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Journal Cover Pharmaceuticals
  [SJR: 1.245]   [H-I: 26]   [5 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1424-8247
   Published by MDPI Homepage  [151 journals]
  • Pharmaceuticals, Vol. 10, Pages 33: An Updated View on an Emerging Target:
           Selected Papers from the 8th International Conference on Protein Kinase

    • Authors: Joachim Jose, Marc Le-Borgne, Lorenzo Pinna, Mathias Montenarh
      First page: 33
      Abstract: n/a
      PubDate: 2017-03-23
      DOI: 10.3390/ph10020033
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 34: Pathophysiological Significance of
           Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders

    • Authors: Shuji Mizumoto, Tomoki Kosho, Shuhei Yamada, Kazuyuki Sugahara
      First page: 34
      Abstract: The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and biglycan cause congenital stromal dystrophy of the cornea, spondyloepimetaphyseal dysplasia, and Meester-Loeys syndrome. Furthermore, mutations in human genes encoding the glycosyltransferases, epimerases, and sulfotransferases responsible for the biosynthesis of DS chains cause connective tissue disorders including Ehlers-Danlos syndrome and spondyloepimetaphyseal dysplasia with joint laxity characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, and by severe skeletal disorders such as kyphoscoliosis, short trunk, dislocation, and joint laxity. Glycobiological approaches revealed that mutations in DS-biosynthetic enzymes cause reductions in enzymatic activities and in the amount of synthesized DS and also disrupt the formation of collagen bundles. This review focused on the growing number of glycobiological studies on recently reported genetic diseases caused by defects in the biosynthesis of DS and DS-PGs.
      PubDate: 2017-03-27
      DOI: 10.3390/ph10020034
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 35: Modulation of TRP Channel Activity by
           Hydroxylation and Its Therapeutic Potential

    • Authors: Yagnesh Nagarajan, Grigori Y. Rychkov, Daniel J. Peet
      First page: 35
      Abstract: Two transient receptor potential (TRP) channels—TRPA1 and TRPV3—are post-translationally hydroxylated, resulting in oxygen-dependent regulation of channel activity. The enzymes responsible are the HIF prolyl hydroxylases (PHDs) and the asparaginyl hydroxylase factor inhibiting HIF (FIH). The PHDs and FIH are well characterized for their hydroxylation of the hypoxic inducible transcription factors (HIFs), mediating their hypoxic regulation. Consequently, these hydroxylases are currently being targeted therapeutically to modulate HIF activity in anemia, inflammation, and ischemic disease. Modulating the HIFs by targeting these hydroxylases may result in both desirable and undesirable effects on TRP channel activity, depending on the physiological context. For the best outcomes, these hydroxylases could be therapeutically targeted in pathologies where activation of both the HIFs and the relevant TRP channels are predicted to independently achieve positive outcomes, such as wound healing and obesity.
      PubDate: 2017-03-27
      DOI: 10.3390/ph10020035
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 36: Development of a Glycosaminoglycan
           Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial
           Cell Dysfunction

    • Authors: James Wodicka, Andrea Chambers, Gurneet Sangha, Craig Goergen, Alyssa Panitch
      First page: 36
      Abstract: Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.
      PubDate: 2017-03-29
      DOI: 10.3390/ph10020036
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 37: Development of TRPM8 Antagonists to
           Treat Chronic Pain and Migraine

    • Authors: Andy Weyer, Sonya Lehto
      First page: 37
      Abstract: A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress.
      PubDate: 2017-03-30
      DOI: 10.3390/ph10020037
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 38: Systematic Analysis of Pharmaceutical
           Preparations of Chondroitin Sulfate Combined with Glucosamine

    • Authors: Gustavo Santos, Adriana Piquet, Bianca Glauser, Ana Tovar, Mariana Pereira, Eduardo Vilanova, Paulo Mourão
      First page: 38
      Abstract: Glycosaminoglycans are carbohydrate-based compounds widely employed as nutraceuticals or prescribed drugs. Oral formulations of chondroitin sulfate combined with glucosamine sulfate have been increasingly used to treat the symptoms of osteoarthritis and osteoarthrosis. The chondroitin sulfate of these combinations can be obtained from shark or bovine cartilages and hence presents differences regarding the proportions of 4- and 6-sulfated N-acetyl β-d-galactosamine units. Herein, we proposed a systematic protocol to assess pharmaceutical batches of this combination drug. Chemical analyses on the amounts of chondroitin sulfate and glucosamine in the batches were in accordance with those declared by the manufacturers. Anion-exchange chromatography has proven more effective than electrophoresis to determine the type of chondroitin sulfate present in the combinations and to detect the presence of keratan sulfate, a common contaminant found in batches prepared with shark chondroitin sulfate. 1D NMR spectra revealed the presence of non-sulfated instead of sulfated glucosamine in the formulations and thus in disagreement with the claims declared on the label. Moreover, 1D and 2D NMR analyses allowed a precise determination on the chemical structures of the chondroitin sulfate present in the formulations. The set of analytical tools suggested here could be useful as guidelines to improve the quality of this medication.
      PubDate: 2017-04-01
      DOI: 10.3390/ph10020038
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 39: Role of TRPM7 in Cancer: Potential as
           Molecular Biomarker and Therapeutic Target

    • Authors: Nelson Yee
      First page: 39
      Abstract: The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies.
      PubDate: 2017-04-05
      DOI: 10.3390/ph10020039
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 40: Novel Proteasome Inhibitors and
           Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

    • Authors: Saurabh Chhabra
      First page: 40
      Abstract: The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat.
      PubDate: 2017-04-11
      DOI: 10.3390/ph10020040
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 41: Biotinylated Chlorin and Its Zinc and
           Indium Complexes: Synthesis and In Vitro Biological Evaluation for
           Photodynamic Therapy

    • Authors: Meden Isaac-Lam, Dewana Hammonds
      First page: 41
      Abstract: The synthesis and characterization of biotinylated chlorin photosensitizer and the corresponding zinc and indium complexes are described for potential applications in photodynamic therapy (PDT) for cancer. Phototoxicity of the biotin-chlorin conjugate and the metallated complexes was determined in colon carcinoma CT26 cell lines known to overexpress biotin (Vit B7) receptors. Cell survival assay indicated that the biotinylated chlorin and indium complex showed increased cell growth inhibition than the zinc complex and the starting chlorin (methyl pheophorbide). Fluorescence microcopy studies revealed the generation of apoptotic cells upon light irradiation of colon cells treated with the indium complex. Targeting biotin receptors in cancer cells can improve specificity of photosensitizers for PDT applications.
      PubDate: 2017-04-15
      DOI: 10.3390/ph10020041
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 42: Glycosaminoglycan Binding and
           Non-Endocytic Membrane Translocation of Cell-Permeable Octaarginine
           Monitored by Real-Time In-Cell NMR Spectroscopy

    • Authors: Yuki Takechi-Haraya, Kenzo Aki, Yumi Tohyama, Yuichi Harano, Toru Kawakami, Hiroyuki Saito, Emiko Okamura
      First page: 42
      Abstract: Glycosaminoglycans (GAGs), which are covalently-linked membrane proteins at the cell surface have recently been suggested to involve in not only endocytic cellular uptake but also non-endocytic direct cell membrane translocation of arginine-rich cell-penetrating peptides (CPPs). However, in-situ comprehensive observation and the quantitative analysis of the direct membrane translocation processes are challenging, and the mechanism therefore remains still unresolved. In this work, real-time in-cell NMR spectroscopy was applied to investigate the direct membrane translocation of octaarginine (R8) into living cells. By introducing 4-trifluoromethyl-l-phenylalanine to the N terminus of R8, the non-endocytic membrane translocation of 19F-labeled R8 (19F-R8) into a human myeloid leukemia cell line was observed at 4 °C with a time resolution in the order of minutes. 19F NMR successfully detected real-time R8 translocation: the binding to anionic GAGs at the cell surface, followed by the penetration into the cell membrane, and the entry into cytosol across the membrane. The NMR concentration analysis enabled quantification of how much of R8 was staying in the respective translocation processes with time in situ. Taken together, our in-cell NMR results provide the physicochemical rationale for spontaneous penetration of CPPs in cell membranes.
      PubDate: 2017-04-15
      DOI: 10.3390/ph10020042
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 43: Information Phage Therapy Research
           Should Report

    • Authors: Stephen T. Abedon
      First page: 43
      Abstract: Bacteriophages, or phages, are viruses which infect bacteria. A large subset of phages infect bactericidally and, consequently, for nearly one hundred years have been employed as antibacterial agents both within and outside of medicine. Clinically these applications are described as phage or bacteriophage therapy. Alternatively, and especially in the treatment of environments, this practice instead may be described as a phage-mediated biocontrol of bacteria. Though the history of phage therapy has involved substantial clinical experimentation, current standards along with drug regulations have placed a premium on preclinical approaches, i.e., animal experiments. As such, it is important for preclinical experiments not only to be held to high standards but also to be reported in a manner which improves translation to clinical utility. Here I address this latter issue, that of optimization of reporting of preclinical as well as clinical experiments. I do this by providing a list of pertinent information and data which, in my opinion, phage therapy experiments ought to present in publications, along with tips for best practices. The goal is to improve the ability of readers to gain relevant information from reports on phage therapy research, to allow other researchers greater potential to repeat or extend findings, to ease transitions from preclinical to clinical development, and otherwise simply to improve phage therapy experiments. Targeted are not just authors but also reviewers, other critical readers, writers of commentaries, and, perhaps, formulators of guidelines or policy. Though emphasizing therapy, many points are applicable to phage-mediated biocontrol of bacteria more generally.
      PubDate: 2017-04-30
      DOI: 10.3390/ph10020043
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 44: Pathogenesis and Inhibition of
           Flaviviruses from a Carbohydrate Perspective

    • Authors: So Kim, Bing Li, Robert Linhardt
      First page: 44
      Abstract: Flaviviruses are enveloped, positive single stranded ribonucleic acid (RNA) viruses with various routes of transmission. While the type and severity of symptoms caused by pathogenic flaviviruses vary from hemorrhagic fever to fetal abnormalities, their general mechanism of host cell entry is similar. All pathogenic flaviviruses, such as dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, and Zika virus, bind to glycosaminglycans (GAGs) through the putative GAG binding sites within their envelope proteins to gain access to the surface of host cells. GAGs are long, linear, anionic polysaccharides with a repeating disaccharide unit and are involved in many biological processes, such as cellular signaling, cell adhesion, and pathogenesis. Flavivirus envelope proteins are N-glycosylated surface proteins, which interact with C-type lectins, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) through their glycans. In this review, we discuss both host and viral surface receptors that have the carbohydrate components, focusing on the surface interactions in the early stage of flavivirus entry. GAG-flavivirus envelope protein interactions as well as interactions between flavivirus envelope proteins and DC-SIGN are discussed in detail. This review also examines natural and synthetic inhibitors of flaviviruses that are carbohydrate-based or carbohydrate-targeting. Both advantages and drawbacks of these inhibitors are explored, as are potential strategies to improve their efficacy to ultimately help eradicate flavivirus infections.
      PubDate: 2017-05-04
      DOI: 10.3390/ph10020044
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 45: Novel Radiolabeled Bisphosphonates for
           PET Diagnosis and Endoradiotherapy of Bone Metastases

    • Authors: Nina Pfannkuchen, Marian Meckel, Ralf Bergmann, Michael Bachmann, Chandrasekhar Bal, Mike Sathekge, Wolfgang Mohnike, Richard Baum, Frank Rösch
      First page: 45
      Abstract: Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020045
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 46: PKC in Regenerative Therapy: New
           Insights for Old Targets

    • Authors: Marta Rui, Rita Nasti, Emanuele Bignardi, Serena Della Volpe, Giacomo Rossino, Daniela Rossi, Simona Collina
      First page: 46
      Abstract: Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020046
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 47: Synthesis and Pharmacological
           Properties of Novel Esters Based on Monoterpenoids and Glycine

    • Authors: Mariia Nesterkina, Iryna Kravchenko
      First page: 47
      Abstract: Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by 1H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020047
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 48: Announcing the 2017 Pharmaceuticals
           Travel Award for Young Post-Doctoral Researchers

    • Authors: Jean Vanden Eynde
      First page: 48
      Abstract: Last year, for the first time in its history, our Journal was able to offer a travel grant of 800 CHF to a young researcher in the field of medicinal chemistry
      PubDate: 2017-05-22
      DOI: 10.3390/ph10020048
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 49: Syntheses of Radioiodinated
           Pyrimidine-2,4,6-Triones as Potential Agents for Non-Invasive Imaging of
           Matrix Metalloproteinases

    • Authors: Hans-Jörg Breyholz, Klaus Kopka, Michael Schäfers, Stefan Wagner
      First page: 49
      Abstract: Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [123I]9 potentially useful for MMP SPECT imaging and [124I]9 for MMP PET imaging.
      PubDate: 2017-05-30
      DOI: 10.3390/ph10020049
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 50: Chiral Derivatives of Xanthones:
           Investigation of the Effect of Enantioselectivity on Inhibition of
           Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum

    • Authors: Carla Fernandes, Andreia Palmeira, Inês Ramos, Carlos Carneiro, Carlos Afonso, Maria Tiritan, Honorina Cidade, Paula Pinto, M. Saraiva, Salette Reis, Madalena Pinto
      First page: 50
      Abstract: Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.
      PubDate: 2017-05-31
      DOI: 10.3390/ph10020050
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 51: Advances in Drug Discovery of New
           Antitubercular Multidrug-Resistant Compounds

    • Authors: Guilherme Fernandes, Chung Man Chin, Jean Dos Santos
      First page: 51
      Abstract: Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.
      PubDate: 2017-06-01
      DOI: 10.3390/ph10020051
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 52: Anti-Mycobacterial Evaluation of
           7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure–Activity
           Relationship (HQSAR) Modeling of Amino–Imino Tautomers

    • Authors: Marcelle Bispo, Camilo Lima, Laura Cardoso, André Candéa, Flávio Bezerra, Maria Lourenço, Maria Henriques, Ricardo Alencastro, Carlos Kaiser, Marcus Souza, Magaly Albuquerque
      First page: 52
      Abstract: In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01–D21). Considering the active compounds of series A (A01–A13), B (B01–B13), C (C01–C07), and D (D01–D09), we compose a data set of 42 compounds and carried out hologram quantitative structure–activity relationship (HQSAR) analysis. The amino–imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q2) = 0.80, squared correlation coefficient (r2) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q2 = 0.77, r2 = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.
      PubDate: 2017-06-09
      DOI: 10.3390/ph10020052
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 53: In Vitro and In Vivo Studies of
           Alar-Nasal Cartilage Using Autologous Micro-Grafts: The Use of the
           Rigenera® Protocol in the Treatment of an Osteochondral Lesion of the

    • Authors: Gabriele Ceccarelli, Pietro Gentile, Marco Marcarelli, Martina Balli, Flavio Ronzoni, Laura Benedetti, Maria Cusella De Angelis
      First page: 53
      Abstract: Cartilage defects represent a serious problem due to the poor regenerative properties of this tissue. Regarding the nose, nasal valve collapse is associated with nasal blockage and persistent airway obstruction associated with a significant drop in the quality of life for patients. In addition to surgical techniques, several cell-based tissue-engineering strategies are studied to improve cartilage support in the nasal wall, that is, to ameliorate wall insufficiency. Nevertheless, there are no congruent data available on the benefit for patients during the follow-up time. In this manuscript, we propose an innovative approach in the treatment of cartilage defects in the nose (nasal valve collapse) based on autologous micro-grafts obtained by mechanical disaggregation of a small portion of cartilage tissue (Rigenera® protocol). In particular, we first analyzed in vitro murine and human cartilage micro-grafts; secondly, we analyzed the clinical results of a patient with pinched nose deformity treated with autologous micro-grafts of chondrocytes obtained by Rigenera® protocol. The use of autologous micro-graft produced promising results in surgery treatment of cartilage injuries and could be safely and easily administrated to patients with cartilage tissue defects.
      PubDate: 2017-06-13
      DOI: 10.3390/ph10020053
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 54: The Good the Bad and the Ugly of
           Glycosaminoglycans in Tissue Engineering Applications

    • Authors: Bethanie I. Ayerst, Catherine L.R. Merry, Anthony J. Day
      First page: 54
      Abstract: High sulfation, low cost, and the status of heparin as an already FDA- and EMA- approved product, mean that its inclusion in tissue engineering (TE) strategies is becoming increasingly popular. However, the use of heparin may represent a naïve approach. This is because tissue formation is a highly orchestrated process, involving the temporal expression of numerous growth factors and complex signaling networks. While heparin may enhance the retention and activity of certain growth factors under particular conditions, its binding ‘promiscuity’ means that it may also inhibit other factors that, for example, play an important role in tissue maintenance and repair. Within this review we focus on articular cartilage, highlighting the complexities and highly regulated processes that are involved in its formation, and the challenges that exist in trying to effectively engineer this tissue. Here we discuss the opportunities that glycosaminoglycans (GAGs) may provide in advancing this important area of regenerative medicine, placing emphasis on the need to move away from the common use of heparin, and instead focus research towards the utility of specific GAG preparations that are able to modulate the activity of growth factors in a more controlled and defined manner, with less off-target effects.
      PubDate: 2017-06-13
      DOI: 10.3390/ph10020054
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 55: Exploring Wound-Healing Genomic
           Machinery with a Network-Based Approach

    • Authors: Francesca Vitali, Simone Marini, Martina Balli, Hanne Grosemans, Maurilio Sampaolesi, Yves Lussier, Maria Cusella De Angelis, Riccardo Bellazzi
      First page: 55
      Abstract: The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties. Lastly, we perform a procedure for in-silico simulation of a treatment action in a biological pathway. The findings obtained by applying the developed pipeline, including gene expression analysis, confirms how a network-based bioinformatics method is able to prioritize candidate genes for in vitro analysis, thus speeding up the understanding of molecular mechanisms and supporting the discovery of potential drug targets.
      PubDate: 2017-06-21
      DOI: 10.3390/ph10020055
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 56: The Beginning and Development of the
           Theranostic Approach in Nuclear Medicine, as Exemplified by the
           Radionuclide Pair 86Y and 90Y

    • Authors: Frank Rösch, Hans Herzog, Syed Qaim
      First page: 56
      Abstract: In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the “best one” for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair 86Y/90Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide 90Y (t½ = 2.7 d) had been available for a long time via the 90Sr/90Y generator system, the β+ emitter 86Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of 86Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90Y-labelled compound in terms of mGy or mSv per MBq 90Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed.
      PubDate: 2017-06-20
      DOI: 10.3390/ph10020056
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 57: A Short-Term Biological Indicator for
           Long-Term Kidney Damage after Radionuclide Therapy in Mice

    • Authors: Giovanni Pellegrini, Klaudia Siwowska, Stephanie Haller, Daniel Antoine, Roger Schibli, Anja Kipar, Cristina Müller
      First page: 57
      Abstract: Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage.
      PubDate: 2017-06-21
      DOI: 10.3390/ph10020057
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 5: D11-Mediated Inhibition of Protein

    • Authors: Susanne Schaefer, Tina Svenstrup, Mette Fischer, Barbara Guerra
      First page: 5
      Abstract: Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer types including glioblastoma. We have recently identified 1,3-dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl]dibenzo(b,d)furan-2,7-diol (D11) as a potent and selective inhibitor of protein kinase CK2. In this study, we have further characterized this compound and demonstrated that it suppresses CK2 kinase activity by mixed type inhibition (KI 7.7 nM, KI′ 42 nM). Incubation of glioblastoma cells with D11 induces cell death and upon hypoxia the compound leads to HIF-1α destabilization. The analysis of differential mRNA expression related to human hypoxia signaling pathway revealed that D11-mediated inhibition of CK2 caused strong down-regulation of genes associated with the hypoxia response including ANGPTL4, CA9, IGFBP3, MMP9, SLC2A1 and VEGFA. Taken together, the results reported here support the notion that including D11 in future treatment regimens might turn out to be a promising strategy to target tumor hypoxia to overcome resistance to radio- and chemotherapy.
      PubDate: 2017-01-01
      DOI: 10.3390/ph10010005
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 6: Identification of a Potent Allosteric
           Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library

    • Authors: Christian Nienberg, Claudia Garmann, Andreas Gratz, Andre Bollacke, Claudia Götz, Joachim Jose
      First page: 6
      Abstract: Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 105 variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH) was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM). Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST) the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM).
      PubDate: 2017-01-05
      DOI: 10.3390/ph10010006
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 7: CK2—An Emerging Target for
           Neurological and Psychiatric Disorders

    • Authors: Julia Castello, Andre Ragnauth, Eitan Friedman, Heike Rebholz
      First page: 7
      Abstract: Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders.
      PubDate: 2017-01-05
      DOI: 10.3390/ph10010007
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 8: Development of Pharmacophore Model for
           Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database

    • Authors: Samer Haidar, Zouhair Bouaziz, Christelle Marminon, Tuomo Laitinen, Antti Poso, Marc Le Borgne, Joachim Jose
      First page: 8
      Abstract: Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM.
      PubDate: 2017-01-09
      DOI: 10.3390/ph10010008
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 9: Structural Hypervariability of the Two
           Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex

    • Authors: Karsten Niefind, Nils Bischoff, Andriy Golub, Volodymyr Bdzhola, Anatoliy Balanda, Andriy Prykhod’ko, Sergiy Yarmoluk
      First page: 9
      Abstract: Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations.
      PubDate: 2017-01-11
      DOI: 10.3390/ph10010009
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 10: Acknowledgement to Reviewers of
           Pharmaceuticals in 2016

    • Authors: Pharmaceuticals Editorial Office
      First page: 10
      Abstract: The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.
      PubDate: 2017-01-10
      DOI: 10.3390/ph10010010
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 11: Exploring the CK2 Paradox: Restless,
           Dangerous, Dispensable

    • Authors: Cinzia Franchin, Christian Borgo, Silvia Zaramella, Luca Cesaro, Giorgio Arrigoni, Mauro Salvi, Lorenzo Pinna
      First page: 11
      Abstract: The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined.
      PubDate: 2017-01-20
      DOI: 10.3390/ph10010011
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 12: 188Re(V) Nitrido Radiopharmaceuticals
           for Radionuclide Therapy

    • Authors: Alessandra Boschi, Petra Martini, Licia Uccelli
      First page: 12
      Abstract: The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is readily available from an 188W/188Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications.
      PubDate: 2017-01-19
      DOI: 10.3390/ph10010012
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 13: Ablation of Protein Kinase CK2β in
           Skeletal Muscle Fibers Interferes with Their Oxidative Capacity

    • Authors: Nane Eiber, Luca Simeone, Said Hashemolhosseini
      First page: 13
      Abstract: The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers. Hind limb muscles gastrocnemius, plantaris, and soleus of adult wildtype and CK2β-deficient mice were dissected, cross-sectioned, and stained histochemically by Gomori trichrome and for nicotinamide adenine dinucleotide (NADH) dehydrogenase and succinate dehydrogenase (SDH) enzymatic activities. A reduction of oxidative enzymatic activity was determined for CK2β-deficient muscle fibers in comparison with wildtype controls. Importantly, the CK2β-deficient fibers, muscle fibers that typically exhibit high NADH dehydrogenase and SDH activities, like slow-type fibers, showed a marked reduction in these activities. Altogether, our data indicate additional impairments in the absence of CK2β in skeletal muscle fibers, pointing to an eventual mitochondrial myopathy.
      PubDate: 2017-01-19
      DOI: 10.3390/ph10010013
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 14: Aptamers in Bordeaux, 24–25 June

    • Authors: Jean-Jacques Toulmé, Paloma Giangrande, Günter Mayer, Beatrix Suess, Frédéric Ducongé, Bruce Sullenger, Vittorio de Franciscis, Fabien Darfeuille, Eric Peyrin
      First page: 14
      Abstract: The symposium covered the many different aspects of the selection and the characterization of aptamers as well as their application in analytical, diagnostic and therapeutic areas. Natural and artificial riboswitches were discussed. Recent advances for the design of mutated polymerases and of chemically modified nucleic acid bases that provide aptamers with new properties were presented. The power of aptamer platforms for multiplex analysis of biomarkers of major human diseases was described. The potential of aptamers for the treatment of cancer or cardiovascular diseases was also presented. Brief summaries of the lectures presented during the symposium are given in this report. A second edition of “Aptamers in Bordeaux” will take place on September 2017 (
      PubDate: 2017-01-20
      DOI: 10.3390/ph10010014
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 15: Relationship between Surface
           Properties and In Vitro Drug Release from Compressed Matrix Containing
           Polymeric Materials with Different Hydrophobicity Degrees

    • Authors: Cristhian Yarce, Juan Echeverri, Mario Palacio, Carlos Rivera, Constain Salamanca
      First page: 15
      Abstract: This work is the continuation of a study focused on establishing relations between surface thermodynamic properties and in vitro release mechanisms using a model drug (ampicillin trihydrate), besides analyzing the granulometric properties of new polymeric materials and thus establishing the potential to be used in the pharmaceutical field as modified delivery excipients. To do this, we used copolymeric materials derived from maleic anhydride with decreasing polarity corresponding to poly(isobutylene-alt-maleic acid) (hydrophilic), sodium salt of poly(maleic acid-alt-octadecene) (amphiphilic), poly(maleic anhydride-alt-octadecene) (hydrophobic) and the reference polymer hydroxyl-propyl-methyl-cellulose (HPMC). Each material alone and in blends underwent spectroscopic characterization by FTIR, thermal characterization by DSC and granulometric characterization using flow and compaction tests. Each tablet was prepared at different polymer ratios of 0%, 10%, 20%, 30% and 40%, and the surface properties were determined, including the roughness by micro-visualization, contact angle and water absorption rate by the sessile drop method and obtaining Wadh and surface free energy (SFE) using the semi-empirical models of Young–Dupré and  Owens-Wendt-Rabel-Käelbe (OWRK), respectively. Dissolution profiles were determined simulating physiological conditions in vitro, where the kinetic models of order-zero, order-one, Higuchi and Korsmeyer–Peppas were evaluated. The results showed a strong relationship between the proportion and nature of the polymer to the surface thermodynamic properties and kinetic release mechanism.
      PubDate: 2017-01-24
      DOI: 10.3390/ph10010015
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 16: In Search of Small Molecule Inhibitors
           Targeting the Flexible CK2 Subunit Interface

    • Authors: Benoît Bestgen, Zakia Belaid-Choucair, Thierry Lomberget, Marc Le Borgne, Odile Filhol, Claude Cochet
      First page: 16
      Abstract: Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way.
      PubDate: 2017-02-03
      DOI: 10.3390/ph10010016
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 17: “The 24th Conference” of the
           Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A)

    • Authors: Jean-Jacques Hélesbeux, Olivier Duval
      First page: 17
      Abstract: The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity relationships. s of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collated in this report.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010017
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 18: CK2 in Cancer: Cellular and
           Biochemical Mechanisms and Potential Therapeutic Target

    • Authors: Melissa Chua, Charina Ortega, Ayesha Sheikh, Migi Lee, Hussein Abdul-Rassoul, Kevan Hartshorn, Isabel Dominguez
      First page: 18
      Abstract: CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer including inhibition of apoptosis, modulation of signaling pathways, DNA damage response, and cell cycle regulation. A number of CK2 inhibitors are now available and have been shown to have activity against various cancers in vitro and in pre-clinical models. Some of these inhibitors are now undergoing exploration in clinical trials as well. In this review, we will examine some of the major cancers in which CK2 inhibition has promise based on in vitro and pre-clinical studies, the proposed cellular and signaling mechanisms of anti-cancer activity by CK2 inhibitors, and the current or recent clinical trials using CK2 inhibitors.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010018
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 19: Barriers to the Access of Bevacizumab
           in Patients with Solid Tumors and the Potential Impact of Biosimilars: A
           Physician Survey

    • Authors: Bradley Monk, Philip Lammers, Thomas Cartwright, Ira Jacobs
      First page: 19
      Abstract: Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non–small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they “definitely” or “probably” would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010019
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 20: Second International Electronic
           Conference on Medicinal Chemistry (ECMC-2)

    • Authors: Annie Mayence, Jean Eynde
      First page: 20
      Abstract: The second International Electronic Conference on Medicinal Chemistry, organized and sponsored by the publisher MDPI AG and the Journal Pharmaceuticals, took place in November 2016 on the SciForum website ( More than 150 authors from 22 countries participated in the event. Selected works presented during the scientific meeting are disclosed in this report.
      PubDate: 2017-01-31
      DOI: 10.3390/ph10010020
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 21: The Link between Protein Kinase CK2
           and Atypical Kinase Rio1

    • Authors: Konrad Kubiński, Maciej Masłyk
      First page: 21
      Abstract: The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors.
      PubDate: 2017-02-07
      DOI: 10.3390/ph10010021
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 22: Inhibition of Protein Kinase CK2
           Prevents Adipogenic Differentiation of Mesenchymal Stem Cells Like
           C3H/10T1/2 Cells

    • Authors: Lisa Schwind, Sarah Schetting, Mathias Montenarh
      First page: 22
      Abstract: Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. Mesenchymal stem cells (MSCs) are multipotent cells which can be differentiated into adipocytes in vitro. Thus, MSCs and in particular C3H/10T1/2 cells are excellent tools to study a possible role of CK2 in adipogenesis. We found downregulation of the CK2 catalytic subunits as well as a decrease in CK2 kinase activity with progression of differentiation. Inhibition of CK2 using the potent inhibitor CX-4945 impeded differentiation of C3H/10T1/2 cells into adipocytes. The inhibited cells lacked the observed decrease in CK2 expression, but showed a constant expression of all three CK2 subunits. Furthermore, inhibition of CK2 resulted in decreased cell proliferation in the early differentiation phase. Analysis of the main signaling cascade revealed an elevated expression of C/EBPβ and C/EBPδ and reduced expression of the adipogenic master regulators C/EBPα and PPARγ2. Thus, CK2 seems to be implicated in the regulation of different steps early in the adipogenic differentiation of MSC.
      PubDate: 2017-02-09
      DOI: 10.3390/ph10010022
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 23: RNA-Eluting Surfaces for the
           Modulation of Gene Expression as A Novel Stent Concept

    • Authors: Olivia Koenig, Diane Zengerle, Nadja Perle, Susanne Hossfeld, Bernd Neumann, Andreas Behring, Meltem Avci-Adali, Tobias Walker, Christian Schlensak, Hans Wendel, Andrea Nolte
      First page: 23
      Abstract: Presently, a new era of drug-eluting stents is continuing to improve late adverse effects such as thrombosis after coronary stent implantation in atherosclerotic vessels. The application of gene expression–modulating stents releasing specific small interfering RNAs (siRNAs) or messenger RNAs (mRNAs) to the vascular wall might have the potential to improve the regeneration of the vessel wall and to inhibit adverse effects as a new promising therapeutic strategy. Different poly (lactic-co-glycolic acid) (PLGA) resomers for their ability as an siRNA delivery carrier against intercellular adhesion molecule (ICAM)-1 with a depot effect were tested. Biodegradability, hemocompatibility, and high cell viability were found in all PLGAs. We generated PLGA coatings with incorporated siRNA that were able to transfect EA.hy926 and human vascular endothelial cells. Transfected EA.hy926 showed significant siICAM-1 knockdown. Furthermore, co-transfection of siRNA and enhanced green fluorescent protein (eGFP) mRNA led to the expression of eGFP as well as to the siRNA transfection. Using our PLGA and siRNA multilayers, we reached high transfection efficiencies in EA.hy926 cells until day six and long-lasting transfection until day 20. Our results indicate that siRNA and mRNA nanoparticles incorporated in PLGA films have the potential for the modulation of gene expression after stent implantation to achieve accelerated regeneration of endothelial cells and to reduce the risk of restenosis.
      PubDate: 2017-02-10
      DOI: 10.3390/ph10010023
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 24: Targeting Protein Kinase CK2:
           Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in
           Immunocompetent Mice

    • Authors: Laura Ferrer-Font, Lucia Villamañan, Nuria Arias-Ramos, Jordi Vilardell, Maria Plana, Maria Ruzzene, Lorenzo Pinna, Emilio Itarte, Carles Arús, Ana Candiota
      First page: 24
      Abstract: Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.
      PubDate: 2017-02-12
      DOI: 10.3390/ph10010024
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 25: CK2 Molecular Targeting—Tumor
           Cell-Specific Delivery of RNAi in Various Models of Cancer

    • Authors: Janeen Trembley, Betsy Kren, Md. Abedin, Rachel Vogel, Claire Cannon, Gretchen Unger, Khalil Ahmed
      First page: 25
      Abstract: Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells. The latter is particularly important since CK2 is a ubiquitous signal that is essential for survival. To achieve these goals, we have developed a nanocapsule that has the properties of delivering an anti-CK2 RNAi therapeutic cargo, in a protected manner, specifically to cancer cells. Tenfibgen (TBG) is used as the ligand to target tenascin-C receptors, which are elevated in cancer cells. This strategy is effective for inhibiting growth and inducing death in several types of xenograft tumors, and the nanocapsule elicits no safety concerns in animals. Further investigation of this therapeutic approach for its translation is warranted.
      PubDate: 2017-02-21
      DOI: 10.3390/ph10010025
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 26: The Development of CK2 Inhibitors:
           From Traditional Pharmacology to in Silico Rational Drug Design

    • Authors: Giorgio Cozza
      First page: 26
      Abstract: Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising.
      PubDate: 2017-02-20
      DOI: 10.3390/ph10010026
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 27: Protein Kinase CK2: Intricate
           Relationships within Regulatory Cellular Networks

    • Authors: Teresa Nuñez de Villavicencio-Diaz, Adam Rabalski, David Litchfield
      First page: 27
      Abstract: Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory participant in intricately controlled cellular processes. To resolve this apparent paradox, we have performed a systematic analysis of the published literature using text mining as well as mining of proteomic databases together with computational assembly of networks that involve CK2. These analyses reinforce the notion that CK2 is involved in a broad variety of biological processes and also reveal an extensive interplay between CK2 phosphorylation and other post-translational modifications. The interplay between CK2 and other post-translational modifications suggests that CK2 does have intricate roles in orchestrating cellular events. In this respect, phosphorylation of specific substrates by CK2 could be regulated by other post-translational modifications and CK2 could also have roles in modulating other post-translational modifications. Collectively, these observations suggest that the actions of CK2 are precisely coordinated with other constituents of regulatory cellular networks.
      PubDate: 2017-03-05
      DOI: 10.3390/ph10010027
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 28: Targeted Drugs as Maintenance Therapy
           after Autologous Stem Cell Transplantation in Patients with Mantle Cell

    • Authors: Fengting Yan, Ajay Gopal, Solomon Graf
      First page: 28
      Abstract: The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL.
      PubDate: 2017-03-10
      DOI: 10.3390/ph10010028
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 29: Theranostic Value of Multimers:
           Lessons Learned from Trimerization of Neurotensin Receptor Ligands and
           Other Targeting Vectors

    • Authors: Simone Maschauer, Jürgen Einsiedel, Dominik Reich, Harald Hübner, Peter Gmeiner, Hans-Jürgen Wester, Olaf Prante, Johannes Notni
      First page: 29
      Abstract: Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target for the diagnosis of these cancers types by positron emission tomography (PET) [...]
      PubDate: 2017-03-10
      DOI: 10.3390/ph10010029
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 30: Current Status of Radiopharmaceuticals
           for the Theranostics of Neuroendocrine Neoplasms

    • Authors: Melpomeni Fani, Petra Peitl, Irina Velikyan
      First page: 30
      Abstract: : Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
      PubDate: 2017-03-15
      DOI: 10.3390/ph10010030
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 31: Anacardic Acid Constituents from
           Cashew Nut Shell Liquid: NMR Characterization and the Effect of
           Unsaturation on Its Biological Activities

    • Authors: Selene Morais, Katherine Silva, Halisson Araujo, Icaro Vieira, Daniela Alves, Raquel Fontenelle, Artur Silva
      First page: 31
      Abstract: Anacardic acids are the main constituents of natural cashew nut shell liquid (CNSL), obtained via the extraction of cashew shells with hexane at room temperature. This raw material presents high technological potential due to its various biological properties. The main components of CNSL are the anacardic acids, salicylic acid derivatives presenting a side chain of fifteen carbon atoms with different degrees of unsaturation (monoene–15:1, diene–15:2, and triene–15:3). Each constituent was isolated by column chromatography using silica gel impregnated with silver nitrate. The structures of the compounds were characterized by nuclear magnetic resonance through complete and unequivocal proton and carbon assignments. The effect of the side chain unsaturation was also evaluated in relation to antioxidant, antifungal and anticholinesterase activities, and toxicity against Artemia salina. The triene anacardic acid provided better results in antioxidant activity assessed by the inhibition of the free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), higher cytotoxicity against A. salina, and acetylcholinesterase (AChE) inhibition. Thus, increasing the unsaturation of the side chain of anacardic acid increases its action against free radicals, AChE enzyme, and A. salina nauplii. In relation to antifungal activity, an inverse result was obtained, and the linearity of the molecule plays an important role, with monoene being the most active. In conclusion, the changes in structure of anacardic acids, which cause differences in polarity, contribute to the increase or decrease in the biological activity assessed.
      PubDate: 2017-03-16
      DOI: 10.3390/ph10010031
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 32: Aptamers: Biomedical Interest and

    • Authors: Cristina Romero-López, Alfredo Berzal-Herranz
      First page: 32
      Abstract: Aptamers are short DNA or RNA oligonucleotides specialized in the specific and efficient binding to a target molecule. They are obtained by in vitro selection or evolution processes. It was in 1990 that two independent research groups described the bases of a new in vitro technology for the identification of RNA molecules able to specifically bind to a target [1,2]. Tuerk and Gold established the principals of the in vitro selection process that was named SELEX (Systematic Evolution of Ligands by Exponential enrichment), which is based on iterative cycles of binding, partitioning, and amplification of oligonucleotides from a pool of variant sequences [2]. Ellington and Szostak coined the term aptamer to define the selected molecules by the application of this method [1]. To date, numerous reports have described the isolation of aptamers directed against a great variety of targets covering a wide diversity of molecules varying in nature, size, and complexity ranging from ions to whole cells, including small molecules (e.g., aminoacids, nucleotides, antibiotics), peptides, proteins, nucleic acids, and viruses, among others (for example, see [3–6]). Modifications and optimization of the SELEX procedure aimed to get newly modified aptamers has also attracted much interest (examples can be found in [7,8]). These advances along with the parallel progresses in the nucleic acids chemistry and cellular delivery fields have allowed for the rise of a new hope in developing aptamers as efficient molecular tools for diagnostics and therapeutics (for recent comprehensive reviews, see [9–11]).
      PubDate: 2017-03-16
      DOI: 10.3390/ph10010032
      Issue No: Vol. 10, No. 1 (2017)
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