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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)
Tribology Series     Full-text available via subscription   (Followers: 2)
Tsinghua Science & Technology     Full-text available via subscription   (SJR: 0.173, h-index: 16)
Tuberculosis     Hybrid Journal   (Followers: 2, 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)
Ultrasound Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.162, h-index: 5)
Ultrasound in Medicine & Biology     Full-text available via subscription   (Followers: 6, SJR: 0.864, h-index: 85)
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)
Urological Science     Full-text available via subscription   (Followers: 1, SJR: 0.109, h-index: 1)
Urology     Hybrid Journal   (Followers: 125, SJR: 1.036, h-index: 129)
Urology Case Reports     Open Access  
Utilities Policy     Hybrid Journal   (Followers: 1, SJR: 0.719, h-index: 22)
Vaccine     Hybrid Journal   (Followers: 9, SJR: 1.36, h-index: 117)
Vacunas     Full-text available via subscription   (SJR: 0.135, h-index: 5)
Vacuum     Hybrid Journal   (Followers: 3, SJR: 0.495, h-index: 49)
Value in Health     Hybrid Journal   (Followers: 13)
Vascular Pharmacology     Hybrid Journal   (Followers: 2, SJR: 0.923, h-index: 65)
Veterinary Clinics of North America: Equine Practice     Full-text available via subscription   (Followers: 8)
Veterinary Clinics of North America: Exotic Animal Practice     Full-text available via subscription   (Followers: 7, SJR: 0.226, h-index: 18)
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Veterinary Immunology and Immunopathology     Hybrid Journal   (Followers: 9, SJR: 0.713, h-index: 61)
Veterinary Microbiology     Hybrid Journal   (Followers: 8, SJR: 1.221, h-index: 75)
Veterinary Parasitology     Hybrid Journal   (Followers: 9, SJR: 0.996, h-index: 74)
Vibrational Spectroscopy     Hybrid Journal   (Followers: 8, SJR: 0.492, h-index: 42)
Video J. and Encyclopedia of GI Endoscopy     Open Access  
Virology     Hybrid Journal   (Followers: 11, SJR: 1.428, h-index: 126)
Virus Research     Hybrid Journal   (Followers: 2, SJR: 0.999, h-index: 72)
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Vitamins & Hormones     Full-text available via subscription   (SJR: 0.957, h-index: 47)
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Water Research     Hybrid Journal   (Followers: 32, SJR: 2.552, h-index: 155)
Water Resources and Economics     Hybrid Journal   (Followers: 4)
Water Resources and Industry     Open Access   (Followers: 3)
Wave Motion     Hybrid Journal   (Followers: 2, SJR: 0.855, h-index: 34)
Wavelet Analysis and Its Applications     Full-text available via subscription   (Followers: 3)
Wear     Hybrid Journal   (Followers: 15, SJR: 1.239, h-index: 82)
Weather and Climate Extremes     Open Access   (Followers: 2)
Web Semantics: Science, Services and Agents on the World Wide Web     Hybrid Journal   (Followers: 9, SJR: 3.259, h-index: 42)
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Women's Health Issues     Full-text available via subscription   (Followers: 5, SJR: 0.71, h-index: 32)
Women's Studies Intl. Forum     Hybrid Journal   (Followers: 2, SJR: 0.407, h-index: 24)
World Crop Pests     Full-text available via subscription   (Followers: 1)
World Development     Hybrid Journal   (Followers: 37, SJR: 1.488, h-index: 82)
World Neurosurgery     Hybrid Journal   (Followers: 1, SJR: 0.525, h-index: 57)
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Zeitschrift für Medizinische Physik     Full-text available via subscription   (Followers: 1, SJR: 0.406, h-index: 15)
Zoologischer Anzeiger - A J. of Comparative Zoology     Hybrid Journal   (Followers: 1, SJR: 0.533, h-index: 24)
Zoology     Hybrid Journal   (Followers: 6, SJR: 0.538, h-index: 28)

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Journal Cover Pharmacological Research
   [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]
  • Targeting opioid receptors with pharmacological chaperones
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): Ulla E. Petäjä-Repo , Jarkko J. Lackman
      G protein-coupled receptors (GPCRs) are polytopic membrane proteins that have a pivotal role in cellular signaling. Like other membrane proteins, they fold in the endoplasmic reticulum (ER) before they are transported to the plasma membrane. The ER quality control monitors the folding process and misfolded proteins and slowly folding intermediates are targeted to degradation in the cytosol via the ubiquitin–proteasome pathway. The high efficiency of the quality control machinery may lead to the disposal of potentially functional receptors. This is the major underlying course for loss-of-function conformational diseases, such as retinitis pigmentosa, nephrogenic diabetes insipidus and early onset obesity, which involve mutant GPCRs. During the past decade, it has become increasingly evident that small-molecular lipophilic and pharmacologically selective receptor ligands, called pharmacological chaperones (PCs), can rescue these mutant receptors from degradation by stabilizing newly synthesized receptors in the ER and enhancing their transport to the cell surface. This has raised the interesting prospect that PCs might have therapeutic value for the treatment of conformational diseases. At the same time, accumulating evidence has indicated that wild-type receptors might also be targeted by PCs, widening their therapeutic potential. This review focuses on one GPCR subfamily, opioid receptors that have been useful models to unravel the mechanism of action of PCs. In contrast to most other GPCRs, compounds that act as PCs for opioid receptors, including widely used opioid drugs, target wild-type receptors and their common natural variants.
      Graphical abstract image

      PubDate: 2014-06-02T15:13:57Z
       
  • 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
       
  • Transitioning pharmacoperones to therapeutic use: In vivo
           proof-of-principle and design of high throughput screens
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): P. Michael Conn , David C. Smithson , Peter S. Hodder , M. David Stewart , Richard R. Behringer , Emery Smith , Alfredo Ulloa-Aguirre , Jo Ann Janovick
      A pharmacoperone (from “pharmacological chaperone“) is a small molecule that enters cells and serves as molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell. Pharmacoperones have broad therapeutic applicability since a large number of diseases have their genesis in the misfolding of proteins and resultant misrouting within the cell. Misrouting may result in loss-of-function and, potentially, the accumulation of defective mutants in cellular compartments. Most known pharmacoperones were initially derived from receptor antagonist screens and, for this reason, present a complex pharmacology, although these are highly target specific. In this summary, we describe efforts to produce high throughput screens that identify these molecules from chemical libraries as well as a mouse model which provides proof-of-principle for in vivo protein rescue using existing pharmacoperones.
      Graphical abstract image

      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
       
  • Vasopressin receptors and pharmacological chaperones: From functional
           rescue to promising therapeutic strategies
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): Bernard Mouillac , Christiane Mendre
      Conformational diseases result from protein misfolding and/or aggregation and constitute a major public health problem. Congenital Nephrogenic Diabetes Insipidus is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor gene leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists (vaptans), agonists as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacochaperones. These compounds represent a potential therapeutic treatment of this X-linked genetic pathology.
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      PubDate: 2014-06-02T15:13:57Z
       
  • Editorial Board
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83




      PubDate: 2014-06-02T15:13:57Z
       
  • “Pharmacoperone”: What's in a word'
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): P. Michael Conn , Alfredo Ulloa-Aguirre , Jo Ann Janovick



      PubDate: 2014-06-02T15:13:57Z
       
  • Pharmacoperones and the calcium sensing receptor: Exogenous and endogenous
           regulators
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): Gerda E. Breitwieser
      Calcium sensing receptor (CaSR) mutations or altered expression cause disorders of calcium handling. Recent studies suggest that reduced targeting to the plasma membrane is a feature common to many CaSR loss-of-function mutations. Allosteric agonists (calcimimetics) can rescue signaling of a subset of CaSR mutants. This review evaluates our current understanding of the subcellular site(s) for allosteric modulator rescue of CaSR mutants. Studies to date make a strong case for calcimimetic potentiation of signaling not only at plasma membrane-localized CaSR, but at the endoplasmic reticulum, acting as pharmacoperones to assist in navigation of multiple quality control checkpoints. The possible role of endogenous pharmacoperones, calcium and glutathione, in folding and stabilization of the CaSR extracellular and transmembrane domains are considered. Finally, the possibility that dihydropyridines act as unintended pharmacoperones of CaSR is proposed. While our understanding of pharmacoperone rescue of CaSR requires refinement, promising results to date argue that this may be a fruitful avenue for drug discovery.
      Graphical abstract image

      PubDate: 2014-06-02T15:13:57Z
       
  • Defining the blanks – Pharmacochaperoning of SLC6 transporters and
           ABC transporters
    • Abstract: Publication date: May 2014
      Source:Pharmacological Research, Volume 83
      Author(s): Peter Chiba , Michael Freissmuth , Thomas Stockner
      SLC6 family members and ABC transporters represent two extremes: SLC6 transporters are confined to the membrane proper and only expose small segments to the hydrophilic milieu. In ABC transporters the hydrophobic core is connected to a large intracellular (eponymous) ATP binding domain that is comprised of two discontiguous repeats. Accordingly, their folding problem is fundamentally different. This can be gauged from mutations that impair the folding of the encoded protein and give rise to clinically relevant disease phenotypes: in SLC6 transporters, these cluster at the protein–lipid interface on the membrane exposed surface. Mutations in ABC-transporters map to the interface between nucleotide binding domains and the coupling helices, which provide the connection to the hydrophobic core. Folding of these mutated ABC-transporters can be corrected with ligands/substrates that bind to the hydrophobic core. This highlights a pivotal role of the coupling helices in the folding trajectory. In contrast, insights into pharmacochaperoning of SLC6 transporters are limited to monoamine transporters – in particular the serotonin transporter (SERT) – because of their rich pharmacology. Only ligands that stabilize the inward facing conformation act as effective pharmacochaperones. This indicates that the folding trajectory of SERT proceeds via the inward facing conformation. Mutations that impair folding of SLC6 family members can be transmitted as dominant or recessive alleles. The dominant phenotype of the mutation can be rationalized, because SLC6 transporters are exported in oligomeric form from the endoplasmic reticulum (ER). Recessive transmission requires shielding of the unaffected gene product from the mutated transporter in the ER. This can be accounted for by a chaperone-COPII (coatomer protein II) exchange model, where proteinaceous ER-resident chaperones engage various intermediates prior to formation of the oligomeric state and subsequent export from the ER. It is likely that the action of pharmacochaperones is contingent on and modulated by these chaperones.
      Graphical abstract image

      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
       
  • Editorial Board
    • Abstract: Publication date: June 2014
      Source:Pharmacological Research, Volume 84




      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
       
  • Adenosine Kinase Inhibition Protects The Kidney Against
           Streptozotocin-Induced Diabetes Through Anti-inflammatory and Anti-oxidant
           Mechanisms
    • Abstract: Publication date: Available online 17 May 2014
      Source:Pharmacological Research
      Author(s): Chelsey Pye , Nehal M. Elsherbiny , Ahmed S. Ibrahim , Gregory I. Liou , Ahmed Chadli , Mohamed Al-Shabrawey , Ahmed A. Elmarakby
      Adenosine provides anti-inflammatory effects in cardiovascular disease via the activation of adenosine A2A receptors; however, the physiological effect of adenosine could be limited due to its phosphorylation by adenosine kinase. We hypothesized that inhibition of adenosine kinase exacerbates extracellular adenosine levels to reduce renal inflammation and injury in streptozotocin-induced diabetes. Diabetes was induced in male C57BL/6 mice by daily injection of streptozotocin (50mg/kg/day, i.p. for 5 days). Control and diabetic mice were then treated with the adenosine kinase inhibitor ABT702 (1.5mg/kg, i.p two times a week for 8 weeks, n=7-8/group) or the vehicle (5% DMSO). ABT702 treatment reduced blood glucose level in diabetic mice (∼ 20%; p<0.05). ABT702 also reduced albuminuria and markers of glomerular injury, nephrinuria and podocalyxin excretion levels, in diabetic mice. Renal NADPH oxidase activity and urinary thiobarbituric acid reactive substances (TBARS) excretion, indices of oxidative stress, were also elevated in diabetic mice and ABT702 significantly reduced these changes. ABT702 increased renal endothelial nitric oxide synthase expression (eNOS) and nitrate/nitrite excretion levels in diabetic mice. In addition, the diabetic mice displayed an increase in renal macrophage infiltration, in association with increased renal NFκB activation. Importantly, treatment with ABT702 significantly reduced all these inflammatory parameters (P<0.05). Furthermore, ABT702 decreased glomerular permeability and inflammation and restored the decrease in glomerular occludin expression in vitro in high glucose treated human glomerular endothelial cells. Collectively, the results suggest that the reno-protective effects of ABT702 could be attributed to the reduction in renal inflammation and oxidative stress in diabetic mice.
      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
       
  • Editorial Board
    • Abstract: Publication date: April 2014
      Source:Pharmacological Research, Volume 82




      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
       
  • Selective inhibition of OCTN2 is more effective than inhibition of
           Gamma-butyrobetaine dioxygenase to decrease the availability of
           L-carnitine and to reduce myocardial infarct size
    • Abstract: Publication date: Available online 14 May 2014
      Source:Pharmacological Research
      Author(s): Edgars Liepinsh , Marina Makrecka , Janis Kuka , Helena Cirule , Elina Makarova , Eduards Sevostjanovs , Solveiga Grinberga , Reinis Vilskersts , Daina Lola , Einars Loza , Ilmars Stonans , Osvalds Pugovics , Maija Dambrova
      L-Carnitine is a cofactor in the energy metabolism pathways where it drives the uptake and oxidation of long chain fatty acids (LCFA) by mitochondria. LCFA lipotoxicity causes mitochondrial damage and results in an insufficient energy supply and a decrease in L-carnitine content limits LCFA flux and protects mitochondria. Here, we tested whether the inhibition of GBB dioxygenase (BBOX) or organic cation transporter 2 (OCTN2) is the most effective strategy to decrease L-carnitine content. The activity of 51 compounds was tested and we identified selective inhibitors of OCTN2. In contrast to selective inhibitors of BBOX, OCTN2 inhibitors induced a 10-fold decrease in L-carnitine content in the heart tissues and a significant 35% reduction of myocardial infarct size. In addition, OCTN2 inhibition correlated with the inhibitor content in the heart tissues, and OCTN2 could potentially be an efficient target to increase drug transport into tissues and to reduce drug elimination by urine. In conclusion, the results of this study confirm that selective inhibition of OCTN2, compared to selective inhibition of BBOX, is a far more effective approach to decrease L-carnitine content and to induce cardioprotective effects. OCTN2 could potentially be an efficient tool to increase drug transport in tissues and to reduce drug elimination via urine.
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      PubDate: 2014-05-16T03:59:20Z
       
  • 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.
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      PubDate: 2014-05-16T03:59:20Z
       
  • Sulforaphane alleviates scopolamine-induced memory impairment in mice
    • Abstract: Publication date: Available online 14 May 2014
      Source:Pharmacological Research
      Author(s): Siyoung Lee , Jisung Kim , Sang Gwon Seo , Bo-Ryoung Choi , Jung-Soo Han , Ki Won Lee , Jiyoung Kim
      Sulforaphane, an organosulfur compound present in cruciferous vegetables, has been shown to exert neuroprotective effects in experimental in vitro and in vivo models of neurodegeneration. To determine whether sulforaphane can preserve cognitive function, we examined its effects on scopolamine-induced memory impairment in mice using the Morris water maze test. Sulforaphane (10 or 50mg/kg) was administered to C57BL/6 mice by oral gavage for 14 days (days 1–14), and memory impairment was induced by intraperitoneal injection of scopolamine (1mg/kg) for 7 days (days 8–14). Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity in the hippocampus and frontal cortex, as indicated by a decreased acetylcholine (ACh) level and an increased acetylcholinesterase (AChE) activity. Sulforaphane significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex. These effects of sulforaphane on cholinergic system reactivity were confirmed in vitro. Sulforaphane (10 or 20μM) increased the ACh level, decreased the AChE activity, and increased ChAT expression in scopolamine-treated primary cortical neurons. These observations suggest that sulforaphane might exert a significant neuroprotective effect on cholinergic deficit and cognitive impairment.
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      PubDate: 2014-05-16T03:59:20Z
       
  • Is Generic Rifaximin Still a Poorly Absorbed Antibiotic' A Comparison
           of Branded and Generic Formulations in Healthy Volunteers
    • Abstract: Publication date: Available online 14 May 2014
      Source:Pharmacological Research
      Author(s): Corrado Blandizzi , Giuseppe Claudio Viscomi , Antonio Marzo , Carmelo Scarpignato
      Rifaximin is an antibiotic, locally acting in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The branded rifaximin formulation contains the polymorph αrifaximin-α, whose systemic bioavailability is very limited. This study was performed to compare the pharmacokinetics of this formulation with that of a generic product, whose composition in terms of solid state forms of the active pharmaceutical ingredient was found to be different. Two tablets (2×200mg) of branded and generic formulations were given to 24 healthy volunteers of either sex, according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urinary samples were collected at preset times (for 24h or 48h, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. Rifaximin plasma and urine concentration-time profiles showed relevant differences when generic and branded rifaximin were compared. Most pharmacokinetic parameters were significantly higher after administration of generic rifaximin than after rifaximin-α. In particular, the differences for Cmax, AUC and cumulative urinary excretion between the generic formulation and the branded product ranged from 165% to 345%. The few adverse events recorded were not serious and not related to study medications. The results of the present investigation demonstrate different systemic bioavailablity of generic and branded formulations of rifaximin. As a consequence, the therapeutic results obtained with rifaximin α should not be translated sic et simpliciter to the generic formulations of rifaximin, which do not claim containing only rifaximin α and will display significantly higher systemic absorption in both health and disease.
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      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.
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      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.
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      PubDate: 2014-05-06T06:17:46Z
       
  • Statins Role in the Prevention and Treatment of Sepsis
    • Abstract: Publication date: Available online 2 May 2014
      Source:Pharmacological Research
      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.
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      PubDate: 2014-05-06T06:17:46Z
       
  • Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through
           inhibiting microglial activation
    • Abstract: Publication date: Available online 28 April 2014
      Source:Pharmacological Research
      Author(s): Qun Zhang , Lin Yuan , Dexiang Liu , Jianmei Wang , Shuanglian Wang , Qingrui Zhang , Yanfen Gong , Hongda Liu , Aijun Hao , Zhen Wang
      Endogenously produced hydrogen sulfide (H2S) may have multiple functions in the brain including potent anti-inflammatory effects. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic injuries in the developing brain. The aim of this study is to investigate the potential role of H2S in altering hypoxia-induced neurotoxicity via its anti-inflammatory actions as examined in vitro and in vivo models. Using the BV-2 microglial cell line, we found that sodium hydrosulfide (NaHS), a H2S donor, significantly inhibited hypoxia-induced microglial activation and suppressed subsequent pro-inflammatory factor release. In addition, treating murine primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, an effect that was reversed by CM treated with NaHS. Further, NaHS inhibited phosphorylation of the p65 subunit of NF-κB, phosphorylation of ERK and p38 but not JNK MAPK in these hypoxia-induced microglia. When administered in vivo to neonatal mice subjected to hypoxia, NaHS was found to attenuate neuron death, an effect that was associated with suppressed microglial activation, pro-inflammatory cytokines and NO levels. Taken together, H2S exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effect in microglia. This effect appears to be attributable to inhibition of iNOS, NF-κB, ERK and p38 MAPK signaling pathways. Our results suggest a potential therapeutic application of H2S releasing drugs in hypoxic brain damage treatment.
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      PubDate: 2014-05-01T06:15:37Z
       
  • Detection and distribution of opioid peptide receptors in porcine
           myocardial tissue
    • Abstract: Publication date: Available online 28 April 2014
      Source:Pharmacological Research
      Author(s): Marc Michael Theisen , Silke Schlottmann , Christian August , Christine Herzog , Gregor Theilmeier , Matthias Maas , Jonas Martin Blumenstiel , Thomas Peter Weber , Hugo Karel Van Aken , Kristoffer Tim Kaerlein
      There is growing evidence that opioid peptide receptors (OPR) play an important role in cardiovascular function. Many studies have been conducted in swine, in view of their anatomic and physiologic similarities to humans. Until now, the presence and particularly distribution of OPRs has been unclear. Porcine myocardial tissue was obtained from both the left and right atria and ventricles. Expression of mRNA for μ-, δ- and κ-OPR was determined by reverse transcription PCR. OPR proteins were detected by Western blot, distribution and cellular location were identified using immunohistochemistry. Homogenous expression of mRNA and protein for δ- and κ-OPRs were demonstrated in all porcine myocardial tissue tested, whereas expression of μ-OPR mRNA was not demonstrated in any of the tissues tested. This study demonstrates the expression of δ- and κ-OPRs in porcine myocardial tissue. No differences in distribution of δ- and κ-OPRs were found between the four heart cavities. Modulation of cardiac function by δ- and κ-OPR agonists or antagonists is therefore possible, while μ-OPR–mediated direct cardiac effects appear unlikely, due to nonexpression of the receptor. This study demonstrates that porcine studies can further elucidate the role of OPRs in cardiac (patho–)physiology.
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      PubDate: 2014-05-01T06:15:37Z
       
  • A novel biological role of dehydroascorbic acid: inhibition of
           Na+-dependent transport of ascorbic acid
    • Abstract: Publication date: Available online 24 April 2014
      Source:Pharmacological Research
      Author(s): Mara Fiorani , Catia Azzolini , Andrea Guidarelli , Liana Cerioni , Orazio Cantoni
      A U937 cell clone, in which low micromolar concentrations of ascorbic acid (AA) and dehydroascorbic acid (DHA) are taken up at identical rates, was used to investigate possible interactions between transport systems mediating cellular uptake of the two forms of the vitamin. Results obtained with different experimental approaches showed that DHA potently and reversibly inhibits AA uptake through Na+-AA cotransporters. Hence, a progressive increase in extracellular DHA concentrations in the presence of a fixed amount of AA caused an initial decrease in the net amount of vitamin C accumulated, and eventually, at higher levels, it caused an accumulation of the vitamin solely based on DHA uptake through hexose transporters. DHA-dependent inhibition of AA uptake was also detected in various other cell types. Taken together, our results provide evidence of a novel biological effect mediated by concentrations of DHA compatible with those produced at inflammatory sites.
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      PubDate: 2014-04-25T10:33:32Z
       
  • 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
       
  • Exendin-4 inhibits endothelial protein C receptor shedding in vitro and in
           vivo
    • Abstract: Publication date: Available online 24 April 2014
      Source:Pharmacological Research
      Author(s): Sae-Kwang Ku , Min-Su Han , Eun Ji Park , Dong Hee Na , Jong-Sup Bae
      Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury, inflammatory and oxidative responses. Increasing evidence has demonstrated that beyond its role in activation of protein C, endothelial cell protein C receptor (EPCR) is involved in vascular inflammation. EPCR activity is markedly decreased by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of EX4 on EPCR shedding. Data from this study showed that EX4 induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-induced EPCR shedding in mice. EX4 also inhibited expression and activity of TACE induced by PMA in HUVECs. In addition, treatment with EX4 resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of EX4 as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.
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      PubDate: 2014-04-25T10:33:32Z
       
  • Naltrexone/bupropion for obesity: An investigational combination
           pharmacotherapy for weight loss
    • Abstract: Publication date: Available online 19 April 2014
      Source:Pharmacological Research
      Author(s): Sonja K. Billes , Puspha Sinnayah , Michael A. Cowley
      The mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss.


      PubDate: 2014-04-20T12:05:36Z
       
  • Using pharmacological chaperones to restore proteostasis
    • Abstract: Publication date: Available online 18 April 2014
      Source:Pharmacological Research
      Author(s): Ya-Juan Wang , Xiao-Jing Di , Ting-Wei Mu
      Normal organismal physiology depends on the maintenance of proteostasis in each cellular compartment to achieve a delicate balance between protein synthesis, folding, trafficking, and degradation while minimizing misfolding and aggregation. Defective proteostasis leads to numerous protein misfolding diseases. Pharmacological chaperones are cell-permeant small molecules that promote the proper folding and trafficking of a protein via direct binding to that protein. They stabilize their target protein in a protein-pharmacological chaperone state, increasing the natively folded protein population that can effectively engage trafficking machinery for transport to the final destination for function. Here, as regards the application of pharmacological chaperones, we focus on their capability to promote the folding and trafficking of lysosomal enzymes, G protein coupled receptors (GPCRs), and ion channels, each of which is presently an important drug target. Pharmacological chaperones hold great promise as potential therapeutics to ameliorate a variety of protein misfolding diseases.
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      PubDate: 2014-04-20T12:05:36Z
       
  • 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.
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      PubDate: 2014-04-20T12:05:36Z
       
  • Ionic channels underlying the ventricular action potential in zebrafish
           embryo
    • Abstract: Publication date: Available online 18 April 2014
      Source:Pharmacological Research
      Author(s): Aintzane Alday , Hiart Alonso , Monica Gallego , Janire Urrutia , Ainhoa Letamendia , Carles Callol , Oscar Casis
      Over the last years zebrafish has become a popular model in the study of cardiac physiology, pathology and pharmacology. Recently, the application of the 3Rs regulation and the characteristics of the embryo have reduced the use of adult zebrafish use in many studies. However, the zebrafish embryo cardiac physiology is poorly characterized since most works have used indirect techniques and direct recordings of cardiac action potential and ionic currents are scarce. In order to optimize the zebrafish embryo model, we used electrophysiological, pharmacological and immunofluorescence tools to identify the characteristics and the ionic channels involved in the ventricular action potentials of zebrafish embryos. The application of Na+ or T-type Ca+2 channel blockers eliminated the cardiac electrical activity, indicating that the action potential upstroke depends on Na+ and T-type Ca+2 currents. The plateau phase depends on L-type Ca+2 channels since it is abolished by specific blockade. The direct channel blockade indicates that the action potential repolarization and diastolic potential depends on ERG K+ channels. The presence in the embryonic heart of the Nav1.5, Cav1.2, Cav3.2 and ERG channels was also confirmed by immunofluorescence, while the absence of effect of specific blockers and immunostaining indicate that two K+ repolarizing currents present in human heart, Ito and IKs, are absent in the embryonic zebrafish heart. Our results describe the ionic channels present and its role in the zebrafish embryo heart and support the use of zebrafish embryos to study human diseases and their use for drug testing.
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      PubDate: 2014-04-20T12:05:36Z
       
  • Nucleoside monophosphorothioates as the new hydrogen sulfide precursors
           with unique properties Pharmacological Research, 81, 2014, Pages 34-43
    • Abstract: Publication date: Available online 13 April 2014
      Source:Pharmacological Research
      Author(s): Jerzy Beltowski



      PubDate: 2014-04-16T06:49:22Z
       
  • Dapagliflozin: glucuretic action and beyond
    • Abstract: Publication date: Available online 3 April 2014
      Source:Pharmacological Research
      Author(s): Pitchai Balakumar , Karupiah Sundram , Sokkalingam A. Dhanaraj
      Diabetes mellitus is a greatly challenging disease of the 21 century, and the mortality rate due to this insidious disease is increasing worldwide in spite of availability of effective oral hypoglycemic agents. Satisfactory management of glycemic control in patients afflicted with type 2 diabetes mellitus (T2DM) remains a major clinical challenge. Identification of potential pharmacological target sites is therefore continuing as an integral part of the diabetic research. The sodium-glucose co-transporter type 2 (SGLT2) expressed in the renal proximal tubule plays an essential role in glucose reabsorption. Pharmacological blockade of SGLT2 prevents glucose reabsorption and subsequently induces the elimination of filtered glucose via urine, the process is known as ‘glucuresis’. Dapagliflozin is a selective inhibitor of SGLT2. The US FDA approved dapagliflozin in January 2014 to improve glycemic control along with diet and exercise in adult patients afflicted with T2DM. It has a potential to decrease glycated hemoglobin and to promote weight loss. Although the mechanism of action of dapagliflozin is not directly linked with insulin or insulin sensitivity, reduction of plasma glucose by dapagliflozin via induction of glucosuria could improve muscle insulin sensitivity. Moreover, dapagliflozin could cause diuresis and subsequently fall in blood pressure. In addition to general discussion on the pharmacology of dapagliflozin, we propose in this review the possibilities of dual antidiabetic effect of dapagliflozin and its possible additional beneficial actions in hypertensive-obese-T2DM patients through its indirect blood pressure-lowering action and reduction of body calories and weight. Long-term clinical studies are however needed to clarify this contention.
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      PubDate: 2014-04-06T01:32:49Z
       
  • 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.
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      PubDate: 2014-04-06T01:32:49Z
       
  • α,β-Unsaturated Aldehyde Crotonaldehyde Triggers Cardiomyocyte
           Contractile Dysfunction: Role of TRPV1 and Mitochondrial Function
    • Abstract: Publication date: Available online 3 April 2014
      Source:Pharmacological Research
      Author(s): Zhaohui Pei , Zhiqiang Zhuang , Hanfei Sang , Zhenbiao Wu , Rongsen Meng , Emily Y. He , Glenda I. Scott , Jackie R. Maris , Ruiman Li , Jun Ren
      Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential α,β-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca2+ decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate and 8-hydroxy-2′-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca2+ property including depressed PS,±dL/dt, ΔFFI and SERCA activity, as well as prolonged TR90 and intracellular Ca2+ decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1α and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism.
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      PubDate: 2014-04-06T01:32:49Z
       
  • IL-1Ra selectively protects intestinal crypt epithelial cells, but not
           tumor cells, from chemotoxicity via p53-mediated upregulation of p21WAF1
           and p27KIP1
    • Abstract: Publication date: Available online 28 March 2014
      Source:Pharmacological Research
      Author(s): Xia Wang , Shunying Zhu , Lan Qian , Jing Gao , Mingyuan Wu , Jin Gao , Yang Zhang , Gerald L. Chan , Yan Yu , Wei Han
      Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect, resulting from the nonspecific cytoablative actions of chemoagents, including 5-fluorouracil (5-FU) and irinotecan (CPT-11). Preventive strategies are urgently needed for the predictable CIM. Previously, we have demonstrated an important role of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) in the prevention of cyclophosphamide-induced mucositis in mice. In this study, the preventive role of rhIL-1Ra was further evaluated in 5-FU- and CPT-11-induced mucositis mouse models. rhIL-1Ra pretreatment reduced the incidence, severity, and duration of chemotherapy-induced diarrhea, through attenuating crypt apoptosis and improving crypt survival in wild-type mice, but not in IL-1RI −/−, p53 −/−, and p21 −/− mice. Further studies demonstrated that rhIL-1Ra promoted the cell cycle arrest of intestinal crypt epithelia (ICE) through elevating the cellular level of p21WAF1 and p27KIP1, which was abolished in IL-1RI −/− and p53 −/− mice, and in p21 WAF1 and p27 KIP1 silenced IEC-6 cells. Importantly, the tumor growth and sensitivity to chemotherapy were not affected by rhIL-1Ra in cultures of tumor cell lines and in a syngeneic tumor-transplantation mouse model. The present study demonstrated that rhIL-1Ra effectively and specifically protected ICE from chemotoxicity through reversible reduction of the basal level of IL-1 signaling to promote normal cell cycle arrest, but not tumor cells. Our findings support the clinical development of rhIL-1Ra in the prevention of CIM.
      Graphical abstract image

      PubDate: 2014-03-31T19:55:34Z
       
  • 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
       
  • Editorial Board
    • Abstract: Publication date: March 2014
      Source:Pharmacological Research, Volume 81




      PubDate: 2014-03-31T19:55:34Z
       
  • STATINS: FROM CHOLESTEROL-LOWERING DRUGS TO NOVEL IMMUNOMODULATORS FOR THE
           TREATMENT OF TH17-MEDIATED AUTOIMMUNE DISEASES
    • Abstract: Publication date: Available online 21 March 2014
      Source:Pharmacological Research
      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: 2014-03-21T15:52:07Z
       
  • Back to the Heart: The Protective Role of Adiponectin
    • Abstract: Publication date: Available online 20 March 2014
      Source:Pharmacological Research
      Author(s): C. Caselli , A. D’Amico , M. Cabiati , T. Prescimone , S. Del Ry , D. Giannessi
      Cardiovascular disease (CVD) is the leading cause of death worldwide and the prevalence of obesity and diabetes are increasing. In obesity, adipose tissue increases the secretion of bioactive mediators (adipokines) that may represent a key mechanism linking obesity to CVD. Adiponectin, extensively studied in metabolic diseases, exerts anti-diabetic, anti-atherogenic and anti-inflammatory activities. Due to these positive actions, the role of adiponectin in cardiovascular protection has been evaluated in recent years. In particular, for its potential therapeutic benefits in humans, adiponectin has become the subject of intense preclinical research. In the cardiovascular context, understanding of the cellular and molecular mechanisms underlying the adiponectin system, throughout its secretion, regulation and signaling, is critical for designing new drugs that target adiponectin system molecules. This review focused on recent advances regarding molecular mechanisms related to protective effects of the adiponectin system on both cardiac and vascular compartments and its potential use as a target for therapeutic intervention of CVD.
      Graphical abstract image

      PubDate: 2014-03-21T15:52:07Z
       
  • Role of statins in the treatment of multiple sclerosis
    • Abstract: Publication date: Available online 20 March 2014
      Source:Pharmacological Research
      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: 2014-03-21T15:52:07Z
       
  • The pharmacology of statins
    • Abstract: Publication date: Available online 20 March 2014
      Source:Pharmacological Research
      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, eg 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: 2014-03-21T15:52:07Z
       
  • ‘How can I halt thee'’ The puzzles involved in autophagic
           inhibition
    • Abstract: Publication date: Available online 21 March 2014
      Source:Pharmacological Research
      Author(s): V. Vinod , C.J. Padmakrishnan , Bejoy Vijayan , Srinivas Gopala
      The strategy for interpreting the role of autophagy on the basis of evidence obtained through autophagic inhibition sounds logical, but is beset with practical constraints. The knock down of autophagy–related (ATG) gene(s) or blockage of class III PI3-Kinase are the most common approaches for inhibiting autophagy. However, during stressful conditions, autophagy may operate in synchrony with other processes such as apoptosis; autophagy-related genes, unlike what their name implies, exert their regulation on apoptosis as well. Knocking down such genes not only blocks autophagy but also renders apoptosis defective, making the interpretation of autophagic roles unreliable. Similarly, class III PI3-Kinase aids in initiating autophagy but it is not a quintessential autophagic regulator. Class III PI3-Kinase also has a role in regulating almost all membrane transport in cells. Blocking it not only inhibits autophagy, but also hampers all the membrane trades, including endosomal transport. The pharmacological inhibitors used to block autophagy by blocking class III PI3-Kinase further compound these limitations with their off-target effects. Knowing the limitations involved in blocking a target or using an autophagy-blocking tool is a prerequisite for designing the experiments meant for analyzing autophagic functions. This review attempts to provide a detailed overview about the practical constraints involved in using autophagic inhibition as a strategy to understand autophagy.
      Graphical abstract image

      PubDate: 2014-03-21T15:52:07Z
       
  • Cardiovascular Effects of Statins, Beyond Lipid-lowering Properties
    • Abstract: Publication date: Available online 12 March 2014
      Source:Pharmacological Research
      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 includes 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: 2014-03-12T07:17:50Z
       
  • Targeting inflammation: new therapeutic approaches in Chronic Kidney
           Disease (CKD)
    • Abstract: Publication date: Available online 3 March 2014
      Source:Pharmacological Research
      Author(s): Daniela Impellizzeri , Emanuela Esposito , James Attley , Salvatore Cuzzocrea
      Chronic inflammation and oxidative stress, features that are closely associated with nuclear factor (NF-κB) activation, play a key role in the development and progression of chronic kidney disease (CKD). Several animal models and clinical trials have clearly demonstrated the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to improve glomerular/tubulointerstitial damage, reduce proteinuria, and decrease CKD progression, but CKD treatment still represents a clinical challenge. Bardoxolone methyl, a first-in-class oral Nrf-2 (nuclear factor erythroid 2-related factor 2) agonist that until recently showed considerable potential for the management of a range of chronic diseases, had been shown to improve kidney function in patients with advanced diabetic nephropathy (DN) with few adverse events in a Phase 2 trial, but a large phase 3 study in patients with diabetes and CKD was halted due to emerging toxicity and death in a number of patients. Instead, palmitoylethanolamide (PEA) a member of the fatty acid ethanolamine family, is a novel non-steroidal, kidney friendly anti-inflammatory and anti-fibrotic agent with a well-documented safety profile, that may represent a potential candidate in treating CKD probably by a combination of pharmacological properties, including some activity at the peroxisome proliferator activated receptor alpha (PPAR-α). The aim of this review is to discuss new therapeutic approaches for the treatment of CKD, with particular reference to the outcome of two therapies, bardoxolone methyl and PEA, to improve our understanding of which pharmacological properties are responsible for the anti-inflammatory effects necessary for the effective treatment of renal disease.
      Graphical abstract image

      PubDate: 2014-03-06T07:21:12Z
       
  • Pharmacological chaperoning of nAChRs: A therapeutic target for
           Parkinson's disease
    • Abstract: Publication date: Available online 1 March 2014
      Source:Pharmacological Research
      Author(s): Rahul Srinivasan , Brandon J. Henderson , Henry A. Lester , Christopher I. Richards
      Chronic exposure to nicotine results in an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs) at the cellular plasma membrane. nAChR upregulation occurs via nicotine-mediated pharmacological receptor chaperoning and is thought to contribute to the addictive properties of tobacco as well as relapse following smoking cessation. At the subcellular level, pharmacological chaperoning by nicotine and nicotinic ligands causes profound changes in the structure and function of the endoplasmic reticulum (ER), ER exit sites, the Golgi apparatus and secretory vesicles of cells. Chaperoning-induced changes in cell physiology exert an overall inhibitory effect on the ER stress/unfolded protein response. Cell autonomous factors such as the repertoire of nAChR subtypes expressed by neurons and the pharmacological properties of nicotinic ligands (full or partial agonist versus competitive antagonist) govern the efficiency of receptor chaperoning and upregulation. Together, these findings are beginning to pave the way for developing pharmacological chaperones to treat Parkinson's disease and nicotine addiction.
      Graphical abstract image

      PubDate: 2014-03-02T05:04:16Z
       
  • Pharmacological Chaperoning: A Primer on Mechanism and Pharmacology
    • Abstract: Publication date: Available online 14 February 2014
      Source:Pharmacological Research
      Author(s): Nancy J. Leidenheimer , Katelyn G. Ryder
      Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.
      Graphical abstract image

      PubDate: 2014-02-15T04:41:22Z
       
 
 
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