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  Subjects -> CHEMISTRY (Total: 891 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (621 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (45 journals)
    - ORGANIC CHEMISTRY (51 journals)
    - PHYSICAL CHEMISTRY (70 journals)

CHEMISTRY (621 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 43)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 21)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 26)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 41)
ACS Nano     Full-text available via subscription   (Followers: 274)
ACS Photonics     Full-text available via subscription   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Full-text available via subscription   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 6)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 66)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 21)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Environmental Chemistry     Open Access   (Followers: 5)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Polymer Science     Hybrid Journal   (Followers: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 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: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 64)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 17)
American Journal of Chemistry     Open Access   (Followers: 30)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 165)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 244)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 2)
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  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 350)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 10)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Full-text available via subscription   (Followers: 21)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 128)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
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: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 10)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 191)
Chemical Science     Open Access   (Followers: 24)
Chemical Technology     Open Access   (Followers: 24)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
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: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 7)
Chemistry - A European Journal     Hybrid Journal   (Followers: 163)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 254)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 11)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access   (Followers: 1)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
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 Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
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  

        1 2 3 4 | Last

Journal Cover
Biochemical Pharmacology
Journal Prestige (SJR): 1.832
Citation Impact (citeScore): 5
Number of Followers: 10  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0006-2952
Published by Elsevier Homepage  [3163 journals]
  • Nano-delivery systems for encapsulation of dietary polyphenols: An
           experimental approach for neurodegenerative diseases and brain tumors
    • Authors: T. Squillaro; A. Cimini; G. Peluso; A. Giordano; MAB. Melone
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): T. Squillaro, A. Cimini, G. Peluso, A. Giordano, M.A.B. Melone
      Neurodegenerative diseases (NDs) and brain tumors are severe, disabling, and incurable disorders that represent a critical problem regarding human suffering and the economic burden on the healthcare system. Because of the lack of effective therapies to treat NDs and brain tumors, the challenge for physicians is to discover new drugs to improve their patients’ quality of life. In addition to risk factors such as genetics and environmental influences, increased cellular oxidative stress has been reported as one of the potential common etiologies in both disorders. Given their antioxidant and anti-inflammatory potential, dietary polyphenols are considered to be one of the most bioactive natural agents in chronic disease prevention and treatment. Despite the protective activity of polyphenols, their inefficient delivery systems and poor bioavailability strongly limit their use in medicine and functional food. A potential solution lies in polymeric nanoparticle-based polyphenol delivery systems that are able to enhance their absorption across the gastrointestinal tract, improve their bioavailability, and transport them to target organs. In the present manuscript, we provide an overview of the primary polyphenols used for ND and brain tumor prevention and treatment by focusing on recent findings, the principal factors limiting their application in clinical practice, and a promising delivery strategy to improve their bioavailability.
      Graphical abstract image

      PubDate: 2018-05-31T09:38:04Z
      DOI: 10.1016/j.bcp.2018.05.016
      Issue No: Vol. 154 (2018)
       
  • Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic
           drug suppressing IgE-mediated mast cells and allergic responses via the
           inhibition of Lyn and Fyn
    • Authors: Young Hwan Park; Do Kyun Kim; Hyun Woo Kim; Hyuk Soon Kim; Dajeong Lee; Min Bum Lee; Keun Young Min; Jimo Koo; Su Jeong Kim; Changhee Kang; Young Mi Kim; Hyung Sik Kim; Wahn Soo Choi
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Young Hwan Park, Do-Kyun Kim, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Keun Young Min, Jimo Koo, Su Jeong Kim, Changhee Kang, Young Mi Kim, Hyung Sik Kim, Wahn Soo Choi
      Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC50, ∼27.9 nM) and BMMCs (IC50, ∼99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activated T cells (LAT), phospholipase (PL) Cγ1, Akt, and mitogen-activated protein (MAP) kinases (Erk1/2, p38, and JNK) in mast cells. In in vitro protein kinase assay, AZD7762 inhibited the activity of Lyn and Fyn kinases, which are important for the activation of Syk in mast cells. Furthermore, AZD7762 also suppressed the degranulation of LAD2 human mast cells (IC50, ∼49.9 nM) and activation of Syk in a dose-dependent manner. As observed in experiments with mast cells in vitro, AZD7762 inhibited antigen-mediated passive cutaneous anaphylaxis in mice (ED50, ∼35.8 mg/kg). Altogether, these results suggest that AZD7762 could be used as a new therapeutic agent for mast cell-mediated allergic diseases.
      Graphical abstract image

      PubDate: 2018-05-31T09:38:04Z
      DOI: 10.1016/j.bcp.2018.05.012
      Issue No: Vol. 154 (2018)
       
  • Globular adiponectin protects rat hepatocytes against
           acetaminophen-induced cell death via modulation of the inflammasome
           activation and ER stress: Critical role of autophagy induction
    • Authors: Eun Hye Kim; Pil-Hoon Park
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Eun Hye Kim, Pil-Hoon Park
      Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. In the present study, we examined the protective effect of globular adiponectin (gAcrp) on APAP-induced hepatocyte death and its underlying mechanisms. We found that APAP (2 mM)-induced hepatocyte death was prevented by inhibition of the inflammasome. In addition, treatment with gAcrp (0.5 and 1 μg/ml) inhibited APAP-induced activation of the inflammasome, judged by suppression of interleukin-1β maturation, caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation, suggesting that protective effects of gAcrp against APAP-induced hepatocyte death is mediated via modulation of the inflammasome. APAP also induced ER stress and treatment with tauroursodeoxycholic acid (TUDCA), an ER chaperone and inhibitor of ER stress, abolished APAP-induced inflammasomes activation, implying that ER stress acts as signaling event leading to the inflammasome activation in hepatocytes stimulated with APAP. Moreover, gAcrp significantly suppressed APAP-induced expression of ER stress marker genes. Finally, the modulatory effects of gAcrp on ER stress and inflammasomes activation were abrogated by treatment with autophagy inhibitors, while an autophagy inducer (rapamycin) suppressed APAP-elicited ER stress, demonstrating that autophagy induction plays a crucial role in the suppression of APAP-induced inflammasome activation and ER stress by gAcrp. Taken together, these results indicate that gAcrp protects hepatocytes against APAP-induced cell death by modulating ER stress and the inflammasome activation, at least in part, via autophagy induction.
      Graphical abstract image

      PubDate: 2018-05-31T09:38:04Z
      DOI: 10.1016/j.bcp.2018.05.014
      Issue No: Vol. 154 (2018)
       
  • Tanovea® for the treatment of lymphoma in dogs
    • Authors: Erik De Clercq
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Erik De Clercq
      Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or “double” prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin’s lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.010
      Issue No: Vol. 154 (2018)
       
  • A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on
           HBV-positive hepatocellular carcinoma with high expression of cIAP2 by
           inducing apoptosis and enhancing innate anti-tumor immunity
    • Authors: Wentao Pan; Qiuyun Luo; Xianglei Yan; Luping Yuan; Hanjie Yi; Lin Zhang; Baoxia Li; Yuxin Zhang; Jian Sun; Miao-Zhen Qiu; Da-Jun Yang
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Wentao Pan, Qiuyun Luo, Xianglei Yan, Luping Yuan, Hanjie Yi, Lin Zhang, Baoxia Li, Yuxin Zhang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang
      Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-κB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.04.020
      Issue No: Vol. 154 (2018)
       
  • New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase
           I/II but reveal different p53-dependency in inducing G2/M arrest and
           apoptosis
    • Authors: Qian-Ting Tian; Chun-Yong Ding; Shan-Shan Song; Ying-Qing Wang; Ao Zhang; Ze-Hong Miao
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Qian-Ting Tian, Chun-Yong Ding, Shan-Shan Song, Ying-Qing Wang, Ao Zhang, Ze-Hong Miao
      Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). With significantly improved water solubility, S222 and S439 displayed 12- and 14-times more potent proliferative inhibition than their parent tanshinone-1 in a panel of 15 cancer cell lines. Both retained tanshinone-1’s anti-MDR and anti-angiogenesis properties and its capability to reduce the phosphorylation of Stat3 at Tyr705 with apparently enhanced efficacy and in these regards, S439 was also slightly more potent than S222. Both derivatives and tanshinone-1 directly inhibited Top1 and Top2 at molecular and cellular levels; the derivatives displayed similar potency but both were more potent than tanshinone-1. The inhibition of S222 and S439 on Top1 and Top2 was also more potent than that of the Top1 inhibitor hydroxylcamptothecin and the Top2 inhibitor etoposide, respectively. Consistently, tanshinone-1 and its derivatives induced DNA double-strand breaks, G2/M arrest and apoptosis. Unexpectedly, the derivatives demonstrated different p53-dependency in inducing both cell cycle arrest and apoptosis. S222 showed no obvious p53-dependency. In contrast, S439 induced more G2/M arrest in p53-proficient cells than in p53-deficient cells while its apoptotic induction was the opposite. However, their proliferative inhibition was independent of the p53 status. Due to their structures different from the known Top1, Top2 and dual Top1/2 inhibitors, our results indicate that tanshinone-1 and its derivatives are a new type of dual Top1/2 inhibitors.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.006
      Issue No: Vol. 154 (2018)
       
  • Identification of a pyrogallol derivative as a potent and selective human
           TLR2 antagonist by structure-based virtual screening
    • Authors: Maria Grabowski; Manuela S. Murgueitio; Marcel Bermudez; Jörg Rademann; Gerhard Wolber; Günther Weindl
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Maria Grabowski, Manuela S. Murgueitio, Marcel Bermudez, Jörg Rademann, Gerhard Wolber, Günther Weindl
      Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293-hTLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-CPT22. Concentration ratio analysis identified both compounds as competitive antagonists of Pam3CSK4- and Pam2CSK4-induced responses. Schild plot analysis yielded apparent pA2 values of 5.73 and 6.15 (TLR2/1), and 5.80 and 6.65 (TLR2/6) for CU-CPT22 and MMG-11, respectively. MMG-11 neither shows cellular toxicity nor interference with signaling induced by other TLR agonists, IL-1β or TNF. Taken together, we demonstrate that MMG-11 is a potent and selective TLR2 antagonist with low cytotoxicity rendering it a promising pharmacological tool for the investigation of TLR signaling and a suitable lead structure for further chemical optimization.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.04.018
      Issue No: Vol. 154 (2018)
       
  • Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting
           miR-186 in human chondrosarcoma cells
    • Authors: Chen-Ming Su; Chih-Hsin Tang; Meng-Ju Chi; Chih-Yang Lin; Yi-Chin Fong; Yueh-Ching Liu; Wei-Cheng Chen; Shih-Wei Wang
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Chen-Ming Su, Chih-Hsin Tang, Meng-Ju Chi, Chih-Yang Lin, Yi-Chin Fong, Yueh-Ching Liu, Wei-Cheng Chen, Shih-Wei Wang
      Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Accumulating evidence shows that resistin, a cytokine secreted from adipocytes and monocytes, also promotes tumor pathogenesis. Notably, chondrosarcoma can easily metastasize. In this study, we demonstrate that resistin enhances VEGF-C expression and lymphatic endothelial cells (LECs)-associated lymphangiogenesis in human chondrosarcoma cells. We also show that resistin triggers VEGF-C-dependent lymphangiogenesis via the c-Src signaling pathway and down-regulating micro RNA (miR)-186. Overexpression of resistin in chondrosarcoma cells significantly enhanced VEGF-C production and LECs-associated lymphangiogenesis in vitro and tumor-related lymphangiogenesis in vivo. Resistin levels were positively correlated with VEGF-C-dependent lymphangiogenesis via the down-regulation of miR-186 expression in clinical samples from chondrosarcoma tissue. This study is the first to evaluate the mechanism underlying resistin-induced promotion of LECs-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.001
      Issue No: Vol. 154 (2018)
       
  • Probing the binding site of novel selective positive allosteric modulators
           at the M1 muscarinic acetylcholine receptor
    • Authors: Elham Khajehali; Celine Valant; Manuela Jörg; Andrew B. Tobin; P. Jeffrey Conn; Craig W. Lindsley; Patrick M. Sexton; Peter J. Scammells; Arthur Christopoulos
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Elham Khajehali, Celine Valant, Manuela Jörg, Andrew B. Tobin, P. Jeffrey Conn, Craig W. Lindsley, Patrick M. Sexton, Peter J. Scammells, Arthur Christopoulos
      Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one). Given these diverse scaffolds and pharmacodynamics, the current study combined pharmacological analysis and site-directed mutagenesis to explore the potential binding site and function of newer M1 mAChR PAMs relative to BQCA. Interestingly, the mechanism of action of the novel PAMs was consistent with a common model of allostery, as previously described for BQCA. Key residues involved in the activity of BQCA, including Y179 in the second extracellular loop (ECL) and W4007.35 in transmembrane domain (TM) 7, were critical for the activity of all PAMs tested. Overall, our data indicate that structurally distinct PAMs share a similar binding site with BQCA, specifically, an extracellular allosteric site defined by residues in TM2, TM7 and ECL2. These findings provide valuable insights into the structural basis underlying modulator binding, cooperativity and signaling at the M1 mAChR, which is essential for the rational design of PAMs with tailored pharmacological properties.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.009
      Issue No: Vol. 154 (2018)
       
  • The aryl hydrocarbon receptor is indispensable for dioxin-induced defects
           in sexually-dimorphic behaviors due to the reduction in fetal
           steroidogenesis of the pituitary-gonadal axis in rats
    • Authors: Yukiko Hattori; Tomoki Takeda; Arisa Nakamura; Kyoko Nishida; Yuko Shioji; Haruki Fukumitsu; Hideyuki Yamada; Yuji Ishii
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Yukiko Hattori, Tomoki Takeda, Arisa Nakamura, Kyoko Nishida, Yuko Shioji, Haruki Fukumitsu, Hideyuki Yamada, Yuji Ishii
      Many forms of the toxic effects produced by dioxins and related chemicals take place following activation of the aryl hydrocarbon receptor (AHR). Our previous studies have demonstrated that treating pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic dioxin, attenuates the pituitary expression of gonadotropins to reduce testicular steroidogenesis during the fetal stage, resulting in the impairment of sexually-dimorphic behaviors after the offspring reach maturity. To investigate the contribution of AHR to these disorders, we examined the effects of TCDD on AHR-knockout (AHR-KO) Wistar rats. When pregnant AHR-heterozygous rats were given an oral dose of 1 µg/kg TCDD at gestational day (GD) 15, TCDD reduced the expression of pituitary gonadotropins and testicular steroidogenic proteins in male wild-type fetuses at GD20 without affecting body weight, sex ratio and litter size. However, the same defect did not occur in AHR-KO fetuses. Further, fetal exposure to TCDD impaired the activity of masculine sexual behavior after reaching adulthood only in the wild-type offspring. Also, in female offspring, not only the fetal gonadotropins production but also sexual dimorphism, such as saccharin preference, after growing up were suppressed by TCDD only in the wild-type. Interestingly, in the absence of TCDD, deleting AHR reduced masculine sexual behavior, as well as fetal steroidogenesis of the pituitary-gonadal axis. These results provide novel evidence that 1) AHR is required for TCDD-produced defects in sexually-dimorphic behaviors of the offspring, and 2) AHR signaling plays a role in gonadotropin synthesis during the developmental stage to acquire sexual dimorphism after reaching adulthood.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.008
      Issue No: Vol. 154 (2018)
       
  • In vitro assessment of competitive and time-dependent inhibition of the
           nevirapine metabolism by nortriptyline in rats
    • Authors: Iris Usach; José-Maria Ferrer; José-Esteban Peris
      Pages: 1 - 9
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Iris Usach, José-Maria Ferrer, José-Esteban Peris
      Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-NVP) where competitively inhibited with similar inhibitory constant values (Ki = 4.01, 3.97 and 4.40 μM, respectively). Time-dependent inhibition of the NVP metabolism was also detected, with a 2.5-fold reduction in the IC50 values of NT for 2-, 3-, and 12-OH-NVP formation when NT was preincubated with the microsomal suspension in the presence of an NADPH-generating system. A concentration-dependent inhibition of the formation of NVP metabolites by the main NT metabolite (10-OH-NT) was also observed, however, the inhibitory potency of 10-OH-NT was much lower than that of the parent drug. The apparent hepatic intrinsic clearance of NVP determined in these in vitro experiments was used to predict the in vivo clearance of NVP using the “well-stirred” and the “parallel-tube” models, resulting in values close to those previously observed in vivo clearance. Finally, a good prediction of the increase in the plasma concentrations of NVP when co-administered with NT was obtained employing the inhibitory constant of NT determined in vitro and the estimated plasma concentration of NT entering the liver.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.016
      Issue No: Vol. 154 (2018)
       
  • Ribociclib shows potential for pharmacokinetic drug-drug interactions
           being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450
           isoforms in vitro
    • Authors: Ales Sorf; Jakub Hofman; Radim Kučera; Frantisek Staud; Martina Ceckova
      Pages: 10 - 17
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Ales Sorf, Jakub Hofman, Radim Kučera, Frantisek Staud, Martina Ceckova
      Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods. Our data showed accelerated ABCB1 inhibitor LY335979-sensitive, basolateral-to-apical transport of ribociclib across MDCKII-ABCB1 cell monolayers, which identified ribociclib as an ABCB1 substrate. The antiproliferative studies supported this finding by demonstrating significantly higher EC50 value in ABCB1-, but not ABCG2- or ABCC1-expressing MDCKII cells, than in the parent MDCKII cell line. Furthermore, we observed significant inhibitory effects of ribociclib on ABCB1 and ABCG2 transporters and CYP1A2, CYP3A4, CYP3A5, and CYP2C9 isoform activity in human CYP-expressing insect microsomes. The ribociclib-induced ABCB1 and ABCG2 inhibition further reversed daunorubicin and mitoxantrone resistance in MDCKII and human MCF-7 breast carcinoma cell lines, indicating a synergistic antiproliferative effect, without affecting ABCB1 or ABCG2 expression. In summary, our data indicate that ABCB1 affects ribociclib transport across the membranes and the high potential of ribociclib for drug-drug interactions (DDIs) through ABCB1 and ABCG2 transporters and CYP isoforms. Moreover, we demonstrate the beneficial MDR-reversing potential of ribociclib, which could be further exploited in novel anticancer treatment strategies.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.013
      Issue No: Vol. 154 (2018)
       
  • Baicalin modulates the Treg/Teff balance to alleviate uveitis by
           activating the aryl hydrocarbon receptor
    • Authors: Wenjie Zhu; Xiaoqing Chen; Jianfeng Yu; Yichen Xiao; Yingqi Li; Shangtao Wan; Wenru Su; Dan Liang
      Pages: 18 - 27
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Wenjie Zhu, Xiaoqing Chen, Jianfeng Yu, Yichen Xiao, Yingqi Li, Shangtao Wan, Wenru Su, Dan Liang
      Autoimmune uveitis is a sight-threatening ocular inflammatory disorder. Immunological inflammation is regarded as the key to pathogenesis in autoimmune uveitis. Baicalin, the major bioactive component of Scutellaria baicalensis, possesses immunomodulatory properties. However, the role of baicalin in uveitis and its underlying mechanisms remain unclear. In the current study, we found that baicalin treatment obviously inhibited the intraocular inflammatory process in mice with experimental autoimmune uveitis, along with clear declines in infiltrated inflammatory cells and inflammatory cytokine transcription in the retina and draining lymph nodes. Furthermore, baicalin treatment increased the frequency and number of regulatory T cells and decreased the frequency and number of effector T cells (Th1 and Th17 cells) in the draining lymph nodes of mice with experimental autoimmune uveitis. In vitro, baicalin treatment suppressed interphotoreceptor retinoid binding protein-specific CD4+ T cell proliferation and converted CD4+ T cell differentiation. Furthermore, the expression of aryl hydrocarbon receptor was activated by baicalin treatment. Baicalin-mediated modulation of CD4+ T cell differentiation was partially abrogated by the suppression of aryl hydrocarbon receptor. These findings suggest that baicalin modulates the Treg/Teff balance and CD4+ T cell proliferation to ameliorate experimental autoimmune uveitis by activating the aryl hydrocarbon receptor.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.006
      Issue No: Vol. 154 (2018)
       
  • Inhibitory effects of drugs on the metabolic activity of mouse and human
           aldehyde oxidases and influence on drug–drug interactions
    • Authors: Naoki Takaoka; Seigo Sanoh; Katsuhiro Okuda; Yaichiro Kotake; Go Sugahara; Ami Yanagi; Yuji Ishida; Chise Tateno; Yoshitaka Tayama; Kazumi Sugihara; Shigeyuki Kitamura; Mami Kurosaki; Mineko Terao; Enrico Garattini; Shigeru Ohta
      Pages: 28 - 38
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Naoki Takaoka, Seigo Sanoh, Katsuhiro Okuda, Yaichiro Kotake, Go Sugahara, Ami Yanagi, Yuji Ishida, Chise Tateno, Yoshitaka Tayama, Kazumi Sugihara, Shigeyuki Kitamura, Mami Kurosaki, Mineko Terao, Enrico Garattini, Shigeru Ohta
      As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug–drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O 6-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC50 values. We also evaluated the potential DDI between an AOX substrate (O 6-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0–24) of O 6-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.017
      Issue No: Vol. 154 (2018)
       
  • Sorafenib suppresses TGF-β responses by inducing caveolae/lipid
           raft-mediated internalization/degradation of cell-surface type II TGF-β
           receptors: Implications in development of effective adjunctive therapy for
           hepatocellular carcinoma
    • Authors: Chih-Ling Chung; Shih-Wei Wang; Wei-Chih Sun; Chih-Wen Shu; Yu-Chen Kao; Meng-Shin Shiao; Chun-Lin Chen
      Pages: 39 - 53
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Chih-Ling Chung, Shih-Wei Wang, Wei-Chih Sun, Chih-Wen Shu, Yu-Chen Kao, Meng-Shin Shiao, Chun-Lin Chen
      Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.014
      Issue No: Vol. 154 (2018)
       
  • Dengue virus NS2 and NS4: Minor proteins, mammoth roles
    • Authors: Sindhoora Bhargavi Gopala Reddy; Wei-Xin Chin; Nanjunda Swamy Shivananju
      Pages: 54 - 63
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Sindhoora Bhargavi Gopala Reddy, Wei-Xin Chin, Nanjunda Swamy Shivananju
      Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A–2K cleavage and NS4A–NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B–NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.008
      Issue No: Vol. 154 (2018)
       
  • Drug-DNA adducts as biomarkers for metabolic activation of the
           nitro-aromatic nitrogen mustard prodrug PR-104A
    • Authors: Alessia Stornetta; Kai-Cheng Kieren Deng; Sara Danielli; H.D. Sarath Liyanage; Shana J. Sturla; William R. Wilson; Yongchuan Gu
      Pages: 64 - 74
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Alessia Stornetta, Kai-Cheng Kieren Deng, Sara Danielli, H.D. Sarath Liyanage, Shana J. Sturla, William R. Wilson, Yongchuan Gu
      PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R2 = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.004
      Issue No: Vol. 154 (2018)
       
  • Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice
           endogenously synthesizing long-chain n-3 fatty acids
    • Authors: Ruibing Feng; Yang Wang; Conghui Liu; Chunyan Yan; Hang Zhang; Huanxing Su; Jing X. Kang; Chang-Zhen Shang; Jian-Bo Wan
      Pages: 75 - 88
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Ruibing Feng, Yang Wang, Conghui Liu, Chunyan Yan, Hang Zhang, Huanxing Su, Jing X. Kang, Chang-Zhen Shang, Jian-Bo Wan
      Acetaminophen (APAP) overdose-induced hepatotoxicity is the most commonly cause of drug-induced liver failure characterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFA) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1)/mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) – mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose.
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      PubDate: 2018-05-03T09:23:20Z
      DOI: 10.1016/j.bcp.2018.04.019
      Issue No: Vol. 154 (2018)
       
  • Effect of a long-term treatment with metformin in dystrophic mdx mice: A
           reconsideration of its potential clinical interest in Duchenne muscular
           dystrophy
    • Authors: Paola Mantuano; Francesca Sanarica; Elena Conte; Maria Grazia Morgese; Roberta Francesca Capogrosso; Anna Cozzoli; Adriano Fonzino; Angelo Quaranta; Jean-Francois Rolland; Michela De Bellis; Giulia Maria Camerino; Luigia Trabace; Annamaria De Luca
      Pages: 89 - 103
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Paola Mantuano, Francesca Sanarica, Elena Conte, Maria Grazia Morgese, Roberta Francesca Capogrosso, Anna Cozzoli, Adriano Fonzino, Angelo Quaranta, Jean-Francois Rolland, Michela De Bellis, Giulia Maria Camerino, Luigia Trabace, Annamaria De Luca
      The pharmacological stimulation of AMP-activated protein kinase (AMPK) via metabolic enhancers has been proposed as potential therapeutic strategy for Duchenne muscular dystrophy (DMD). Metformin, a widely-prescribed anti-hyperglycemic drug which activates AMPK via mitochondrial respiratory chain, has been recently tested in DMD patients in synergy with nitric oxide (NO)-precursors, with encouraging results. However, preclinical data supporting the use of metformin in DMD are still poor, and its actions on skeletal muscle appear controversial. Therefore, we investigated the effects of a long-term treatment with metformin (200 mg/kg/day in drinking water, for 20 weeks) in the exercised mdx mouse model, characterized by a severe mechanical-metabolic maladaptation. Metformin significantly ameliorated histopathology in mdx gastrocnemius muscle, in parallel reducing TGF-β1 with a recovery score (r.s) of 106%; this was accompanied by a decreased plasma matrix-metalloproteinase-9 (r.s. 43%). In addition, metformin significantly increased mdx diaphragm twitch and tetanic tension ex vivo (r.s. 44% and 36%, respectively), in spite of minor effects on in vivo weakness. However, no clear protective actions on dystrophic muscle metabolism were observed, as shown by the poor metformin effect on AMPK activation measured by western blot, on the expression of mechanical-metabolic response genes analyzed by qPCR, and by the lack of fast-to-slow fiber-type-shift assessed by SDH staining in tibialis anterior muscle. Similar results were obtained in the milder phenotype of sedentary mdx mice. The lack of metabolic effects could be, at least partly, due to metformin inability to increase low mdx muscle levels of l-arginine, l-citrulline and taurine, found by HPLC. Our findings encourage to explore alternative, metabolism-independent mechanisms of action to differently repurpose metformin in DMD, supporting its therapeutic combination with NO-sources.
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      PubDate: 2018-05-03T09:23:20Z
      DOI: 10.1016/j.bcp.2018.04.022
      Issue No: Vol. 154 (2018)
       
  • Angiotensin II cyclic analogs as tools to investigate AT1R biased
           signaling mechanisms
    • Authors: David St-Pierre; Jérôme Cabana; Brian J. Holleran; Élie Besserer-Offroy; Emanuel Escher; Gaétan Guillemette; Pierre Lavigne; Richard Leduc
      Pages: 104 - 117
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): David St-Pierre, Jérôme Cabana, Brian J. Holleran, Élie Besserer-Offroy, Emanuel Escher, Gaétan Guillemette, Pierre Lavigne, Richard Leduc
      G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Understanding both receptor and ligand conformation is of the utmost importance for the design of new drugs targeting GPCRs. In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (AT1R). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([Sar1Hcy3,5]AngII, [Sar1Cys3Hcy5]AngII and [Sar1Cys3,5]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and β-arrestin (βarr) signaling pathways via AT1R. Interestingly, [Sar1Hcy3,5]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy barrier associated with the insertion of residue Phe8 of AngII within the hydrophobic core of AT1R, associated with Gq/11 activation, is increased with [Sar1Hcy3,5]AngII. These results suggest that constraining the movements of molecular determinants within a given ligand by introducing cyclic structures may lead to the generation of novel ligands providing more efficient biased agonism.
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      PubDate: 2018-05-03T09:23:20Z
      DOI: 10.1016/j.bcp.2018.04.021
      Issue No: Vol. 154 (2018)
       
  • Biphasic modulation of cAMP levels by the contraceptive nomegestrol
           acetate. Impact on P-glycoprotein expression and activity in hepatic cells
           
    • Authors: Guillermo Nicolás Tocchetti; Camila Juliana Domínguez; Felipe Zecchinati; Maite Rocío Arana; María Laura Ruiz; Silvina Stella Maris Villanueva; Johanna Weiss; Aldo Domingo Mottino; Juan Pablo Rigalli
      Pages: 118 - 126
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Guillermo Nicolás Tocchetti, Camila Juliana Domínguez, Felipe Zecchinati, Maite Rocío Arana, María Laura Ruiz, Silvina Stella Maris Villanueva, Johanna Weiss, Aldo Domingo Mottino, Juan Pablo Rigalli
      ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp.
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      PubDate: 2018-05-03T09:23:20Z
      DOI: 10.1016/j.bcp.2018.04.023
      Issue No: Vol. 154 (2018)
       
  • Angiotensin II promotes pulmonary metastasis of melanoma through the
           activation of adhesion molecules in vascular endothelial cells
    • Authors: Shin Ishikane; Hiroshi Hosoda; Takashi Nojiri; Takeshi Tokudome; Tetsuya Mizutani; Koichi Miura; Yoshiharu Akitake; Toru Kimura; Yoshitaka Imamichi; Shinya Kawabe; Yumiko Toyohira; Nobuyuki Yanagihara; Fumi Takahashi-Yanaga; Mikiya Miyazato; Kaoru Miyamoto; Kenji Kangawa
      Pages: 136 - 147
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Shin Ishikane, Hiroshi Hosoda, Takashi Nojiri, Takeshi Tokudome, Tetsuya Mizutani, Koichi Miura, Yoshiharu Akitake, Toru Kimura, Yoshitaka Imamichi, Shinya Kawabe, Yumiko Toyohira, Nobuyuki Yanagihara, Fumi Takahashi-Yanaga, Mikiya Miyazato, Kaoru Miyamoto, Kenji Kangawa
      Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. However, its precise mechanisms have not been fully understood. In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 μg/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/kg/day), but not the calcium channel blocker amlodipine (5 or 10 mg/kg/day), significantly suppressed the effect of Ang II. In endothelium-specific Agtr1a knockout mice, Ang II-mediated acceleration of lung metastases of melanoma cells was significantly diminished. Ang II treatment significantly increased E-selectin mRNA expression in vascular endothelial cells collected from lung tissues, and thus promoted adherence of melanoma cells to the vascular endothelium. Ang II-accelerated lung metastases of melanoma cells were also suppressed by treatment with anti-E-selectin antibody (20 mg/kg). Taken together, Ang II-treatment exacerbates hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells.
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      PubDate: 2018-05-03T09:23:20Z
      DOI: 10.1016/j.bcp.2018.04.012
      Issue No: Vol. 154 (2018)
       
  • RACking up ceramide-induced islet β-cell dysfunction
    • Authors: Anjaneyulu Kowluru; Renu A. Kowluru
      Pages: 161 - 169
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Anjaneyulu Kowluru, Renu A. Kowluru
      The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. It is widely accepted that the onset of type 2 diabetes is due to an intricate interplay between genetic expression of the disease and a multitude of factors including increased oxidative and endoplasmic reticulum stress consequential to glucolipotoxicity and inflammation. Compelling experimental evidence from in vitro and in vivo studies implicates intracellular generation of ceramide (CER), a biologically-active sphingolipid, as a trigger in the onset of β-cell demise under above pathological conditions. Recent pharmacological and molecular biological evidence affirms regulatory roles for Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G protein, in the islet β-cell function in health and diabetes. In this Commentary, we overviewed the emerging evidence implicating potential cross-talk between Rac1 and ceramide signaling pathways in the onset of metabolic dysregulation of the islet β-cell culminating in impaired physiological insulin secretion, loss of β-cell mass and the onset of diabetes. Further, we propose a model depicting contributory roles of defective protein lipidation (prenylation) pathway in the induction of metabolic defects in the β-cell under metabolic stress conditions. Potential avenues for the identification of novel therapeutic targets for the prevention/treatment of diabetes and its associated complications are highlighted.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.04.026
      Issue No: Vol. 154 (2018)
       
  • Exploiting methionine restriction for cancer treatment
    • Authors: Sushma Chaturvedi; Robert M. Hoffman; Joseph R. Bertino
      Pages: 170 - 173
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Sushma Chaturvedi, Robert M. Hoffman, Joseph R. Bertino
      Normal cells can synthesize sufficient methionine for growth requirements from homocysteine and 5-methyltetrahydrofolate and vitamin B12. However, many cancer-cell types require exogenous methionine for survival and therefore methionine restriction is a promising avenue for treatment. While the lack of the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) deficiency is associated with methionine dependence in cancer cells, there are other causes for tumors to require exogenous methionine. In this review we describe studies that show restricting methionine to certain cancers by diet or by enzyme depletion, alone or in combination with certain chemotherapeutics is a promising antitumor strategy. The basis for methionine dependence in tumor cells is also briefly reviewed.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.003
      Issue No: Vol. 154 (2018)
       
  • Corrigendum to “In vivo α-hydroxylation of a 2-alkylindole antagonist
           of the OXE receptor for the eosinophil chemoattractant
           5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys” [Biochem. Pharmacol.
           138 (2017) 107–118]
    • Authors: Shishir Chourey; Qiuji Ye; Chintam Nagendra Reddy; Chantal Cossette; Sylvie Gravel; Matthias Zeller; Irina Slobodchikova; Dajana Vuckovic; Joshua Rokach; William S. Powell
      First page: 174
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Shishir Chourey, Qiuji Ye, Chintam Nagendra Reddy, Chantal Cossette, Sylvie Gravel, Matthias Zeller, Irina Slobodchikova, Dajana Vuckovic, Joshua Rokach, William S. Powell


      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.04.025
      Issue No: Vol. 154 (2018)
       
  • Lansoprazole reduces renal cyst in polycystic kidney disease via
           inhibition of cell proliferation and fluid secretion
    • Authors: Jiriporn Nantavishit; Varanuj Chatsudthipong; Sunhapas Soodvilai
      Pages: 175 - 182
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Jiriporn Nantavishit, Varanuj Chatsudthipong, Sunhapas Soodvilai
      Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Here, lansoprazole’s pharmacological effect and underlying mechanism on renal cyst development and expansion in in vitro; human ADPKD cyst-lining epithelial cell line and Type I Mardin Darby Canine Kidney (MDCK) cells, and in vivo models was investigated. Lansoprazole inhibited cyst development via inhibition of cell proliferation. In renal cells, lansoprazole’s anti-proliferative effect was mediated by inhibition of mTOR/S6K and extracellular signal-regulated kinase (ERK) signaling proteins. In addition, lansoprazole inhibited CFTR-mediated fluid secretion via reduction of CFTR protein expression. In PCK rats, administering lansoprazole (50 mg/kgBW) for 4 weeks produced significant decreases in the cystic area and improved renal function by reduction of plasma creatinine and blood urea nitrogen. Inhibition of mTOR/S6K, ERK, and CFTR protein expression was observed in PCK rat kidney following lansoprazole treatment. The findings point to potential therapeutic application of lansoprazole in ADPKD.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.005
      Issue No: Vol. 154 (2018)
       
  • Tabersonine attenuates lipopolysaccharide-induced acute lung injury via
           suppressing TRAF6 ubiquitination
    • Authors: Depeng Zhang; Xiaozong Li; Yudong Hu; Hongchao Jiang; Yaxian Wu; Yunhe Ding; Kaikai Yu; Huiqiong He; Jingsong Xu; Lei Sun; Feng Qian
      Pages: 183 - 192
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Depeng Zhang, Xiaozong Li, Yudong Hu, Hongchao Jiang, Yaxian Wu, Yunhe Ding, Kaikai Yu, Huiqiong He, Jingsong Xu, Lei Sun, Feng Qian
      Sepsis caused by Gram-negative bacteria is one of major causes for the progression of acute lung injury (ALI) with limited treatment and effective medicines. Tabersonine is an indole alkaloid mainly isolated from Catharanthus roseus, and a potential drug candidate for treatment of cancer and Alzheimer’s disease (AD), however, its anti-inflammatory effect has not been revealed. In this study, we reported that tabersonine ameliorated lipopolysaccharides (LPS)-induced ALI in vivo and inhibited LPS-mediated macrophage activation in vitro. By using murine ALI model, we found that tabersonine significantly attenuated LPS-induced pathological injury in the lung. Tabersonine also inhibited LPS-mediated neutrophil infiltration, elevation of MPO activity and the production of TNF-α, IL-6 and IL-1β. Furthermore, tabersonine inhibited LPS-induced the production of pro-inflammatory mediators such as iNOS, NO and cytokines by suppressing NF-κB and p38 MAPK/MK2 signaling cascades. Tabersonine reduced the K63-linked polyubiquitination of TRAF6. Taken together, these results suggested that tabersonine has anti-inflammatory activities in vitro and in vivo, and is a potential therapeutic candidate for the treatment of ALI/ARDS.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.004
      Issue No: Vol. 154 (2018)
       
  • New insights about the peculiar role of the 28–38 C-terminal segment and
           some selected residues in PACAP for signaling and neuroprotection
    • Authors: Mathilde Poujol de Molliens; Myriam Létourneau; Dominic Devost; Terence E. Hébert; Alain Fournier; David Chatenet
      Pages: 193 - 202
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Mathilde Poujol de Molliens, Myriam Létourneau, Dominic Devost, Terence E. Hébert, Alain Fournier, David Chatenet
      The pituitary adenylate cyclase-activating polypeptide (PACAP), which exists in two isoforms of 27 and 38 amino acids, can induce neuronal protection in vitro and in vivo following the activation of PAC1, a class B G protein-coupled receptor (GPCR). With its potent neuroprotective and anti-inflammatory effects, this peptide represents a promising avenue for the development of therapeutic strategies to potentially cure or at least slow the progression of neurodegenerative disorders. Beyond the canonical G protein signal effectors, GPCRs are also coupled to a multitude of intracellular signaling pathways that can be independently activated by biased ligands, thereby expanding vastly the potential for discovering new drugs. Interestingly, some studies have demonstrated distinct signaling features for the PACAP isoforms. With this observation in mind, we assessed the impact of chemical and structural modifications introduced into specific regions of the PACAP isoforms on their neuroprotective effects, and determined the role played by these physico-chemical and structural features on their signaling signatures. Each compound was also evaluated for its ability to bind the PACAP receptors, promote cell survival in a cellular model of Parkinson’s disease and stimulate the signaling partners associated with PAC1 activation, including Gs and Gq, as well as β-arrestin 1 and 2. Our results demonstrate that PACAP38 and its related analogs exert a more potent neuroprotective action than their 27-amino acid counterparts and that this neuroprotective effect is dependent on both Gq and Gs-dependent signaling. This study will definitely improve our understanding of the molecular and cellular mechanisms associated with PACAP neuroprotection.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.04.024
      Issue No: Vol. 154 (2018)
       
  • Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2
           macrophage polarization
    • Authors: Hong Lu; Lianfeng Wu; Leping Liu; Qingqing Ruan; Xing Zhang; Weilong Hong; Shijia Wu; Guihua Jin; Yongheng Bai
      Pages: 203 - 212
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Hong Lu, Lianfeng Wu, Leping Liu, Qingqing Ruan, Xing Zhang, Weilong Hong, Shijia Wu, Guihua Jin, Yongheng Bai
      Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Further study revealed that quercetin inhibited the infiltration of CD68+ macrophages in renal interstitium. Moreover, the decrease in levels of iNOS and IL-12, as well as the proportion of F4/80+/CD11b+/CD86+ macrophages, indicated quercetin-mediated inhibition of M1 macrophage polarization in the injured kidneys. In cultured macrophages, lipopolysaccharide-induced inflammatory polarization was suppressed by quercetin treatment, resulting in the reduction of the release of inflammatory factors. Notably, quercetin-induced inhibitory effects on inflammatory macrophage polarization were associated with down-regulated activities of NF-κB p65 and IRF5, and thus led to the inactivation of upstream signaling TLR4/Myd88. Interestingly, quercetin also inhibited the polarization of F4/80+/CD11b+/CD206+ M2 macrophages, and reduced excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing the TGF-β1/Smad2/3 signaling. Thus, quercetin ameliorates kidney injury via modulating macrophage polarization, and may have therapeutic potential for patients with kidney injury.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.007
      Issue No: Vol. 154 (2018)
       
  • Inhibition of BET bromodomains restores corticosteroid responsiveness in a
           mixed granulocytic mouse model of asthma
    • Authors: Ahmed Nadeem; Sheikh F. Ahmad; Naif O. Al-Harbi; Nahid Siddiqui; Khalid E. Ibrahim; Sabry M. Attia
      Pages: 222 - 233
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Ahmed Nadeem, Sheikh F. Ahmad, Naif O. Al-Harbi, Nahid Siddiqui, Khalid E. Ibrahim, Sabry M. Attia
      Asthma is a heterogeneous disease characterized by different endotypes/phenotypes. Th2/Th17 driven mixed granulocytic asthma is one of them and shows resistance to corticosteroid therapy. Bromodomain and extra-terminal (BET) proteins are required for differentiation of Th17 cells which play a pivotal role in neutrophilic inflammation. Therefore, we sought to characterize the differential effects of BET inhibitor versus corticosteroids, and their potential synergism in cockroach allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model of asthma having Th2/Th17 endotype. Effects of BET inhibitor, (+)JQ-1 alone and in combination with dexamethasone (Dexa) were assessed on airway inflammation as well as Th2/Th17 related airway immune responses in CE-induced mixed granulocytic asthma. Markers of steroid resistance [histone deacetylase 2 (HDAC2), and oxidative stress] were also assessed in the lungs of mice and primary human bronchial epithelial cells (HBECs). BET inhibitor, (+)JQ-1 abolished Th17 driven neutrophilic inflammation in CE-induced mixed granulocytic asthma. Dexa had limited effect on overall airway inflammation despite having significant reductions in Th2 driven immune responses. However, combination of (+)JQ-1 with Dexa completely blocked both Th2 and /Th17 driven immune responses in the lung which led to significant reductions in eosinophils, neutrophils, and mucin secretion. (+)JQ-1 also reversed CE- and IL-17A-induced decrease in HDAC2 expression in murine and human airway epithelial cells respectively.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.05.011
      Issue No: Vol. 154 (2018)
       
  • Diamond Jubilee Special Issue: Celebrating 60 years of Excellence
    • Authors: S.J. Enna; Jacques G. Piette
      First page: 1
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): S.J. Enna, Jacques G. Piette


      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.03.001
      Issue No: Vol. 153 (2018)
       
  • Role of tenofovir alafenamide (TAF) in the treatment and prophylaxis of
           HIV and HBV infections
    • Authors: Erik De Clercq
      Pages: 2 - 11
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Erik De Clercq
      Tenofovir (TFV) is the cornerstone of the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((−)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophylaxis of HIV infection is momentarily based upon Truvada®, the combination of F with TDF, which in the future may also be replaced by TAF. TAF (Vemlidy®) has also replaced TDF (Viread®) for the treatment of hepatitis B virus (HBV) infections. Both TDF and TAF offer little or no risk for virus-drug resistance. As compared to TDF, TAF limits the risk for nephrotoxicity and loss of bone mineral density. What remains to be settled, however, before the universal use of TAF could be recommended, is its safety during pregnancy and its applicability in the treatment of tuberculosis, in combination with rifampicin.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2017.11.023
      Issue No: Vol. 153 (2018)
       
  • Stress-induced cellular responses in immunogenic cell death: Implications
           for cancer immunotherapy
    • Authors: Flavia Radogna; Marc Diederich
      Pages: 12 - 23
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Flavia Radogna, Marc Diederich
      Cancer is evading the host’s defense mechanisms leading to avoidance of immune destruction. During tumor progression, immune-evading cancer cells arise due to selective pressure from the hypoxic and nutrient-deprived microenvironment. Thus, therapies aiming at re-establishing immune destruction of pathological cells constitute innovating anti-cancer strategies. Accumulating evidence suggests that selected conventional chemotherapeutic drugs increase the immunogenicity of stressed and dying cancer cells by triggering a form of cell death called immunogenic cell death (ICD), which is characterized by the release of danger-associated molecular patterns (DAMPs). In this review, we summarize the effects of ICD inducers on DAMP signaling leading to adjuvanticity and antigenicity. We will discuss the associated stress response pathways that cause the release of DAMPs leading to improved immune recognition and their relevance in cancer immunotherapy. Our aim is to highlight the contribution of adaptive immunity to the long-term clinical benefits of anticancer treatments and the properties of immune memory that can protect cancer patients against relapse.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.006
      Issue No: Vol. 153 (2018)
       
  • 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
      Pages: 24 - 34
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      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: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.007
      Issue No: Vol. 153 (2018)
       
  • The biology and therapeutic management of melanoma brain metastases
    • Authors: Daniel Abate-Daga; Maria C. Ramello; Inna Smalley; Peter A. Forsyth; Keiran S.M. Smalley
      Pages: 35 - 45
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Daniel Abate-Daga, Maria C. Ramello, Inna Smalley, Peter A. Forsyth, Keiran S.M. Smalley
      The recent years have seen significant progress in the development of systemic therapies to treat patients with advanced melanoma. Use of these new treatment modalities, which include immune checkpoint inhibitors and small molecule BRAF inhibitors, lead to increased overall survival and better outcomes. Although revolutionary, these therapies are often less effective against melanoma brain metastases, and frequently the CNS is the major site of treatment failure. The development of brain metastases remains a serious complication of advanced melanoma that is associated with significant morbidity and mortality. New approaches to both prevent the development of brain metastases and treat established disease are urgently needed. In this review we will outline the mechanisms underlying the development of melanoma brain metastases and will discuss how new insights into metastasis biology are driving the development of new therapeutic strategies. Finally, we will describe the latest data from the ongoing clinical trials for patients with melanoma brain metastases.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2017.12.019
      Issue No: Vol. 153 (2018)
       
  • The potentially conflicting cell autonomous and cell non-autonomous
           functions of autophagy in mediating tumor response to cancer therapy
    • Authors: David A. Gewirtz; Liliya Tyutyunyk-Massey; Joseph W. Landry
      Pages: 46 - 50
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): David A. Gewirtz, Liliya Tyutyunyk-Massey, Joseph W. Landry
      Autophagy, a virtually uniform response to external stress such as that induced by chemotherapy and radiation, is generally considered to be cytoprotective in function, providing a foundation for multiple clinical trials designed to enhance therapeutic response via autophagy inhibition. However, this cell autonomous response can also be cytotoxic or nonprotective, with the consequence that autophagy inhibition would be counterproductive or ineffective, respectively. The non-cell autonomous function of autophagy remains quite controversial, with evidence both for and against autophagy-mediated activation of the immune system. If autophagy inhibition antagonizes the immune response, this would likely interfere with the potential sensitization resulting from suppression of the cell autonomous protective function. An additional complication, which has rarely been considered, is the nature of the contribution of therapy-induced autophagy in the tumor microenvironment, particularly the tumor stroma. Taken together, it is likely that the outcome of the current clinical trials, whether positive or negative, will be difficult to interpret given the complexity of the role of autophagy relating to the tumor cell (cell autonomous), the immune system (cell non-autonomous) and the tumor microenvironment.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.048
      Issue No: Vol. 153 (2018)
       
  • Autophagy inducers in cancer
    • Authors: Maria Russo; Gian Luigi Russo
      Pages: 51 - 61
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Maria Russo, Gian Luigi Russo
      Autophagy is a complex, physiological process devoted to degrade and recycle cellular components. Proteins and organelles are first phagocytized by autophagosomes, then digested in lysosomes, and finally recycled to be utilized again during cellular metabolism. Moreover, autophagy holds an important role in the physiopathology of several diseases. In cancer, excellent works demonstrated the dual functions of autophagy in tumour biology: autophagy activation can promote cancer cells survival (protective autophagy), or contribute to cancer cell death (cytotoxic/nonprotective autophagy). A better understanding of the dichotomy roles of autophagy in cancer biology can help to identify or design new drugs able to induce/enhance (or block) autophagic flux. These features will necessary be tissue-dependent and confined to a specific time of treatment. The intent of this review is to focus on the different potentialities of autophagy inducers in cancer prevention versus therapy in order to elicit a desirable clinical response. Few promising synthetic and natural compounds have been identified and the pros and cons of their role in autophagy regulation is reviewed here. In the complex framework of autophagy modulation, “connecting the dots” is not a simple work and the lack of clinical studies further complicates the scenario, but the final goal to obtain clinically relevant autophagy inducers can reveal an unexpected landscape.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.007
      Issue No: Vol. 153 (2018)
       
  • The G protein-coupled receptors deorphanization landscape
    • Authors: Céline Laschet; Nadine Dupuis; Julien Hanson
      Pages: 62 - 74
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Céline Laschet, Nadine Dupuis, Julien Hanson
      G protein-coupled receptors (GPCRs) are usually highlighted as being both the largest family of membrane proteins and the most productive source of drug targets. However, most of the GPCRs are understudied and hence cannot be used immediately for innovative therapeutic strategies. Besides, there are still around 100 orphan receptors, with no described endogenous ligand and no clearly defined function. The race to discover new ligands for these elusive receptors seems to be less intense than before. Here, we present an update of the various strategies employed to assign a function to these receptors and to discover new ligands. We focus on the recent advances in the identification of endogenous ligands with a detailed description of newly deorphanized receptors. Replication being a key parameter in these endeavors, we also discuss the latest controversies about problematic ligand-receptor pairings. In this context, we propose several recommendations in order to strengthen the reporting of new ligand-receptor pairs.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.016
      Issue No: Vol. 153 (2018)
       
  • The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class
           of LXR modulator activating lethal autophagy in cancers
    • Authors: Marc Poirot; Sandrine Silvente-Poirot
      Pages: 75 - 81
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Marc Poirot, Sandrine Silvente-Poirot
      Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3β,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors. Importantly, by binding the liver X receptor (LXR), DDA activates the expression of genes controlling autophagy. These genes include NR4A1, NR4A3, LC3 and TFEB. The canonical LXR ligands 22(R)hydroxycholesterol, TO901317 and GW3965 did not induce these effects indicating that DDA delineates a new class of selective LXR modulator (SLiM). The induction of lethal autophagy by DDA was associated with the accumulation in cancer cells of lysosomes and of the pro-lysosomal cholesterol precursor zymostenol due to the inhibition of the 3β-hydroxysteroid-Δ8Δ7-isomerase enzyme (D8D7I). The anti-cancer efficacy of DDA was established on different mouse and human cancers such as breast cancers, melanoma and acute myeloid leukemia, including patient derived xenografts, and did not discriminate bulk cancer cells from cancer cell progenitors. Together these data highlight that the mammalian metabolite DDA is a promising anticancer compound with a broad range of anticancer applications. In addition, DDA and LXR are new actors in the transcriptional control of autophagy and DDA being a “first in line” driver of lethal autophagy in cancers via the LXR.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.046
      Issue No: Vol. 153 (2018)
       
  • 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
      Pages: 82 - 90
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      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: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.014
      Issue No: Vol. 153 (2018)
       
  • Evolving mechanisms of vascular smooth muscle contraction highlight key
           targets in vascular disease
    • Authors: Zhongwei Liu; Raouf A. Khalil
      Pages: 91 - 122
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Zhongwei Liu, Raouf A. Khalil
      Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca2+ has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined. Biochemical studies have also suggested that stimulation of Gq protein-coupled membrane receptors activates phospholipase C and promotes the hydrolysis of membrane phospholipids into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates initial Ca2+ release from the sarcoplasmic reticulum, and is buttressed by Ca2+ influx through voltage-dependent, receptor-operated, transient receptor potential and store-operated channels. In order to prevent large increases in cytosolic Ca2+ concentration ([Ca2+]c), Ca2+ removal mechanisms promote Ca2+ extrusion via the plasmalemmal Ca2+ pump and Na+/Ca2+ exchanger, and Ca2+ uptake by the sarcoplasmic reticulum and mitochondria, and the coordinated activities of these Ca2+ handling mechanisms help to create subplasmalemmal Ca2+ domains. Threshold increases in [Ca2+]c form a Ca2+-calmodulin complex, which activates myosin light chain (MLC) kinase, and causes MLC phosphorylation, actin–myosin interaction, and VSM contraction. Dissociations in the relationships between [Ca2+]c, MLC phosphorylation, and force have suggested additional Ca2+ sensitization mechanisms. DAG activates protein kinase C (PKC) isoforms, which directly or indirectly via mitogen-activated protein kinase phosphorylate the actin-binding proteins calponin and caldesmon and thereby enhance the myofilaments force sensitivity to Ca2+. PKC-mediated phosphorylation of PKC-potentiated phosphatase inhibitor protein-17 (CPI-17), and RhoA-mediated activation of Rho-kinase (ROCK) inhibit MLC phosphatase and in turn increase MLC phosphorylation and VSM contraction. Abnormalities in the Ca2+ handling mechanisms and PKC and ROCK activity have been associated with vascular dysfunction in multiple vascular disorders. Modulators of [Ca2+]c, PKC and ROCK activity could be useful in mitigating the increased vasoconstriction associated with vascular disease.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.012
      Issue No: Vol. 153 (2018)
       
  • 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
      Pages: 123 - 133
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      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.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.024
      Issue No: Vol. 153 (2018)
       
  • Extracellular vesicles: A new therapeutic strategy for joint conditions
    • Authors: Miguel Tofiño-Vian; Maria Isabel Guillén; Maria José Alcaraz
      Pages: 134 - 146
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Miguel Tofiño-Vian, Maria Isabel Guillén, Maria José Alcaraz
      Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.004
      Issue No: Vol. 153 (2018)
       
  • Promise and challenges for direct small molecule AMPK activators
    • Authors: Séverine Olivier; Marc Foretz; Benoit Viollet
      Pages: 147 - 158
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Séverine Olivier, Marc Foretz, Benoit Viollet
      AMP-activated protein kinase (AMPK) is an evolutionary conserved and ubiquitously expressed serine/threonine kinase playing a central role in the coordination of energy homeostasis. Based on the beneficial outcomes of its activation on metabolism, AMPK has emerged as an attractive target for the treatment of metabolic diseases. Identification of novel downstream targets of AMPK beyond the regulation of energy metabolism has renewed considerable attention in exploiting AMPK signaling for novel therapeutic targeting strategies including treatment of cancer and inflammatory diseases. The complexity of AMPK system with tissue- and species-specific expression of multiple isoform combination regulated by various inputs, post-traductional modifications and subcellular locations presents unique challenges for drug discovery. Here, we review the most recent advances in the understanding of the mechanism(s) of action of direct small molecule AMPK activators and the potential therapeutic opportunities.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.01.049
      Issue No: Vol. 153 (2018)
       
  • The macrophage heme-heme oxygenase-1 system and its role in inflammation
    • Authors: Vijith Vijayan; Frank A.D.T.G. Wagener; Stephan Immenschuh
      Pages: 159 - 167
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Vijith Vijayan, Frank A.D.T.G. Wagener, Stephan Immenschuh
      Heme oxygenase (HO)-1, the inducible isoform of the heme-degrading enzyme HO, plays a critical role in inflammation and iron homeostasis. Regulatory functions of HO-1 are mediated via the catalytic breakdown of heme, which is an iron-containing tetrapyrrole complex with potential pro-oxidant and pro-inflammatory effects. In addition, the HO reaction produces the antioxidant and anti-inflammatory compounds carbon monoxide (CO) and biliverdin, subsequently converted into bilirubin, along with iron, which is reutilized for erythropoiesis. HO-1 is up-regulated by a plethora of stimuli and injuries in most cell types and tissues and provides salutary effects by restoring physiological homeostasis. Notably, HO-1 exhibits critical immuno-modulatory functions in macrophages, which are a major cell population of the mononuclear phagocyte system. Macrophages play key roles as sentinels and regulators of the immune system and HO-1 in these cells appears to be of critical importance for driving resolution of inflammatory responses. In this review, the complex functions and regulatory mechanisms of HO-1 in macrophages will be high-lighted. A particular focus will be the intricate interactions of HO-1 with its substrate heme, which play a contradictory role in distinct physiological and pathophysiological settings. The therapeutic potential of targeted modulation of the macrophage heme-HO-1 system will be discussed in the context of inflammatory disorders.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.010
      Issue No: Vol. 153 (2018)
       
  • Lipid bilayer stress in obesity-linked inflammatory and metabolic
           disorders
    • Authors: Marco A. Gianfrancesco; Nicolas Paquot; Jacques Piette; Sylvie Legrand-Poels
      Pages: 168 - 183
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Marco A. Gianfrancesco, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels
      The maintenance of the characteristic lipid compositions and physicochemical properties of biological membranes is essential for their proper function. Mechanisms allowing to sense and restore membrane homeostasis have been identified in prokaryotes for a long time and more recently in eukaryotes. A membrane remodeling can result from aberrant metabolism as seen in obesity. In this review, we describe how such lipid bilayer stress can account for the modulation of membrane proteins involved in the pathogenesis of obesity-linked inflammatory and metabolic disorders. We address the case of the Toll-like receptor 4 that is implicated in the obesity-related low grade inflammation and insulin resistance. The lipid raft-mediated TLR4 activation is promoted by an enrichment of the plasma membrane with saturated lipids or cholesterol increasing the lipid phase order. We discuss of the plasma membrane Na, K-ATPase that illustrates a new concept according to which direct interactions between specific residues and particular lipids determine both stability and activity of the pump in parallel with indirect effects of the lipid bilayer. The closely related sarco(endo)-plasmic Ca-ATPase embedded in the more fluid ER membrane seems to be more sensitive to a lipid bilayer stress as demonstrated by its inactivation in cholesterol-loaded macrophages or its inhibition mediated by an increased PtdCho/PtdEtn ratio in obese mice hepatocytes. Finally, we describe the model recently proposed for the activation of the conserved IRE-1 protein through alterations in the ER membrane lipid packing and thickness. Such IRE-1 activation could occur in response to abnormal lipid synthesis and membrane remodeling as observed in hepatocytes exposed to excess nutrients. Since the IRE-1/XBP1 branch also stimulates the lipid synthesis, this pathway could create a vicious cycle “lipogenesis-ER lipid bilayer stress-lipogenesis” amplifying hepatic ER pathology and the obesity-linked systemic metabolic defects.
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      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.022
      Issue No: Vol. 153 (2018)
       
  • Effects of cytochrome P450 single nucleotide polymorphisms on methadone
           metabolism and pharmacodynamics
    • Authors: Taha Ahmad; Monica A. Valentovic; Gary O. Rankin
      Pages: 196 - 204
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Taha Ahmad, Monica A. Valentovic, Gary O. Rankin
      Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6*6/*6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6*4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
      DOI: 10.1016/j.bcp.2018.02.020
      Issue No: Vol. 153 (2018)
       
  • Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in
           cynomolgus and rhesus monkeys and common marmosets in preclinical studies
           for humans
    • Authors: Yasuhiro Uno; Shotaro Uehara Hiroshi Yamazaki
      Abstract: Publication date: July 2018
      Source:Biochemical Pharmacology, Volume 153
      Author(s): Yasuhiro Uno, Shotaro Uehara, Hiroshi Yamazaki
      Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non-human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects.
      Graphical abstract image

      PubDate: 2018-05-28T09:37:25Z
       
 
 
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