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  Subjects -> CHEMISTRY (Total: 852 journals)
    - ANALYTICAL CHEMISTRY (52 journals)
    - CHEMISTRY (598 journals)
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    - INORGANIC CHEMISTRY (41 journals)
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CHEMISTRY (598 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 10)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 38)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 252)
ACS Photonics     Full-text available via subscription   (Followers: 12)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 23)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chimica Slovenica     Open Access  
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 57)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
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: 5)
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: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 66)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 15)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 39)
Angewandte Chemie     Hybrid Journal   (Followers: 179)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 229)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
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: 8)
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: 16)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 326)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
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: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
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: 120)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 85)
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: 2)
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: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 5)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 68)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
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: 15)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 25)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 21)
Chemical Reviews     Full-text available via subscription   (Followers: 184)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 246)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 10)
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: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
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: 19)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
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: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
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 Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 18)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 64)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  

        1 2 3 | Last

Journal Cover Biochemical Pharmacology
  [SJR: 2.263]   [H-I: 160]   [10 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-2952
   Published by Elsevier Homepage  [3118 journals]
  • Zerumbone protects human skin keratinocytes against UVA-irradiated damages
           through Nrf2 induction
    • Authors: Hsin-Ling Yang; Chin-Ling Lee; Mallikarjuna Korivi; Jiunn-Wang Liao; Peramaiyan Rajendran; Jia-Jiuan Wu; You-Cheng Hseu
      Pages: 130 - 146
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Hsin-Ling Yang, Chin-Ling Lee, Mallikarjuna Korivi, Jiunn-Wang Liao, Peramaiyan Rajendran, Jia-Jiuan Wu, You-Cheng Hseu
      Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2–10 μM) substantially suppressed UVA (15 J/cm2)-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner. UVA-induced excessive ROS production, DNA single-strand breaks, apoptotic DNA fragmentation and a dysregulated Bax/Bcl-2 ratio were remarkably reversed by zerumbone in keratinocytes. Zerumbone-mediated cytoprotective properties were associated with increased nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by induction of heme oxygenase-1 (HO-1) and γ-glutamyl cysteine ligase (γ-GCLC) genes in zerumbone-treated keratinocytes. Zerumbone-induced Nrf2 transcriptional activation was mediated by the p38 MAPK, PI3K/AKT and PKC signaling cascades. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished zerumbone-mediated cytoprotective effects, as evidenced by impaired antioxidant genes, uncontrolled ROS/apoptotic DNA fragmentation and keratinocytes death, following UVA irradiation. In vivo evidence demonstrated that zerumbone treatment to nude mice (55 and 110 μg/day) significantly ameliorated UVA (15 J/cm2/every 2-day/14-day) cytotoxicity via increased nuclear localization of Nrf2 and Nrf2-dependent antioxidant genes (HO-1 and γ-GCLC) in UVA-treated skin tissues. Our findings emphasized the significance of Nrf2/ARE-signaling in zerumbone-mediated induction of antioxidant genes against UVA-toxicity. The molecular evidence suggests zerumbone can be a natural medicine to treat/prevent UVA-induced skin damage/photoaging.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2017.12.014
      Issue No: Vol. 148 (2018)
       
  • Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the
           Mrgprx2 pathway in vitro and in vivo
    • Authors: Nan Wang; Delu Che; Tao Zhang; Rui Liu; Jiao Cao; Jue Wang; Tingting Zhao; Pengyu Ma; Xinzhong Dong; Langchong He
      Pages: 147 - 154
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Nan Wang, Delu Che, Tao Zhang, Rui Liu, Jiao Cao, Jue Wang, Tingting Zhao, Pengyu Ma, Xinzhong Dong, Langchong He
      Pseudo-allergic reactions-adverse, non-immunologic, anaphylaxis-like sudden onset reactions mediated through an IgE-independent pathway—are activated by various basic compounds and occur at least as frequently as IgE-mediated reactions to drugs. A large family of G protein coupled receptors (Mas-related genes; Mrgprs) is closely related to pseudo-allergies. However, few therapies can directly target pseudo-allergies and related Mrgprs. Saikosaponin A (SSA) is effective in the treatment of passive cutaneous anaphylaxis (PCA), adjuvant arthritis, and delayed hypersensitiveness. In this study, we investigated the anti-pseudo-allergy effect of SSA and its underlying mechanism. We examined the effect of SSA on both IgE-independent and IgE-dependent responses using PCA and active systemic anaphylaxis models, as well as in vitro-cultured mast cells. We also evaluated whether the anti-allergy effect is related to Mrgprs by using in vitro Mrgprx2-expressing HEK293 cells. SSA dose dependently suppressed compound 48/80 (C48/80)-induced PCA and mast cell degranulation in mice. When SSA and C48/80 were administered together through the vein, C48/80-induced systemic anaphylaxis did not occur, and C48/80-induced shock ratio decreased dose-dependently upon SSA treatment. However, SSA did not affect IgE-dependent allergy. When administered topically 24 h before antigen challenge, Evans blue leakage and paw swelling were induced in the SSA-treated group and the vehicle group. Our in vitro studies revealed that SSA reduced C48/80-induced calcium flux and suppressed degranulation in LAD2 cells. SSA could also dose-dependently inhibit C48/80-induced Mrgprx2-expressing HEK293 cell activation. As a conclusion, SSA could inhibits IgE-independent allergy, but not IgE-dependent allergy, and this effect involves the Mrgprx2 pathway. This study provided a new sight on pseudo-allergy and its therapy.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2017.12.017
      Issue No: Vol. 148 (2018)
       
  • Dopamine promotes cellular iron accumulation and oxidative stress
           responses in macrophages
    • Authors: Stefanie Dichtl; David Haschka; Manfred Nairz; Markus Seifert; Chiara Volani; Oliver Lutz; Günter Weiss
      Pages: 193 - 201
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Stefanie Dichtl, David Haschka, Manfred Nairz, Markus Seifert, Chiara Volani, Oliver Lutz, Günter Weiss
      Iron is essential for many biological functions including neurotransmitter synthesis, where the metal is a co-factor of tyrosine hydroxylase, which converts tyrosine to dopamine and further to norepinephrine. As the shared chemical structure, called catechol, may potentially bind iron we questioned whether tyrosine derived hormones would impact on cellular iron homeostasis in macrophages, which are central for the maintenance of body iron homeostasis. Using murine bone marrow-derived macrophages (BMDMs), we investigated the effect of catecholamines and found that only dopamine but neither tyrosine, nor norepinephrine, affected cellular iron homeostasis. Exposure of macrophages to dopamine increased the uptake of non-transferrin bound iron into cells. The expansion of intracellular iron upon dopamine treatment resulted in oxidative stress responses as evidenced by increased expression of nuclear factor erythroid 2-related factor (Nrf2) and hypoxia inducible factor-1α. As a consequence, the transcriptional expression of stress response genes such as heme oxygenase-1 and the iron export protein ferroportin1 were significantly increased. Genetic deletion of Nrf2 abolished these effects of dopamine. Dopamine directly affects cellular iron homeostasis by increasing iron incorporation into macrophages and subsequently promoting intracellular oxidative stress responses. Our observations are of interest for disorders involving dopamine and iron dyshomeostasis such as Parkinson’s disease and restless legs syndrome, partly enlightening the underlying pathology or the therapeutic efficacy of dopamine agonists to overcome neuronal iron deficiency.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2017.12.001
      Issue No: Vol. 148 (2018)
       
  • Atorvastatin Impaired Glucose Metabolism in C2C12 Cells Partly via
           Inhibiting Cholesterol–dependent Glucose Transporter 4 Translocation
    • Authors: Binbin Sun; Zeyu Zhong; Fan Wang; Jiong Xu; Feng Xu; Weimin Kong; Zhaoli Ling; Nan Shu; Ying Li; Tong Wu; Mian Zhang; Liang Zhu; Xiaodong Liu; Li Liu
      Abstract: Publication date: Available online 13 January 2018
      Source:Biochemical Pharmacology
      Author(s): Binbin Sun, Zeyu Zhong, Fan Wang, Jiong Xu, Feng Xu, Weimin Kong, Zhaoli Ling, Nan Shu, Ying Li, Tong Wu, Mian Zhang, Liang Zhu, Xiaodong Liu, Li Liu
      Skeletal muscle accounts for approximately 75% of glucose disposal in body and statins impair glucose metabolism. We aimed to investigate the effect of atorvastatin on glucose metabolism in C2C12 cells. Glucose metabolism and expression of glucose transporter 4 (GLUT4) and hexokinase II (HXKII) were measured following incubation with atorvastatin or pravastatin. Roles of cholesterol in atorvastatin-induced glucose metabolism impairment were investigated via adding cholesterol or mevalonic acid and confirmed by cholesterol depletion with methyl-β-cyclodextrin. Hypercholesterolemia mice induced by high fat diet (HFD) feeding, orally received atorvastatin (6 and 12 mg/kg) or pravastatin (12mg/kg) for 22 days. Results showed that atorvastatin not pravastatin concentration-dependently impaired glucose consumption, glucose uptake and GLUT4 membrane translocation in C2C12 cells without affecting expression of HXKII or total GLUT4 protein. The atorvastatin-induced alterations were reversed by cholesterol or mevalonic acid. Cholesterol depletion exerted similar impact to atorvastatin, which could be alleviated by cholesterol supplement. Glucose consumption or GLUT4 translocation was positively associated with cellular cholesterol levels. In HFD mice, atorvastatin not pravastatin significantly increased blood glucose levels following glucose or insulin dose and decreased expression of membrane not total GLUT4 protein in muscle. Glucose exposure following glucose or insulin dose was negatively correlated to muscular free cholesterol concentration. Expression of membrane GLUT4 protein was positively related to free cholesterol in muscle. In conclusion, atorvastatin impaired glucose utilization in muscle cells partly via inhibiting GLUT4 membrane translocation due to inhibition of cholesterol synthesis by atorvastatin, at least, partly contributing to glucose intolerance in HFD mice.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.021
       
  • Baicalein and baicalin alleviate acetaminophen-induced liver injury by
           activating Nrf2 antioxidative pathway: the involvement of ERK1/2 and PKC
    • Authors: Liang Shi; Zhanxia Hao; Shaobo Zhang; Mengjuan Wei; Bin Lu; Zhengtao Wang; Lili Ji
      Abstract: Publication date: Available online 12 January 2018
      Source:Biochemical Pharmacology
      Author(s): Liang Shi, Zhanxia Hao, Shaobo Zhang, Mengjuan Wei, Bin Lu, Zhengtao Wang, Lili Ji
      Acetaminophen (APAP)-induced hepatotoxicity is the main cause of drug-induced liver injury. This study investigated the protection of baicalin and its aglycone baicalein against APAP-induced hepatotoxicity and its mechanism. Baicalein and baicalin alleviated APAP-induced hepatotoxicity both in vitro and in vivo. Moreover, baicalin-provided this protection was not diminished in hepatocytes or mice treated with β-glucuronidase inhibitor. Results of liver glutathione (GSH) and reactive oxygen species (ROS) formation demonstrated the alleviation of baicalein and baicalin on APAP-induced liver oxidative stress injury. Baicalein and baicalin induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the expression of its downstream antioxidant genes. Baicalein and baicalin-provided the protection was diminished after the application of Nrf2 siRNA in hepatocytes and Nrf2 knock-out mice. Molecular docking results indicate the potential interaction of baicalein and baicalin with kelch-like ECH-associated protein-1 (Keap1). Baicalein and baicalin induced the sustained phosphorylation of extracellular regulated protein kinases (ERK)1/2 and protein kinase C (PKC). Moreover, ERK1/2 and PKC inhibitors both abrogated Nrf2 phosphorylation and its subsequent activation, and the protection against APAP-induced hepatotoxicity induced by baicalein and baicalin. In summary, baicalein and baicalin alleviate APAP-induced hepatotoxicity by activating Nrf2 via blocking the binding of Nrf2 with Keap1 and inducing Nrf2 phosphorylation. ERK1/2 and PKC are both critical for regulating the phosphorylation of Nrf2 induced by baicalein or baicalin.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.026
       
  • Hypothalamic Inflammation and Malfunctioning Glia in the Pathophysiology
           of Obesity and Diabetes: Translational Significance
    • Authors: Md Habibur Rahman; Anup Bhusal; Won-Ha Lee; In-Kyu Lee; Kyoungho Suk
      Abstract: Publication date: Available online 11 January 2018
      Source:Biochemical Pharmacology
      Author(s): Md Habibur Rahman, Anup Bhusal, Won-Ha Lee, In-Kyu Lee, Kyoungho Suk
      Preclinical studies have suggested that chronic inflammation in the brain might be associated with multiple metabolic disorders, including obesity and diabetes. In particular, hypothalamic inflammation interferes with the endocrine system and modulates nutritional homeostasis, leading to metabolic alterations and consequent pathologies. With regard to the mechanisms underlying molecular and cellular pathogenesis, neurons, non-neuronal cells, and the crosstalk between them have gained particular attention. Specifically, malfunctioning glia have recently been implicated as an important component of pathological hypothalamic inflammation. Hypothalamic inflammation modulates food intake, energy expenditure, insulin secretion, hepatic glucose production, and glucose and fatty acid metabolism. Moreover, growing evidence suggests that hypothalamic inflammation is intrinsically associated with the pathogenesis of obesity, diabetes, and their dysfunctional consequences. However, the translational significance of hypothalamic inflammation has not yet been fully explored. In this review, we cover recent advances suggesting that hypothalamic inflammation and glia play a central role in the ontology of obesity, diabetes, and their complications. Finally, we explore the possibilities and challenges of targeting hypothalamic inflammation as a potential therapeutic strategy.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.024
       
  • Mouse lung fibroblasts are highly susceptible to necroptosis in a reactive
           oxygen species-dependent manner
    • Authors: Muadh Hussain; Vanessa Zimmermann; Sjoerd J.L. van Wijk; Simone Fulda
      Abstract: Publication date: Available online 11 January 2018
      Source:Biochemical Pharmacology
      Author(s): Muadh Hussain, Vanessa Zimmermann, Sjoerd J.L. van Wijk, Simone Fulda
      Mouse embryonic fibroblasts (MEFs) have extensively been used to study necroptosis, a recently identified form of programmed cell death. However, very little is yet known about the role of necroptosis and its regulation by reactive oxygen species (ROS) in cell types naturally exposed to high oxygen levels such as mouse lung fibroblasts (MLFs). Here, we discover that MLFs are highly susceptible to undergo necroptosis in a ROS-dependent manner upon exposure to a prototypic death receptor-mediated necroptotic stimulus, i.e. cotreatment with TNFα, Smac mimetic and the caspase inhibitor zVAD.fmk (TSZ). Kinetic analysis revealed that TSZ rapidly induces cell death in MLFs. Pharmacological inhibition of receptor-interacting protein kinase (RIPK)1 by necrostatin-1 (Nec-1) or RIPK3 by GSK’872 significantly rescues TSZ-stimulated cell death. Also, genetic silencing of RIPK3 or mixed lineage kinase domain-like pseudokinase (MLKL) significantly protects MLFs from TSZ-mediated cell death. Prior to cell death, TSZ significantly increases production of ROS. Importantly, addition of radical scavengers such as butylated hydroxyanisole (BHA) or α-Tocopherol (α-Toc) significantly suppresses TSZ-induced cell death in parallel with a significant reduction of ROS generation. Consistently, BHA prevented TSZ-triggered phosphorylation of MLKL similar to the addition of GSK’872. Thus, our study demonstrates for the first time that MLFs are prone to undergo necroptosis in response to a prototypic necroptotic stimulus and identifies ROS as important mediators of TSZ-triggered necroptosis.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.025
       
  • Williams Tribute Special Issue preface
    • Authors: Michael F. Jarvis; S.J. Enna
      Abstract: Publication date: Available online 10 January 2018
      Source:Biochemical Pharmacology
      Author(s): Michael F. Jarvis, S.J. Enna


      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.020
       
  • Acknowledgment
    • Abstract: Publication date: Available online 10 January 2018
      Source:Biochemical Pharmacology


      PubDate: 2018-01-16T14:04:37Z
       
  • The structural determinants of the bitopic binding mode of a negative
           allosteric modulator of the dopamine D2 receptor
    • Authors: Christopher J. Draper-Joyce; Mayako Michino; Ravi Kumar Verma; Carmen Klein Herenbrink; Jeremy Shonberg; Anitha Kopinathan; Peter J. Scammells; Ben Capuano; David M. Thal; Jonathan A. Javitch; Arthur Christopoulos; Lei Shi; J. Robert Lane
      Abstract: Publication date: Available online 9 January 2018
      Source:Biochemical Pharmacology
      Author(s): Christopher J. Draper-Joyce, Mayako Michino, Ravi Kumar Verma, Carmen Klein Herenbrink, Jeremy Shonberg, Anitha Kopinathan, Peter J. Scammells, Ben Capuano, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane
      SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E952.65) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D2R with tailored competitive versus allosteric properties.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.002
       
  • Protein complexes as psychiatric and neurological drug targets
    • Authors: Akihiko S. Kato; Jeffrey M. Witkin
      Abstract: Publication date: Available online 9 January 2018
      Source:Biochemical Pharmacology
      Author(s): Akihiko S. Kato, Jeffrey M. Witkin
      The need for improved medications for psychiatric and neurological disorders is clear. Difficulties in finding such drugs demands that all strategic means be utilized for their invention. The discovery of forebrain specific AMPA receptor antagonists, which selectively block the specific combinations of principal and auxiliary subunits present in forebrain regions but spare targets in the cerebellum, was recently disclosed. This discovery raised the possibility that other auxiliary protein systems could be utilized to help identify new medicines. Discussion of the TARP-dependent AMPA receptor antagonists has been presented elsewhere. Here we review the diversity of protein complexes of neurotransmitter receptors in the nervous system to highlight the broad range of protein/protein drug targets. We briefly outline the structural basis of protein complexes as drug targets for G-protein-coupled receptors, voltage-gated ion channels, and ligand-gated ion channels. This review highlights heterodimers, subunit-specific receptor constructions, multiple signaling pathways, and auxiliary proteins with an emphasis on the later. We conclude that the use of auxiliary proteins in chemical compound screening could enhance the detection of specific, targeted drug searches and lead to novel and improved medicines for psychiatric and neurological disorders.
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      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.018
       
  • Stargazin differentially modulates ampakine gating kinetics and
           pharmacology
    • Authors: Daniel P. Radin; Yong-Xin Li; Gary Rogers; Richard Purcell; Arnold Lippa
      Abstract: Publication date: Available online 9 January 2018
      Source:Biochemical Pharmacology
      Author(s): Daniel P. Radin, Yong-Xin Li, Gary Rogers, Richard Purcell, Arnold Lippa
      It was previously reported that Stargazin (STG) enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a class of AMPA receptor positive allosteric modulators that modify rates of transmitter binding, channel activity and desensitization parameters. As such, they have shown efficacy in animal models of neurodegenerative diseases, where excitatory synaptic transmission is compromised. Given the functional similarities between STG and ampakines, the current study sought to probe interactions between STG and ampakine gating properties. The effects of the high impact ampakines, CX614 and cyclothiazide (CTZ), were compared on homomeric GluR1-flip (Glur1i) and GluR2-flop (Glur2o) receptors expressed on HEK293 cells by transient transfection with or without STG gene. STG dramatically enhanced the surface expression of AMPA receptors and increased glutamate-induced steady-state currents during desensitization. STG also increased ratios of 500 μM kainate and 500 μM glutamate activated steady-state currents. STG reduced association rates of ampakines and differentially affected the dissociation rates for both CX614 and CTZ on desensitized receptors. The estimated Kd value for CX614 was lowered from 340 μM to 70 μM, whereas that for CTZ was lowered from 170 μM to 6 μM by STG. The data suggest that Stargazin can dramatically alter the conformation of the receptor dimer interface where CX614 and CTZ are known to bind. This work also demonstrates the importance of considering STG interactions when developing ampakines to treat neurodegenerative diseases in which AMPAergic signaling is compromised.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.019
       
  • Regulation of vascular tone homeostasis by NO and H2S: Implications in
           hypertension
    • Authors: Sevda Gheibi; Sajad Jeddi; Khosrow Kashfi; Asghar Ghasemi
      Abstract: Publication date: Available online 9 January 2018
      Source:Biochemical Pharmacology
      Author(s): Sevda Gheibi, Sajad Jeddi, Khosrow Kashfi, Asghar Ghasemi
      Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the vasculature and contribute to the regulation of vascular tone. NO and H2S are synthesized in both vascular smooth muscle and endothelial cells; NO functions primarily through the sGC/cGMP pathway, and H2S mainly through activation of the ATP-dependent potassium channels; both leading to relaxation of vascular smooth muscle cells. A deficit in the NO/H2S homeostasis is involved in the pathogenesis of various cardiovascular diseases, especially hypertension. It is now becoming increasingly clear that there are important interactions between NO and H2S and that have a profound impact onvascular tone and this may provide insights into the new therapeutic interventions. The aim of this review is to provide a better understanding of individual and interactive roles of NO and H2S in vascular biology. Overall, available data indicate that both NO and H2S contribute in vascular (patho)physiology and in regulating blood pressure. In addition, boosting NO and H2S using various dietary sources or donors could be a hopeful therapeutic strategy in the management of hypertension.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.017
       
  • Biochemical basis for pharmacological intervention as a reprogramming
           strategy against hypertension and kidney disease of developmental origin
    • Authors: You-Lin Tain; Samuel H.H. Chan; Julie Y.H. Chan
      Abstract: Publication date: Available online 6 January 2018
      Source:Biochemical Pharmacology
      Author(s): You-Lin Tain, Samuel H.H. Chan, Julie Y.H. Chan
      The concept of “developmental origins of health and disease” (DOHaD) stipulates that both hypertension and kidney disease may take origin from early-life insults. The DOHaD concept also offers reprogramming strategies aiming at shifting therapeutic interventions from adulthood to early life, even before clinical symptoms are evident. Based on those two concepts, this review will present the evidence for the existence of, and the programming mechanisms in, kidney developmental programming that may lead to hypertension and kidney disease. This will be followed by potential pharmacological interventions that may serve as a reprogramming strategy to counter the rising epidemic of hypertension and kidney disease. We point out that before patients could benefit from this strategy, the most pressing issue is for the growing body of evidence from animal studies in support of pharmacological intervention as a reprogramming strategy to long-term protect against hypertension and kidney disease of developmental origins to be validated clinically and the critical window, drug dose, dosing regimen, and therapeutic duration identified.
      Graphical abstract image

      PubDate: 2018-01-16T14:04:37Z
      DOI: 10.1016/j.bcp.2018.01.014
       
  • Cracking the Regulatory Code of Biosynthetic Gene Clusters as a Strategy
           for Natural Product Discovery
    • Authors: Sébastien Rigali; Sinaeda Anderssen; Aymeric Naômé; Gilles P. van Wezel
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Sébastien Rigali, Sinaeda Anderssen, Aymeric Naômé, Gilles P. van Wezel
      The World Health Organization (WHO) describes antibiotic resistance as “one of the biggest threats to global health, food security, and development today”, as the number of multi- and pan-resistant bacteria is rising dangerously. Acquired resistance phenomena also impair antifungals, antivirals, anti-cancer drug therapy, while herbicide resistance in weeds threatens the crop industry. On the positive side, it is likely that the chemical space of natural products goes far beyond what has currently been discovered. This idea is fueled by genome sequencing of microorganisms which unveiled numerous so-called cryptic biosynthetic gene clusters (BGCs), many of which are transcriptionally silent under laboratory culture conditions, and by the fact that most bacteria cannot yet be cultivated in the laboratory. However, brute force antibiotic discovery does not yield the same results as it did in the past, and researchers have had to develop creative strategies in order to unravel the hidden potential of microorganisms such as Streptomyces and other antibiotic-producing microorganisms. Identifying the cis elements and their corresponding transcription factors(s) involved in the control of BGCs through bioinformatic approaches is a promising strategy. Theoretically, we are a few ‘clicks’ away from unveiling the culturing conditions or genetic changes needed to activate the production of cryptic metabolites or increase the production yield of known compounds to make them economically viable. In this opinion article, we describe and illustrate the idea beyond ‘cracking’ the regulatory code for natural product discovery, by presenting a series of proofs of concept, and discuss what still should be achieved to increase the rate of success of this strategy.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.007
       
  • Time and dose-dependenceevaluation of nitroheterocyclic drugs for
           improving efficacy following Trypanosoma cruzi infection: a pre-clinical
           study
    • Authors: Ana Lia Mazzeti; Lívia de F. Diniz; Karolina R. Gonçalves; Alvaro F.S. Nascimento; Pollyanna A.F. Spósito; Vanessa C.F. Mosqueira; George L.L. Machado-Coelho; Isabela Ribeiro; Maria T. Bahia
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Ana Lia Mazzeti, Lívia de F. Diniz, Karolina R. Gonçalves, Alvaro F.S. Nascimento, Pollyanna A.F. Spósito, Vanessa C.F. Mosqueira, George L.L. Machado-Coelho, Isabela Ribeiro, Maria T. Bahia
      Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3 to 10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.005
       
  • Dichotomous function of IL-33 in health and disease: from biology to
           clinical implications
    • Authors: Harald Braun; Inna S. Afonina; Christina Mueller; Rudi Beyaert
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Harald Braun, Inna S. Afonina, Christina Mueller, Rudi Beyaert
      Interleukin (IL)-33 is a cytokine that is released from epithelial and endothelial cells at barrier surfaces upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of T helper (Th) 2 type immune responses. Therefore, IL-33 has attracted a lot of interest as a potential therapeutic target in asthma and other allergic diseases. Over the years, it has become clear that IL-33 has a much broader activity and also contributes to Th1 immunity, expanding the possibilities for therapeutic modulation of IL-33 activity to multiple inflammatory diseases. However, more recently IL-33 has also been shown to mediate immunosuppression and tissue repair by activating regulatory T cells (Treg) and promoting M2 macrophage polarization. These pleiotropic activities of IL-33 illustrate the need for a tight molecular regulation of IL-33 activity, and have to be taken into account when IL-33 or its receptor are targeted for therapeutic modulation. Here we review the multiple molecular mechanisms that regulate IL-33 activity and describe how IL-33 can shape innate and adaptive immune responses by promoting Th1, Th2 and Treg function. Finally, we will discuss the possibilities for therapeutic modulation of IL-33 signaling as well as possible safety issues.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.010
       
  • Activation of nuclear receptor PXR impairs glucose tolerance and
           dysregulates GLUT2 expression and subcellular localization in liver
    • Authors: Fatemeh Hassani-Nezhad-Gashti; Jaana Rysä; Outi Kummu; Juha Näpänkangas; Marcin Buler; Mikko Karpale; Janne Hukkanen; Jukka Hakkola
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Fatemeh Hassani-Nezhad-Gashti, Jaana Rysä, Outi Kummu, Juha Näpänkangas, Marcin Buler, Mikko Karpale, Janne Hukkanen, Jukka Hakkola
      Pregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance and characterize the mechanisms involved. We used PXR knockout mice model to investigate the significance of this nuclear receptor in the regulation of glucose tolerance. PXR ligand pregnenolone-16ɑ-carbonitrile (PCN) impaired glucose tolerance in the wildtype mice but not in the PXR knockout mice. Furthermore, DNA microarray and bioinformatics analysis of differentially expressed genes and glucose metabolism relevant pathways in PCN treated primary hepatocytes indicated that PXR regulates genes involved in glucose uptake. PCN decreased the expression of glucose transporter 2 (GLUT2) in mouse liver and in the wildtype mouse hepatocytes but not in the PXR knockout cells. Data mining of published chromatin immunoprecipitation-sequencing results indicate that Glut2 gene is a direct PXR target. Furthermore, PCN induced internalization of GLUT2 protein from the plasma membrane to the cytosol in the liver in vivo and repressed glucose uptake in the primary hepatocytes. Our results indicate that the activation of PXR impairs glucose tolerance and thus PXR represents a novel diabetogenic pathway. PXR activation dysregulates GLUT2 function by two different mechanisms. These findings may partly explain the diabetogenic effects of medications and environmental contaminants.
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.001
       
  • Kinetics of Oxytocin and Deaminooxytocin Displacement from the
           Oxtr-Receptor Compartment in Rat Uterus Ex Vivo.
    • Authors: Vladimir Pliska; Guido Jutz
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Vladimir Pliska, Guido Jutz
      The oil immersion method suggested earlier by Kalsner and Nickerson for analysing actions of sympathomimetic drugs in smooth muscle tissues was applied to isometric preparations of rat myometrium stimulated by oxytocin and deaminooxytocin. An exchange of the aqueous medium by mineral oil allows monitoring the displacement of the peptides from their receptor compartment in absence of free diffusion transport between tissue and organ medium. Exponential analysis of the data from the uterotonic decay phase allows several inferences to be drawn: 1) Transport rate constants (roughly equal for the two peptides) are higher than rate constants of (irreversible) elimination from the receptor compartment. 2) The response decay rate in the oil immersion phase is proportional solely to the peptide elimination and thus offers estimates of elimination rate constants. 3) Peptide elimination kinetics in the receptor compartment is only insignificantly influenced by the kinetics of ligand-receptor binding. 4) As expected, the elimination rate constant of deaminooxytocin is considerably lower than for oxytocin. The apparent concentration of receptors in the paracellular space of the myometrium (“apparent”, since receptor molecules are embedded in the cell membrane and hence not exposed to a diffusive flux), estimated from histometric parameters, appears rather high: 7 and 120 μM for high and low affinity receptors, respectively. Concentration-response curves for rat uterus stimulated by oxytocin or deaminooxytocin indicate that only about 0.25 to 5 per cent of the available receptors are involved in eliciting a maximal uterus contraction. The remnant receptor pool is likely to behave as a receptor reserve (“spare receptors”).
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.006
       
  • Molecular dissection of the human A3 adenosine receptor coupling with
           β-arrestin2
    • Authors: Jolien Storme; Annelies Cannaert; Kathleen Van Craenenbroeck; Christophe P. Stove
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Jolien Storme, Annelies Cannaert, Kathleen Van Craenenbroeck, Christophe P. Stove
      Besides classical G protein coupling, G protein-coupled receptors (GPCRs) are nowadays well known to show significant signalling via other adaptor proteins, such as β-arrestin2 (βarr2). The elucidation of the molecular mechanism of the GPCR-βarr2 interaction is a prerequisite for the structure-activity based design of biased ligands, which introduces a new chapter in drug discovery. The general mechanism of the interaction is believed to rely on phosphorylation sites, exposed upon agonist binding. However, it is not known whether this mechanism is universal throughout the GPCR family or if GPCR-specific patterns are involved. In recent years, promising orally active agonists for the human A3 adenosine receptor (A3AR), a GPCR highly expressed in inflammatory and cancer cells, have been evaluated in clinical trials for the treatment of rheumatoid arthritis, psoriasis, and hepatocellular carcinoma. In this study, the effect of cytoplasmic modifications of the A3AR on βarr2 recruitment was evaluated in transiently transfected HEK293T cells, using a live-cell split-reporter system (NanoBit®, Promega), based on the structural complementation of NanoLuc luciferase, allowing real-time βarr2 monitoring. The A3AR-selective reference agonist 2-Cl-IB-MECA yielded a robust, concentration dependent (5 nM to 1 µM) recruitment of βarr2 (logEC50: -7.798 ± 0.076). The role of putative phosphorylation sites, located in the C-terminal part and cytoplasmic loops, and the role of the ‘DRY’ motif was evaluated. It was shown that the A3AR C-terminus was dispensable for βarr2 recruitment. This contrasts with studies in the past for the rat A3AR, which pointed at crucial C-terminal phosphorylation sites. When combining truncation of the A3AR with modification of the ‘DRY’ motif to ‘AAY’, the βarr2 recruitment was drastically reduced. Recruitment could be partly rescued by back-mutation to ‘NQY’, or by extending the C-terminus again. In conclusion, other parts of the human A3AR, either cytosolic or exposed upon receptor activation, rather than the C-terminus alone, are responsible for βarr2 recruitment in a complementary or synergistic way.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.008
       
  • Doxorubicin resistance in breast cancer: A novel role for the human
           protein AHNAK
    • Authors: Tanja Davis; Gustav van Niekerk; Jade Peres; Sharon Prince; Ben Loos; Anna-Mart Engelbrecht
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Tanja Davis, Gustav van Niekerk, Jade Peres, Sharon Prince, Ben Loos, Anna-Mart Engelbrecht
      Understanding the response of cancer cells to anti-cancer therapies is crucial to unraveling and preventing the development of therapeutic resistance. The human AHNAK protein is a giant scaffold protein implicated in several diverse cellular functions. The role of AHNAK in cancer is however unclear as the protein has previously been described as a tumor suppressor, as well as being essential for tumor metastasis and invasion, while also being implicated in selected chemotherapeutic responses. To clarify the role of AHNAK in cancer, we investigated the effect of doxorubicin treatment on AHNAK in doxorubicin-sensitive MCF-7 and doxorubicin-resistant MDA-MB-231 breast cancer cell lines, as well as in a tumor-bearing mouse model. The role of AHNAK in the cellular response of breast cancer cells to doxorubicin was also investigated. We report here, for the first time, an association between AHNAK and resistance to doxorubicin. While treatment with doxorubicin modulated AHNAK protein expression both in vitro and in vivo in a dose-dependent manner, no changes in its cellular localization were observed. AHNAK knockdown prevented doxorubicin-induced modulation of cleaved caspase 7 protein expression and cell cycle arrest, while its overexpression decreased cleaved caspase 7 and cleaved PARP levels and induced S-phase arrest, changes that were comparable to the effects of doxorubicin. This novel association was restricted to doxorubicin-resistant cells, implicating the protein in therapeutic resistance. These findings confirm that AHNAK does indeed function in the chemotherapeutic response of breast cancer cells while also emphasizing the need for further investigation into potential implications for AHNAK in terms of predicting and modulating treatment response.
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.012
       
  • Manipulating Cell Fate While Confronting Reproducibility Concerns
    • Authors: Jeannette M. Osterloh; Kevin Mullane
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Jeannette M. Osterloh, Kevin Mullane
      Biomedical research is being transformed by the discovery and use of human pluripotent stem cells (hPSCs). Remarkable progress has been made, and assorted clinical trials are underway related to the application of stem cell therapy, including transplantation of hPSC-derived cells, in situ reprogramming or transdifferentiation, and utilization of targets and compounds identified from patient-derived stem cells. However, the pace of discovery is overwhelming efforts to replicate the work of others, prompting a concern over validity and reproducibility. Here, we address some sources of variability in reprogramming, maintaining, and differentiating hPSCs that impact interpretation of studies involving their use, and how it relates to efforts to move the field forward. The commitment in time and resources required to generate and maintain cell-lines, coupled with marked variations between hPSCs derived from patients with the same disease, has resulted in a fundamental change in how research is conducted. Dr. Michael Williams has championed the need to appropriately validate all cell-lines before use to limit sources of variability, although defining what constitutes a validated hPSC in the era of single cell –omics can be challenging.
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.016
       
  • Anti-thrombotic efficacy of S007-867: pre-clinical evaluation in
           experimental models of thrombosis in vivo and in vitro
    • Authors: Ankita Misra; Prem Prakash; Hobby Aggarwal; Priyanka Dhankani; Sachin Kumar; Chandra Prakash Pandey; Nicholas Pugh; Dominique Bihan; Manoj Kumar Barthwal; Richard W. Farndale; Dinesh Kumar Dikshit; Madhu Dikshit
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Ankita Misra, Prem Prakash, Hobby Aggarwal, Priyanka Dhankani, Sachin Kumar, Chandra Prakash Pandey, Nicholas Pugh, Dominique Bihan, Manoj Kumar Barthwal, Richard W. Farndale, Dinesh Kumar Dikshit, Madhu Dikshit
      Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2 fold) and maintained a sustained blood flow velocity for >30 minutes. Comparatively, clopidogrel showed significant prolongation in TTO (1.3 fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained haemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7 fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300µM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV50 (53.4±5.7%). Mechanistically, S007-867 (10-300μM) inhibited collagen-induced ATP release, thromboxane A2 (TxA2) generation, intra-platelet [Ca+2] flux and global tyrosine phosphorylation including PLCγ2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.013
       
  • Adipokine apelin ameliorates chronic colitis in Il-10-/- mice by promoting
           intestinal lymphatic functions
    • Authors: Yuanyuan Ge; Yi Li; Qin Chen; Weiming Zhu; Lugen Zuo; Zhen Guo; Jianfeng Gong; Lei Cao; Lili Gu; Jieshou Li
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Yuanyuan Ge, Yi Li, Qin Chen, Weiming Zhu, Lugen Zuo, Zhen Guo, Jianfeng Gong, Lei Cao, Lili Gu, Jieshou Li
      Both mesenteric adipose tissue (MAT) and lymphatic vessels (LVs) play important roles in the pathogenesis of Crohn’s disease (CD), and adipokines have been implicated in the crosstalk between MAT and LVs. Apelin, a newly identified adipokine, has been demonstrated to be crucial in the development and stabilization of LVs. We aimed to identify the expression of apelin in MAT of CD patients and explore whether apelin influences the disease course in murine colitis and determine its contributions to LVs. Expression of apelin in MAT specimens from patients with CD (n=24) and without CD (control, n=12) was detected. Il-10 deficient (Il-10-/- ) mice with established colitis were administered apelin, and untreated and wild-type mice served as controls (n=8 for each group). Disease activity and colonic inflammation was evaluated. The LV density, lymphatic drainage function and related signaling pathways were also analyzed. We found that MAT from CD patients expressed a higher level of apelin compared with that from controls. Systemic delivery of apelin significantly ameliorated chronic colitis in Il-10 -/- mice, demonstrated by decreased disease activity index and inflammatory scores, and lower levels of Tnf-α, Il-1β and Il-6. Increased LV density and podoplanin levels indicated that apelin promoted lymphangiogenesis. Evans blue dye and fluorescent lymphangiography revealed an enhanced lymphatic drainage function in apelin-treated mice. The role of apelin was found to be related to the activation of the Akt and Erk signaling pathways. These results indicate that the adipokine apelin was highly expressed in MAT of CD patients and has a promising role in ameliorating experimental colitis by promoting intestinal lymphatic functions, suggesting the potential crosstalk between adipokines and LVs in MAT in CD status. Therapies with adipokines, such as apelin, may be a novel approach for the treatment of CD.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.011
       
  • Heme oxygenase-1 induction by rosiglitazone via PKCα/AMPKα/p38
           MAPKα/SIRT1/PPARγ pathway suppresses lipopolysaccharide-mediated
           pulmonary inflammation
    • Authors: Rou-Ling Cho; Wei-Ning Lin; Chen-yu Wang; Chien-Chung Yang; Li-Der Hsiao; Chih-Chung Lin; Chuen-Mao Yang
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Rou-Ling Cho, Wei-Ning Lin, Chen-yu Wang, Chien-Chung Yang, Li-Der Hsiao, Chih-Chung Lin, Chuen-Mao Yang
      HO-1 (heme oxygenase-1), an antioxidant enzyme, induced by rosiglitazone (PPAR ligands) can be a potential treatment of inflammation. However, the mechanisms of rosiglitazone-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-κB activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKCα (Gö6976), AMPKα (Compound C), p38 MAPKα (p38i VIII), SIRT1 (Sirtinol), or PPARγ (T0070907) and transfection with siRNA of PKCα, AMPKα, p38 MAPKα, SIRT1, or PPARγ abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Further studies indicated that rosiglitazone stimulated SIRT1 deacetylase leading to PGC1α translocation from the cytosol into the nucleus, promoting fragmentation of NCoR and phosphorylation of PPARγ. Subsequently, PPARγ was activated by phosphorylation of PKCα, AMPKα, p38 MAPKα, and SIRT1, which turned on transcription of HO-1 gene by binding to PPAR response element (PPRE) and enhancing PPARγ promoter activity. These results suggested that rosiglitazone-induced HO-1 expression is mediated through PKCα/AMPKα/p38 MAPKα/SIRT1-dependent deacetylation of Ac-PGC1α and fragmentation of NCoR/PPARγ activation in HPAEpiCs. Up-regulation of HO-1 protected against the inflammatory responses triggered by LPS, at least in part, through attenuation of NF-κB.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.024
       
  • Heme oxygnease-1 induction by methylene blue protects RAW264.7 cells from
           hydrogen peroxide-induced injury
    • Authors: Xiao-tong Zhang; Xue-qiang Sun; Chen Wu; Jun-liang Chen; Jia-jia Yuan; Qing-feng Pang; Zhi-ping Wang
      Abstract: Publication date: Available online 5 January 2018
      Source:Biochemical Pharmacology
      Author(s): Xiao-tong Zhang, Xue-qiang Sun, Chen Wu, Jun-liang Chen, Jia-jia Yuan, Qing-feng Pang, Zhi-ping Wang
      Althoughmethylene blue (MB) has showed strong antioxidant effect, its effect related with heme oxygenase-1(HO-1) is still unclear. Thus, we investigated the effects of MB on HO-1 protein content and enzyme activity, and its protective effect against hydrogen peroxide (H2O2)- induced oxidative damage in RAW264.7 macrophage. The cellviability and the release of lactate dehydrogenase of RAW264.7 were determined. The mitochondrial functions were valuated through these indexes: content of adenosine triphosphate, superoxide dismutase, concentration of reactive oxygen species and mitochondrial membrane potential. Meanwhile, high content screening tested generation of ROS, MMP and intracellular concentration of calcium ion. qRT-PCR valuated macrophage phenotype markers expression. Lastly, flow cytometry and caspase-3 detection analyzed RAW264.7 apoptosis. Our data showed that (1) Both pretreatment and posttreatment of MB increased HO-1 protein content and enzyme activity; (2) MB rescued cells from H2O2-induced mitochondrial dysfunction; (3) High content screening revealed that MB alleviated the changes including generation of reactive oxygen species, mitochondrial membrane potential and intracellular concentration of calcium ion in H2O2 exposed RAW264.7; (4) MB attenuated H2O2-induced apoptosis; (5) MB pretreatment decreased the expression of M1 macrophage markers (Tnf and Nos2) while increasing the expression of M2 macrophage markers (Mrc1 and Il10); (6) The beneficial effect of MB was abolished by zinc protoporphyrin IX (HO-1 activity inhibitor) or HO-1 siRNA. In summary, MB protects RAW264.7 cells from H2O2-induced injury through up-regulation HO-1.
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.015
       
  • Hydrogen sulfide in the regulation of insulin secretion and insulin
           sensitivity: Implications for the pathogenesis and treatment of diabetes
           mellitus
    • Authors: Jerzy Bełtowski; Grażyna Wójcicka; Anna Jamroz-Wiśniewska
      Abstract: Publication date: Available online 4 January 2018
      Source:Biochemical Pharmacology
      Author(s): Jerzy Bełtowski, Grażyna Wójcicka, Anna Jamroz-Wiśniewska
      Insulin secretion and sensitivity play an essential role in maintaining normal glucose level and their abnormalities result in diabetes mellitus. H2S-synthesizing enzymes, CBS and/or CSE, are expressed in insulin-secreting pancreatic β cells and H2S inhibits insulin secretion by activating ATP-sensitive K+ channels. In addition, H2S has been reported to have either pro- or antiapoptotic effects on β cells. Studies in the animal models suggest that excess of H2S in pancreatic islets may contribute to both type 1 and type 2 diabetes. H2S has also been demonstrated to regulate insulin sensitivity. In the liver, H2S stimulates gluconeogenesis and glycogenolysis and inhibits glucose utilization and glycogen storage. Its effect on insulin-stimulated glucose uptake in the adipose tissue is controversial; both stimulation and inhibition have been reported. H2S may also regulate adipose tissue lipolysis, adipokine production and inflammation; the processes important for local and systemic insulin sensitivity. Little is known about the effect of H2S on skeletal muscle metabolism. High fat diet, obesity and insulin resistance affect CBS/CSE/H2S system in the liver and adipose tissue, although the effect depends on diet composition, animals species and time of high-fat feeding. Most studies indicate that blood H2S concentration decreases in animal models of diabetes and in diabetic humans.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.004
       
  • Integration of biological/pathophysiogical contexts to help clarify
           genotype-phenotype mismatches in monogenetic diseases. Childhood
           epilepsies associated with SCN2A as a case study.
    • Authors: Raymond J. Winquist; Charles J. Cohen
      Abstract: Publication date: Available online 4 January 2018
      Source:Biochemical Pharmacology
      Author(s): Raymond J. Winquist, Charles J. Cohen
      Monogenetic diseases offer clear human validation for launching drug discovery programs in Pharma designed to develop important new medicines for unmet medical needs. However, mismatches in the genotype-phenotype of presenting patients complicates both the preclinical ‘research target profile’ and the clinical development strategy. Additional biological and pathophysiological data associated with the identified mutations are necessary for more optimal prosecution of these drug discovery programs. This added contextual setting goes beyond identification of modifier genes and needs to encompass microenvironmental factors which can differentially affect the phenotype of patients harboring the same mutation. The Early Infantile Epileptic Encephalopathies (EIEEs) associated with de novo mutations in voltage gated sodium channels are interesting case studies that include examples of genotype-phenotype mismatches. With EIEE11, associated with mutations in SCN2A, incorporation of biological/pathophysiological contexts are helpful in clarifying the apparent genotype-phenotype mismatches which are captured with more reductionist approaches.
      Graphical abstract image

      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2018.01.003
       
  • A Binding Kinetics Study of Human Adenosine A3 Receptor Agonists
    • Authors: Lizi Xia; Athina Kyrizaki; Dilip K. Tosh; Tirsa T. van Duijl; Jacomina Cornelia Roorda; Kenneth A. Jacobson; Adriaan P. IJzerman; Laura H. Heitman
      Abstract: Publication date: Available online 3 January 2018
      Source:Biochemical Pharmacology
      Author(s): Lizi Xia, Athina Kyrizaki, Dilip K. Tosh, Tirsa T. van Duijl, Jacomina Cornelia Roorda, Kenneth A. Jacobson, Adriaan P. IJzerman, Laura H. Heitman
      The human adenosine A3 (hA3) receptor has been suggested as a viable drug target in inflammatory diseases and in cancer. So far, a number of selective hA3 receptor agonists (e.g. IB-MECA and 2-Cl-IB-MECA) inducing anti-inflammatory or anticancer effects are under clinical investigation. Drug-target binding kinetics is increasingly recognized as another pharmacological parameter, next to affinity, for compound triage in the early phases of drug discovery. However, such a kinetics-driven analysis has not yet been performed for the hA3 receptor. In this study, we first validated a competition association assay for adenosine A3 receptor agonists to determine the target interaction kinetics. Affinities and Kinetic Rate Index (KRI) values of 11 ribofurano and 10 methanocarba nucleosides were determined in radioligand binding assays. Afterwards, 15 analogues were further selected (KRI <0.70 or KRI >1.35) for full kinetics characterization. The structure-kinetics relationships (SKRs) were derived and longer residence times were associated with methanocarba and enlarged adenine N 6 and C2 substitutions. In addition, from a kon-koff-KD kinetic map we divided the agonists into three subgroups. A residence time “cliff” was observed, which might be relevant to (N)-methanocarba derivatives’ rigid C2-arylalkynyl substitutions. Our findings provide substantial evidence that, next to affinity, additional knowledge of binding kinetics is useful for developing and selecting new hA3R agonists in the early phase of the drug discovery process.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.026
       
  • Expression and regulation of proton-coupled oligopeptide transporters in
           colonic tissue and immune cells of mice
    • Authors: Yuqing Wang; Yongjun Hu; Ping Li; Yayun Weng; Nobuhiko Kamada; Huidi Jiang; David E. Smith
      Abstract: Publication date: Available online 3 January 2018
      Source:Biochemical Pharmacology
      Author(s): Yuqing Wang, Yongjun Hu, Ping Li, Yayun Weng, Nobuhiko Kamada, Huidi Jiang, David E. Smith
      A number of studies have implicated proton-coupled oligopeptide transporters (POTs) in the initiation and/or progression of inflammatory bowel disease and immune cell signaling. With this in mind, the aim of this study was to delineate the expression of POTs in mouse colonic tissues and immune cells, and characterize the potential role of these transporters in nucleotide-binding oligomerization domain (NOD) signaling. Using a dextran sodium sulfate (DSS)-induced colitis mouse model, we found that DSS down regulated Pht1 gene expression and up regulated Pht2 gene expression in colonic tissue and immune cells. In contrast, PEPT1 protein was absent from the colonic tissue and immune cells of normal and DSS-treated mice. NOD ligands, muramyl dipeptide (MDP) and L-Ala-γ-D-Glu-meso-diaminopimelic acid (tri-DAP), were shown to be substrates of PHT2 in MDCK-hPHT219,20AA cells. Subsequent studies revealed that the immune response of lamina propia mononuclear cells may be regulated by PHT1 and PHT2, and that PHT2 facilitated the NOD-dependent immune response in RAW264.7 macrophages. These results clarified the expression of POTs in mouse colonic segments, cells and subtypes, and the role of increased Pht2 expression during chemically-indiced colitis in facilitating NOD-dependent immune response. The findings further suggest that intestinal PHT2 may serve as a therapeutic target for IBD therapy.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.025
       
  • Microglia-derived extracellular vesicles in Alzheimer’s Disease: a
           double-edged sword
    • Authors: Teresa Trotta; Maria Antonietta Panaro; Antonia Cianciulli; Giorgio Mori; Adriana Di Benedetto; Chiara Porro
      Abstract: Publication date: Available online 3 January 2018
      Source:Biochemical Pharmacology
      Author(s): Teresa Trotta, Maria Antonietta Panaro, Antonia Cianciulli, Giorgio Mori, Adriana Di Benedetto, Chiara Porro
      Extracellular vesicles (EVs), based on their origin or size, can be classified as apoptotic bodies, microvesicles (MVs)/microparticles (MPs), and exosomes. EVs are one of the new emerging modes of communication between cells that are providing new insights into the pathophysiology of several diseases. EVs released from activated or apoptotic cells contain specific proteins (signaling molecules, receptors, integrins, cytokines), bioactive lipids, nucleic acids (mRNA, miRNA, small non coding RNAs, DNA) from their progenitor cells. In the brain, EVs contribute to intercellular communication through their basal release and uptake by surrounding cells, or release into the cerebrospinal fluid (CSF) and blood. In the central nervous system (CNS), EVs have been suggested as potential carriers in the intercellular delivery of misfolded proteins associated to neurodegenerative disorders, such as tau and amyloid β in Alzheimer’s Diseases (AD), α-synuclein in Parkinson’s disease (PD), superoxide dismutase (SOD)1 in amyotrophic lateral sclerosis and huntingtin in Huntington’s disease. Multiple studies indicate that EVs are involved in the pathogenesis of AD, although their role has not been completely elucidated. The focus of this review is to analyze the new emerging role of EVs in AD progression, paying particular attention to microglia EVs. Recent data shows that microglia are the first myeloid cells to be activated during neuroinflammation. Microglial EVs in fact, could have both a beneficial and a detrimental action in AD. The study of EVs may provide specific, precise information regarding the AD transition stage that may offer possibilities to intervene in order to retain cognition. In chronic neurodegenerative diseases EVs could be a novel biomarker to monitor the progression of the pathology and also represent a new therapeutical approach to CNS diseases.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.020
       
  • Astrocytes in Primary Cultures Express Serine Racemase, Synthesize
           D-Serine and Acquire A1 Reactive Astrocyte Features
    • Authors: Suyan Li; Yota Uno; Uwe Rudolph; Johanna Cobb; Jing Liu; Thea Anderson; Deborah Levy; Darrick T. Balu; Joseph T. Coyle
      Abstract: Publication date: Available online 3 January 2018
      Source:Biochemical Pharmacology
      Author(s): Suyan Li, Yota Uno, Uwe Rudolph, Johanna Cobb, Jing Liu, Thea Anderson, Deborah Levy, Darrick T. Balu, Joseph T. Coyle
      D-Serine is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although D-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize D-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized D-serine synthesis and the expression of enzymes involved in its disposition in primary glial cultures. The levels of SR were quite low early in culture and increased markedly in all astrocytes with the duration in vitro. The concentration of D-serine in the culture medium increased in parallel with SR expression in the astrocytes. Microglia, identified by robust expression of Iba1, did not express SR. While the levels of glial fibrillary acidic protein (GFAP), glycine decarboxylase (GLDC) and phosphoglycerate dehydrogenase (PHGDH), the initial enzyme in the pathway converting glycine to L-serine, remained constant in culture, the expression of lipocalin-2, a marker for pan-reactive astrocytes, increased several-fold. The cultured astrocytes also expressed Complement-3a, a marker for a subpopulation of reactive astrocytes (A1). Astrocytes grown from mice with a copy number variant associated with psychosis, which have four copies of the GLDC gene, showed a more rapid production of D-serine and a reduction of glycine in the culture medium. These results substantiate the conclusion that A1 reactive astrocytes express SR and release D-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDARs.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.023
       
  • Opening of Voltage Dependent Anion Channels Promotes Reactive Oxygen
           Species Generation, Mitochondrial Dysfunction and Cell Death in Cancer
           Cells
    • Authors: David N. DeHart; Diana Fang; Kareem Heslop; Li Li; John J. Lemasters; Eduardo N. Maldonado
      Abstract: Publication date: Available online 28 December 2017
      Source:Biochemical Pharmacology
      Author(s): David N. DeHart, Diana Fang, Kareem Heslop, Li Li, John J. Lemasters, Eduardo N. Maldonado
      Enhancement of aerobic glycolysis and suppression of mitochondrial metabolism characterize the pro-proliferative Warburg phenotype of cancer cells. High free tubulin in cancer cells closes voltage dependent anion channels (VDAC) to decrease mitochondrial membrane potential (ΔΨ), an effect antagonized by erastin, the canonical promotor of ferroptosis. Previously, we identified six compounds (X1-X6) that also block tubulin-dependent mitochondrial depolarization. Here, we hypothesized that VDAC opening after erastin and X1-X6 increases mitochondrial metabolism and reactive oxygen species (ROS) formation, leading to ROS-dependent mitochondrial dysfunction, bioenergetic failure and cell death. Accordingly, we characterized erastin and the two most potent structurally unrelated lead compounds, X1 and X4, on ROS formation, mitochondrial function and cell viability. Erastin, X1 and X4 increased ΔΨ followed closely by an increase of mitochondrial ROS generation within 30 to 60 min. Subsequently, mitochondria began to depolarize after an hour or longer indicative of mitochondrial dysfunction. N-acetylcysteine (NAC, glutathione precursor and ROS scavenger) and MitoQ (mitochondrially targeted antioxidant) blocked increased ROS formation after X1 and prevented mitochondrial dysfunction. Erastin, X1 and X4 selectively promoted cell killing in HepG2 and Huh7 human hepatocarcinoma cells compared to primary rat hepatocytes. X1 and X4-dependent cell death was blocked by NAC. These results suggest that ferroptosis induced by erastin and our erastin-like lead compounds was caused by VDAC opening, leading to increased ΔΨ, mitochondrial ROS generation and oxidative stress-induced cell death.
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      PubDate: 2018-01-05T18:56:15Z
      DOI: 10.1016/j.bcp.2017.12.022
       
  • Syk and Src-targeted anti-inflammatory activity of aripiprazole, an
           atypical antipsychotic
    • Authors: Sulgi Yoo; Mi-Yeon Kim; Jae Youl Cho
      Pages: 1 - 12
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Sulgi Yoo, Mi-Yeon Kim, Jae Youl Cho
      Aripiprazole (ARP) is a partial agonist of dopamine D2 receptors that is commonly prescribed to treat schizophrenia and bipolar disorder. The anti-inflammatory effect of ARP was recently documented in a few studies, but its molecular mechanisms have not been fully elucidated. In this study, peptidoglycan (PGN)-treated macrophages (RAW264.7 cells), reporter gene assay, an overexpression strategy, immunoprecipitation, and immunoblotting analysis were employed to clarify the anti-inflammatory mechanism of ARP. ARP was found to dose-dependently inhibit production of nitric oxide (NO) and prostaglandin E2 (PGE2) without exhibiting cytotoxicity. In agreement with this result, ARP was found to suppress the mRNA expression levels of inflammatory genes such as cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and tumor necrosis factor (TNF)-α. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1) and nuclear factor (NF)-κB are targeted by ARP. Similar to these data, c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), MKK7, and transforming growth factor beta-activated kinase 1 (TAK1) for AP-1 activation, and inhibitor of κBα (IκBα), IκBαkinase α/β (IKKα/β), AKT, phosphatidylinositide 3-kinases (PI3K), spleen tyrosine kinase (Syk), and Src for NF-κB activation were revealed to be inhibited by ARP treatment. These results suggest that ARP can suppress inflammatory responses triggered by Gram positive bacteria through suppression of both AP-1 and NF-κB pathways.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.12.006
      Issue No: Vol. 148 (2017)
       
  • Targeting PI3K, mTOR, ERK, and Bcl-2 signaling network shows superior
           antileukemic activity against AML ex vivo
    • Authors: Yongwei Su; Xinyu Li; Jun Ma; Jianyun Zhao; Shuang Liu; Guan Wang; Holly Edwards; Jeffrey W. Taub; Hai Lin; Yubin Ge
      Pages: 13 - 26
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Yongwei Su, Xinyu Li, Jun Ma, Jianyun Zhao, Shuang Liu, Guan Wang, Holly Edwards, Jeffrey W. Taub, Hai Lin, Yubin Ge
      Acute myeloid leukemia (AML) remains challenging to treat and needs more effective treatments. The PI3K/mTOR pathway is involved in cell survival and has been shown to be constitutively active in 50–80% of AML patients. However, targeting the PI3K/mTOR pathway results in activation of the ERK pathway, which also plays an important role in cell survival. In addition, AML cells often overexpress antiapoptotic Bcl-2 family proteins (e.g., Bcl-2), preventing cell death. Thus, our strategy here is to target the PI3K, mTOR (by VS-5584, a PI3K and mTOR dual inhibitor), ERK (by SCH772984, an ERK-selective inhibitor), and Bcl-2 (by ABT-199, a Bcl-2-selective inhibitor) signaling network to kill AML cells. In this study, we show that while inhibition of PI3K, mTOR, and ERK showed superior induction of cell death compared to inhibition of PI3K and mTOR, the levels of cell death were modest in some AML cell lines and primary patient samples tested. Although simultaneous inhibition of PI3K, mTOR, and ERK caused downregulation of Mcl-1 and upregulation of Bim, immunoprecipitation of Bcl-2 revealed increased binding of Bim to Bcl-2, which was abolished by the addition of ABT-199, suggesting that Bim was bound to Bcl-2 which prevented cell death. Treatment with combined VS-5584, SCH772984, and ABT-199 showed significant increase in cell death in AML cell lines and primary patient samples and significant reduction in AML colony formation in primary patient samples, while there was no significant effect on colony formation of normal human CD34+ hematopoietic progenitor cells. Taken together, our findings show that inhibition of PI3K, mTOR, and ERK synergistically induces cell death in AML cells, and addition of ABT-199 enhances cell death further. Thus, our data support targeting the PI3K, mTOR, ERK, and Bcl-2 signaling network for the treatment of AML.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.11.022
      Issue No: Vol. 148 (2017)
       
  • α1A-Adrenoceptors activate mTOR signalling and glucose uptake in
           cardiomyocytes
    • Authors: Masaaki Sato; Bronwyn A. Evans; Anna L. Sandström; Ling Yeong Chia; Saori Mukaida; Bui San Thai; Anh Nguyen; Linzi Lim; Christina Y.R. Tan; Jo-Anne Baltos; Paul J. White; Lauren T. May; Dana S. Hutchinson; Roger J. Summers; Tore Bengtsson
      Pages: 27 - 40
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Masaaki Sato, Bronwyn A. Evans, Anna L. Sandström, Ling Yeong Chia, Saori Mukaida, Bui San Thai, Anh Nguyen, Linzi Lim, Christina Y.R. Tan, Jo-Anne Baltos, Paul J. White, Lauren T. May, Dana S. Hutchinson, Roger J. Summers, Tore Bengtsson
      The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α1A-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α1A-AR signalling in CHO-K1 cells co-expressing the human α1A-AR and GLUT4 (CHOα1AGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca2+ mobilization, and phosphorylation of mTOR, Akt, 5′ adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the α1A-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another α1-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHOα1AGLUT4myc cells, siRNA directed against rictor but not raptor suppressed α1A-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by α1A-AR agonists. Our findings identify a novel link between the α1A-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of α1A-AR selective agonists as tools in the treatment of cardiac dysfunction.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.11.016
      Issue No: Vol. 148 (2017)
       
  • CK2α promotes advanced glycation end products-induced expressions of
           fibronectin and intercellular adhesion molecule-1 via activating MRTF-A in
           glomerular mesangial cells
    • Authors: Zhiquan Chen; Qiuhong Chen; Junying Huang; Wenyan Gong; Yezi Zou; Lei Zhang; Peiqing Liu; Heqing Huang
      Pages: 41 - 51
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Zhiquan Chen, Qiuhong Chen, Junying Huang, Wenyan Gong, Yezi Zou, Lei Zhang, Peiqing Liu, Heqing Huang
      Advanced glycation end products’ (AGEs) modification of extracellular matrix proteins induces crosslinking, which results in thickening of the basement membrane and activating several intracellular signaling cascades, eventually promoting the pathological progression of diabetic nephropathy (DN). We have previously confirmed that casein kinase 2α (CK2α) activates the nuclear factor of kappaB (NF-κB) signaling pathway to enhance high glucose-induced expressions of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1) in glomerular mesangial cells (GMCs). However, to date, the mechanism by which CK2α regulates diabetic renal fibrosis is not fully understood. In view of the regulation of inflammation and fibrosis by myocardin-related transcription factor A (MRTF-A), we are highly concerned whether CK2α promotes AGEs-induced expressions of FN and ICAM-1 in glomerular mesangial cells via activation of MRTF-A, thus affecting the pathogenesis of DN. We found that CK2α and MRTF-A proteins were overexpressed in AGEs-induced diabetic kidneys. Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed the upregulation of FN and ICAM-1 expressions in GMCs induced by AGEs. MRTF-A knockdown compromised the expressions of FN and ICAM-1 in GMCs induced by AGEs. Moreover, inhibition of CK2α kinase activity or knockdown of CK2α protein expression restrained the protein expression and nuclear aggregation of MRTF-A. CK2α interacted with MRTF-A. Furthermore, knockdown of MRTF-A while overexpression of CK2α blocked the upregulation effect of CK2α on the protein expressions of FN and ICAM-1. These findings suggest that CK2α promotes diabetic renal fibrosis via activation of MRTF-A and upregulation of inflammatory genes.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.12.002
      Issue No: Vol. 148 (2017)
       
  • Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects
           induced by the activation of heme oxygenase 1/carbon monoxide signaling
           pathway in the central nervous system of mice with neuropathic pain
    • Authors: Gabriela Riego; Alejandro Redondo; Sergi Leánez; Olga Pol
      Pages: 52 - 63
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Gabriela Riego, Alejandro Redondo, Sergi Leánez, Olga Pol
      The administration of a carbon monoxide-releasing compound (tricarbonyldichlororuthenium(II)dimer, CORM-2) or an heme oxygenase 1 (HO-1) inductor (cobalt protoporphyrin IX, CoPP) exerts potent antinociceptive effects during chronic pain, but their actions in the central nervous system of animals with neuropathic pain have not been evaluated. Our objective is to investigate the effects of these treatments on the oxidative, inflammatory and molecular changes induced by sciatic nerve injury in several brain areas. In male C57BL6 mice with neuropathic pain induced by the chronic constriction of sciatic nerve (CCI), we evaluated the effects of CORM-2 and CoPP on the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1 and NAD(P)H:quinone oxidoreductase-1 (NQO1), the microglial marker (CD11b/c), and the mitogen-activated protein kinases (MAPK) (JNK, ERK½ and P38) in the amygdala, prefrontal cortex, hippocampus, hypothalamus and spinal cord, by using western blot assay. Our results showed that, although CORM-2 and CoPP did not alter the protein levels of Nrf2 and NQO1in none of the areas evaluated, both treatments increased the HO-1 expression and inhibited the overexpression of CD11b/c and/or MAPK phosphorylation caused by nerve injury in the spinal cord, hippocampus and amygdala and/or prefrontal cortex. This study demonstrates that treatment with CORM-2 and/or CoPP further to exert potent anti-allodynic and anti-hyperalgesic actions also produce anti-oxidative and anti-inflammatory effects and inhibit MAPK activated by sciatic nerve injury in specific brain areas. In conclusion, these data reveal new mechanism of action of CORM-2 and CoPP in the central nervous system of animals with persistent neuropathic pain.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.12.007
      Issue No: Vol. 148 (2017)
       
  • Ginsenoside Rh4 induces apoptosis and autophagic cell death through
           activation of the ROS/JNK/p53 pathway in colorectal cancer cells
    • Authors: Qian Wu; Jianjun Deng; Daidi Fan; Zhiguang Duan; Chenhui Zhu; Rongzhan Fu; Shanshan Wang
      Pages: 64 - 74
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Qian Wu, Jianjun Deng, Daidi Fan, Zhiguang Duan, Chenhui Zhu, Rongzhan Fu, Shanshan Wang
      The use of ginsenosides in cancer therapy has been intensively investigated. The ginsenoside Rh4 (Rh4), a rare saponin obtained from Panax notoginseng, dissolves in water more readily than total saponins, making this compound easier to use in anti-cancer pharmaceutics. Here, we investigated the antiproliferative activity and mechanisms of Rh4 in colorectal cancer, both in vivo and in vitro. A colorectal cancer xenograft model showed that Rh4 significantly inhibited tumor growth with few side effects. CCK-8 assays, flow cytometric analysis, Western blotting and immunohistochemistry revealed that Rh4 effectively suppressed colorectal cancer cell proliferation via inducing G0/G1 phase arrest, caspase-dependent apoptosis and autophagic cell death but was not significantly cytotoxic to normal colon epithelial cells. Furthermore, apoptosis played a dominant role in Rh4-induced cell death, as the pan-caspase inhibitor Z-VAD-FMK blocked cell death to a greater extent than the autophagy inhibitor 3-methyladenine. Moreover, Rh4 increased reactive oxygen species (ROS) accumulation and subsequently activated the JNK-p53 pathway. An ROS scavenger and JNK and p53 inhibitors significantly attenuated Rh4-induced apoptosis and autophagy. Thus, the present study is the first to illustrate that Rh4 triggers apoptosis and autophagy via activating the ROS/JNK/p53 pathway in colorectal cancer cells, providing basic scientific evidence that Rh4 shows great potential as an anti-cancer agent.
      Graphical abstract image

      PubDate: 2017-12-26T18:30:32Z
      DOI: 10.1016/j.bcp.2017.12.004
      Issue No: Vol. 148 (2017)
       
  • LST-3TM12 is a member of the OATP1B family and a functional transporter
    • Authors: Vanessa Malagnino; Janine Hussner; Isabell Seibert; Antje Stolzenburg; Christoph P. Sager; Henriette E. Meyer zu Schwabedissen
      Pages: 75 - 87
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): Vanessa Malagnino, Janine Hussner, Isabell Seibert, Antje Stolzenburg, Christoph P. Sager, Henriette E. Meyer zu Schwabedissen
      Organic anion transporting polypeptides (OATPs) and particularly the two members of the OATP1B family are known for their role in pharmacokinetics. Both SLCO1B3 and SLCO1B1 are located on chromosome 12 encompassing the gene locus SLCO1B7. Hitherto, this particular gene has been assumed to be a pseudogene, even though there are published mRNA sequences linked to this chromosomal area. It was aim of this study to further investigate SLCO1B7 and the associated mRNA LST-3TM12. In a first step, we aligned all mRNAs linked to the chromosomal region of SLCO1B-transporters. This in silico analysis revealed that LST-3TM12 is a product of splicing of SLCO1B3 and SLCO1B7, and encodes for a protein with twelve transmembrane domains. The existence of LST-3TM12 mRNA was verified by polymerase chain reaction showing liver enriched expression. In addition, immunohistological staining showed that LST-3TM12 protein was expressed in the endoplasmic reticulum (ER) of hepatocytes. Localization in the ER was further verified by immunoblot analysis showing high amounts of LST-3TM12 in liver microsomes. Function of LST-3TM12 was assessed by transport studies after heterologous expression in HeLa cells, where the transporter was shown to be expressed not only in the ER but also in the plasma membrane. Overexpression of LST-3TM12 was associated with enhanced cellular accumulation of dehydroepiandrosterone sulfate (Vmax 300.2 pmol mg−1 min−1; Km 34.2 µm) and estradiol 17β-glucuronide (Vmax 29.9 mol mg−1 min−1 and Km 32.8 µM). In conclusion, LST-3TM12 is a functional splice variant of SLCO1B3 and SLCO1B7 expressed in the ER of human liver.
      Graphical abstract image

      PubDate: 2017-12-26T18:30:32Z
      DOI: 10.1016/j.bcp.2017.12.012
      Issue No: Vol. 148 (2017)
       
  • Quantification of 11β-hydroxysteroid dehydrogenase 1 kinetics and
           pharmacodynamic effects of inhibitors in brain using mass spectrometry
           imaging and stable-isotope tracers in mice
    • Authors: D.F. Cobice; D.E.W. Livingstone; A. McBride; C.L. MacKay; B.R. Walker; S.P. Webster; R. Andrew
      Pages: 88 - 99
      Abstract: Publication date: February 2018
      Source:Biochemical Pharmacology, Volume 148
      Author(s): D.F. Cobice, D.E.W. Livingstone, A. McBride, C.L. MacKay, B.R. Walker, S.P. Webster, R. Andrew
      11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11β-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11β-HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11β-HSD1 inhibitor that accesses the brain. [9,11,12,12-2H]4-Cortisol was infused (1.75 mg/day) by minipump for 2 days into C57Bl6 mice (male, age 12 weeks, n = 3/group) after which an 11β-HSD1 inhibitor (UE2316) was administered (25 mg/kg oral gavage) and animals culled immediately or 1, 2 and 4 h post-dosing. Mice with global genetic disruption of Hsd11B1 were studied similarly. Turnover of d4-cortisol to d3-cortisone (by loss of the 11-deuterium) and regeneration of d3-cortisol (by 11β-HSD1-mediated reduction) were assessed in plasma, liver and brain using matrix assisted laser desorption ionization coupled to Fourier transform cyclotron resonance mass spectrometry. The tracer d4-cortisol was detected in liver and brain following a two day infusion. Turnover to d3-cortisone and on to d3-cortisol was slower in brain than liver. In contrast, d3-cortisol was not detected in mice lacking 11β-HSD1. UE2316 impaired d3-cortisol generation measured in whole body (assessed in plasma; 53.1% suppression in rate of appearance in d3-cortisol), liver and brain. Differential inhibition in brain regions was observed; active glucocorticoids were suppressed to a greater in extent hippocampus or cortex than in amygdala. These data confirm that the contribution of 11β-HSD1 to the tissue glucocorticoid pool, and the consequences of enzyme inhibition on active glucocorticoid concentrations, are substantial, including in the brain. They further demonstrate the value of mass spectrometry imaging in pharmacokinetic and pharmacodynamic studies.
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      PubDate: 2017-12-26T18:30:32Z
      DOI: 10.1016/j.bcp.2017.12.013
      Issue No: Vol. 148 (2017)
       
  • A look into centrosome abnormalities in colon cancer cells, how they arise
           and how they might be targeted therapeutically
    • Authors: Lauren E. Harrison; Marina Bleiler; Charles Giardina
      Pages: 1 - 8
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Lauren E. Harrison, Marina Bleiler, Charles Giardina
      Cancer cells have long been noted for alterations in centrosome structure, number, and function. Colorectal cancers are interesting in this regard since two frequently mutated genes, APC and CTNNB1 (β-catenin), encode proteins that directly interact with the centrosome and affect its ability to direct microtubule growth and establish cell polarity. Colorectal cancers also frequently display centrosome over-duplication and clustering. Efforts have been directed toward understanding how supernumerary centrosomes cluster and whether disrupting this clustering may be a way to induce aberrant/lethal mitoses of cancer cells. Given the important role of the centrosome in establishing spindle polarity and regulating some apoptotic signaling pathways, other approaches to centrosome targeting may be fruitful as well. Basic information on the nature and extent of centrosome defects in colorectal cancer, including why they over-duplicate and whether this over-duplication compensates for their functional defects, could provide a framework for the development of novel approaches for the therapeutic targeting of colorectal cancer.
      Graphical abstract image

      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.11.003
      Issue No: Vol. 147 (2017)
       
  • A partnership with the proteasome; the destructive nature of GSK3
    • Authors: Holly Robertson; John D. Hayes; Calum Sutherland
      Pages: 77 - 92
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Holly Robertson, John D. Hayes, Calum Sutherland
      Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates include alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (β-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-β-TrCP ‘destruction hit-list’ that allows co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-β-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.10.016
      Issue No: Vol. 147 (2017)
       
  • Targeting CXCR7 improves the efficacy of breast cancer patients with
           tamoxifen therapy
    • Authors: Mingang Hao; Xiaoling Weng; Yingying Wang; Xueqin Sun; Tingting Yan; Yu Li; Lidan Hou; Xiangjun Meng; Jianhua Wang
      Pages: 128 - 140
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Mingang Hao, Xiaoling Weng, Yingying Wang, Xueqin Sun, Tingting Yan, Yu Li, Lidan Hou, Xiangjun Meng, Jianhua Wang
      Chemokine (C-X-C motif) receptor 7 (CXCR7) has been established to be involved in breast cancer (BCa) progression. However, the role of CXCR7 in different subtype of BCa still remains unclear. Here we note that CXCR7 expression is significantly amplified in Luminal type BCa tissues as compared with Her2 and TNBC types through data-mining in TCGA datasets, and its protein level positively correlates with ERα expression by staining of human BCa tissue. Interestingly, alteration of CXCR7 expression in Luminal type BCa cells is able to modulate the expression of ERα through ubiquitination at post-translational level. Additionally, overexpression of CXCR7 in these cells greatly induces 4-OHT insensitivity in vitro and is associated with earlier recurrence in patients with tamoxifen therapy. Notably, silencing ERα expression potentially rescues the sensitivity of the above cells to 4-OHT, suggesting that elevated level of ERα is responsible for CXCR7-induced 4-OHT insensitivity in Luminal type BCa. Finally, mechanistic analyses show that the reduced BRCA1 (ubiquitin E3 ligase) and elevated OTUB1 (deubiquitinase) expression, which are regulated by CXCR7/ERK1/2 signaling pathway, are responsible for stabilizing ERα protein. In conclusion, our results suggest that targeting CXCR7 may serve as a potential therapeutic strategy for improving the efficacy of BCa patients with tamoxifen therapy.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.11.013
      Issue No: Vol. 147 (2017)
       
  • How to effectively treat acute leukemia patients bearing
           MLL-rearrangements '
    • Authors: Dieter Steinhilber; Rolf Marschalek
      Pages: 183 - 190
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Dieter Steinhilber, Rolf Marschalek
      Chromosomal translocations - leading to the expression of fusion genes - are well-studied genetic abberrations associated with the development of leukemias. Most of them represent altered transcription factors that affect transcription or epigenetics, while others - like BCR-ABL - are enhancing signaling. BCR-ABL has become the prototype for rational drug design, and drugs like Imatinib and subsequently improved drugs have a great impact on cancer treatments. By contrast, MLL-translocations in acute leukemia patients are hard to treat, display a high relapse rate and the overall survival rate is still very poor. Therefore, new treatment modalities are urgently needed. Based on the molecular insights of the most frequent MLL rearrangements, BET-, DOT1L-, SET- and MEN1/LEDGF-inhibitors have been developed and first clinical studies were initiated. Not all results of these studies have are yet available, however, a first paper reports a failure in the DOT1L-inhibitor study although it was the most promising drug based on literature data. One possible explanation is that all of the above mentioned drugs also target the cognate wildtype proteins. Here, we want to strengthen the fact that efforts should be made to develop drugs or strategies to selectively inhibit only the fusion proteins. Some examples will be given that follow exactly this guideline, and proof-of-concept experiments have already demonstrated their feasibility and effectiveness. Some of the mentioned approaches were using drugs that are already on the market, indicating that there are existing opportunities for the future which should be implemented in future therapy strategies.
      Graphical abstract image

      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.09.007
      Issue No: Vol. 147 (2017)
       
  • Auxiliary subunits of AMPA receptors: The discovery of a
           forebrain-selective antagonist, LY3130481/CERC-611
    • Authors: Akihiko S. Kato; Jeffrey M. Witkin
      Pages: 191 - 200
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Akihiko S. Kato, Jeffrey M. Witkin
      Drugs originate from the discovery of compounds, natural or synthetic, that bind to proteins (receptors, enzymes, transporters, etc.), the interaction of which modulates biological cascades that have potential therapeutic benefit. Rational strategies for identifying novel drug therapies are typically based on knowledge of the structure of the target proteins and the design of new chemical entities that modulate these proteins in a beneficial manner. The present review discusses a novel approach to drug discovery based on the identification and characterization of auxiliary proteins, the transmembrane AMPA receptor regulatory proteins (TARPs) that are associated with AMPA receptors. Utilizing these auxiliary proteins in compound screening led to the discovery of the TARP-dependent-AMPA forebrain selective receptor antagonist (TDAA), LY3130481/CERC-611 that is currently in clinical development for epilepsy.
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      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.09.015
      Issue No: Vol. 147 (2017)
       
  • Pharmacological targeting of exercise adaptations in skeletal muscle:
           Benefits and pitfalls
    • Authors: Martin Weihrauch; Christoph Handschin
      Pages: 211 - 220
      Abstract: Publication date: January 2018
      Source:Biochemical Pharmacology, Volume 147
      Author(s): Martin Weihrauch, Christoph Handschin
      Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping. In contrast, dietary supplements with a higher safety margin exert milder outcomes. In recent years, the design of pharmacological agents that activate the training program, so-called “exercise mimetics”, has been proposed, although the feasibility of such an approach is highly debated. In this review, the most recent insights into key regulatory factors and therapeutic approaches aimed at leveraging exercise adaptations are discussed.
      Graphical abstract image

      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.10.006
      Issue No: Vol. 147 (2017)
       
  • Characterisation of signalling and regulation of common calcitonin
           receptor splice variants and polymorphisms
    • Authors: Emma Dal Maso; Rasmus Just; Caroline Hick; Arthur Christopoulos; Patrick M. Sexton; Denise Wootten; Sebastian G.B. Furness
      Abstract: Publication date: Available online 23 December 2017
      Source:Biochemical Pharmacology
      Author(s): Emma Dal Maso, Rasmus Just, Caroline Hick, Arthur Christopoulos, Patrick M. Sexton, Denise Wootten, Sebastian G.B. Furness
      The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget’s disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding.
      Graphical abstract image

      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.12.016
       
  • Current mechanistic insights into the CCCP-induced cell survival response
    • Authors: Mariame Selma Kane; Aurelien Paris; Philippe Codron; Julien Cassereau; Vincent Procaccio; Guy Lenaers; Pascal Reynier; Arnaud Chevrollier
      Abstract: Publication date: Available online 22 December 2017
      Source:Biochemical Pharmacology
      Author(s): Mariame Selma Kane, Aurelien Paris, Philippe Codron, Julien Cassereau, Vincent Procaccio, Guy Lenaers, Pascal Reynier, Arnaud Chevrollier
      The ring-substituted derivatives of carbonyl cyanide phenylhydrazone, CCCP and FCCP, are routinely used for the analysis of the mitochondrial function in living cells, tissues, and isolated mitochondrial preparations. CCCP and FCCP are now being increasingly used for investigating the mechanisms of autophagy by inducing mitochondrial degradation through the disruption of the mitochondrial membrane potential (ΔΨm). Sustained perturbation of ΔΨm, which is normally tightly controlled to ensure cell proliferation and survival, triggers various stress pathways as part of the cellular adaptive response, the main components of which are mitophagy and autophagy. We here review current mechanistic insights into the induction of mitophagy and autophagy by CCCP and FCCP. In particular, we analyze the cellular modifications produced by the activation of two major pathways involving the signaling of the nuclear factor erythroid 2–related factor 2 (Nrf2) and the transcription factor EB (TFEB), and discuss the contribution of these pathways to the integrated cellular stress response.
      Graphical abstract image

      PubDate: 2017-12-24T18:24:52Z
      DOI: 10.1016/j.bcp.2017.12.018
       
 
 
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