerhard Burckhardt , Yohannes Hagos
      The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [3H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The K i values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration,
           and proliferation – Impact of Ras-/Rho-prenylation
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Sarah Afshordel , Beatrice Kern , Jasmin Clasohm , Hildegard König , Maike Priester , Jakob Weissenberger , Donat Kögel , Gunter P. Eckert
      Alterations in small GTPase mediated signal transduction pathways have emerged as a central step in the molecular pathogenesis of glioblastoma (GBM), the most common malignant brain tumor in adults. Farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) are derived from mevalonate, whose production is catalyzed by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Prenylation by FPP and GGPP is required for membrane insertion and oncogenic function of Ras- and Rho-proteins, within the stimulation of the Ras–Raf–MEK–ERK pathway. A straightforward prediction from HMG-CoA reductase inhibitor studies is that statins decrease FPP and GGPP levels and diminish ERK signaling ensuring less proliferation and migration of cancer cells. Perillyl alcohol (POH), a naturally occurring monoterpene inhibits prenyltransferases and is able to inhibit cancer cell growth, but the underlying mechanism is still unclear. We here report that lovastatin (LOV) and POH impair the regulation of the mevalonate- and the Ras–Raf–MEK–ERK pathway in U87 and U343 glioblastoma cells. Both compounds affected the post-translational modification of H-Ras and Rac1. While LOV diminished the substrates of the transferase reaction that catalyze prenylation, POH inhibited the enzymes itself. Our data highlight the impact of isoprenoids for post-translational modification of small GTPases promoting proliferation, migration and invasion capabilities in glioma cells.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Chronic heart damage following doxorubicin treatment is alleviated by
           lovastatin
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Christian Henninger , Stefanie Huelsenbeck , Philip Wenzel , Moritz Brand , Johannes Huelsenbeck , Arno Schad , Gerhard Fritz
      The anticancer efficacy of anthracyclines is limited by cumulative dose-dependent early and delayed cardiotoxicity resulting in congestive heart failure. Mechanisms responsible for anthracycline-induced heart damage are controversially discussed and effective preventive measures are preferable. Here, we analyzed the influence of the lipid lowering drug lovastatin on anthracycline-induced late cardiotoxicity three month after treatment of C57BL/6 mice with five low doses of doxorubicin (5×3mg/kg BW; i.p.). Doxorubicin increased the cardiac mRNA levels of BNP, IL-6 and CTGF, while the expression of ANP remained unchanged. Lovastatin counteracted these persisting cardiac stress responses evoked by the anthracycline. Doxorubicin-induced fibrotic alterations were neither detected by histochemical collagen staining of heart sections nor by analysis of the mRNA expression of collagens. Extensive qRT-PCR-array based analyses revealed a large increase in the mRNA level of heat shock protein Hspa1b in doxorubicin-treated mice, which was mitigated by lovastatin co-treatment. Electron microscopy together with qPCR-based analysis of mitochondrial DNA content indicate that lovastatin attenuates doxorubicin-stimulated hyperproliferation of mitochondria. This was not paralleled by increased expression of oxidative stress responsive genes or senescence-associated proteins. Echocardiographic analyses disclosed that lovastatin protects from the doxorubicin-induced decrease in the left ventricular posterior wall diameter (LVPWD), while constrictions in fractional shortening (FS) and ejection fraction (EF) evoked by doxorubicin were not amended by the statin. Taken together, the data suggest beneficial effects of lovastatin against doxorubicin-induced delayed cardiotoxicity. Clinical studies are preferable to scrutinize the usefulness of statins for the prevention of anthracycline-induced late cardiotoxicity.
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      PubDate: 2015-01-14T20:41:24Z
       
  • PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and
           spinal neuronal sensitization in neuropathic mice
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): F. Guida , R. Lattanzi , S. Boccella , D. Maftei , R. Romano , V. Marconi , G. Balboni , S. Salvadori , M.A. Scafuro , V. de Novellis , L. Negri , S. Maione , L. Luongo
      Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Diacerein is a potent and selective inhibitor of palmitoylethanolamide
           inactivation with analgesic activity in a rat model of acute inflammatory
           pain
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Stefania Petrosino , Akbar Ahmad , Gabriele Marcolongo , Emanuela Esposito , Marco Allarà , Roberta Verde , Salvatore Cuzzocrea , Vincenzo Di Marzo
      Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Hyperoxic gassing with Tiron enhances bradykinin-induced
           endothelium-dependent and EDH-type relaxation through generation of
           hydrogen peroxide
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Pui San Wong , Richard E. Roberts , Michael D. Randall
      Oxygenation with 95%O2 is routinely used in organ bath studies. However, hyperoxia may affect tissue responses, particularly in studies which involve reactive oxygen species (ROS). Here, the effects of the antioxidant, Tiron, were investigated under different gassing conditions in the porcine isolated coronary artery (PCA). Distal PCAs from male and female pigs were mounted in a wire myograph gassed with either 95%O2/5%CO2 or 95% air/5%CO2 and pre-contracted with U46619. Concentration–response curves to bradykinin were constructed in the presence of Tiron (1mM), a cell permeable superoxide scavenger and catalase (1000Uml−1) to breakdown H2O2. The H2O2 level in Krebs’–Henseleit solution was detected using Amplex Red. Bradykinin produced concentration-dependent vasorelaxations in male and female PCAs when gassed with either 95%O2 or air, with no differences in the R max or EC50. Tiron increased the potency of bradykinin only when gassed with 95%O2 in PCAs from both sexes. At 95%O2, catalase prevented the leftward shift caused by Tiron in both sexes indicating that catalase prevented the formation of H2O2 by Tiron. In female PCAs, addition of catalase to Tiron significantly reduced the R max. In the EDH-type response (using L-NAME and indomethacin), Tiron enhanced the potency of the bradykinin-induced vasorelaxation when gassed with 95%O2 in PCAs from both sexes. Biochemical analysis using Amplex Red demonstrated that H2O2 was generated in Krebs’–Henseleit solution when gassed with 95%O2, but not with air. Therefore, hyperoxic gassing conditions could alter the environment generating superoxide within the Krebs’–Henseleit buffer, which may, in turn, influence the in vitro pharmacological responses.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial
           dysfunction through mitochondrial biogenesis improvement
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Pedro Bullón , Lourdes Román-Malo , Fabiola Marín-Aguilar , José Miguel Alvarez-Suarez , Francesca Giampieri , Maurizio Battino , Mario D. Cordero
      Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Tranilast: A review of its therapeutic applications
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Sara Darakhshan , Ali Bidmeshki Pour
      Tranilast (N-[3′,4′-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. Initially, tranilast was identified as an anti-allergic agent, and used in the treatment of inflammatory diseases, such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Subsequently, the results showed that it could be also effective in the management of a wide range of conditions. The beneficial effects of tranilast have also been seen in a variety of disease states, such as fibrosis, proliferative disorders, cancer, cardiovascular problems, autoimmune disorders, ocular diseases, diabetes and renal diseases. Moreover, several trials have shown that it has very low adverse effects and it is generally well tolerated by patients. In this review, we have attempted to accurately summarize previously published studies relating to the use of tranilast for a range of disorders and discuss the drug's possible mode of action. The major mode of the drug's efficacy appears to be the suppression of the expression and/or action of the TGF-β pathway, but the drug affects other factors as well. The findings presented in this review demonstrate the potential of tranilast for the control of a vast array of pathological situations, furthermore, it is a prescribed drug without severe side effects.
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      PubDate: 2015-01-14T20:41:24Z
       
  • The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Elango Bhakkiyalakshmi , Dornadula Sireesh , Palanisamy Rajaguru , Ramasamy Paulmurugan , Kunka Mohanram Ramkumar
      The pathogenic processes involving in the development of diabetes range from autoimmune destruction of pancreatic β-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The major contributing factor for excessive β-cell death includes oxidative stress-mediated mitochondrial damage, which creates an imbalance in redox homeostasis. Yet, β-cells have evolved adaptive mechanisms to endure a wide range of stress conditions to safeguard its potential functions. These include ‘Nrf2/Keap1’ pathway, a key cellular defense mechanism, to combat oxidative stress by regulating phase II detoxifying and antioxidant genes. During diabetes, redox imbalance provokes defective Nrf2-dependent signaling and compromise antioxidant capacity of the pancreas which turnout β-cells to become highly vulnerable against various insults. Hence, identification of small molecule activators of Nrf2/Keap1 pathway remains significant to enhance cellular defense to overcome the burden of oxidative stress related disturbances. This review summarizes the molecular mechanism behind Nrf2 activation and the impact of Nrf2 activators in diabetes and its complications.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Enhancement of vascular endothelial growth factor release in long-term
           drug-treated breast cancer via transient receptor potential channel
           5-Ca2+-hypoxia-inducible factor 1α pathway
    • Abstract: Publication date: Available online 9 January 2015
      Source:Pharmacological Research
      Author(s): Yifei Zhu , Qiongxi Pan , Huan Meng , Yueshui Jiang , Aiqin Mao , Teng Wang , Dong Hua , Xiaoqiang Yao , Jian Jin , Xin Ma
      Chemotherapy targeting anti-angiogenesis in tumors may have insufficient efficacy, but little is known about the underlying mechanisms. Here, we showed that the Ca2+-permeable channel, TrpC5, is highly expressed in human breast cancer after long-term chemotherapy drug-treatment. It mediates downstream hypoxia-inducible factor 1α accumulation in the nucleus, and then activates the transcription of vascular endothelial growth factor which promotes tumor angiogenesis, leading to a poor chemotherapeutic outcome. We verified this mechanism at both the cellular and xenograft levels. Moreover, in samples from patients, high TrpC5 expression was correlated with enhanced tumor vasculature after chemotherapy. Taken together, our research demonstrated the essential role of TrpC5 in tumor angiogenesis when facing the challenge of chemotherapy and presents a new potential target for overcoming the high vasculature of human breast cancer after chemotherapy.
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      PubDate: 2015-01-14T20:41:24Z
       
  • Editorial Board
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91




      PubDate: 2015-01-14T20:41:24Z
       
  • Hydrocodone extended-release: Pharmacodynamics, pharmacokinetics and
           behavioral pharmacology of a controversy
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Harry J. Gould III , Dennis Paul
      Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro®, an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDA's Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to the Expert Panel's opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Endothelialization of drug eluting stents and its impact on dual
           anti-platelet therapy duration
    • Abstract: Publication date: March 2015
      Source:Pharmacological Research, Volume 93
      Author(s): Anwer Habib , Aloke V. Finn
      Coronary artery disease is a leading cause of death and disability worldwide with contemporary treatment strategies employing both optimal medical therapy and catheter based percutaneous coronary intervention (PCI) with drug eluting stents (DES). While DES have dramatically reduced restenosis rates, their use has been associated with an increased risk of late stent thrombosis and accelerated neointimal atherosclerosis (i.e. “neoatherosclerosis”) both major contributors to late stent failure. The underlying substrate of late DES failure is likely related to vascular endothelial dysfunction such as poor endothelial regrowth and barrier function (i.e. “endothelial healing”). Initial concerns with 1st generation DES have lead to improvements in mechanical and biologic properties of current 2nd generation DES, which inhibit endothelial regrowth to a lesser extent, lessening late stent failure and resulting in an overall improved safety profile. Current guidelines recommend duration of at least one year of dual anti-platelet therapy with aspirin and a thienopyridine agent such as clopidogrel or prasugrel as sufficient to prevent late thrombotic complications. Recent studies, however, suggest a shorter duration of dual anti-platelet therapy may be equally as safe and efficacious in preventing stent thrombosis with newer generation DES. However, higher risk populations such as patients receiving 1st generation DES or those with increased risk for future ischemic events may benefit from a longer duration (i.e. 30 months) of DAPT to prevent major cardiovascular events with the caveat that such an approach may be associated with an increased risk for bleeding. This review examines the vascular responses to 1st and second generation DES and recent clinical trials examining DAPT duration.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • GABA and GABA receptors in the gastrointestinal tract: from motility to
           inflammation
    • Abstract: Publication date: March 2015
      Source:Pharmacological Research, Volume 93
      Author(s): Michelangelo Auteri , Maria Grazia Zizzo , Rosa Serio
      Although an extensive body of literature confirmed γ-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Natural inhibitors of PI3K/AKT signaling in breast cancer: Emphasis on
           newly-discovered molecular mechanisms of action
    • Abstract: Publication date: March 2015
      Source:Pharmacological Research, Volume 93
      Author(s): Yaghoub Safdari , Masoumeh Khalili , Mohammad Ali Ebrahimzadeh , Yaghoub Yazdani , Safar Farajnia
      Epidermal growth factor receptor (EGFR) plays a critical role in the initiation and progression of a variety of human cancers, including breast cancer. An important signaling pathway downstream of EGFR is the PI3K/AKt pathway, which regulates cellular processes as diverse as cell growth, survival, proliferation and migration. Deregulated activity of this pathway may lead to uncontrolled cell growth, survival, migration and invasion, contributing to tumor formation. In this review, we evaluate natural compounds that, in vitro (breast cancer cell lines) and/or in vivo (animal model, clinical) studies, suppress breast cancer cells or tumors mainly by suppressing the PI3K/AKT signaling pathway. The effect of these compounds on cell cycle arrest, inhibition of cell migration and invasion, tumor angiogenesis and metastasis in breast cancer are discussed.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Pin1-based diagnostic and therapeutic strategies for breast cancer
    • Abstract: Publication date: March 2015
      Source:Pharmacological Research, Volume 93
      Author(s): Jing-Zhang Wang , Bao-Guo Liu , Yong Zhang
      Pin1 is the only known cis-to-trans isomerase that recognizes the phosphorylated pThr/pSer-Pro motifs in many signaling molecules, playing unique roles in the pathogenesis of breast cancer. First, Pin1 is prevalently over-expressed in kinds of breast cancer cell lines and tissues, such as MDA-MB-231 cell, MCF-7 cell, Her2+, ERα+, and basal-like breast cancer subtypes. Second, Pin1 amplifies many oncogenic signaling pathways, inhibits multiple tumor suppressors, promotes the angiogenesis and metastasis of breast cancer cells, and enhances the resistance of breast cancer cells to anti-tumor medicines. Third, inhibiting Pin1 blocks most of these detrimental effects in a great number of breast cancer cell lines. These findings suggest Pin1 as a promising diagnostic biomarker as well as an efficient therapeutic target for breast cancer. It is strongly expected that a Pin1-positive subtype of breast cancers should be extremely concerned and that the therapeutic efficacy of Pin1 inhibitors on breast cancer patients should be evaluated as soon as possible. Nonetheless, Pin1-based therapeutic strategies for breast cancer still deserve some debates. Hence, we give the predictions of several important issues, such as application precondition, side effects, and personalized medication, when Pin1 inhibitors are used in the breast cancer therapy. These proposals are meaningful for the further development of Pin1-based diagnostic and therapeutic strategies in order to conquer breast cancer.
      Graphical abstract image

      PubDate: 2015-01-14T20:41:24Z
       
  • Erythroid induction of K562 cells treated with mithramycin is associated
           with inhibition of raptor gene transcription and mammalian target of
           rapamycin complex 1 (mTORC1) functions
    • Abstract: Publication date: Available online 3 December 2014
      Source:Pharmacological Research
      Author(s): Alessia Finotti , Nicoletta Bianchi , Enrica Fabbri , Monica Borgatti , Giulia Breveglieri , Jessica Gasparello , Roberto Gambari
      Rapamycin, an inhibitor of mTOR activity, is a potent inducer of erythroid differentiation and fetal hemoglobin production in β-thalassemic patients. Mithramycin (MTH) was studied to see if this inducer of K562 differentiation also operates through inhibition of mTOR. We can conclude from the study that the mTOR pathway is among the major transcript classes affected by mithramycin-treatment in K562 cells and a sharp decrease of raptor protein production and p70S6 kinase is detectable in mithramycin treated K562 cells. The promoter sequence of the raptor gene contains several Sp1 binding sites which may explain its mechanism of action. We hypothesize that the G+C-selective DNA-binding drug mithramycin is able to interact with these sequences and to inhibit the binding of Sp1 to the raptor promoter due to the following results: (a) MTH strongly inhibits the interactions between Sp1 and Sp1-binding sites of the raptor promoter (studied by electrophoretic mobility shift assays, EMSA); (b) MTH strongly reduces the recruitment of Sp1 transcription factor to the raptor promoter in intact K562 cells (studied by chromatin immunoprecipitation experiments, ChIP); (c) Sp1 decoy oligonucleotides are able to specifically inhibit raptor mRNA accumulation in K562 cells. In conclusion, raptor gene expression is involved in mithramycin-mediated induction of erythroid differentiation of K562 cells and one of its mechanism of action is the inhibition of Sp1 binding to the raptor promoter.
      Graphical abstract image

      PubDate: 2014-12-07T02:49:27Z
       
 
 
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