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Tribology and Interface Engineering Series     Full-text available via subscription   (Followers: 3)
Tribology Intl.     Hybrid Journal   (Followers: 8, SJR: 1.25, h-index: 56)
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Tsinghua Science & Technology     Full-text available via subscription   (SJR: 0.173, h-index: 16)
Tuberculosis     Hybrid Journal   (Followers: 3, SJR: 1.077, h-index: 59)
Tunnelling and Underground Space Technology     Hybrid Journal   (Followers: 3, SJR: 1.208, h-index: 35)
Tzu Chi Medical J.     Full-text available via subscription   (SJR: 0.106, h-index: 6)
Ultramicroscopy     Hybrid Journal   (SJR: 1.603, h-index: 71)
Ultrasonics     Hybrid Journal   (Followers: 3, SJR: 0.639, h-index: 51)
Ultrasonics Sonochemistry     Hybrid Journal   (Followers: 2, SJR: 1.267, h-index: 60)
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Urban Forestry & Urban Greening     Hybrid Journal   (Followers: 7, SJR: 0.755, h-index: 22)
Urologic Clinics of North America     Full-text available via subscription   (Followers: 1, SJR: 0.626, h-index: 57)
Urologic Oncology: Seminars and Original Investigations     Hybrid Journal   (Followers: 5)
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Vascular Pharmacology     Hybrid Journal   (Followers: 1, SJR: 0.923, h-index: 65)
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Video J. and Encyclopedia of GI Endoscopy     Open Access  
Virology     Hybrid Journal   (Followers: 11, SJR: 1.428, h-index: 126)
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Wave Motion     Hybrid Journal   (Followers: 2, SJR: 0.855, h-index: 34)
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Zoology     Hybrid Journal   (Followers: 6, SJR: 0.538, h-index: 28)

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Journal Cover Pharmacological Research
   Journal TOC RSS feeds Export to Zotero [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  [2563 journals]   [SJR: 1.248]   [H-I: 76]
  • Corrigendum to “Nucleoside monophosphorothioates as the new hydrogen
           sulfide precursors with unique properties” [Pharmacol. Res. 81
           (2014) 34–43]
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Jerzy Bełtowski , Andrzej Guranowski , Anna Jamroz-Wiśniewska , Agnieszka Korolczuk , Andrzej Wojtak



      PubDate: 2014-08-16T01:35:57Z
       
  • 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: 2014-08-16T01:35:57Z
       
  • 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: 2014-08-16T01:35:57Z
       
  • Editorial Board
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87




      PubDate: 2014-08-16T01:35:57Z
       
  • Role of statins in the treatment of multiple sclerosis
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Rosella Ciurleo , Placido Bramanti , Silvia Marino
      Statins as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely prescribed for hypercholesterolemia treatment. In the last years, statins have also been shown to exert immunomodulatory and anti-inflammatory effects which appear to be related to inhibition of isoprenylation of small GTP-binding proteins and, at least in part, independent of their cholesterol-lowering effects. These “pleiotropic” effects make statins an attractive treatment option for immune-mediated disorders such as multiple sclerosis. Studies in vitro and in experimental autoimmune encephalomyelitis animal model seem to support not only the efficacy of statins as immunomodulatory agents but also their potential neuroprotective properties, although the exact mechanism with which statins exert these effects has not yet been fully understood. The immunomodulatory, anti-inflammatory and neuroprotective properties of statins provided the incentive for several clinical trials in multiple sclerosis, in which they were tested not only as mono-therapy but also in combination with interferon-β. However, the attempt to translate the results of animal model studies in humans produced conflicting results. Further large, prospective, randomized, double-blind, placebo-controlled trials, designed to evaluate the long-term effects of statins alone or in add-on to other disease-modifying therapies, are needed to support their routine clinical use in multiple sclerosis.
      Graphical abstract image

      PubDate: 2014-08-16T01:35:57Z
       
  • The pharmacogenomics of statins
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Ingrid C. Gelissen , Andrew J. McLachlan
      The statin class of cholesterol-lowering drugs have been used for decades to successfully lower plasma cholesterol concentrations and cardiovascular risk. Adverse effects of statins are generally considered mild, but increase with age of patients and polypharmacy. One aspect of statin therapy that is still difficult for prescribers to predict is the individual's response to statin therapy. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect statin efficacy and safety. In this review, a number of candidates that affect statin pharmacokinetics and pharmacodynamics are discussed. Some of these candidates, in particular those involved in import and efflux of statins, have now been linked to increased risk of side effects. Furthermore, pharmacogenomic studies continue to reveal new players that are involved in the fine-tuning of the complex regulation of cholesterol homeostasis and response to statins.
      Graphical abstract image

      PubDate: 2014-08-16T01:35:57Z
       
  • Editorial Board
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88




      PubDate: 2014-08-16T01:35:57Z
       
  • 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: 2014-08-16T01:35:57Z
       
  • Statins: From cholesterol-lowering drugs to novel immunomodulators for the
           treatment of Th17-mediated autoimmune diseases
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Cristina Ulivieri , Cosima T. Baldari
      Statins, a class of drugs that act as inhibitors of cholesterol biosynthesis and protein isoprenylation, have been proposed as immunomodulatory agents due to their potent effects both on T lymphocytes and on antigen presenting cells. Unfortunately to date the benefits of statin therapy have not been unequivocally established due to contrasting results obtained in the setting of several autoimmune diseases. A major hurdle is our limited mechanistic understanding of the pleiotropic mechanisms underlying statin-mediated immunomodulation. Accumulating evidence has highlighted two CD4+ T cell subsets, the Th17 and Treg cells, as important disease-related targets of statins. Here we shall review recent findings on the activity of statins on Th17 and Treg differentiation and effector function. Statin-based therapies of multiple sclerosis, a Th17 cell-mediated autoimmune disease, and of Systemic Lupus Erithematosus, characterized by a Th17/Treg imbalance, will be also discussed, based on animal models and clinical trials.
      Graphical abstract image

      PubDate: 2014-08-16T01:35:57Z
       
  • Statins, bone metabolism and treatment of bone catabolic diseases
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Yijia Zhang , Aaron D. Bradley , Dong Wang , Richard A. Reinhardt
      The discovery that statins had bone anabolic properties initiated many investigations into their use for treatment of bone catabolic diseases, such as osteoporosis. This paper reviews the molecular basis of statin's role in bone metabolism, and animal and human studies on the impact of systemic statins on osteoporosis-induced bone fracture incidence and healing, and on bone density. Limitations of systemic statins are described along with alternative dosing strategies, including local applications and bone-targeting systemic preparations. The principal findings of this review are: (1) traditional oral dosing with statins results in minimal efficacy in the treatment of osteoporosis; (2) local applications of statins show promise in the treatment of accessible bony defects, such as periodontitis; and (3) systemically administered statins which can target bone or inflammation near bone may be the safest and most effective strategy in the treatment of osseous deficiencies.
      Graphical abstract image

      PubDate: 2014-08-16T01:35:57Z
       
  • Statins role in the prevention and treatment of sepsis
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Paul P. Dobesh , Keith M. Olsen
      Sepsis is a complex disease with typically poor outcomes. While the onset of sepsis is typically infectious, the detrimental consequences follow pathogen toxin release that produces activation of numerous cytokines and a pro-inflammatory response. These same cytokines also stimulate activation of coagulation and inhibit natural fibrinolysis. Despite decades of research targeted against these pathways the development of sepsis and mortality in patients with sepsis remains high. While statins were developed for reducing cholesterol in patients with atherosclerotic disease, we now know they have a number of other properties which may be helpful in the prevention and treatment of sepsis. Statins have demonstrated the ability to reduce a number of pro-inflammatory cytokines known to be detrimental in the development and progression of sepsis. Statins have also demonstrated the ability to limit the coagulation response and promote fibrinolysis in the setting of sepsis. Based on these encouraging pharmacologic properties of statins a number of trials have been conducted evaluating the impact of statins on the prevention and treatment of sepsis. Most of the trials to date have been retrospective cohort trials, with very few prospective randomized trials. While some trials fail to demonstrate a benefit of statins, most trials suggest a reduction in the development of sepsis and/or other important sepsis related outcomes. While the laboratory and early clinical experience with statins are encouraging, randomized controlled trials will be need to fully define the role of statins in the prevention and treatment of sepsis.
      Graphical abstract image

      PubDate: 2014-08-16T01:35:57Z
       
  • 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: Available online 4 August 2014
      Source:Pharmacological Research
      Author(s): Daisuke Shimizu , Yoichi Ishitsuka , Keishi Miyata , Yoshiro Tomishima , Yuki Kondo , Mitsuru Irikura , Takao Iwawaki , Yuichi Oike , Tetsumi Irie



      PubDate: 2014-08-08T00:57:05Z
       
  • The rise, fall, and resurgence of immunotherapy in type 1 diabetes
    • Abstract: Publication date: Available online 6 August 2014
      Source:Pharmacological Research
      Author(s): Moufida Ben Nasr , Francesca D’Addio , Vera Usuelli , Sara Tezza , Reza Abdi , Paolo Fiorina
      Despite considerable effort to halt or delay destruction of β-cells in autoimmune type 1 diabetes (T1D), success remains elusive. Over the last decade, we have seen a proliferation of knowledge on the pathogenesis of T1D that emerged from studies performed in non-obese diabetic (NOD) mice. However, while results of these preclinical studies appeared to hold great promise and boosted patients’ hopes, none of these approaches, once tested in clinical settings, induced remission of autoimmune diabetes in individuals with T1D. The primary obstacles to translation reside in the differences between the human and murine autoimmune responses and in the contribution of many environmental factors associated with the onset of disease. Moreover, inaccurate dosing as well as inappropriate timing and uncertain length of drug exposure have played a central role in the negative outcomes of such therapeutic interventions. In this review, we summarize the most important approaches tested thus far in T1D, beginning with the most successful preclinical studies in NOD mice and ending with the latest disappointing clinical trials in humans. Finally, we highlight recent stem cell-based trials, for which expectations in the scientific community and among individuals with T1D are high.
      Graphical abstract image

      PubDate: 2014-08-08T00:57:05Z
       
  • Pharmacological activation of AMPK ameliorates perivascular
           adipose/endothelial dysfunction in a manner interdependent on AMPK and
           SIRT1
    • Abstract: Publication date: Available online 7 August 2014
      Source:Pharmacological Research
      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: 2014-08-08T00:57:05Z
       
  • The flavonoid quercetin induces acute vasodilator effects in healthy
           volunteers: correlation with beta-glucuronidase activity
    • Abstract: Publication date: Available online 27 July 2014
      Source:Pharmacological Research
      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: 2014-07-31T00:32:51Z
       
  • Protection afforded by pre- or post-treatment with 4-phenylbutyrate
           against liver injury induced by acetaminophen overdose in mice
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Daisuke Shimizu , Yoichi Ishitsuka , Keishi Miyata , Yoshiro Tomishima , Yuki Kondo , Mitsuru Irikura , Takao Iwawaki , Yuichi Oike , Tetsumi Irie
      Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100–200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X-box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP-induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4-PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP-induced hepatotoxicity in mice. Although post-treatment with 4-PBA did not show any effects on hepatic Xbp1 mRNA splicing and JNK phosphorylation, it drastically attenuated the DNA fragmentation induced by APAP. The precise molecular mechanisms of the protection afforded by 4-PBA against APAP hepatotoxicity in mice are unclear, but they seem to involve inhibition of hepatocellular DNA fragmentation. We suggest that 4-PBA is a promising candidate as an antidote against APAP-induced liver injury.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • Statins upregulate cystathionine γ-lyase transcription and H2S
           generation via activating Akt signaling in macrophage
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Yuan Xu , Hua-Ping Du , Jiaojiao Li , Ran Xu , Ya-Li Wang , Shou-Jiang You , Huihui Liu , Fen Wang , Yong-Jun Cao , Chun-Feng Liu , Li-Fang Hu
      Hydrogen sulfide (H2S), the third gaseous transmitter, is implicated in various pathophysiologic processes. In the cardiovascular system, H2S exerts effects of cardioprotection, vascular tone regulation, and atherogenesis inhibition. Recent studies demonstrated that atorvastatin, the inhibitor of 3-hydroxyl-3-methyl coenzyme A reductase, affected H2S formation in kidney and other organs. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of three different statins (fluvastatin, atorvastatin and pravastatin) on H2S formation in raw264.7 macrophages. There was a remarkable rise in H2S level in fluvastatin- and atorvastatin-stimulated macrophages, while pravastatin failed to show any significant effect on it. Moreover, fluvastatin and atorvastatin enhanced the mRNA and protein expression of cystathionine γ-lyase (CSE) in dose- and time-dependent manners. Fluvastatin also markedly enhanced the CSE activity. However, fluvastatin did not alter the mRNA or protein expression of another H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase. Blockade of CSE with its inhibitor dl-propargylglycine (PAG) or siRNA markedly reduced the H2S level in fluvastatin-stimulated macrophages. In addition, fluvastatin elevated Akt phosphorylation, which occurred as early as 15min after treatment, peaked at 1h, and lasted at least 3h. Both PI3K inhibitor LY294002 (10μM) and Akt inhibitor perifosine (10μM) were able to reverse the increases of CSE mRNA and H2S production in fluvastatin-stimulated macrophages. Last, we showed that fluvastatin reduced the mRNA levels of pro-inflammatory molecules such as IL-1β and MCP-1 in LPS-treated macrophages, which were completely reversed by CSE inhibitor PAG. Taken together, the findings demonstrate that statins may up-regulate CSE expression/activity and subsequently elevate H2S generation by activating Akt signaling pathway and also imply that CSE–H2S pathway plays a critical role in the anti-inflammation elicited by statins.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • Statins in neurological disorders: An overview and update
    • Abstract: Publication date: Available online 19 June 2014
      Source:Pharmacological Research
      Author(s): Anna Maria Malfitano , Giuseppe Marasco , Maria Chiara Proto , Chiara Laezza , Patrizia Gazzerro , Maurizio Bifulco
      Statins have, at present, the potential to provide a new therapeutic target for various neurological diseases. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggest that statins have additional properties such as endothelial protection via action on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These properties might have potential therapeutic implication not only in stroke but also in neurological disorders such as Alzheimer disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In addition to their potent anti-atherosclerotic and cardio-protective effects, compelling clinical and preclinical studies delineate the neuro-protective efficacy of statins in all these neurological disorders. It is apparent from these studies that most patients with central nervous system disorders probably benefit to some extent from lipid-lowering therapy. But data are not univocal, and we must also consider the adverse effects due to the administration of lipid-lowering therapy. Thus, in these scenarios the effectiveness of statins in treating stroke, Alzheimer's disease, Parkinson disease, multiple sclerosis, and primary brain tumors have to be conclusively proven in vivo and/or in adequate clinical trials.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • Novel prospects of statins as therapeutic agents in cancer
    • Abstract: Publication date: Available online 5 July 2014
      Source:Pharmacological Research
      Author(s): Simona Pisanti , Paola Picardi , Elena Ciaglia , Alba D’Alessandro , Maurizio Bifulco
      Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Editorial Board
    • Abstract: Publication date: July 2014
      Source:Pharmacological Research, Volume 85




      PubDate: 2014-07-27T00:24:02Z
       
  • Statins in chronic kidney disease and kidney transplantation
    • Abstract: Publication date: Available online 1 July 2014
      Source:Pharmacological Research
      Author(s): Theodoros I. Kassimatis , David J.A. Goldsmith
      HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins’ beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent “pleiotropic” properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins’ CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Novel immunological strategies for islet transplantation
    • Abstract: Publication date: Available online 8 July 2014
      Source:Pharmacological Research
      Author(s): Sara Tezza , Moufida Ben Nasr , Andrea Vergani , Alessandro Valderrama Vasquez , Anna Maestroni , Reza Abdi , Antonio Secchi , Paolo Fiorina
      Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Statin: New life for an old drug
    • Abstract: Publication date: Available online 14 July 2014
      Source:Pharmacological Research
      Author(s): Maurizio Bifulco , Akira Endo



      PubDate: 2014-07-27T00:24:02Z
       
  • Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal
           death through oxidative stress
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Elsa Gouix , Alain Buisson , André Nieoullon , Lydia Kerkerian-Le Goff , Joseph S. Tauskela , Nicolas Blondeau , Laurence Had-Aissouni
      Understanding the role of astrocytes in stroke is assuming increasing prominence, not only as an important component on its own within the neurovascular unit, but also because astrocytes can influence neuronal outcome. Ischemia may induce astrogliosis and other phenotypic changes, but these remain poorly understood, in part due to limitations in reproducing these changes in vitro. Dibutyryl cyclic AMP-differentiated cultured astrocytes are more representative of the in vivo astroglial cell phenotype, and were much more susceptible than undifferentiated astrocytes to an ischemic-like stress, oxygen-glucose deprivation (OGD). OGD altered the expression/distribution and activity of glial glutamate transporters, impaired cellular glutamate uptake and decreased intracellular levels of glutathione preferentially in differentiated astrocytes. Resistance to OGD was conferred by inhibiting caspase-3 with DEVD-CHO and oxidative stress by the antioxidant N-acetylcysteine (NAC). The resistance of undifferentiated astrocytes to OGD may result from a transient but selective morphological transformation into Alzheimer type II astrocytes, an intermediary stage prior to transforming into reactive astrocytes. Co-culture of neurons with OGD-exposed astrocytes resulted in neurotoxicity, but at surprisingly lower levels with dying differentiated astrocytes. The antioxidant NAC or the 5-LOX inhibitor AA861 added upon co-culture delayed (day 1) but did not prevent neurotoxicity (day 3). Astrocytes undergoing apoptosis as a result of ischemia may represent a transient neuroprotective mechanism via ischemia-induced release of glutathione, but oxidative stress was responsible for neuronal demise when ischemia compromised astrocyte supportive functions.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Editorial Board
    • Abstract: Publication date: August 2014
      Source:Pharmacological Research, Volume 86




      PubDate: 2014-07-27T00:24:02Z
       
  • 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: Available online 22 July 2014
      Source:Pharmacological Research
      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: 2014-07-27T00:24:02Z
       
  • Mechanisms underlying increased serotonin-induced contraction in carotid
           arteries from chronic type 2 diabetic Goto-Kakizaki rats
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Takayuki Matsumoto , Shun Watanabe , Kumiko Taguchi , Tsuneo Kobayashi
      Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the cardiovascular system; however, the relationship between 5-HT-induced vasocontraction and the arterial 5-HT system including metabolism and signal transduction, in the presence of chronic type 2 diabetes (T2D) remains unclear. Therefore, we investigated 5-HT-induced contraction and associated mechanisms in carotid arteries from chronic T2D Goto-Kakizaki (GK) rats. Contractions in response to 5-HT were examined in carotid arteries from GK rats (42–46 weeks old). To investigate the response mechanisms of arterial smooth muscle, we constructed concentration–response curves for TCB2 (5-HT2A-receptor agonist), BW723C86 (5-HT2B-receptor agonist), and 5-HT in the presence of various inhibitors using endothelium-denuded preparations. Carotid arterial expressions of monoamine oxidase-A (MAO-A), serotonin transporter (SERT), and 5-HT2A were detected by immunoblotting. 5-HT-induced contraction was increased in carotid arteries from GK compared to control Wistar rats in both endothelium-intact and -denuded preparations. In denuded preparations, we found that: (1) TCB2-induced contraction was increased in GK rat arteries (vs. Wistar); (2) MAO-A inhibitor did not affect 5-HT-induced contraction, whereas SERT inhibitor augmented such contractions in both groups; and (3) differences in 5-HT-induced contractions were abolished by p38 MAPK, PI3K, and Rho kinase inhibitors. Carotid arterial expressions of MAO-A, SERT, and 5-HT2A remained unchanged in the groups. The results suggest that 5-HT-induced contraction is augmented in T2D GK rat carotid arteries. This augmentation is due to smooth muscle activation partly mediated by p38 MAPK, PI3K, and Rho kinases, and may also be partly due to arterial SERT activity.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Functional and biochemical interaction between PPARα receptors and
           TRPV1 channels: Potential role in PPARα agonists-mediated analgesia
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Paolo Ambrosino , Maria Virginia Soldovieri , Michela De Maria , Claudio Russo , Maurizio Taglialatela
      Transient receptor potential vanilloid type-1 (TRPV1) channels expressed in primary afferent neurons play a critical role in nociception triggered by endogenous and exogenous compounds. In the present study, the functional and biochemical interaction between TRPV1 channels and type-α peroxisome proliferator-activated receptors (PPARα) has been investigated. In TRPV1-expressing CHO cells, patch-clamp studies revealed that acute application of the PPARα agonists clofibrate (CLO; 0.1–100μM), WY14643 (1–300μM), or GW7647 (0.1–100nM) activated TRPV1 currents in a concentration-dependent manner, with EC50s of 5.3±0.8μM, 13.0±1.2μM, and 12.7±0.3nM, respectively. The role of PPARα in these pharmacological responses was confirmed by the ability of the PPARα antagonist GW6471 (10μM) to block CLO-, WY14643- and GW7647-induced TRPV1 activation, and by the observation that modulation of PPARα levels via siRNA-mediated suppression or PPARα over-expression affected TRPV1 channel activation by PPARα agonists accordingly. In cells cotransfected with PPARα and TRPV1, PPARα receptors were detected in TRPV1-immunoprecipitated fractions. When compared to capsaicin (CAP), TRPV1 currents activated by PPARα agonists showed a higher degree of acute desensitization and tachyphylaxis; moreover, GW7647, when pre-incubated at a concentration (1nM) unable to activate TRPV1 currents per se, desensitized CAP-induced TRPV1 currents. Finally, a sub-effective concentration of each PPARα agonist inhibited TRPV1-dependent bradykinin-induced [Ca2+] i transients in sensory neurons. Collectively, these results provide evidence for a PPARα-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARα agonists in vivo.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor
           cells via NRF2-dependent mechanism
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Laura Gambari , Gina Lisignoli , Luca Cattini , Cristina Manferdini , Andrea Facchini , Francesco Grassi
      Hydrogen sulfide (H2S), which recently emerged as a potent regulator of tissues and organs, is broadly produced in mammalian cells but whether it can regulate bone cell function is still elusive. The main objective of this study was to establish the role of H2S in the regulation of human osteoclast differentiation and function. Sodium hydrosulfide (NaHS), a common H2S-donor, was administered in vitro to CD11b+ human monocytes, the pool of circulating osteoclasts precursors which are critically involved in osteoclast development and function in bone. NaHS dose-dependently decreased human osteoclast differentiation at concentrations which did not induce toxicity. The inhibition of human osteoclast differentiation was associated with a down-regulation in RANKL-dependent intracellular ROS levels in human pre-osteoclasts cells. Furthermore, NaHS up-regulated NRF2 protein expression, its nuclear translocation, and the transcription of the two key downstream antioxidant genes Peroxiredoxin-1 and NAD(P)H dehydrogenase quinone 1, suggesting that NRF2 activation may inhibit human osteoclast differentiation by activating a sustained antioxidant response in osteoclast progenitors; furthermore, NRF2 activators Sulforaphane and Tert-butylhydroquinone inhibited in vitro human osteoclast differentiation. Moreover, silencing NRF2 in human pre-osteoclasts totally abolished NaHS-mediated inhibition of osteoclastogenesis, suggesting that NRF2 is essential to the inhibitory function of NaHS in osteoclast development. Finally, we found that NaHS also downregulated the RANKL/OPG mRNA ratio in human mesenchymal stem cells, the key osteoclast-supporting cells. Our results suggest that NaHS shows a potential therapeutical role in erosive diseases of bone by regulating both direct and indirect mechanisms controlling the differentiation of circulating osteoclasts precursors.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Sodium-phosphate cotransporter mediates reabsorption of lithium in rat
           kidney
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Yuichi Uwai , Ryosuke Arima , Chihiro Takatsu , Ryo Furuta , Tatsuya Kawasaki , Tomohiro Nabekura
      Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats. Their intravenous administration stimulated urinary excretion of phosphate or glucose. After the intravenous injection of lithium chloride as a bolus, plasma concentration of lithium decreased time-dependently. The renal clearance of lithium was calculated to be 0.740ml/min/kg in control rats, and this was 26.7% of creatinine clearance. Foscarnet and PTH significantly increased the renal clearance of lithium and its ratio to creatinine clearance, suggesting that they prevented the reabsorption of lithium. No effect of phlorizin on the renal handling of lithium was recognized. In control rats, the renal clearance of lithium showed a strong correlation with the renal excretion rate of phosphate, compared with creatinine clearance. These findings suggest that sodium-phosphate cotransporter reabsorbs lithium in the rat kidney. Furthermore, its contribution was estimated to be more than 65.9% in the lithium reabsorption. And, this study raised the possibility that therapeutic outcome of lithium is related with the functional expression of sodium-phosphate cotransporter in the kidney.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Structural determinants of peripheral O-arylcarbamate FAAH inhibitors
           render them dual substrates for Abcb1 and Abcg2 and restrict their access
           to the brain
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Guillermo Moreno-Sanz , Borja Barrera , Andrea Armirotti , Sine M. Bertozzi , Rita Scarpelli , Tiziano Bandiera , Julio G. Prieto , Andrea Duranti , Giorgio Tarzia , Gracia Merino , Daniele Piomelli
      The blood–brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family – breast cancer resistance protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) – play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3′-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested – even those able to enter the CNS in vivo – were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Critical role of large-conductance calcium- and voltage-activated
           potassium channels in leptin-induced neuroprotection of
           N-methyl-d-aspartate-exposed cortical neurons
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Maria Mancini , Maria Virginia Soldovieri , Guido Gessner , Bianka Wissuwa , Vincenzo Barrese , Francesca Boscia , Agnese Secondo , Francesco Miceli , Cristina Franco , Paolo Ambrosino , Lorella Maria Teresa Canzoniero , Michael Bauer , Toshinori Hoshi , Stefan H. Heinemann , Maurizio Taglialatela
      In the present study, the neuroprotective effects of the adipokine leptin, and the molecular mechanism involved, have been studied in rat and mice cortical neurons exposed to N-methyl-d-aspartate (NMDA) in vitro. In rat cortical neurons, leptin elicited neuroprotective effects against NMDA-induced cell death, which were concentration-dependent (10–100ng/ml) and largest when the adipokine was preincubated for 2h before the neurotoxic stimulus. In both rat and mouse cortical neurons, leptin-induced neuroprotection was fully antagonized by paxilline (Pax, 0.01–1μM) and iberiotoxin (Ibtx, 1–100nM), with EC50s of 38±10nM and 5±2nM for Pax and Ibtx, respectively, close to those reported for Pax- and Ibtx-induced Ca2+- and voltage-activated K+ channels (Slo1 BK channels) blockade; the BK channel opener NS1619 (1–30μM) induced a concentration-dependent protection against NMDA-induced excitotoxicity. Moreover, cortical neurons from mice lacking one or both alleles coding for Slo1 BK channel pore-forming subunits were insensitive to leptin-induced neuroprotection. Finally, leptin exposure dose-dependently (10–100ng/ml) increased intracellular Ca2+ levels in rat cortical neurons. In conclusion, our results suggest that Slo1 BK channel activation following increases in intracellular Ca2+ levels is a critical step for leptin-induced neuroprotection in NMDA-exposed cortical neurons in vitro, thus highlighting leptin-based intervention via BK channel activation as a potential strategy to counteract neurodegenerative diseases.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and
           the decrease in aquaporins in the colon
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Hiroyasu Sakai , Atsunobu Sagara , Kenjiro Matsumoto , Ara Jo , Akiko Hirosaki , Kazuhide Takase , Ryoto Sugiyama , Ken Sato , Daigo Ikegami , Syunji Horie , Motohiro Matoba , Minoru Narita
      Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Genders and the concurrent use of cocaine and alcohol: Pharmacological
           aspects
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Manuela Graziani , Paolo Nencini , Robert Nisticò
      Aims Gender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. Methods The MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. Results Besides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. Conclusions The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.
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      PubDate: 2014-07-27T00:24:02Z
       
  • ErbB/HER protein-tyrosine kinases: Structures and small molecule
           inhibitors
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Robert Roskoski Jr.
      The epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). These receptors consist of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. The ErbB proteins function as homo and heterodimers. Growth factor binding to EGFR induces a large conformational change in the extracellular domain. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric dimer. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas. Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer and lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Moreover, monoclonal antibodies that target the extracellular domain of ErbB2 are used for the treatment of ErbB2-positive breast cancer and monoclonal antibodies that target ErbB1 and are used for the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them, and a current goal of research is to develop drugs that are effective against drug-resistant tumors.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Roles of fatty acid ethanolamides (FAE) in traumatic and ischemic brain
           injury
    • Abstract: Publication date: Available online 26 May 2014
      Source:Pharmacological Research
      Author(s): Emanuela Esposito , Marika Cordaro , Salvatore Cuzzocrea
      Ethanolamides of long-chain fatty acids are a class of endogenous lipid mediators generally referred to as N-acylethanolamines (NAEs). NAEs include anti-inflammatory and analgesic palmitoylethanolamide, anorexic oleoylethanolamide, stearoylethanolamide, and the endocannabinoid anandamide. Traumatic brain injury (TBI), associated with a high morbidity and mortality and no specific therapeutic treatment, has become a pressing public health and medical problem. TBI is a complex process evoking systemic immune responses as well as direct local responses in the brain tissues. The direct (primary) damage disrupts the blood–brain barrier (BBB), injures the neurons and initiates a cascade of inflammatory reactions including chemokine production and activation of resident immune cells. The effect of TBI is not restricted to the brain; it can cause multi-organ damage and evoke systemic immune response with cytokine and chemokine production. This facilitates the recruitment of immune cells to the site of injury and progression of the inflammatory reaction. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Moreover, TBI leads to increased catabolism of phospholipids, resulting in a series of phospholipid breakdown products, some of which have potent biological activity. Ischemia-reperfusion (I/R) injury resulting from stroke leads to metabolic distress, oxidative stress and neuroinflammation, making it likely that multiple therapeutic intervention strategies may be needed for successful treatment. Current therapeutic strategies for stroke need complimentary neuroprotective treatments to provide a better outcome. Prior studies on NAEs have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of neurodegenerative and acute cerebrovascular disorders. The present review will summarize our knowledge of the biological role of these lipid signaling molecules in brain and highlights their therapeutic effect from multipotential actions on neuronal cell death and neuroinflammatory pathways.
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      PubDate: 2014-06-02T15:13:57Z
       
  • Urinary metabolomic fingerprinting after consumption of a probiotic strain
           in women with mastitis
    • Abstract: Publication date: Available online 29 May 2014
      Source:Pharmacological Research
      Author(s): Rosa Vázquez-Fresno , Rafael Llorach , Jelena Marinic , Sara Tulipani , Mar Garcia-Aloy , Irene Espinosa-Martos , Esther Jiménez , Juan Miguel Rodríguez , Cristina Andrés-Lacueva
      Infectious mastitis is a common condition among lactating women, with staphylococci and streptococci being the main aetiological agents. In this context, some lactobacilli strains isolated from breast milk appear to be particularly effective for treating mastitis and, therefore, constitute an attractive alternative to antibiotherapy. A 1H NMR-based metabolomic approach was applied to detect metabolomic differences after consuming a probiotic strain (Lactobacillus salivarius PS2) in women with mastitis. Before 24h urine of women with lactational mastitis was collected at baseline and after 21 days of probiotic (PB) administration. Multivariate (OSC-PLS-DA and hierarchical clustering) analysis showed metabolome differences after PB treatment. The discriminant metabolites detected at baseline of the intervention were lactose, and ibuprofen and acetaminophen (two pharmacological drugs commonly used for mastitis pain), while, after PB intake, creatine and the gut microbial co-metabolites hippurate and TMAO were detected. In addition, a voluntary desertion of the pharmacological drugs ibuprofen and acetaminophen was observed after probiotic administration. The application of NMR-based metabolomics enabled the identification of the overall effects of probiotic consumption among women suffering from mastitis and highlighted the potential of this approach in evaluating the outcomes of probiotics consumption. To our knowledge; this is the first time that this approach has been applied in women with mastitis during lactation.
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      PubDate: 2014-06-02T15:13:57Z
       
  • In vivo sex differences in leukotriene biosynthesis in zymosan-induced
           peritonitis
    • Abstract: Publication date: Available online 1 June 2014
      Source:Pharmacological Research
      Author(s): Antonietta Rossi , Carlo Pergola , Simona Pace , Olof Rådmark , Oliver Werz , Lidia Sautebin
      Leukotrienes (LTs) are 5-lipoxygenase (5-LO) metabolites which are implicated in sex-dependent inflammatory diseases (asthma, autoimmune diseases, etc). We have recently reported sex differences in LT biosynthesis in in vitro models such as human whole blood, neutrophils and monocytes, due to down-regulation of 5-LO product formation by androgens. Here we present evidences for sex differences in LT synthesis and related inflammatory reactions in an in vivo model of inflammation (mouse zymosan-induced peritonitis). On the cellular level, differential 5-LO subcellular compartmentalization in peritoneal macrophages (PM) from male and female mice might be the basis for these differences. Sex differences in vascular permeability and neutrophil recruitment (cell number and myeloperoxidase activity) into peritoneal cavity were evident upon intraperitoneal zymosan injection, with more prominent responses in female mice. This was accompanied by higher levels of LTC4 and LTB4 in peritoneal exudates of female compared to male mice. Interestingly, LT peritoneal levels in orchidectomized mice were higher than in sham male mice. In accordance with the in vivo results, LT formation in stimulated PM from female mice was higher than in male PM, accompanied by alterations in 5-LO subcellular localization. The increased formation of LTC4 in incubations of PM from orchidectomized mice confirms a role of sex hormones. In conclusion, sex differences observed in LT biosynthesis during peritonitis in vivo may be related, at least in part, to a variant 5-LO localization in PM from male and female mice.
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      PubDate: 2014-06-02T15:13:57Z
       
  • The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the
           behavioral despair induced by stress in rats and modulates the HPA-axis
    • Abstract: Publication date: Available online 23 May 2014
      Source:Pharmacological Research
      Author(s): Andrea Navarria , Alessandra Tamburella , Fabio A. Iannotti , Vincenzo Micale , Giovanni Camillieri , Lucia Gozzo , Roberta Verde , Roberta Imperatore , Gian Marco Leggio , Filippo Drago , Vincenzo Di Marzo
      In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal, stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rats behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.
      Graphical abstract image

      PubDate: 2014-05-26T11:15:42Z
       
  • Classical and pleiotropic actions of dipyridamole: Not enough light to
           illuminate the dark tunnel'
    • Abstract: Publication date: Available online 24 May 2014
      Source:Pharmacological Research
      Author(s): Pitchai Balakumar , Nyo Ying Hui , Raja Renushia , Devarajan Raaginey , Oh Ann Nah , Rajavel Varatharajan , Sokkalingam A. Dhanaraj
      Dipyridamole is a platelet inhibitor indicated for the secondary prevention of transient ischemic attack. It inhibits the enzyme phosphodiesterase, elevates cAMP and cGMP levels and prevents platelet aggregation. Dipyridamole inhibits the cellular uptake of adenosine into red blood cells, platelets and endothelial cells that results in increased extracellular availability of adenosine, leading to modulation of cardiovascular function. The antiplatelet action of dipyridamole might offer therapeutic benefits in secondary stroke prevention in combination with aspirin. Inflammation and oxidative stress play an important role in atherosclerosis and thrombosis development, leading to stroke progression. Studies demonstrated anti-inflammatory, anti-oxidant and anti-proliferative actions of dipyridamole. These pleiotropic potentials of dipyridamole might contribute to improved therapeutic outcomes when used with aspirin in preventing secondary stroke. Dipyridamole was documented as a coronary vasodilator 5 decades ago. The therapeutic failure of dipyridamole as a coronary vasodilator is linked with induction of ‘coronary Steal’ phenomenon in which by dilating resistance vessels in non-ischemic zone, dipyridamole diverts the already reduced blood flow away from the area of ischemic myocardium. Dipyridamole at high-dose could cause a marked ‘coronary steal’ effect. Dipyridamole, however, at low-dose could have a minimal hemodynamic effect. Low-dose dipyridamole treatment has a therapeutic potential in partially preventing diabetes mellitus-induced experimental vascular endothelial and renal abnormalities by enhancing endothelial nitric oxide signals and inducing renovascular reduction of oxidative stress. In spite of plenteous research on dipyridamole's use in clinics, its precise clinical application is still obscure. This review sheds lights on pleiotropic pharmacological actions and therapeutic potentials of dipyridamole
      Graphical abstract image

      PubDate: 2014-05-26T11:15:42Z
       
  • TGF-β signaling pathway as a pharmacological target in liver diseases
    • Abstract: Publication date: Available online 17 May 2014
      Source:Pharmacological Research
      Author(s): Sen Zhang , Wu-Yi Sun , Jing-Jing Wu , Wei Wei
      Transforming growth factor β (TGF-β) belongs to a class of pleiotropic cytokines that are involved in the processes of embryonic development, wound healing, cell proliferation, and differentiation. Moreover, TGF-β is also regarded as a central regulator in the pathogenesis and development of various liver diseases because it contributes to almost all of the stages of disease progression. A range of liver cells are considered to secrete TGF-β ligands and express related receptors and, consequently, play a crucial role in the progression of liver disease via different signal pathways. In this manuscript, we review the role of the TGF-β signaling pathway in liver disease and the potential of targeting the TGF-β signaling in the pharmacological treatment of liver diseases.
      Graphical abstract image

      PubDate: 2014-05-21T06:35:21Z
       
  • Palmitoylethanolamide in CNS health and disease
    • Abstract: Publication date: Available online 17 May 2014
      Source:Pharmacological Research
      Author(s): Giuseppina Mattace Raso , Roberto Russo , Antonio Calignano , Rosaria Meli
      The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca+2-activated intermediate- and/or big-conductance K+ channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl− currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases.
      Graphical abstract image

      PubDate: 2014-05-21T06:35:21Z
       
  • Reply to Letter to Editor: Kriek R. Marketing messages in pharmacological
           papers and scientific chapters: The case of palmitoylethanolamide and its
           formulations. Pharmacol Res (2014),
           http://dx.doi.org/10.1016/j.phrs.2014.04.007
    • Abstract: Publication date: Available online 20 May 2014
      Source:Pharmacological Research
      Author(s): Salvatore Cuzzocrea



      PubDate: 2014-05-21T06:35:21Z
       
  • Statins and skeletal muscles toxicity: from clinical trials to everyday
           practice
    • Abstract: Publication date: Available online 13 May 2014
      Source:Pharmacological Research
      Author(s): Giuseppe Danilo Norata , Gianpaolo Tibolla , Alberico Luigi Catapano
      The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the results of observational studies and clinical trials provide compelling evidence that skeletal muscle toxicity is a frequent, dose-dependent, adverse event associated with all statins. It has been suggested that reduced availability of metabolites produced by the mevalonate pathway rather than intracellular cholesterol lowering per se might be the primary trigger of toxicity, however other alternative explanations have gained credibility in recent years. Aim of this review is: i) to describe the molecular mechanisms associated to statin induced myopathy including defects in isoprenoids synthesis followed by altered prenylation of small GTPase, such as Ras and Rab proteins; ii) to present the emerging aspects on pharmacogenetics, including CYP3A4, OATP1B1 and glycine amidinotransferase (GATM) polymorphisms impacting either statin bioavailability or creatine synthesis; iii) to summarize the available epidemiological evidences; and iii) to discuss the concepts that would be of interest to the clinicians for the daily management of patients with statin induced myopathy. The interplay between drug-environment and drug-drug interaction in the context of different genetic settings contribute to statins and skeletal muscles toxicity. Until specific assays/algorithms able to combine genetic scores with drug-drug-environment interaction to identify patients at risk of myopathies will become available, clinicians should continue to monitor carefully patients on polytherapy which include statins and be ready to reconsider dose, statin or switching to alternative treatments. The beneficial effects of adding agents to provide the muscle with the metabolites, such as CoQ10, affected by statin treatment will also be addressed.
      Graphical abstract image

      PubDate: 2014-05-16T03:59:20Z
       
  • Inhibition of vascular calcification by block of intermediate conductance
           calcium-activated potassium channels with TRAM-34
    • Abstract: Publication date: Available online 6 May 2014
      Source:Pharmacological Research
      Author(s): Christian Freise , Uwe Querfeld
      Vascular calcifications are a hallmark of advanced cardiovascular disease in patients with chronic kidney disease. A key event is the transition of contractile vascular smooth muscle cells (VSMC) into an osteoblast-like phenotype, promoting a coordinated process of vascular remodelling resembling bone mineralization. Intermediate-conductance calcium-activated potassium channels (KCa3.1) are expressed in various tissues including VSMC. Aiming for novel therapeutic targets in vascular calcification, we here studied effects of KCa3.1-inhibition on VSMC calcification by the specific KCa3.1 inhibitor TRAM-34. Calcification in the murine VSMC cell line MOVAS-1 and primary rat VSMC was induced by calcification medium (CM) containing elevated levels of PO4 3− and Ca2+. Cell signalling, calcification markers, and release of nitric oxide and alkaline phosphatase were assesed by luciferase reporter plasmids, RT-PCR and specific enzymatic assays, respectively. KCa3.1 gene silencing was achieved by siRNA experiments. TRAM-34 at 10 nmol/l, decreased CM-induced calcification and induced NO release of VSMC accompanied by decreased TGF-β signalling. The CM-induced mRNA expressions of osterix, osteocalcin, matrix-metalloproteinases (MMP)-2/-9 were reduced by TRAM-34 while osteopontin expression was increased. Further, TRAM-34 attenuated the CM- and TNF-α-induced activation of NF-κB and reduced the release of MMP-2/-9 by VSMC. Finally, TRAM-34 abrogated CM-induced apoptosis and KCa3.1 gene silencing protected VSMC from CM-induced onset of calcification. In summary, TRAM-34 interferes with calcification relevant signalling of NF-κB and TGF-β thereby blocking the phenotypic transition/calcification of VSMC. We conclude that the results provide a rationale for further studies regarding a possible therapeutic role of KCa3.1 inhibition by TRAM-34 or other inhibitors in vascular calcification.
      Graphical abstract image

      PubDate: 2014-05-11T03:15:37Z
       
  • nAdvances in the discovery of N-acylethanolamine acid amidase inhibitors
    • Abstract: Publication date: Available online 4 May 2014
      Source:Pharmacological Research
      Author(s): Tiziano Bandiera , Stefano Ponzano , Daniele Piomelli
      N-acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator-activated receptor-α. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors.
      Graphical abstract image

      PubDate: 2014-05-06T06:17:46Z
       
  • Marketing messages in pharmacological papers and scientific chapters: the
           case of palmitoylethanolamide and its formulations.
    • Abstract: Publication date: Available online 24 April 2014
      Source:Pharmacological Research
      Author(s): R. Kriek



      PubDate: 2014-04-25T10:33:32Z
       
  • New players in the fatty acyl ethanolamide metabolism
    • Abstract: Publication date: Available online 18 April 2014
      Source:Pharmacological Research
      Author(s): Iffat Ara Sonia Rahman , Kazuhito Tsuboi , Toru Uyama , Natsuo Ueda
      Fatty acyl ethanolamides represent a class of endogenous bioactive lipid molecules and are generally referred to as N-acylethanolamines (NAEs). NAEs include palmitoylethanolamide (anti-inflammatory and analgesic substance), oleoylethanolamide (anorexic substance), and anandamide (endocannabinoid). The endogenous levels of NAEs are mainly regulated by enzymes responsible for their biosynthesis and degradation. In mammalian tissues, the major biosynthetic pathway starts from glycerophospholipids and is composed of two enzyme reactions. The first step is N-acylation of ethanolamine phospholipids catalyzed by Ca2+-dependent N-acyltransferase and the second step is the release of NAEs from N-acylated ethanolamine phospholipids by N-acylphosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D (NAPE-PLD). As for the degradation of NAEs, fatty acid amide hydrolase plays the central role. However, recent studies strongly suggest the involvement of other enzymes in the NAE metabolism. These enzymes include members of the HRAS-like suppressor family (also called phospholipase A/acyltransferase family), which were originally discovered as tumor suppressors but can function as Ca2+-independent NAPE-forming N-acyltransferases; multiple enzymes involved in the NAPE-PLD-independent multi-step pathways to generate NAE from NAPE, which came to light by the analysis of NAPE-PLD-deficient mice; and a lysosomal NAE-hydrolyzing acid amidase as a second NAE hydrolase. These newly recognized enzymes may become the targets for the development of new therapeutic drugs. Here, we focus on recent enzymological findings in this area.
      Graphical abstract image

      PubDate: 2014-04-20T12:05:36Z
       
  • Targeting the interaction between fatty acid ethanolamides and nicotinic
           receptors: therapeutic perspectives
    • Abstract: Publication date: Available online 1 April 2014
      Source:Pharmacological Research
      Author(s): Miriam Melis , Marco Pistis
      Nicotine is one of the drugs of abuse that frequently causes addiction and relapse during abstinence. Nicotine's strong addicting properties reside in its ability to enhance dopamine transmission, and to induce specific changes in synaptic plasticity. Currently, approved therapies for smoking cessation increase the chances of remaining abstinent, but lack high levels of efficacy and are associated with significant adverse side effects. As a result, there is an urgent need for more effective antismoking medications. Studies have revealed that drugs targeting the peroxisome proliferator-activated-receptor-α (PPARα) show promise for the treatment of nicotine addiction. These drugs include synthetic PPARα ligands, such as the clinically available hypolipidemic fibrates, and drugs that increase levels of endogenous endocannabinoid-like fatty acid ethanolamides (FAEs) that act as PPARα agonists.In this review, we will discuss the specific interaction between PPARα and nicotine, and the molecular mechanisms whereby these intracellular receptors regulate nicotinic acetylcholine receptor functions in neurons. Modulation of neurophysiological, neurochemical and behavioral effects of nicotine by PPARα will be also reviewed. Indeed, a picture is emerging where FAEs are endogenous regulators of acetylcholine transmission. Notably, the implications of this specific cross talk extend beyond nicotine addiction, and might bear relevance for psychiatric disorders and epilepsy.
      Graphical abstract image

      PubDate: 2014-04-06T01:32:49Z
       
  • Role of anorectic N-acylethanolamines in intestinal physiology and satiety
           control with respect to dietary fat
    • Abstract: Publication date: Available online 28 March 2014
      Source:Pharmacological Research
      Author(s): Harald S. Hansen
      Anandamide is a well-known agonist for the cannabinoid receptors. Along with endogenous anandamide other non-endocannabinoid N-acylethanolamines are also formed, apparently in higher amounts. These include mainly oleoylethanolamide (OEA), palmitoyelethanolamide (PEA) and linoleoylethanolamide (LEA), and they have biological activity by themselves being anorectic and anti-inflammatory. It appears that the major effect of dietary fat on the level of these molecules is in the gastrointestinal system, where OEA, PEA and LEA in the enterocytes may function as homeostatic signals, which are decreased by prolonged consumption of a high-fat diet. These lipid amides appear to mediate their signaling activity via activation of PPARα in the enterocyte followed by activation of afferent vagal fibers leading to the brain. Through this mechanism OEA, PEA and LEA may both reduce the consumption of a meal as well as increase the reward value of the food. Thus, they may function as homeostatic intestinal signals involving hedonic aspects that contribute to the regulation of the amounts of dietary fat to be ingested.


      PubDate: 2014-03-31T19:55:34Z
       
 
 
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