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  Subjects -> CHEMISTRY (Total: 895 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (629 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (43 journals)
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    - PHYSICAL CHEMISTRY (71 journals)

CHEMISTRY (629 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 28)
ACS Catalysis     Hybrid Journal   (Followers: 44)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 22)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 26)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 42)
ACS Nano     Hybrid Journal   (Followers: 305)
ACS Photonics     Hybrid Journal   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 8)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 60)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 73)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 23)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Environmental Chemistry     Open Access   (Followers: 7)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 26)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Polymer Science     Hybrid Journal   (Followers: 45)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 8)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alchemy : Journal of Chemistry     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 69)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 32)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 16)
Anadolu University Journal of Science and Technology A : Applied Sciences and Engineering     Open Access  
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 180)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 258)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 24)
Applied Surface Science     Hybrid Journal   (Followers: 32)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 3)
Asian Journal of Chemistry and Pharmaceutical Sciences     Open Access  
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 3)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry     Hybrid Journal   (Followers: 379)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 11)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Hybrid Journal   (Followers: 22)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 140)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 88)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 11)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 70)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 11)
Cellulose     Hybrid Journal   (Followers: 9)
Cereal Chemistry     Full-text available via subscription   (Followers: 5)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 22)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 75)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 27)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 206)
Chemical Science     Open Access   (Followers: 27)
Chemical Technology     Open Access   (Followers: 32)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 33)
Chemistry & Industry     Hybrid Journal   (Followers: 8)
Chemistry - A European Journal     Hybrid Journal   (Followers: 166)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Open Access   (Followers: 3)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Hybrid Journal   (Followers: 268)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 20)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 12)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 23)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Cogent Chemistry     Open Access   (Followers: 2)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 4)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 7)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 8)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 9)
Current Science     Open Access   (Followers: 73)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 4)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)

        1 2 3 4 | Last

Journal Cover
Biochemical Pharmacology
Journal Prestige (SJR): 1.832
Citation Impact (citeScore): 5
Number of Followers: 11  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0006-2952
Published by Elsevier Homepage  [3155 journals]
  • Lung cancer stem cells: origin, features, maintenance mechanisms and
           therapeutic targeting
    • Abstract: Publication date: Available online 14 December 2018Source: Biochemical PharmacologyAuthor(s): Win Sen Heng, Reinoud Gosens, Frank A.E. Kruyt Lung cancer remains the leading cause of cancer-related deaths despite recent breakthroughs in immunotherapy. The widely embraced cancer stem cell (CSC) theory has also been applied for lung cancer, postulating that an often small proportion of tumor cells with stem cell properties are responsible for tumor growth, therapeutic resistance and metastasis. The identification of these CSCs and underlying molecular maintenance mechanisms is considered to be absolutely necessary for developing therapies for their riddance, hence achieving remission. In this review, we will critically address the CSC concept in lung cancer and its advancement thus far. We will describe both normal lung stem cells and their malignant counterparts in order to identify common aspects with respect to their emergence and regulation. Subsequently, the importance of CSCs and their molecular features in lung cancers will be discussed in a preclinical and clinical context. We will highlight some examples on how lung CSCs attain stemness through different molecular modifications and cellular assistance from the tumor microenvironment. The exploitation of these mechanistic features for the development of pharmacological therapy will also be discussed. In summary, the validity of the CSC concept has been evidenced by various studies. Ongoing research to identify molecular mechanisms driving lung CSC have revealed potential new cell intrinsic as well as tumor microenvironment-derived therapeutic targets. Although successfully demonstrated in preclinical models, the clinical benefit of lung CSC targeted therapies has thus far not been demonstrated. Therefore, further research to validate the therapeutic value of CSC concept is required.Graphical abstractGraphical scheme explaining the emergence of lung CSC during regenerative activity in response to injury. Progressive damage leads to chronic inflammation and maintained stem cell activity yielding cancer stem cell.Graphical abstract for this article
       
  • Inositol hexakisphosphate increases the size of platelet aggregates
    • Abstract: Publication date: Available online 14 December 2018Source: Biochemical PharmacologyAuthor(s): Maria A. Brehm, Ulrike Klemm, Christoph Rehbach, Nina Erdmann, Katra Kolšek, Hongying Lin, Camilo Aponte-Santamaría, Frauke Gräter, Bernhard H. Rauch, Andrew M. Riley, Georg W. Mayr, Barry V.L. Potter, Sabine Windhorst The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane.Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. This effect is fibrinogen-dependent, since it is inhibited by an antibody that blocks fibrinogen binding to platelets. Furthermore, InsP6 has only an effect on aggregate size of washed platelets when fibrinogen is present, while it has no influence in presence of von Willebrand factor or collagen. By employing blind docking studies we predicted the binding site for InsP6 at the bundle between the γ and β helical subunit of fibrinogen.Since InsP6 is unable to directly activate platelets and it did not exhibit an effect on thrombin formation or fibrin structure, our data indicate that InsP6 might be a hemostatic agent that is produced by platelets upon stimulation with PLC-activating agonists to promote platelet aggregation by supporting crosslinking of fibrinogen and activated platelets.Graphical abstractGraphical abstract for this article
       
  • Development of a novel, sensitive cell-based Corin Assay
    • Abstract: Publication date: Available online 13 December 2018Source: Biochemical PharmacologyAuthor(s): Pascal Lambertz, Laura Theisen, Natalie Längst, Colin W. Garvie, Bryan T. MacDonald, John Yu, Nadine H. Elowe, Dmitry Zubov, Virendar K. Kaushik, Frank Wunder Corin (atrial natriuretic peptide-converting enzyme, EC 3.4.21) is a transmembrane serine protease expressed in cardiomyocytes. Corin exerts its cardioprotective effects via the proteolytic cleavage and activation of pro-atrial natriuretic peptide (pro-ANP) to ANP. We recently described an ANP reporter cell line stably expressing the ANP receptor, a cGMP-dependent cation channel used as a real-time cGMP biosensor, and the Ca2+-sensitive photoprotein aequorin. Here, we describe the generation of a novel reporter cell line expressing the calcium biosensor GCaMP6 instead of aequorin. In contrast to the luminescence-based assay, ANP stimulation of our novel GCaMP6 reporter cell resulted in stable, long-lasting fluorescence signals. Using this novel reporter system, we were able to detect pro-ANP to ANP conversion by purified, soluble wildtype corin (solCorin), but not the active site mutant solCorin(S985A), resulting in left-shifted concentration-response curves. Furthermore, cellular pro-ANPase activity could be detected on HEK 293 cells after transient expression of wildtype corin. In contrast, corin activity was not detected after transfection with the inactive corin(S985A) variant. In supernatants from cardiomyocyte-derived HL-1 cells pro-ANP to ANP conversion could also be detected, while in HL-1 corin knockout cells no conversion was observed. These findings underline the role of corin as the pro-ANP convertase. Our novel fluorescence-based ANP reporter cell line is well-suited for the sensitive detection of corin activity, and may be used for the identification and characterization of novel corin modulators.Graphical abstractGraphical abstract for this article
       
  • Darpp-32 and t-Darpp protein products of PPP1R1B: old dogs with new tricks
    • Abstract: Publication date: Available online 12 December 2018Source: Biochemical PharmacologyAuthor(s): By Arabo Avanes, Gal Lenz, Jamil Momand The PPP1R1B gene is located on chromosome 17q12 (39,626,208-39,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (Dopamine and cAMP Regulated Phosphoprotein), discovered in the early 1980s, is a protein whose phosphorylation is upregulated in response to cAMP in dopamine-responsive tissues in the brain. It’s phosphorylation profile modulates its ability to bind and inhibit Protein Phosphatase 1 activity, which, in turn, controls the activity of hundreds of phosphorylated proteins. PPP1R1B knockout mice exhibit subtle learning defects. In 2002, the second protein product of PPP1R1B was discovered in gastric cancers: t-Darpp (truncated Darpp-32). The start codon of t-Darpp is amino acid residue 37 of Darpp-32 and it lacks the domain responsible for modulating Protein Phosphatase 1. Aside from gastric cancers, t-Darpp and/or Darpp-32 is overexpressed in tumor cells from breast, colon, esophagus, lung and prostate tissues. More than one research team has demonstrated that these proteins, through mechanisms that to date remain cloudy, activate AKT, a protein whose phosphorylation leads to cell survival and blocks apoptosis. Furthermore, in Her2 positive breast cancers (an aggressive form of breast cancer), t-Darpp/Darpp-32 overexpression causes resistance to the frequently-administered anti-Her2 drug, trastuzumab (Herceptin), likely through AKT activation. Here we briefly describe how Darpp-32 and t-Darpp were discovered and report on the current state of knowledge of their involvement in cancers. We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter.Graphical abstractGraphical abstract for this article
       
  • A new human pyridinium metabolite of furosemide, inhibitor of
           mitochondrial complex I, is a candidate inducer of neurodegeneration
    • Abstract: Publication date: Available online 8 December 2018Source: Biochemical PharmacologyAuthor(s): Céline Laurencé, Narimane Zeghbib, Michael Rivard, Sonia Lehri-Boufala, Isabelle Lachaise, Caroline Barau, Philippe Le Corvoisier, Thierry Martens, Laure Garrigue-Antar, Christophe Morin Pharmaceuticals and their by-products are increasingly a matter of concern, because of their unknown impacts on human health and ecosystems. The lack of information on these transformation products, which toxicity may exceed that of their parent molecules, makes their detection and toxicological evaluation impossible.Recently we characterized the Pyridinium of furosemide (PoF), a new transformation product of furosemide, the most widely used diuretic and an emerging pollutant. Here, we reveal PoF toxicity in SH-SY5Y cells leading to alpha-synuclein accumulation, reactive oxygen species generation, and apoptosis. We also showed that its mechanism of action is mediated through specific inhibition of striatal respiratory chain complex I, both in vitro by direct exposure of striatum mitochondria to PoF, and in vivo, in striatal mitochondria isolated from mice exposed to PoF for 7 days in drinking water and sacrificed 30 days later. Moreover, in mice, PoF induced neurodegenerative diseases hallmarks like phospho-Serine129 alpha-synuclein, tyrosine hydroxylase decrease in striatum, Tau accumulation in hippocampus. Finally, we uncovered PoF as a new metabolite of furosemide present in urine of patients treated with this drug by LC/MS. As a physiopathologically relevant neurodegeneration inducer, this new metabolite warrants further studies in the framework of public health and environment protection.Graphical abstractGraphical abstract for this article
       
  • The pyrrolopyrimidine colchicine-binding site agent PP-13 reduces the
           metastatic dissemination of invasive cancer cells in vitro and in vivo
    • Abstract: Publication date: Available online 7 December 2018Source: Biochemical PharmacologyAuthor(s): Pauline Gilson, Morgane Couvet, Laetitia Vanwonterghem, Maxime Henry, Julien Vollaire, Vladimir Baulin, Marco Werner, Anna Orlowska, Véronique Josserand, Florence Mahuteau-Betzer, Laurence Lafanechère, Jean-Luc Coll, Benoit Busser, Amandine Hurbin Standard chemotherapies that interfere with microtubule dynamics are a chemotherapeutic option used for the patients with advanced malignancies that invariably relapse after targeted therapies. However, major efforts are needed to reduce their toxicity, optimize their efficacy, and reduce cancer chemoresistance to these agents. We previously identified a pyrrolo[2,3d]pyrimidine-based microtubule-depolymerizing agent (PP-13) that binds to the colchicine site of β-tubulin and exhibits anticancer properties in solid human cancer cells, including chemoresistant subtypes. Here, we investigated the therapeutic potential of PP-13 in vitro and in vivo. PP-13 induced a mitotic blockade and apoptosis in several cancer cells cultured in two-dimensions or three-dimensions spheroids, in conjunction with reduced cell proliferation. Capillary-like tube formation assays using HUVECs showed that PP-13 displayed antiangiogenic properties. It also inhibited cancer cell motility and invasion, in in vitro wound-healing and transwell migration assays. Low concentration PP-13 (130 nmol.L-1) treatment significantly reduced the metastatic invasiveness of human cancer cells engrafts on chicken chorioallantoic membrane. In nude mice, 0.5 or 1 mg.kg-1 PP-13 intraperitoneally administered three-times a week reduced the sizes of paclitaxel-refractory orthotopic breast tumors, delayed the progression of metastasis, and decreased the global metastatic load compared to 0.5 mg.kg-1 paclitaxel or vehicle alone. PP-13 did not show any apparent early adverse effect in vivo. These data suggest that PP-13 is a promising alternative to standard chemotherapy in antimitotic drug-refractory tumors, especially through its impact on metastasis.Graphical abstractGraphical abstract for this article
       
  • Loperamide overcomes the resistance of colon cancer cells to bortezomib by
           inducing CHOP-mediated paraptosis-like cell death
    • Abstract: Publication date: Available online 7 December 2018Source: Biochemical PharmacologyAuthor(s): In Young Kim, Min June Shim, Dong Min Lee, A Reum Lee, Mi Ae Kim, Mi Jin Yoon, Mi Ri Kwon, Hae In Lee, Min Ji Seo, Yong Won Choi, Kyeong Sook Choi Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front-line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes various colon cancer cells, but not normal epithelial cells, to PI-mediated cell death. We report that combined treatment with Btz and Lop induces paraptosis-like cell death accompanied by severe endoplasmic reticulum (ER)-derived vacuolation. Furthermore, Lop potentiates Btz-mediated ER stress and ER dilation due to misfolded protein accumulation and Ca2+ imbalance, leading to CHOP upregulation and subsequent paraptosis-like cell death. Taken together, our results show for the first time that a combined regimen of PI and Lop may provide an effective and safe therapeutic strategy against solid tumors, including colon cancer, by enhancing the sensitivity to PIs and reducing the side effects of such treatment.Graphical abstractGraphical abstract for this article
       
  • Alcohol-induced ketonemia is associated with lowering of blood glucose,
           downregulation of gluconeogenic genes, and depletion of hepatic glycogen
           in type 2 diabetic db/db mice
    • Abstract: Publication date: Available online 7 December 2018Source: Biochemical PharmacologyAuthor(s): Mukund P. Srinivasan, Noha M. Shawky, Bhupendra S. Kaphalia, Muthusamy Thangaraju, Lakshman Segar Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., β-hydroxybutyrate; βOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9 days resulted in significant decreases in weight gain (∼19.5% ↓) and caloric intake (∼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (∼37% ↑). Importantly, we observed that ethanol increased systemic βOHB concentration (∼8-fold ↑) with significant decreases in blood glucose (∼ 4 fold ↓) and plasma insulin and HOMA-IR index (∼3 fold ↓). In addition, ethanol enhanced hepatic βOHB content (∼5 fold ↑) and hmgcs2 mRNA expression (∼3.7 fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (∼4 fold ↓). Furthermore, ethanol intake significantly decreased mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3β, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.Graphical abstractAlcohol enhances systemic ketone (e.g., βOHB) with an accompanying lowering of glucose in type 2 diabetic db/db mice. The reduction in blood glucose is associated with downregulation of gluconeogenic genes and depletion of glycogen in the liver.Graphical abstract for this article
       
  • Effects of inorganic nanoparticles on liver fibrosis: Optimizing a
           double-edged sword for therapeutics
    • Abstract: Publication date: Available online 6 December 2018Source: Biochemical PharmacologyAuthor(s): Jie Kai Tee, Fei Peng, Han Kiat Ho Liver fibrosis is a condition of sustained wound healing in response to chronic liver injury caused by various factors such as viral, cholestatic and inflammatory diseases. Despite significant advances in the understanding of the mechanistic details of fibrosis, therapeutic intervention with the use of anti-fibrotic drugs achieved only marginal efficacy. Among which, pharmacokinetics profile of agents leading to off-targeting and suboptimal distribution are the principal limiting factors. Concurrently, inorganic nanoparticles (NPs) have gained significant recognition in biomedicine, owning to their unique physicochemical properties. Since NPs are known to accumulate in well vascularised organs, the intuitive therapeutic targeting of the liver using engineered NPs seems to be a plausible approach in treating liver fibrosis. However, the application of inorganic NPs also raised concerns of its potential long-term impact to humans. Current literatures have reported both negative risks as well as surprising benefits, thus sparking off a needful discussion about the feasibility of using inorganic NPs in treating liver fibrosis. Inorganic NPs entrapped in the liver may pose health risks, particularly due to their non-biodegradability and potential toxicity when accumulated in undesirable concentrations. This highlighted the need to assess the health risk of using inorganic NPs, and also to establish a framework to evaluate the conditions when the beneficial effects of these NPs would outweigh potential risks. Hence, this review takes a balanced approach on assessing the mechanistic details behind inorganic NP-induced biochemical perturbations, which could either alleviate or worsen liver fibrosis. Consequently, it attempts to chart out possibilities for future directions through optimizing therapeutics outcome by design.
       
  • Targeting the DNA-PK complex: its rationale use in cancer and HIV-1
           infection
    • Abstract: Publication date: Available online 6 December 2018Source: Biochemical PharmacologyAuthor(s): C. Schwartz, O. Rohr, C. Wallet The DNA-PK complex is the major component of the predominant mechanism of DSB repair in humans. In addition, this complex is involved in many other processes such as DNA recombination, genome maintenance, apoptosis and transcription regulation. Several studies have linked the decrease of the DNA-PK activity with cancer initiation, due to defects in the repair. On another hand, higher DNA-PK expression and activity have been observed in various other tumor cells and have been linked with a decrease of the efficiency of anti-tumor drugs. It has also been shown that DNA-PK is critical for the integration of the HIV-1 DNA into the cell host genome and promotes replication and transcription of the virus.Targeting this complex makes therefore sense to treat these two pathologies. However, according to the status of HIV-1 replication (active versus latent replication) or to the tumor grade cells (initiation versus metastasis), the way to target this DNA-PK complex might be rather different. In this review, we discuss the importance of DNA-PK complex in two major pathologies i.e. HIV-1 infection and cancer, and the rationale use of therapies aiming to target this complex.Graphical abstractGraphical abstract for this article
       
  • Promising neuroprotective effects of β–caryophyllene against
           LPS-induced oligodendrocyte toxicity: A mechanistic study
    • Abstract: Publication date: Available online 5 December 2018Source: Biochemical PharmacologyAuthor(s): Vahid Reza Askari, Reza Shafiee–Nick Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS–induced oligodendrocytes toxicity may be chosen as an efficient model to evaluate the role of oligodendrocytes in neuroprotective activities of compounds. β–caryophyllene (BCP) is a selective type 2 cannabinoid (CB2) receptor agonist. However, the mechanisms underlying the anti-inflammatory effects of BCP are not completely understood. On this basis, we aimed to investigate the protective effects of a wide range of BCP concentrations against LPS-induced toxicity in a proliferative oligodendrocyte cell line (OLN-93) and evaluate the possible correlation between BCP concentration and selective modulation of CB2, Nrf2, sphingomyelinase (SMase) and peroxisome proliferator-activated receptors (PPAR)-γ signaling pathways. We found that LPS significantly increases the levels of reactive oxygen species (ROS), nitric oxide (NO) metabolite and tumor necrosis factor (TNF)–α production while decreases the level of GSH. BCP could prevent LPS-induced cytotoxicity and excessive production of NO, ROS, and TNF–α. Also, we demonstrated that BCP’s protective effects against LPS–induced oligodendrocytes toxicity were mediated via the CB2 receptor through different pathways including Nrf2/HO–1/anti–oxidant axis, and PPAR–γ, at low (0.2 and 1 µM), and high (10–50 µM) concentrations, respectively. Additionally, we observed that the addition of SMase inhibitors imipramine (IMP) and fluoxetine (FLX) synergistically increased the protective effects of BCP. Finally, BCP at low concentrations exerted promising protective effects that could be considered for the treatment of neurodegenerative disorders such as MS. However, more studies using other models of neurodegenerative diseases should be undertaken to assess different parameters such as the activity or expression of SMase.Graphical abstractGraphical abstract for this article
       
  • Human AHR functions in vascular tissue: Pro- and anti-inflammatory
           responses of AHR agonists in atherosclerosis
    • Abstract: Publication date: Available online 1 December 2018Source: Biochemical PharmacologyAuthor(s): Karl Walter Bock Despite decades of intense research physiologic aryl hydrocarbon receptor (AHR) functions have not been elucidated. Challenges include marked species differences and dependence on cell type and cellular context. A previous commentary on human AHR functions in skin and intestine has been extended to vascular tissue. Similar functions appear to be operating in vascular tissue including microbial defense, modulation of stem/progenitor cells as well as control of immunity and inflammation. However, AHR functions are Janus faced: Detrimental AHR functions in vascular tissue are well documented, e.g., upon exposure to polycyclic aromatic hydrocarbons in cigarette smoke leading to oxidative stress and generation of oxidized LDL. Modified LDL particles accumulate in macrophages and smooth muscle-derived pro-inflammatory foam cells, the hallmark of atherosclerosis. On the other hand, numerous anti-inflammatory AHR agonists have been identified including bilirubin and quercetin. Mechanisms as to how AHR produces pro- and anti-inflammatory responses in the vascular system need further investigation.Graphical abstractGraphical abstract for this article
       
  • Mitochondria targeting to oppose the progression of nonalcoholic fatty
           liver disease
    • Abstract: Publication date: Available online 30 November 2018Source: Biochemical PharmacologyAuthor(s): Ignazio Grattagliano, Liliana P. Montezinho, Paulo J. Oliveira, Gema Frühbeck, Javier Gómez-Ambrosi, Fabrizio Montecucco, Federico Carbone, Mariusz R. Wieckowski, David Q.-H. Wang, Piero Portincasa Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the excessive accumulation of triglycerides in hepatocytes. NAFLD is the most frequent chronic liver disease in developed countries, and is often associated with metabolic disorders such as obesity and type 2 diabetes. NAFLD definition encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL), to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, therefore, represents a global public health issue. Mitochondrial dysfunction occurs in NAFLD, and contributes to the progression to the necro-inflammatory and fibrotic form (NASH). Disrupted mitochondrial function is associated with a decrease in the energy levels and impaired redox balance, and negatively affects cell survival by altering overall metabolism and subcellular trafficking. Such events reduce the tolerance of hepatocytes towards damaging hits, and favour the injurious effects of extra-cellular factors. Here, we discuss the role of mitochondria in NAFLD and focus on potential therapeutic approaches aimed at preserving mitochondrial function.Graphical abstractGraphical abstract for this article
       
  • Mechanisms of vascular dysfunction evoked by ionizing radiation and
           possible targets for its pharmacological correction
    • Abstract: Publication date: Available online 30 November 2018Source: Biochemical PharmacologyAuthor(s): Anatoly I. Soloviev, Igor V. Kizub Ionizing radiation (IR) leads to a variety of the cardiovascular diseases, including the arterial hypertension. A number of studies have demonstrated that blood vessels represent important target for IR, and the endothelium is one of the most vulnerable components of the vascular wall. IR causes an inhibition of nitric oxide (NO)-mediated endothelium-dependent vasodilatation and generation of reactive oxygen (ROS) and nitrogen (RNS) species trigger this process. Inhibition of NO-mediated vasodilatation could be due to endothelial NO synthase (eNOS) down-regulation, inactivation of endothelium-derived NO, and abnormalities in diffusion of NO from the endothelial cells (ECs) leading to a decrease in NO bioavailability. Beside this, IR suppresses endothelial large conductance Ca2+-activated K+ channels (BKCa) activity, which control NO synthesis. IR also leads to inhibition of the BKCa current in vascular smooth muscle cells (SMCs) which is mediated by protein kinase C (PKC). On the other hand, IR-evoked enhanced vascular contractility may result from PKC-mediated increase in SMCs myofilament Ca2+ sensitivity. Also, IR evokes vascular wall inflammation and atherosclerosis development. Vascular function damaged by IR can be effectively restored by quercetin-filled phosphatidylcholine liposomes and mesenchymal stem cells injection. Using RNA-interference technique targeted to different PKC isoforms can also be a perspective approach for pharmacological treatment of IR-induced vascular dysfunction.Graphical abstractGraphical abstract for this article
       
  • The NMDA receptor intracellular C-terminal domains reciprocally interact
           with allosteric modulators
    • Abstract: Publication date: Available online 29 November 2018Source: Biochemical PharmacologyAuthor(s): Kiran Sapkota, Kim Dore, Kang Tang, Mark Irvine, Guangyu Fang, Erica S. Burnell, Roberto Malinow, David E. Jane, Daniel T. Monaghan N-Methyl-D-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR’s intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2’s M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.Graphical abstractGraphical abstract for this article
       
  • Inorganic polyphosphate protects against lipopolysaccharide-induced
           lethality and tissue injury through regulation of macrophage recruitment
    • Abstract: Publication date: Available online 22 November 2018Source: Biochemical PharmacologyAuthor(s): Mikako Terashima-Hasegawa, Takashi Ashino, Yumi Kawazoe, Toshikazu Shiba, Atsufumi Manabe, Satoshi Numazawa Sepsis is an etiologically complex and often fatal inflammatory process involving a multitude of cytokine signaling pathways. Tumor necrosis factor α (TNFα) acts as a central regulator of the acute-phase inflammatory response by recruiting immune cells, including circulating monocyte/macrophages, to sites of infection or tissue damage. Inorganic polyphosphate (polyP), a linear polymer of orthophosphate residues, has been found in almost all cells and tissues, but its functions in immunity remain largely unknown. In this study, we show that pre- or post-treatment of mice with polyP150 (average chain length of 150 phosphate residues) markedly increases survival from lipopolysaccharide (LPS)-induced shock and inhibits macrophage recruitment to the liver and lungs, resulting in protection against tissue injury. In accord with these in vivo results, pretreatment of cultured peritoneal macrophages with polyP150 inhibited chemotaxis and actin polarization in response to TNFα. PolyP150 also inhibited phosphorylation of stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38, two downstream signaling molecules of the TNFα cascade, thereby preventing cyclooxygenase-2 gene expression by macrophages. These findings suggest that polyP150 inhibits recruitment of macrophages into organs by regulating the TNFα–JNK/p38 pathway, which may, in turn, protect against multi-organ dysfunction and lethality induced by LPS. Our findings identify polyP regulation as a novel therapeutic target for sepsis.Graphical abstractGraphical abstract for this article
       
  • BubR1 depletion delays apoptosis in the microtubule-depolymerized cells
    • Abstract: Publication date: Available online 22 November 2018Source: Biochemical PharmacologyAuthor(s): Afsana Naaz, Shazia Ahad, Ankit Rai, Avadhesha Surolia, Dulal Panda We investigated the role of a spindle assembly checkpoint protein, BubR1, in determining the mechanism of cell killing of an anti-microtubule agent CXI-benzo-84. CXI-benzo-84 dampened microtubule dynamics in live MCF-7 cells. The compound arrested MCF-7 cells in mitosis and induced apoptosis in these cells. Though CXI-benzo-84 efficiently depolymerized microtubules in the BubR1-depleted MCF-7 cells, it did not arrest the BubR1-depleted cells at mitosis. Interestingly, apoptosis occurred in the BubR1-depleted MCF-7 cells in the absence of a mitotic block suggesting that the mitotic block is not a prerequisite for the induction of apoptosis by anti-microtubule agents. In the presence of CXI-Benzo-84, the level of apoptosis was initially found to be lesser in the BubR1-depleted MCF-7 cells than the control cells; however, the BubR1-depleted cells displayed a similar level of apoptosis as the control cells at 72 hours of drug treatment. The depletion of BubR1 enhanced DNA damage in MCF-7 cells upon microtubule depolymerization. In addition, CXI-benzo-84 in combination with cisplatin-induced more cell death in BubR1-depleted cells than the BubR1-expressing MCF-7 cells. The results indicated a possibility that the BubR1-compromised cancer patients can be treated with combination therapy.Graphical abstractGraphical abstract for this article
       
  • Clomiphene citrate induces nuclear translocation of the TFEB transcription
           factor and triggers apoptosis by enhancing lysosomal membrane
           permeabilization
    • Abstract: Publication date: Available online 22 November 2018Source: Biochemical PharmacologyAuthor(s): Wei Li, Jieru Lin, Zhichen Shi, Jiren Wen, Yuyin Li, Zhenxing Liu, Aipo Diao The autophagy-lysosome pathway plays a central role in cellular homeostasis by regulating the cellular degradative machinery. The transcription factor EB (TFEB) regulates the biogenesis and function of both lysosomes and autophagosomes, and enhancement of TFEB function has emerged as an attractive therapeutic strategy for lysosome-related disorders. However, little is known about the role of TFEB activation in regulating the cellular fate. Here, we describe that clomiphene citrate (CC), a selective estrogen receptor modulator, promotes nuclear translocation of TFEB and increases lysosomal biogenesis in HeLa and MDA-MB-231 cells. Treatment with CC inhibits cell viability and causes apoptosis by increasing the release of proteases cathepsin B (CatB) and cathepsin D (CatD) from lysosomes into the cytosol. In contrast, knockdown of TFEB rescues the cells from CC-induced cell death. Furthermore, CC-induced TFEB activation also enhances the autophagy flux in HeLa cells. Knockdown of autophagy-related gene 7 (ATG7) significantly decreases the CC-induced CatB and CatD release and cell death, suggesting that autophagy contributes to the lysosomal membrane permeabilization (LMP) caused by CC. Altogether, these findings have broad implications for our understanding of TFEB function and provide new insights into CC pharmacological therapy.Graphical abstractGraphical abstract for this article
       
  • Ribosome biogenesis: an emerging druggable pathway for cancer therapeutics
    • Abstract: Publication date: Available online 20 November 2018Source: Biochemical PharmacologyAuthor(s): Frédéric Catez, Nicole Dalla Venezia, Virginie Marcel, Christiane Zorbas, Denis L.J. Lafontaine, Jean-Jacques Diaz Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis and sustain unrestricted growth. This increase in ribosome biogenesis is reflected by severe morphological alterations of the nucleolus, the cell compartment where the initial steps of ribosome biogenesis take place. Ribosome biogenesis has recently emerged as an effective target in cancer therapy, and several compounds that inhibit ribosome production or function, killing preferentially cancer cells, have entered clinical trials. Recent research indicates that cells express heterogeneous populations of ribosomes and that the composition of ribosomes may play a key role in tumorigenesis, exposing novel therapeutic opportunities. Here, we review recent data demonstrating that ribosome biogenesis is a promising druggable pathway in cancer therapy, and discuss future research perspectives.Graphical abstractGraphical abstract for this article
       
  • Comparison of different chemically modified inhibitors of miR-199b in
           vivo
    • Abstract: Publication date: Available online 16 November 2018Source: Biochemical PharmacologyAuthor(s): Burcu Duygu, Rio Juni, Lara Ottaviani, Nicole Bitsch, Jan B.M. Wit, Leon J. de Windt, Paula A. da Costa Martins MicroRNAs (miRNAs) have recently received great attention for their regulatory roles in diverse cellular processes and for their contribution to several human pathologies. Modulation of miRNAs in vivo provides beneficial therapeutic strategies for the treatment of many diseases as evidenced by various preclinical studies. However, specific issues regarding the in vivo use of miRNA inhibitors (antimiRs) such as organ-specific delivery, optimal dosing and formulation of the best chemistry to obtain efficient miRNA inhibition remain to be addressed. Here, we aimed at comparing the in vivo efficacy of different chemistry-based antimiR oligonucleotides to inhibit cardiac expression of miR-199b, a highly promising therapeutic target for the treatment of pressure overload-induced cardiac dysfunction. For this purpose, four different designs of oligonucleotides to inhibit miR-199b were initially developed. Systemic administration to wildtype mice on three consecutive days was followed by organ harvesting, seven days after the first injection, in order to quantify the dose-dependent changes in miR-199b expression levels. When comparing the efficiency of each inhibitor at the highest applied dose we observed that the antagomir was the only inhibitor inducing complete inhibition of miR-199b in the heart. LNA reduced expression in the heart by 50 percent while the Zen-AMO and F/MOE chemistries failed to repress miR-199b expression in the heart at any given dose in vivo. Further optimization was achieved by subjecting the antagomir and LNA nucleotides to additional chemical modifications. Interestingly, antagomir modification by replacing the cholesterol moiety from the 3’ to the 5’end of the molecule significantly improved the inhibitory capacity as reflected by a 75 percent downregulation of miR-199b expression already at a concentration of 5 mg/kg/day. Similar results could be obtained with a LNA-RNA molecule but upon administration of 80mg/kg/day. These findings show that, from all the chemistries tested by us, an antagomir carrying the cholesterol group at the 5’end was the most efficient inhibitor of miR-199b in the heart, in vivo. Moreover, our data also emphasize the importance of chemistry optimization and best dose range finding to achieve the greatest efficacy in miRNA inhibition in vivo.Graphical abstractGraphical abstract for this article
       
  • The roles of ubiquitination in extrinsic cell death pathways and its
           implications for therapeutics
    • Abstract: Publication date: Available online 16 November 2018Source: Biochemical PharmacologyAuthor(s): Jinho Seo, Min Wook Kim, Kwang-Hee Bae, Sang Chul Lee, Jaewhan Song, Eun-Woo Lee Regulation of cell survival and death, including apoptosis and necroptosis, is important for normal development and tissue homeostasis, and disruption of these processes can cause cancer, inflammatory diseases, and degenerative diseases. Ubiquitination is a cellular process that induces proteasomal degradation by covalently attaching ubiquitin to the substrate protein. In addition to proteolytic ubiquitination, nonproteolytic ubiquitination, such as M1-linked and K63-linked ubiquitination, has been shown to be important in recent studies, which have demonstrated its function in cell signaling pathways that regulate inflammation and cell death pathways. In this review, we summarize the TRAIL- and TNF-induced death receptor signaling pathways along with recent advances in this field and illustrate how different types of ubiquitination control cell death and survival. In particular, we provide an overview of the different types of ubiquitination, target residues, and modifying enzymes, including E3 ligases and deubiquitinating enzymes. Given the relevance of these regulatory pathways in human disease, we hope that a better understanding of the regulatory mechanisms of cell death pathways will provide insights into and therapeutic strategies for related diseases.Graphical abstractGraphical abstract for this article
       
  • Scutellarin alleviates blood-retina-barrier oxidative stress injury
           initiated by activated microglia cells during the development of diabetic
           retinopathy
    • Abstract: Publication date: Available online 14 November 2018Source: Biochemical PharmacologyAuthor(s): Xiyu Mei, Tianyu Zhang, Hao Ouyang, Bin Lu, Zhengtao Wang, Lili Ji The breakdown of blood-retinal barrier (BRB) is an early and typical event during the development of diabetic retinopathy (DR). Scutellarin (SC) is a natural flavonoid. This study aims to investigate the protection of SC from BRB damage via focusing on inhibiting microglia-initiated inflammation and subsequent oxidative stress injury. SC attenuated BRB breakdown and the reduced expression of claudin-1 and claudin-19 in STZ-induced diabetic mice. SC reduced microglia cells activation both in vivo and in vitro. The results of transendothelial/transepithelial electrical resistance (TEER/TER) and fluorescein isothiocyanate (FITC)-conjugated dextran cell permeability assay showed that SC attenuated BRB damage induced by D-glucose (25 mM)-stimulated microglia BV2 cells. SC suppressed nuclear factor κB (NFκB) activation and tumor necrosis factor (TNF)-α expression induced by D-glucose (25 mM) in BV2 cells. SC decreased the phosphorylation of extracellular regulated protein kinase (ERK)1/2 both in vivo and in vitro. MEK1/2 inhibitor U0126 reduced the D-glucose-induced NFκB nuclear accumulation and TNFα expression in BV2 cells. Next, SC improved the decreased expression of claudin-1 and claudin-19, the increased BRB damage and cellular reactive oxygen species (ROS) formation, and enhanced nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in TNFα-treated human retinal endothelial cells (HRECs) and APRE19 cells. Moreover, the SC-provided alleviation on BRB breakdown in STZ-induced diabetic mice was diminished in Nrf2 knock-out mice. In conclusion, SC alleviates BRB breakdown via abrogating retinal inflammatory responses and subsequent oxidative stress injury initiated by microglia cells that is activated by hyperglycemia during DR development.Graphical abstractGraphical abstract for this article
       
  • Emerging roles of ADP-ribosyl-acceptor hydrolases (ARHs) in tumorigenesis
           and cell death pathways
    • Abstract: Publication date: Available online 27 September 2018Source: Biochemical PharmacologyAuthor(s): Xiangning Bu, Jiro Kato, Joel Moss Malignant transformation may occur in the background of post-translational modification, such as ADP-ribosylation, phosphorylation and acetylation. Recent genomic analysis of ADP-ribosylation led to the discovery of more than twenty ADP-ribosyltransferases (ARTs), which catalyze either mono- or poly-ADP-ribosylation. ARTs catalyze the attachment of ADP-ribose to acceptor molecules. The ADP-ribose-acceptor bond can then be cleaved by a family of hydrolases in a substrate-specific manner, which is dependent on the acceptor and its functional group, e.g., arginine (guanidino), serine (hydroxyl), aspartate (carboxyl). These hydrolases vary in structure and function, and include poly-ADP-ribose glycohydrolase (PARG), MacroD1, MacroD2, terminal ADP-ribose protein glycohydrolase 1 (TARG1) and ADP-ribosyl-acceptor hydrolases (ARHs). In murine models, PARG deficiency increased susceptibility to alkylating agents-induced carcinogenesis. Similarly, by cleaving mono-ADP-ribosylated arginine on target proteins, ARH1 appears to inhibit tumor formation, suggesting that ARH1 is a tumor-suppressor gene. Although ARH3 is similar to ARH1 in amino acid sequence and crystal structure, ARH3 does not cleave ADP-ribose-arginine, rather it degrades in an exocidic manner, the PAR polymer and cleaves O-acetyl-ADP-ribose (OAADPr) and the ADP-ribose-serine linkage in acceptor proteins. Under conditions of oxidative stress, ARH3-deficient cells showed increased cytosolic PAR accumulation and PARP-1 mediated cell death. These findings expand our understanding of ADP-ribosylation and provide new therapeutic targets for cancer treatment. In the present review, research on ARH1-regulated tumorigenesis and cell death pathways that are enhanced by ARH3 deficiency are discussed.Graphical abstractGraphical abstract for this article
       
  • About canonical, non-canonical and immunogenic cell death: Basic
           mechanisms and translational applications: A meeting report of the
           International Cell Death Society
    • Abstract: Publication date: Available online 14 September 2018Source: Biochemical PharmacologyAuthor(s): Zahra Zakeri, Richard A. Lockshin, Marc Diederich International Cell Death Society held its 25th meeting, entitled “About canonical, non-canonical, and immunogenic cell death: basic mechanisms and translational applications” in Seoul, South Korea, May 31-June 2, 2018, addressed the most current issues in the field. Now that many types and pathways of cell death are recognized, attention has turned to how the threshold to death is maintained or surpassed, and how and what intracellular signals control the process. Most of the speakers addressed these topics, focusing on mitochondria and on new high-resolution techniques that promise to answer current questions.
       
  • Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular
           matrix turnover in bovine articular cartilage ex vivo
    • Abstract: Publication date: Available online 29 July 2018Source: Biochemical PharmacologyAuthor(s): Cecilie F. Kjelgaard-Petersen, Neha Sharma, Ashref Kayed, Morten A. Karsdal, Ali Mobasheri, Per Hägglund, Anne-Christine Bay-Jensen, Christian S. Thudium ObjectiveCurrently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects.DesignBovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining.ResultsR406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively.ConclusionUsing a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.Graphical abstractGraphical abstract for this article
       
  • Dedicated to the memory of Professor Jacques Gielen
    • Abstract: Publication date: Available online 5 December 2005Source: Biochemical PharmacologyAuthor(s): Jacques Piette
       
  • Note from the Publisher
    • Abstract: Publication date: Available online 5 December 2005Source: Biochemical PharmacologyAuthor(s):
       
  • Isoform-Specific Therapeutic Control of Sulfonation in Humans
    • Abstract: Publication date: Available online 10 November 2018Source: Biochemical PharmacologyAuthor(s): Ian Cook, Ting Wang, Thomas S. Leyh The activities of hundreds, perhaps thousands, of metabolites are regulated by human cytosolic sulfotransferases (SULTs) — a 13-member family of disease relevant enzymes that catalyze transfer of the sulfuryl moiety (-SO3) from PAPS (3’–phosphoadenosine 5’–phosphosulfonate) to the hydroxyls and amines of acceptors. SULTs harbor two independent allosteric sites, one of which, the focus of this work, binds non-steroidal anti-inflammatory drugs (NSAIDs). The structure of the first NSAID-binding site – that of SULT1A1 – was elucidated recently and homology modeling suggest that variants of the site are present in all SULT isoforms. The objective of the current study was to assess whether the NSAID-binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27nM) NSAID-inhibitor of SULT1A1 — the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-invasively. Compounds were given orally in a single therapeutic dose to a healthy, adult male human with a typical APAP-metabolite profile. Mef profoundly decreased APAP sulfonation during first pass metabolism and substantially decreased systemic APAP sulfonation without influencing DHEA sulfonation; thus, it appears the NSAID site can be used to control sulfonation in humans in a SULT-isoform specific manner.Graphical abstractGraphical abstract for this article
       
  • Poly(ADP-ribosylated) proteins in β-amyloid peptide-stimulated
           microglial cells
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Virginia Correani, Sara Martire, Giuseppina Mignogna, Lisa Beatrice Caruso, Italo Tempera, Alessandra Giorgi, Maddalena Grieco, Luciana Mosca, M.Eugenia Schininà, Bruno Maras, Maria d'Erme Amyloid-treated microglia prime and sustain neuroinflammatory processes in the central nervous system activating different signalling pathways inside the cells. Since a key role for PARP-1 has been demonstrated in inflammation and in neurodegeneration, we investigated PARylated proteins in resting and in β-amyloid peptide treated BV2 microglial cells. A total of 1158 proteins were identified by mass spectrometry with 117 specifically modified in the amyloid-treated cells. Intervention of PARylation on the proteome of microglia showed to be widespread in different cellular districts and to affect various cellular pathways, highlighting the role of this dynamic post-translational modification in cellular regulation. Ubiquitination is one of the more enriched pathways, encompassing PARylated proteins like NEDD4, an E3 ubiquitine ligase and USP10, a de-ubiquitinase, both associated with intracellular responses induced by β-amyloid peptide challenge. PARylation of NEDD4 may be involved in the recruiting of this protein to the plasma membrane where it regulates the endocytosis of AMPA receptors, whereas USP10 may be responsible for the increase of p53 levels in amyloid stimulated microglia. Unfolded Protein Response and Endoplasmic Reticulum Stress pathways, strictly correlated with the Ubiquitination process, also showed enrichment in PARylated proteins. PARylation may thus represent one of the molecular switches responsible for the transition of microglia towards the inflammatory microglia phenotype, a pivotal player in brain diseases including neurodegenerative processes. The establishment of trials with PARP inhibitors to test their efficacy in the containment of neurodegenerative diseases may be envisaged.Graphical abstractGraphical abstract for this article
       
  • Acyl-CoA Synthetase-4 is implicated in drug resistance in breast cancer
           cell lines involving the regulation of energy-dependent transporter
           expression
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Ulises Daniel Orlando, Ana Fernanda Castillo, Mayra Agustina Ríos Medrano, Angela Rosaria Solano, Paula Mariana Maloberti, Ernesto Jorge Podesta Acyl-CoA synthetase-4 (ACSL4) is an enzyme implicated in estrogen receptor α (ERα) negative regulation and hormone therapy resistance in breast cancer. In addition, ACSL4 has been associated to certain types of hormone resistance in prostate cancer.Chemotherapeutic treatment of disseminated breast cancer is usually faced with therapy resistance associated to ATP-binding cassette (ABC) transporter expression, which detect and eject anti-cancer drugs from cells. In this context, the aim of the present work was to study the role of ACSL4 in anti-cancer drug resistance and the involvement of ABC transporters in the underlying mechanisms.To this end, we used MCF-7 Tet-Off/ACSL4 and MDA-MB-231 mock cells, which overexpress ACSL4, and control line MCF-7 Tet-Off empty vector, MDA-MB-231 shRNA ACSL4 and MDA-MB-231 wild type cells. Assays were conducted on cell viability (MTT), cell proliferation (BrdU), drug efflux (flow cytometry), ACSL4-responsive drug resistance ABC transporter genes (RNA-Seq), transporter mRNA expression, protein levels and signaling pathway participation (real-time PCR and Western blot).Higher survival rates upon chemotherapeutic treatment were obtained in MCF-7 Tet-Off/ACSL4 and MDA-MB-231 mock cells, an effect counteracted by doxycycline- or shRNA-induced ACSL4 inhibition, respectively. A synergic effect of ACSL4 inhibitor triacsin C and chemotherapeutic drugs was observed on the inhibition of MDA-MB-231 wild type cell proliferation. MCF-7 Tet-Off/ACSL4 cells showed greater doxorubicin, Hoechst 33342 and calcein AM efflux. In contrast, MDA-MB-231 shRNA ACSL4 cells evidenced inhibition of chemotherapeutic drug efflux. ABCG2, ABCC4, and ABCC8 were identified as ACSL4-responsive drug resistance genes whose expression was increased in MCF-7 Tet-Off/ACSL4 cells but inhibited in MDA-MB-231 shRNA ACSL4 cells. Further cell survival assays in the presence of Ko 143 and Ceefourin 1, inhibitors of ABCG2 and ABCC4, respectively, upon chemotherapeutic treatment showed greater participation of ABCG2 in anti-cancer drug resistance in cells overexpressing ACSL4. In addition, ACSL4 inhibition and chemotherapeutic treatment combined with rapamycin-induced mTOR inhibition synergically inhibited proliferation and reduced ABCG2 expression in cells overexpressing ACSL4.In sum, ACSL4 may be regarded as a novel therapeutic target regulating the expression of transporters involved in anticancer drug resistance through the mTOR pathway to restore drug sensitivity in tumors with poor prognosis for disease-free and overall survival.Graphical abstractGraphical abstract for this article
       
  • Donepezil improves neuropathy through activation of AMPK signalling
           pathway in streptozotocin-induced diabetic mice
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Mangreed M. Atef, Norhan M. El-Sayed, Amal A.M. Ahmed, Yasser M. Mostafa Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron. Donepezil can activate AMPK and exerts neuroprotective effects. In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3-5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degenerated neurons in the spinal cord and swollen myelin sheath with inflammatory edema observed in sciatic nerves. In addition, diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. A significant upregulation of the N-Methyl-D-aspartate (NMDA) receptors in both cervical and lumbar regions of spinal cord of diabetic mice was also demonstrated. Donepezil, an AMPK activator, blocked the phosphorylation of AKT/MAPK/4EBP1, down regulate the expression of NMDA receptors and reversed hyperalagesia developed in diabetic mice. Therefore, Donepezil could be a potential pharmacological agent for management of DN.Graphical abstractGraphical abstract for this article
       
  • Constitutive androstane receptor weakens the induction of panaxytriol on
           CYP3A4 by repressing the activation of pregnane X receptor
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Qingqing Hu, Na Yao, Jie Wu, Mingyi Liu, Fanglan Liu, Hong Zhang, Yuqing Xiong, Chunhua Xia Nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) play a vital role in regulating CYP3A4. Our previous studies have demonstrated that panaxytriol (PXT) upregulates the expression of CYP3A4 via the PXR regulatory pathway. This study aimed to explore how CAR mediates the regulation of CYP3A4 in the presence of PXT using HepG2 cell, hCAR-overexpressing HepG2 cell and hCAR-silenced HepG2 cell models. In HepG2 cells, PXT induced the expression of CYP3A4 in a concentration-dependent manner (10-80 μM) and the high concentration of PXT (80 μM) upregulated the expression of CAR. The concentrations of PXT (10-40 μM) had no impact on the expression of CAR, but could significantly induce the expression of CYP2B6 target gene by activating CAR. The dual-luciferase reporter gene assay also showed that CAR-mediated CYP3A4 luciferase activity can be promoted by 80 μM of PXT (1.54-fold), while 5, 10, 20, and 40 μM of PXT had no influence on CAR-mediated CYP3A4 luciferase activity. In hCAR-overexpressing HepG2 cells, PXT concentrations (10-40 μM) that significantly induced PXR and CYP3A4 in HepG2 cells had no impact on the expression of CYP3A4, CAR and PXR, whereas a high concentration of PXT (80 µM) could weakly induce the mRNA and protein levels of CAR and CYP3A4. Moreover, the expression of PXR and CYP3A4 in hCAR-silenced HepG2 cells was markedly elevated compared with the blank control or with normal HepG2 cells treated with 10-80 μM of PXT. In conclusion, CAR significantly weakens the ability of PXT to induce CYP3A4 expression by repressing the activation of PXR. There may be a cross-talk mechanism between PXR and CAR on the regulation of CYP3A4 in the presence of PXT. Additionally, a high concentration of PXT (80 μM) induced CYP3A4 via the CAR regulatory pathway.Graphical abstractGraphical abstract for this article
       
  • From bench to bedside, via desktop. Recent advances in the application of
           cutting-edge in silico tools in the research of drugs targeting
           bromodomain modules
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Vassilios Myrianthopoulos, Emmanuel Mikros The discipline of drug discovery has greatly benefited by computational tools and in silico algorithms aiming at rationalization of many related processes, from the stage of early hit identification to the preclinical phases of drug candidate validation. The various methodologies referred to as molecular modeling tools span a broad spectrum of applications, from straightforward approaches such as virtual screening of compound libraries to more advanced techniques involving the precise estimation of free energy upon binding of the candidate drug to its macromolecular target. To this end, we report an overview of specific studies where implementation of such sophisticated modeling algorithms has shown to be indispensable for addressing challenging systems and biological questions otherwise difficult to answer. We focus our attention on the emerging field of bromodomain inhibitors. Bromodomains are small modules involved in epigenetic signaling and currently comprise high-priority targets for developing both drug candidates and chemical probes for basic biomedical research. We attempt a critical presentation of selected cases utilizing cutting-edge in silico methodologies, with our main emphasis being on absolute or relative free energy simulations, on implementation of quantum-mechanics level calculations and on characterization of solvent thermodynamics. We discuss the advantages and strengths as well as the drawbacks and weaknesses of computational tools utilized in those works and we attempt to comment on specific issues related to their integration into the regular medicinal chemistry practice. Our conclusion is that while such methods indeed represent highly promising resources for further advancing the discipline, their application is not always trivial.Graphical abstractGraphical abstract for this article
       
  • Serine residues in the α4 nicotinic acetylcholine receptor subunit
           regulate surface α4β2* receptor expression and clustering
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): Cristian A. Zambrano, Daniela Escobar, Tania Ramos-Santiago, Ian Bollinger, Jerry Stitzel Background and purposeChronic nicotine exposure upregulates α4β2* nicotinic acetylcholine receptors (nAChRs) in the brain. The goal of this study was to examine the role of three serine residues in the large cytoplasmic loop of the α4 subunit on α4β2* upregulation in neurons.Experimental approachSerine residues S336, S470 and S530 in mouse α4 were mutated to alanine and then re-expressed in primary neurons from cortex, hippocampus and subcortex of α4 KO mice. Mutant and wild type α4 expressing neurons were treated with nicotine (0.1, 1 and 10 μM) and assessed for α4β2* upregulation.Key resultsα4β2* nAChRs expressing S336A or S470A mutants were deficient at cell surface upregulation in both subcortex and hippocampal neurons. S530A α4β2* mutants exhibited aberrant surface upregulation in subcortical neurons. None of the mutants affected surface upregulation in cortical neurons or upregulation of total α4β2* binding sites in any region. Further, dense domains or clusters of α4β2* nAChRs were observed in the neuronal surface. The impact of nicotine exposure on the intensity, area, and density of these clusters was dependent upon individual mutations.Conclusions and implicationsEffects of α4 nAChR mutants on surface upregulation varied among brain regions, suggesting that the cellular mechanism of α4β2* upregulation is complex and involves cellular identity. We also report for the first time that α4β2* nAChRs form clusters on the neuronal surface and that nicotine treatment alters the characteristics of the clusters in an α4 mutant-dependent manner. This finding adds a previously unknown layer of complexity to the effects of nicotine on α4β2* expression and function.Graphical abstractGraphical abstract for this article
       
  • Dormant, quiescent, tolerant and persister cells: four synonyms for the
           same target in cancer
    • Abstract: Publication date: Available online 9 November 2018Source: Biochemical PharmacologyAuthor(s): François M. Vallette, Christophe Olivier, Frédéric Lézot, Lisa Oliver, Denis Cochonneau, Lisenn Lalier, Pierre-François Cartron, Dominique Heymann Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations. Recently, it has been suggested that a subpopulation of drug tolerant cells present in cancer populations and called “persisters” play a major role in this resistance. Recent studies have shown that microorganisms share similar properties. Still, how persister/tolerant cells intervene in the development of resistance is not completely elucidated but seems to be related to epigenetic changes in treated cells and the capacity of persisters to modulate and/or highjack their microenvironment. Due to the complexity of this process, the input from mathematicians, as well as new methods of bioinformatics and statistics, is necessary to fully comprehend the acquisition of resistance/tolerance deriving from and leading to the heterogeneous cell populations. The present review will give a brief overview of the most recent data available on drug tolerant cells in cancers and their similarities with microorganisms.Graphical abstractGraphical abstract for this article
       
  • Non-mitotic effect of albendazole triggers apoptosis of human leukemia
           cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation
    • Abstract: Publication date: Available online 7 November 2018Source: Biochemical PharmacologyAuthor(s): Liang-Jun Wang, Yuan-Chin Lee, Chia-Hui Huang, Yi-Jun Shi, Ying-Jung Chen, Sung-Nan Pei, Yu-Wei Chou, Long-Sen Chang Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MPAK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-α mRNA decay elicited TNF-α upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-α upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-α upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non-mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells.Graphical abstractGraphical abstract for this article
       
  • Endothelial cell transient receptor potential channel C5 (TRPC5) is
           
    • Abstract: Publication date: Available online 7 November 2018Source: Biochemical PharmacologyAuthor(s): Cai Liang, Yunting Zhang, Duan Zhuo, Chun-Yin Lo, Libo Yu, Chi-Wai Lau, Yiu-Wa Kwan, Gary Tse, Yu Huang, Xiaoqiang Yao Augmented endothelium-dependent contractions (EDC) contributes to endothelial dysfunction and vascular disease progression. An early signal in EDC is cytosolic [Ca2+]i rise in endothelial cells, which stimulates the production of contractile prostanoids, leading to vascular contraction. In this study, the molecular identity of Ca2+-permeable channels in endothelial cells and its function were investigated. Vascular tension was measured by wire myograph. EDCs were elicited by acetylcholine (ACH) in the presence of NG-nitro-L-arginine methyl ester (L-NAME). [Ca2+]i was measured using a Ca2+-sensitive fluorescence dye. Enzyme Immunoassay (EIA) was used for prostaglandin measurement. Immunohistochemical staining found the expression of transient receptor potential channel C5 (TRPC5) in endothelial and smooth muscle cells of mouse carotid arteries. ACH-induced EDC in male mouse carotid arteries was found to be substantially reduced in TRPC5 knockout (KO) mice than in wild-type (WT) mice. TRPC5 inhibitors clemizole and ML204 also reduced the EDC. Furthermore, ACH-induced Ca2+ entry in endothelial cells was lower in TRPC5 KO mice than in WT mice. Moreover, the EDC was abolished by a cyclooxygenase-2 (COX-2) inhibitor NS-398, but not affected by a COX-1 inhibitor valeryl salicylate (VAS). Enzyme immunoassay results showed that TRPC5 stimulated the COX-2-linked production of prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2). Exogeneous PGF2α, PGE2, and PGD2 could induce contractions in carotid arteries. Our present study demonstrated that TRPC5 in endothelial cells contributes to EDC by stimulating the production of COX-2-linked prostanoids. The finding extends our knowledge about EDC.Graphical abstractGraphical abstract for this article
       
  • MDM2 and Mitochondrial Function: One Complex Intersection
    • Abstract: Publication date: Available online 1 November 2018Source: Biochemical PharmacologyAuthor(s): Camila Rubio-Patiño, Andrew Paul Trotta, Jerry Edward Chipuk Decades of research reveal that MDM2 participates in cellular processes ranging from macro-molecular metabolism to cancer signaling mechanisms. Two recent studies uncovered a new role for MDM2 in mitochondrial bioenergetics. Through the negative regulation of NDUFS1 (NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1) and MT-ND6 (NADH dehydrogenase 6), MDM2 decreases the function and efficiency of Complex I (CI). These observations propose several important questions: (1) Where does MDM2 affect CI activity? (2) What are the cellular consequences of MDM2-mediated regulation of CI? (3) What are the physiological implications of these interactions? Here, we will address these questions and position these observations within the MDM2 literature.Graphical abstractGraphical abstract for this article
       
  • Hedgehog and Wingless signaling are not essential for autophagy-dependent
           cell death
    • Abstract: Publication date: Available online 26 October 2018Source: Biochemical PharmacologyAuthor(s): Tianqi Xu, Donna Denton, Sharad Kumar Autophagy-dependent cell death is a distinct mode of regulated cell death required in a context specific manner. One of the best validated genetic models of autophagy-dependent cell death is the removal of the Drosophila larval midgut during larval-pupal transition. We have previously shown that down-regulation of growth signaling is essential for autophagy induction and larval midgut degradation. Sustained growth signaling through Ras and PI3K blocks autophagy and consequently inhibits midgut degradation. In addition, the morphogen Dpp plays an important role in regulating the correct timing of midgut degradation. Here we explore the potential roles of Hh and Wg signaling in autophagy dependent midgut cell death. We demonstrate that Hh and Wg signaling are not involved in the regulation of autophagy-dependent cell death. However, surprisingly we found that one key component of these pathways, the Drosophila Glycogen Synthase Kinase 3, Shaggy (Sgg), may regulate midgut cell size independent of Hh and Wg signaling.Graphical abstractGraphical abstract for this article
       
  • Vincristine Ablation of Sirt2 Induces Cell Apoptosis and Mitophagy via
           Hsp70 Acetylation in MDA-MB-231 Cells
    • Abstract: Publication date: Available online 21 October 2018Source: Biochemical PharmacologyAuthor(s): Fanghui Sun, Xiaoxiao Jiang, Xuan Wang, Yong Bao, Guize Feng, Huijuan Liu, Xinhui Kou, Qing Zhu, Lan Jiang, Yonghua Yang Cancer cells are continuously challenged by adverse environmental stress and adopt diverse strategies to survive. Hsp70 plays pivotal roles in invasion, migration, drug resistance, and the survival of tumor cells. Hsp70 functions as molecular chaperone to protect tumor cells from stress-induced cell death. Hsp70 acetylation alters its chaperone activity in cell death pathways, but its relevance in the process of cell death and the underlying mechanisms involved are not well understood. In this study, we demonstrated that vincristine induces mitophagy via the disruption of Hsp70 binding with Sirt2, leading to Hsp70 acetylation at K126 and elevated sequestration of Bcl2 by Hsp70 for autophagosome creation. Acetylation at K126 significantly changes the physiological function of Hsp70 compared to acetylation at other sites. It also attenuates the protein folding and renaturation function of Hsp70 by altering the binding co-chaperones. In addition, acetylation at K126 inhibits Hsp70-mediated tumor cell invasion and migration, and the binding of Hsp70 to AIF1 and Apaf1 for promoting mitochondrial-mediated apoptosis. In conclusion, this study describes the molecular mechanism of vincristine induction of cell apoptosis and mitophagy via ablation of Sirt2 induced Hsp70 acetylation at K126 in MDA-MB-231 cells.Graphical abstractGraphical abstract for this article
       
  • Puerarin reverses cadmium-induced lysosomal dysfunction in primary rat
           proximal tubular cells via inhibiting Nrf2 pathway
    • Abstract: Publication date: Available online 19 October 2018Source: Biochemical PharmacologyAuthor(s): Li-Yuan Wang, Rui-Feng Fan, Du-Bao Yang, Dong Zhang, Lin Wang Previous studies have shown that oxidative stress-induced inhibition of autophagy plays a pivotal role in cadmium (Cd)-mediated cytotoxicity in primary rat proximal tubular (rPT) cells. The objective of this study is to explore the protective effect of puerarin (PU), a potent antioxidant, on Cd-induced autophagy inhibition and oxidative stress in rPT cells. First, Cd-induced blockage of autophagic flux in rPT cells was obviously restored by PU treatment, evidenced by immunoblot analysis of autophagy marker proteins and tandem fluorescent-tagged LC3 method. Resultantly, Cd-induced autophagosome accumulation was significantly alleviated by PU treatment. Also, Cd-induced lysosomal alkalinization and impairment of lysosomal degradation capacity were obviously recovered by PU, demonstrating that PU can restore Cd-induced lysosomal dysfunction. Moreover, Cd-induced lysosomal membrane permeabilization (LMP) was effectively blocked by PU. Cd-stimulated Nrf2 nuclear translocation and subsequent elevated expression of Nrf2-downstream targets were significantly inhibited by PU treatment. Simultaneously, Cd-elevated protein levels of antioxidant enzymes and glutathione synthesis-related proteins in rPT cells were markedly downregulated by PU treatment. In conclusion, these observations indicate that PU alleviates Cd-induced cytotoxicity in rPT cells through restoring autophagy, blocking LMP and inhibiting Nrf2 pathway, which is intimately related with its antioxidant activity.Graphical abstractGraphical abstract for this article
       
  • Evaluating the potential of kinase inhibitors to suppress DNA repair and
           sensitise ovarian cancer cells to PARP inhibitors
    • Abstract: Publication date: Available online 17 October 2018Source: Biochemical PharmacologyAuthor(s): Asima Mukhopadhyay, Yvette Drew, Elizabeth Matheson, Mo Salehan, Lucy Gentles, Jonathan A Pachter, Nicola J Curtin PARP inhibitors (PARPi) represent a major advance in the treatment of ovarian cancer associated with defects in homologous recombination DNA repair (HRR), primarily due to mutations in BRCA genes. Imatinib and PI3K inhibitors are reported to downregulate HRR and, in some cases, sensitise cells to PARPi.We investigated the ability of imatinib, and the PI3K inhibitors: NVP-BEZ235 and VS-5584, to downregulate HRR and sensitise paired ovarian cancer cells with mutant and reconstituted BRCA1 to the PARPi, olaparib and rucaparib. Olaparib and imatinib combinations were also measured in primary cultures of ovarian cancer.NVP-BEZ235 and imatinib reduced RAD51 levels and focus formation (an indication of HRR function), but VS-5584 did not. In colony-forming assays none of the inhibitors sensitised cells to PARPi cytotoxicity, in fact there was a mild protective effect. These conflicting data were resolved by the observation that the kinase inhibitors reduced the S-phase fraction, when HRR proteins are at their peak and cells are sensitive to PARPi cytotoxicity. In contrast, in primary cultures in 96-well plate assays, imatinib did increase olaparib-induced growth inhibition. However, in one primary culture that could be used in colony-formation cytotoxicity assays, imatinib protected from olaparib cytotoxicity.The kinase inhibitors protect from PARPi cytotoxicity by arresting cell growth, but this may be interpreted as synergy on the basis of 96-well cell growth assays. We urge caution before combining these drugs clinically. (228 words)Graphical abstractGraphical abstract for this article
       
  • Differences between acute and chronic stress granules, and how these
           differences may impact function in human disease
    • Abstract: Publication date: Available online 14 October 2018Source: Biochemical PharmacologyAuthor(s): Lucas C. Reineke, Joel R. Neilson Stress granules are macromolecular aggregates of mRNA and proteins assembling in response to stresses that promote the repression of protein synthesis. Most of the work characterizing stress granules has been done under acute stress conditions or during viral infection. Comparatively less work has been done to understand stress granule assembly during chronic stress, specifically regarding the composition and function of stress granules in this alternative context. Here, we describe key aspects of stress granule biology under acute stress, and how these stress granule hallmarks differ in the context of chronic stress conditions. We will provide perspective for future work aimed at further uncovering the form and function of both acute and chronic stress granules and discuss aspects of stress granule biology that have the potential to be exploited in human disease.Graphical abstractGraphical abstract for this article
       
  • Prenylated quinolinecarboxylic acid derivative prevents neuronal cell
           death through inhibition of MKK4
    • Abstract: Publication date: Available online 12 October 2018Source: Biochemical PharmacologyAuthor(s): Masato Ogura, Haruhisa Kikuchi, Norshalena Shakespear, Toshiyuki Suzuki, Junko Yamaki, Miwako K. Homma, Yoshiteru Oshima, Yoshimi Homma The development of neuroprotective agents is necessary for the treatment of neurodegenerative diseases. Here, we report PQA-11, a prenylated quinolinecarboxylic acid (PQA) derivative, as a potent neuroprotectant. PQA-11 inhibits glutamate-induced cell death and caspase-3 activation in hippocampal cultures, as well as inhibits N-Methyl-4-phenylpyridinium iodide- and amyloid β1-42-induced cell death in SH-SY5Y cells. PQA-11 also suppresses mitogen-activated protein kinase kinase 4 (MKK4) and c-jun N-terminal kinase (JNK) signaling activated by these neurotoxins. Quartz crystal microbalance analysis and in vitro kinase assay reveal that PQA-11 interacts with MKK4, and inhibits its sphingosine-induced activation. The administration of PQA-11 by intraperitoneal injection alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice. These results suggest that PQA-11 is a unique MKK4 inhibitor with potent neuroprotective effects in vitro and in vivo. PQA-11 may be a valuable lead for the development of novel neuroprotectants.Graphical abstractGraphical abstract for this article
       
  • PARP inhibition induces Akt-mediated cytoprotective effects through the
           formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome
           
    • Abstract: Publication date: Available online 6 October 2018Source: Biochemical PharmacologyAuthor(s): Antal Tapodi, Zita Bognár, Csaba Szabo, Ferenc Gallyas, Balázs Sümegi, Enikő Hocsák PurposeThe cytoprotective effect of poly(ADP-ribose) polymerase 1 (PARP1) inhibition is well documented in various cell types subjected to oxidative stress. Previously, we have demonstrated that PARP1 inhibition activates Akt, and showed that this response plays a critical role in the maintenance of mitochondrial integrity and in cell survival. However, it has not yet been defined how nuclear PARP1 signals to cytoplasmic Akt.MethodsWRL 68, HeLa and MCF7 cells were grown in culture. Oxidative stress was induced with hydrogen peroxide. PARP was inhibited with the PARP inhibitor PJ34. ATM, mTOR- and NEMO were silenced using specific siRNAs. Cell viability assays were based on the MTT assay. PARP-ATM pulldown experiments were conducted; each protein was visualized by Western blotting. Immunoprecipitation of ATM, phospho-ATM and NEMO was performed from cytoplasmic and mitochondrial cell fractions and proteins were detected by Western blotting. In some experiments, a continually active Akt construct was introduced. Nuclear to cytoplasmic and mitochondrial translocation of phospho-Akt was visualized by confocal microscopy.ResultsHere we present evidence for a PARP1 mediated, PARylation-dependent interaction between ATM and NEMO, which is responsible for the cytoplasmic transport of phosphorylated (thus, activated) ATM kinase. In turn, the cytoplasmic p-ATM and NEMO forms complex with mTOR and Akt, yielding the phospho-ATM-NEMO-Akt-mTOR signalosome, which is responsible for the PARP-inhibition induced Akt activation. The phospho-ATM-NEMO-Akt-mTOR signalosome localizes to the mitochondria and is essential for the PARP-inhibition-mediated cytoprotective effects in oxidatively stressed cells. When the formation of the signalosome is prevented, the cytoprotective effects diminish, but cells can be rescued by constantly active Akt1, further confirming the critical role of Akt activation in cytoprotection.ConclusionsTaken together, the data presented in the current paper are consistent with the hypothesis that PARP inhibition suppresses the PARylation of ATM, which, in turn, forms an ATM-NEMO complex, which exits the nucleus, and combines in the cytosol with mTOR and Act, resulting in Act phosphorylation (i.e. activation), which, in turn, produces the cytoprotective action via the induction of Akt-mediated survival pathways. This mechanism can be important in the protective effect of PARP inhibitor in various diseases associated with oxidative stress. Moreover, disruption of the formation or action of the phospho-ATM-NEMO-Akt-mTOR signalosome may offer potential future experimental therapeutic checkpoints.Graphical abstractGraphical abstract for this article
       
 
 
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