当前期刊: "药学"类期刊
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Development of an ADP-Ribosylation Assay for residual toxicity in C. difficile Binary Toxin CDTa using Automated Capillary Western Blot
    J. Pharmaceut. Biomed. Anal. (IF 2.983) Pub Date : 2020-01-23
    Richard R. Rustandi; Melissa Hamm

    CDTa, an actin ADP-ribosylation transferase, is a binary toxin produced by the bacterium Clostridium difficile which is commonly associated with the hypervirulent strain present in Clostridium difficile infections. The mutated form of CDTa, 4mCDTa, is one of the components in the tetravalent Clostridium difficile vaccine in which the residual toxicity of the ADP-ribosylation activity needs to be monitored for safety reasons. There are several ADP- ribosylation activity methods employing techniques such as ELISA, manual Western blot, or SDS PAGE, but all these methods are usually time consuming and labor intensive. Here we describe the development of new quantitative capillary based western for monitoring the presence of ADP-ribosylation activity in CDTa and 4mCDTa using novel, automated Simple Western™ technology. Furthermore, we have measured for the first time the enzyme’s kinetic parameters, KM (NAD) and kcat for native CDTa using this new quantitative capillary western technology.

    更新日期:2020-01-23
  • Multivariate Quantitative Analysis of Quality Trend Based on Non-volatile Characteristic Components in different Panax notoginseng samples using HPLC
    J. Pharmaceut. Biomed. Anal. (IF 2.983) Pub Date : 2020-01-23
    Chao Li; Yunhua Qin; Qianxu Yang; Junheng You; Zhihua Liu; Jingmei Han; E’xian Li; Chengming Zhang

    In order to identify real and fake Panax notoginseng samples, the high performance liquid chromatography (HPLC) was used to analyze P. notoginseng samples of non-volatile characteristic components in P. notoginseng powder samples with 10%, 30%, 50% ratio, combined with principal component analysis - mahalanobis distance (PCA-MD). The results showed that: (1) The PCA analysis showed that mahalanobis with different stem and leaf powder were divided into four categories, and the gravity center of the pattern (classification) showed that the long axis of the trend chart gradually increased with the increase of the proportion of the stem and leaf powder, and the trend chart was gradually away from the control group; (2) The mahalanobis distance indicated that the range of mahalanobis distance fluctuation (upper limit) of several P. notoginseng powder samples is 395.03∼48252.70. The larger the percentage of the stem and leaf powder in P. notoginseng samples, it is farther away from the normal P. notoginseng samples. It indicated that the product of P. notoginseng samples can be evaluated with the mahalanobis distance. The results of this study can be applied to identification and homogenization evaluation of P. notoginseng between real and fake samples.

    更新日期:2020-01-23
  • Combination of intact, middle-up and bottom-up levels to characterize 7 therapeutic monoclonal antibodies by capillary electrophoresis – mass spectrometry
    J. Pharmaceut. Biomed. Anal. (IF 2.983) Pub Date : 2020-01-23
    Jérémie Giorgetti; Alain Beck; Emmanuelle Leize-Wagner; Yannis-Nicolas François

    Significant growth of biopharmaceuticals requires powerful analytical methods to better understand their structure by establishing a complete characterization. To this end, a combination of bottom-up, middle-up and intact molecule levels with a capillary electrophoresis-mass spectrometry coupling has been performed to have a comprehensive picture of monoclonal antibodies. In this study, 7 worldwide health authorities approved mAbs have been analyzed to get information about their charge heterogeneity, the identification of post translational modifications (PTMs), their location and relative quantitation. Intact mAbs isoforms have been partially separated in less than 12 minutes and enabled to have a global illustration of mAbs heterogeneity and high masses PTMs characterization notably major N-glycosylation forms. Particularly, 2X-glycosylated and 1X-glycosylated forms have been partially separated. To deepen characterize PTMs carried by the backbone structure, advanced investigations at a middle-up level have been performed. Limited IdeS proteolysis allowed to study independently Fc/2 and F(ab)’2 fragments. Following the same separation conditions, isoforms of these fragments have been separated and data interpretation allowed to disclose additional PTMs as K-clip, oxidations or deamidations. A second intermediate level has been examined by adding a reduction step to establish a more precise assessment of PTMs and isoforms from the F(ab)’2 fragment. This reduction step released the light chains from the Fd fragment to get only 25 kDa fragments to analyze. CE-ESI-MS coupling allowed to get more information particularly about low masses PTMs. The precise location and relative quantitation of each PTM has been investigated at the peptidic level induced by a tryptic digestion of the studied mAbs. The concordance of the results shows the efficiency of the CE-ESI-MS coupling to characterize mAbs and highlight the need of the multi-level combination to get a comprehensive characterization of biotherapeutics.

    更新日期:2020-01-23
  • Silibinin attenuates adipose tissue inflammation and reverses obesity and its complications in diet-induced obesity model in mice
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-23
    Mohammad Alsaggar; Shifa Bdour; Qutaibah Ababneh; Tamam El-Elimat; Nidal Qinna; Karem H. Alzoubi

    Obesity is a multifactorial chronic disease that comprises several pathological events, such as adipose hypertrophy, fatty liver and insulin resistance. Inflammation is a key contributer to development of these events, and therefore, targeting inflammation is increasingly considered for management of obesity and its complications. The aim of the current study was to investigate therapeutic outcomes of anti-inflammatory activities of the natural compound Silibinin in reversing obesity and its complication in mice. C57BL/6 male mice were fed high-fat diet for 8 weeks until development of obesity, and then injected with 50 mg/kg silibinin intraperitoneally twice per week, or vehicle for 8 weeks. Throughout the experiment, mice were continuously checked for body weight and food intake, and glucose tolerance test was performed toward the end of the experiment. Animals were sacrificed and serum and tissues were collected for biochemical, histological, and gene expression analysis to assess silibinin effects on adipose inflammation, fat accumulation, liver adipogenesis and glucose homeostasis. Silibinin treatment reversed adipose tissue inflammation and adipocyte hypertrophy, and blocked progression in weight gain and obesity development with no significant effects on rates of food intake. Silibinin also reversed fatty liver disease and restored glucose homeostasis in treated animals, and reversed hyperglycemia, hyperinsulinemia and hypertriglyceridemia. In this study, we demonstrated that silibinin as an anti-inflammatory therapy is a potential alternative to manage obesity, as well as its related complications. Moreover, silibinin-based therapies could further evolve as a novel treatment to manage various inflammation-driven disorders.

    更新日期:2020-01-23
  • An in vitro dissolution–digestion–permeation assay for the study of advanced drug delivery systems
    Eur. J. Pharm. Biopharm. (IF 4.708) Pub Date : 2020-01-23
    Caroline Alvebratt; Janneke Keemink; Khadijah Edueng; Ocean Cheung; Maria Strømme; Christel A.S. Bergström
    更新日期:2020-01-23
  • Novel Approach for Overcoming the Stability Challenges of Lipid-Based Excipients. Part 2: Application of Polyglycerol Esters of Fatty Acids as hot melt coating excipients
    Eur. J. Pharm. Biopharm. (IF 4.708) Pub Date : 2020-01-23
    Sharareh Salar-Behzadi; Carolina Corzo; Diogo Gomes Lopes; Claudia Meindl; Dirk Lochmann; Sebastian Reyer
    更新日期:2020-01-23
  • 更新日期:2020-01-23
  • Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases
    Eur. J. Pharm. Biopharm. (IF 4.708) Pub Date : 2020-01-23
    Maria Inês Teixeira; Carla M. Lopes; Maria Helena Amaral; Paulo C. Costa
    更新日期:2020-01-23
  • Eudragit RL-based film coatings: How to minimize sticking and adjust drug release using MAS
    Eur. J. Pharm. Biopharm. (IF 4.708) Pub Date : 2020-01-23
    Thitiphorn Rongthong; Srisagul Sungthongjeen; Florence Siepmann; Juergen Siepmann; Thaned Pongjanyakul
    更新日期:2020-01-23
  • Therapy for the Individual: Towards Patient Integration into the Manufacturing and Provision of Pharmaceuticals
    Eur. J. Pharm. Biopharm. (IF 4.708) Pub Date : 2020-01-23
    Rydvikha Govender; Susanna Abrahmsén-Alami; Anette Larsson; Staffan Folestad
    更新日期:2020-01-23
  • Should NPS be included in workplace drug testing?
    Drug Test. Anal. (IF 2.799) Pub Date : 2020-01-23
    Alberto Salomone; Joseph J. Palamar; Marco Vincenti
    更新日期:2020-01-23
  • The case of the EPO‐poisoned syringe
    Drug Test. Anal. (IF 2.799) Pub Date : 2020-01-23
    Alexandre Marchand; Laurent Martin; Jean‐Antoine Martin; Magnus Ericsson; Michel Audran
    更新日期:2020-01-23
  • ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Lesley B. Conrad, Ken Y. Lin, Tulip Nandu, Bryan A. Gibson, Jayanthi S. Lea, W. Lee Kraus

    Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

    更新日期:2020-01-23
  • Predictive and Pharmacodynamic Biomarkers of Response to the Phosphatidylinositol 3-Kinase Inhibitor Taselisib in Breast Cancer Preclinical Models
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Heather M. Moore, Heidi M. Savage, Carol O'Brien, Wei Zhou, Ethan S. Sokol, Michael E. Goldberg, Ciara Metcalfe, Lori S. Friedman, Mark R. Lackner, Timothy R. Wilson

    The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA , the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers ( PIK3CA , HER2, PTEN, and ESR1 ). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/ PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/ PIK3CA -mutant cell lines. In a PIK3CA- mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1 ) in metastatic tumors from patients with ER+ breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA -mutant setting with cotreatments determined by the specific subtypes under investigation. This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/19/1?iss=1

    更新日期:2020-01-23
  • Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Usha Malhotra, Sarbajit Mukherjee, Christos Fountzilas, Patrick Boland, Austin Miller, Santosh Patnaik, Kristopher Attwood, Sai Yendamuri, Araba Adjei, Eric Kannisto, Mateusz Opyrchal, Peter Bushunow, Peter Loud, Renuka Iyer, Nikhil Khushalani

    The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS ( P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS ( P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.

    更新日期:2020-01-23
  • Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Jaume Capdevila, Ignacio Matos, Francesco M. Mancuso, Carmela Iglesias, Paolo Nuciforo, Carles Zafon, Hector G. Palmer, Zighereda Ogbah, Laura Muiños, Jorge Hernando, Guillermo Villacampa, Carol E. Peña, Josep Tabernero, Marcia S. Brose, Martin Schlumberger, Ana Vivancos

    Several biomarkers have been suggested to have prognostic value in differentiated thyroid carcinomas (DTC) with no validation in the refractory setting, including all tumor subtypes. We aim to correlate RNA expression profiles with survival based on patients included in the DECISION trial. We obtained 247 samples from the 417 patients included in the DECISION study and performed RNAseq analysis (77 million paired-end reads for each sample on HiSeq2000). After quality control, 125 samples were included in the secondary analysis and mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. Survival analysis was calculated using the Kaplan–Meier method and log-rank test was used for statistical comparison. In this post hoc analysis, we identified three groups of tumors based on their gene expression profile: BRAF-like, RAS-like, and non-BRAF-non-RAS-like (NoBRaL). No significant correlation with sorafenib responders was observed. However, we identified a statistically significant correlation between the RNA-expression profiles and progression-free survival. The BRAF-like profile had a significantly better outcome compared with RAS-like and NoBRaL (11.8, 6.2, and 5.5 months, respectively) [HR: 0.31, 95% confidence interval (CI), 0.17–0.60; P < 0.001 and HR: 0.36 (95% CI, 0.21–0.63); P < 0.001] and HR: 0.36 (95% CI, 0.21–0.63; P < 0.001) and maintained significance as an independent prognostic factor for overall survival in the multivariate analysis for papillary thyroid cancers. To our knowledge, this is the first comprehensive RNA-seq analysis of all histologic subtypes of DTC. The RNA expression profiles identified may suggest a new prognostic parameter to be considered before recommendation of systemic therapies or the design of stratification factors for future clinical trials.

    更新日期:2020-01-23
  • Feeding of particle-based materials in continuous solid dosage manufacturing: a material science perspective
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-23
    Wen-Kai Hsiao; Theresa R. Hörmann; Peter Toson; Amrit Paudel; Patrizia Ghiotti; Fanny Staufer; Finn Bauer; Satu Lakio; Olaf Behrend; Reto Maurer; James Holman; Johannes Khinast

    The pharmaceutical industry today is experiencing a paradigm shift from batch to continuous manufacturing, which promises greater flexibility to target diverse populations, as well as more-consistent product quality to ensure best efficacy. However, shifting to continuous processing means that even basic process steps, such as feeding, can become unexpected but are crucially important. In this review, we will present the fundamental differences between dispensing (batch) and feeding (continuous) and how they impact the formulation design space. We will further outline our rational development approach, applicable to continuous unit operations in general, which includes standardized material and process characterization, as well as predictive modeling based on advanced, multidomain simulation tools.

    更新日期:2020-01-23
  • 更新日期:2020-01-23
  • One-step treatment of periodontitis based on a core-shell micelle-in-nanofiber membrane with time-programmed drug release
    J. Control. Release (IF 7.901) Pub Date : 2020-01-23
    Xiaochen Liu; Wenxin Zhang; Yabing Wang; Yunong Chen; Jian Xie; Jiansheng Su; Chen Huang
    更新日期:2020-01-23
  • Structure-inherent near-infrared bilayer nanovesicles for use as photoacoustic image-guided chemo-thermotherapy
    J. Control. Release (IF 7.901) Pub Date : 2020-01-23
    Ilkoo Noh; MunSik Kim; Jeesu Kim; DaeYong Lee; Donghyeon Oh; Juhwan Kim; Chulhong Kim; Sangyong Jon; Yeu-Chun Kim
    更新日期:2020-01-23
  • Beyond the Randomized Clinical Trial: Innovative Data Science to Close the Pediatric Evidence Gap
    Clin. Pharmacol. Ther. (IF 6.336) Pub Date : 2020-01-22
    Sebastiaan C. Goulooze; Laura B. Zwep; Julia E. Vogt; Elke H.J. Krekels; Thomas Hankemeier; John N. van den Anker; Catherijne A.J. Knibbe

    Despite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from children by using real‐world data from electronic health records, mobile applications, wearables, and social media. The large datasets collected with these approaches enable and may demand the use of artificial intelligence and machine learning to allow the data to be analyzed for decision making. Applications of this approach are presented, which include the prediction of future clinical complications, medical image analysis, identification of new pediatric end points and biomarkers, the prediction of treatment nonresponders, and the prediction of placebo‐responders for trial enrichment. Finally, we discuss how to bring machine learning from science to pediatric clinical practice. We conclude that advantage should be taken of the current opportunities offered by innovations in data science and machine learning to close the pediatric evidence gap.

    更新日期:2020-01-23
  • Chromatographic HILIC indexes to characterize the lipophilicity of zwitterions
    Eur. J. Pharm. Sci. (IF 3.532) Pub Date : 2020-01-23
    Maura Vallaro; Giuseppe Ermondi; Giulia Caron
    更新日期:2020-01-23
  • Anti-inflammatory effects of ozenoxacin, a topical quinolone antimicrobial agent
    J. Antibiot. (IF 2.446) Pub Date : 2020-01-23
    Keisuke Tabara; Rie Tamura; Aki Nakamura; Sachi Mori; Takamichi Kitano; Koki Fujikawa; Mika Fujikawa; Kazuaki Okamoto; Shoji Kanayama; Hideya Uratsuji; Fumiaki Ikeda; Tatsumi Matsumoto
    更新日期:2020-01-23
  • Polyketide glycosides phialotides A to H, new potentiators of amphotericin B activity, produced by Pseudophialophora sp. BF-0158
    J. Antibiot. (IF 2.446) Pub Date : 2020-01-23
    Akiho Yagi; Ryuji Uchida; Keisuke Kobayashi; Hiroshi Tomoda
    更新日期:2020-01-23
  • Widening the window of bromodomain inhibition
    Nat. Rev. Drug. Disc. (IF 57.618) Pub Date : 2020-01-23
    Stacey-Lynn Paiva

    Discover the world’s best science and medicine | Nature.com

    更新日期:2020-01-23
  • Endozepines and their receptors: Structure, functions and pathophysiological significance
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-05
    Marie-Christine Tonon; Hubert Vaudry; Julien Chuquet; Florent Guillebaud; Jinjiang Fan; Olfa Masmoudi-Kouki; David Vaudry; Damien Lanfray; Fabrice Morin; Vincent Prevot; Vassilios Papadopoulos; Jean-Denis Troadec; Jérôme Leprince

    The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein (PBR/TSPO), and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discusses the physiopathological implications of these regulatory gliopeptides.

    更新日期:2020-01-23
  • Molecular and biological rationale of hyperthermia as radio- and chemosensitizer
    Adv. Drug Deliver. Rev. (IF 15.519) Pub Date : 2020-01-23
    A.L. Oei; H.P. Kok; S.B. Oei; M.R. Horsman; L.J.A. Stalpers; N.A.P. Franken; J. Crezee
    更新日期:2020-01-23
  • Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo
    Eur. J. Med. Chem. (IF 4.833) Pub Date : 2020-01-23
    Ritu Ojha; Kunal Nepali; Chun-Han Chen; Kuo-Hsiang Chuang; Tung-Yun Wu; Tony Eight Lin; Kai-Cheng Hsu; Min-Wu Chao; Mei-Jung Lai; Mei-Hsiang Lin; Han-Li Huang; Chao-Di Chang; Shiow-Lin Pan; Mei-Chuan Chen; Jing-Ping Liou
    更新日期:2020-01-23
  • Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells
    Eur. J. Med. Chem. (IF 4.833) Pub Date : 2020-01-23
    Meng Yu; Minghui Zeng; Zhaoping Pan; Fengbo Wu; Li Guo; Gu He
    更新日期:2020-01-23
  • Hi-JAK-ing The Ubiquitin System: The Design and Physicochemical Optimisation of JAK PROTACs
    Bioorg. Med. Chem. (IF 2.802) Pub Date : 2020-01-23
    Rishi R. Shah; Joanna M. Redmond; Andrei Mihut; Malini Menon; John P. Evans; John A. Murphy; Michelle A. Bartholomew; Diane M. Coe
    更新日期:2020-01-23
  • Toggling Preassembly with Single-Site Mutation Switches the Cytotoxic Mechanism of Cationic Amphipathic Peptides
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-23
    Xiaolong Chen; Shuangshuang Ji; Ang Li; Hanjie Liu; Hao Fei
    更新日期:2020-01-23
  • Developing Inhibitors of the p47phox–p22phox Protein–Protein Interaction by Fragment-Based Drug Discovery
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-23
    Sara Marie Øie Solbak; Jie Zang; Dilip Narayanan; Lars Jakobsen Høj; Saskia Bucciarelli; Charlotte Softley; Sebastian Meier; Annette Eva Langkilde; Charlotte Held Gotfredsen; Michael Sattler; Anders Bach
    更新日期:2020-01-23
  • Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-23
    Peter Mubanga Cheuka; Godwin Dziwornu; John Okombo; Kelly Chibale
    更新日期:2020-01-23
  • Guiding Lead Optimization for Solubility Improvement with Physics-Based Modeling
    Mol. Pharmaceutics (IF 4.396) Pub Date : 2020-01-23
    Yuriy A. Abramov; Guangxu Sun; Qiao Zeng; Qun Zeng; Mingjun Yang
    更新日期:2020-01-23
  • Self-assembly of exendin-4 derived dual peptide agonists is mediated by acylation and correlated to length of conjugated fatty acyl chain
    Mol. Pharmaceutics (IF 4.396) Pub Date : 2020-01-23
    Martin Wolff; Anja Schüler; Klaus Gast; Robert Seckler; Andreas Evers; Stefania Pfeiffer-Marek; Michael Kurz; Norbert Nagel; Torsten Haack; Michael Wagner; Anja Thalhammer

    Dual Glucagon-like peptide-1 (GLP-1)/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed for example by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering (SLS/DLS) to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain length in terms of apparent molecular mass and hydrodynamic radius (RS). We employ NMR spectroscopy to get an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of fatty acid chain length using CD and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4 derived dual agonist peptides is exclusively driven by hydrophobic interaction involving the conjugated acyl chains. Fatty acid chain length effects assembly equilibria as well as assembly stability although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly, compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether our study contributes to a thorough understanding of the association characteristics and the tendency towards self-assembly in response to lipidation. This is important not only to achieve the desired in-vivo half-life, but also with respect to physical stability of peptide solutions.

    更新日期:2020-01-23
  • Predictors of Beta-Hexachlorocyclohexane blood levels among people living close to a chemical plant and an illegal dumping site
    Environ. Health-Glob. (IF 4.43) Pub Date : 2020-01-22
    S. Narduzzi; F. Fantini; F. Blasetti; P. Rantakokko; H. Kiviranta; F. Forastiere; P. Michelozzi; D. Porta

    Hexachlorocyclohexane is a synthetic chemical with several isomers, including β-Hexachlorocyclohexane (β-HCH). In 2005, a large contamination of crude milk from some bovine farms along the Sacco River (Central Italy) was detected; it was related to the illegal disposal of large quantities of processing waste by a chemical industry of the area. A biomonitoring study, conducted in 2007 on a sample of the residing population, found high values of β-HCH in people living close to the river. These results led to the establishment of a clinical and epidemiological surveillance program on all the exposed population. The aim of the study was to evaluate the determinants of β-HCH blood levels in people living within 1 Km of the Sacco River, focusing on the role of specific foods, body mass index and risk factors not yet identified. The program involved all people living within 1 km of the river. A descriptive analysis of β-HCH blood levels was done in relation to the potential determinants including specific foods. Regression analysis was used to study the association between potential determinants and (natural log) β-HCH haematic concentration. The results were expressed as geometric mean ratios (GMR). To take into account similarities within the families we adjusted for family clustering. A total of 602 subjects (87.2%) agreed to participate in the surveillance. The β-HCH geometric mean serum concentration was 72 ng/g lipid. The regression analysis showed that being female (GMR: 1.32, 95%CI: 1.14–1.53), elderly (GMR> 70yy: 10.04, 95%CI: 6.65–15.15), obese (GMR: 1.63, 95%CI: 1.28–2.08), eating food of local/own production (GMR 1.47, 95%CI: 1.15–1.88) and using water from private wells (GMRdrink:1.47, 95%CI: 1.00–2.14 and GMRwash: 1.48, 95%CI: 1.17–1.87) were associated with higher β-HCH values. There was inverse association with breastfeeding (GMR: 0.64, 95%CI: 0.47–0.86). The focus on specific foods showed that the most important factors were eggs and beef. The study indicated a greater contamination for older people, and those drinking and washing with water from private wells and consuming locally produced food, especially eggs and beef.

    更新日期:2020-01-23
  • In vitro and in situ study on characterization and mechanism of the intestinal absorption of 2,3,5,4′-tetrahydroxy-stilbene-2-O-β-D-glucoside
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-22
    Cheng Wang; Yimeng Zhou; Xiaohong Gong; Li Zheng; Yunxia Li

    2,3,5,4′-tetrahydroxystilbence-2-O-β-D-glucoside (TSG) is a polyhydroxyphenolic compound, which exhibited a broad spectrum of pharmacological activities, such as anti-inflammatory, anti-depression, anti-oxidation and anti-atherosclerosis. However, the compound had poor bioavailability and the underlying absorption mechanisms had not been studied. Therefore, the purpose of this study was to investigate the intestinal absorption mechanism of TSG. This study used Caco-2 cell monolayer model and single-pass intestinal perfusion model to explore the gastrointestinal absorption mechanisms of TSG. The effects of basic parameters such as drug concentration, time and pH on the intestinal absorption of TSG were analyzed by high performance liquid chromatography. The absorption susceptibility of TSG to three inhibitors, P-gp inhibitors verapamil hydrochloride and quinidine, and MRP2 inhibitor probenecid were also assessed. TSG was poorly absorbed in the intestines and the absorption of TSG in stomach is much higher than that in intestine. Both in vitro and in situ experiments showed that the absorption of TSG was saturated with increasing concentration and it was better absorbed in a weakly acidic environment pH 6.4. Moreover, TSG interacts with P-gp and MRP2, and TSG was not only the substrate of the P-gp and MRP2, but also affected the expression of P-gp and MRP2. It was concluded that the gastrointestinal absorption the most unique active ingredient and considered as the mechanisms of TSG involved processes passive transport and the participation of efflux transporters.

    更新日期:2020-01-23
  • Disease progression model of 4T1 metastatic breast cancer
    J. Pharmacokinet. Pharmacodyn. (IF 2.91) Pub Date : 2020-01-22
    Liang Yang, Ling Yong, Xiao Zhu, Yaoyao Feng, Yu Fu, Daming Kong, Wei Lu, Tian-yan Zhou

    Abstract Cancer metastasis is the main cause of death in various types of cancer. However, in the field of pharmacometrics, cancer disease progression models focus on the growth of primary tumors with tumor volume or weight as target values, while the metastasis process is less mentioned. We propose a series of mathematical models to quantitatively describe and predict the disease progression of 4T1 breast cancer in the aspect of primary breast tumor, lung metastasis and white blood cell. The 4T1 cells were injected into breast fat pad of female BALB/c mice to establish an animal model of breast cancer metastasis. The number and volume of lung metastases at different times were measured. Based on the above data, a disease progression model of breast cancer lung metastasis was established and parameter values were estimated. The white blood cell growth and the primary tumor growth of 4T1 mouse are also modeled. The established models can describe the lung metastasis of 4T1 breast cancer in three aspects: (1) the increase in metastasis number; (2) the growth of metastasis volume; (3) metastasis number-size distribution at different time points. Compared with the prior metastasis models based on von Forester equation, our models distinguished the growth rate of primary tumor and metastasis and got parameter values for 4T1 mouse model. And the current models optimized the metastasis number-size distribution model by utilizing logistic function instead of the prior power function. This study provides a comprehensive description of lung metastasis progression for 4T1 breast cancer model, as well as an alternative disease progression model structure for further pharmacodynamics modeling.

    更新日期:2020-01-23
  • Differential Expression Profile of miR-27b, miR-29a and miR-155 in Chronic Lymphocytic Leukemia and Breast Cancer Patients
    Mol. Ther. Oncolytics (IF 5.710) Pub Date : 2020-01-23
    Farzaneh Raeisi; Esmaeil Mahmoudi; Mina Dehghani-Samani; Seyedeh Sahar Ebrahimi Hosseini; Ameneh Mehri Ghahfarrokhi; Asghar Arshi; Kayvan Forghanparast; Samaneh Ghazanfari

    Over the past decade, studies on microRNA (miRNA) and cancer quickly became known. miRNAs are small non-coding RNAs that play a vital role in regulation of gene expression. In the present study, the expression of miR-27b, miR-29a and miR-155, their prognostic roles and their potential targets in chronic lymphocytic leukemia (CLL) and breast cancer (BC) by RT-qPCR were investigated. In two case-control studies, qRT-PCR was used to analyze the peripheral blood serum of 15 CLL patients and tissue samples of 15 BC patients for the expression of miR-27b, miR-29a and miR-155. MiRNA expression levels were calculated using RT-qPCR method. The results revealed a significant increase in the expression of all miRNAs in patients with BC and CLL compared to respective healthy groups (P<0.001). In BC patients, there is a significant difference between the expression of miR-155 and miR-29a (P<0.05), miR-155 and miR-27b (P<0.01), and miR-27b and miR-29a (P<0.001). In CLL patients, a significant difference between expression both miR-27b and miR-29a compared expression to miR-155 (P<0.001) was found. Furthermore, a significant association between miR-155 and prevascular invasion was found. Significantly, elevated circulating miRNAs showed to be BC specific and could differentiate BC tissues from the controls. It was demonstrated that miRNAs used in this study and their expression profiles can be developed as biomarkers for early diagnosis and prognosis of CLL and BC. Further studies utilizing a larger test group of patients would provide identification of miRNAs as key players in intercellular interactions.

    更新日期:2020-01-23
  • Knockdown of MCM3AP-AS1 Inhibits Proliferation, Invasion and Migration of Prostate Cancer Cells via DNMT1/DNMT3 (A/B) Methylation-Mediated Upregulation of NPY1R
    Mol. Ther. Nucl. Acids (IF 5.919) Pub Date : 2020-01-23
    Xin Li; Jiancheng Lv; Shuai Liu

    Prostate cancer (PCa) is a heterogeneous tumor that commonly occurs among males worldwide. This study explored potential role long non-coding RNA MCM3AP-AS1 plays in PCa progression and investigated its mechanism. MCM3AP-AS1 and neuropeptide Y receptor Y1 (NPY1R) expression was determined in PCa cells. The regulatory of MCM3AP-AS1 in PCa cells was defined using scratch test, Transwell assay, EdU assay and flow cytometry. Methylation-specific PCR (MSP) was used to test the methylation level of NPY1R. Subsequently, the interaction among MCM3AP-AS1, DNA methyltransferase (DNMT)1/DNMT3 (A/B) and NPY1R was investigated using RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Finally, we observed xenograft tumor in nude mice. MCM3AP-AS1 was highly while NPY1R was poorly expressed in PCa. Lentivirus-mediated overexpression of MCM3AP-AS1 promoted proliferation, invasion and migration while suppressing apoptosis of PCa cells, while opposite trends were detected after inhibition of MAPK pathway. MCM3AP-AS1 promoted methylation of NPY1R promoter via recruitment of DNMT1/DNMT3 (A/B), thereby downregulating NPY1R expression to activate the mitogen-activated protein kinase (MAPK) pathway. Furthermore, overexpressed MCM3AP-AS1 was observed to facilitate PCa development in vivo, which could be reversed by overexpressed NPY1R. Altogether, MCM3AP-AS1 silencing inhibits PCa progression by disrupting methylation of the NPY1R promoter to inactivate the MAPK pathway.

    更新日期:2020-01-23
  • MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-talk
    Mol. Ther. Nucl. Acids (IF 5.919) Pub Date : 2020-01-23
    Yue Qiu; Rongchao Cheng; Chaoqi Liang; Yuan Yao; Wenhao Zhang; Jie Zhang; Mingyu Zhang; Baiyan Li; Chaoqian Xu; Rong Zhang

    MicroRNA and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-art techniques. The results demonstrated that Mfn2 was down-regulated and miR-20b was up-regulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by rAAV9-anti-miR-20b or AMO-20b. The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and microRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through down-regulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.

    更新日期:2020-01-23
  • Patriscabrin F from the roots of Patrinia scabra attenuates LPS-induced inflammation by downregulating NF-κB, AP-1, IRF3, and STAT1/3 activation in RAW 264.7 macrophages
    Phytomedicine (IF 4.180) Pub Date : 2020-01-23
    Ji-Sun Shin; Shin-Young Kang; Hwi-Ho Lee; Seo-Yeon Kim; Da Hye Lee; Dae-Sik Jang; Kyung-Tae Lee
    更新日期:2020-01-23
  • Zebrafish bioassay-guided isolation of antiseizure compounds from the Cameroonian medicinal plant Cyperus articulatus L.
    Phytomedicine (IF 4.180) Pub Date : 2020-01-23
    Théo Brillatz; Maxime Jacmin; Emerson Ferreira Queiroz; Laurence Marcourt; Ivan Slacanin; Charlotte Petit; Pierre-Alain Carrupt; Elisabeth Ngo Bum; Paul Herrling; Alexander D. Crawford; Jean-Luc Wolfender

    Background : Epilepsy is a chronic neurological disorder affecting more than 50 million people worldwide, in which 80% live in low- and middle-income countries. Due to the limited availability of antiseizure drugs (ASDs) in these countries, medicinal plants are the first-line treatment for most epilepsy patients. In Cameroon, a decoction of Cyperus articulatus L. rhizomes is traditionally used to treat epilepsy. Purpose : The aim of this study was to identify and isolate the active compounds responsible for the antiseizure activity of C. articulatus in order to confirm both its traditional medicinal usage and previous in vivo studies on extracts of this plant in mouse epilepsy models. Methods : The dried rhizomes of C. articulatus were extracted by solvents with increasing polarities (hexane, dichloromethane, methanol and water). A traditional decoction and an essential oil were also prepared. These extracts were screened for antiseizure activity using a larval zebrafish seizure model with seizures induced by the GABAA antagonist pentylenetetrazole (PTZ). The hexane extract demonstrated the highest antiseizure activity and was therefore selected for bioassay-guided fractionation. The isolated bioactive compounds were characterized by classical spectroscopic methods. Since they were found to be volatile, they were quantified by GC-FID. In addition, the absorption of the active compounds through the gastrointestinal tract and the blood-brain barrier was evaluated using a hexadecane and a blood-brain barrier parallel artificial membrane permeability assays (HDM-PAMPA and PAMPA-BBB). Results : The hexane extract of C. articulatus exhibited the highest antiseizure activity with a reduction of 93% of PTZ-induced seizures, and was therefore subjected to bioassay-guided fractionation in order to isolate the active principles. Four sesquiterpenoids were identified as cyperotundone (1), mustakone (2), 1,2-dehydro-α-cyperone (3) and sesquichamaenol (4) and exhibited significant antiseizure activity. These volatile compounds were quantified by GC in the hexane extract, the essential oil and the simulated traditional decoction. In addition, the constituents of the hexane extract including compounds 1 and 2 were found to cross the gastrointestinal barrier and the major compound 2 crossed the blood-brain barrier as well. Conclusion : These results highlight the antiseizure activity of various sesquiterpene compounds from a hexane extract of C. articulatus dried rhizomes and support its use as a traditional treatment for epilepsy.

    更新日期:2020-01-23
  • Use of embryonic stem cell-derived cardiomyocytes to study cardiotoxicity of bisphenol AF via the GPER/CAM/eNOS pathway
    Toxicology (IF 3.547) Pub Date : 2020-01-23
    Shoufei Yang; Wei Cheng; Xiaolan Li; Fan Liang; Ren Zhou; Hui Wang; Yan Feng; Yan Wang

    Bisphenol AF (BPAF) is a derivative of bisphenol A (BPA) that is widely used in fluorinated polymers, fluorinated rubber, electronic equipment, plastic optical fibers, etc. Studies have shown that BPAF exposure is associated with a number of diseases; however, little is known about the effects of BPAF on cardiomyocytes. We investigated the impact of chronic exposure to BPAF on cardiomyocytes derived from embryonic stem cells (ESCs). The present study showed that chronic exposure to various concentrations of BPAF (0, 8, 200 and 1000 ng/ml) induces cardiomyocyte hypertrophy. The ratios of microfilaments to mitochondrial length and the ratio of microfilaments to cell nuclei and MYH7b levels indicate that BPAF exposure alters the morphology of the cells and mitochondria. Furthermore, BPAF exposure at concentrations from 8 to 1000 ng/ml results in an increase in G protein-coupled estrogen receptor (GPER) expression. Additionally, our results suggest that these effects of BPAF mediate cardiomyocyte hypertrophy apparently due to an increase in the production of reactive nitrogen species (RNS) via an increase in endothelial NO synthase (eNOS). These results imply that ESC-based myocardial differentiation can be an excellent cellular model to study BPAF-induced cardiotoxicity at the cellular and molecular levels.

    更新日期:2020-01-23
  • Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized Guinea pig assay
    Toxicol. Appl. Pharmacol. (IF 3.585) Pub Date : 2020-01-23
    Pierre Morissette; Sebastian Polak; Anne Chain; Jin Zhai; John P. Imredy; Mary Jo Wildey; Jeffrey Travis; Kevin Fitzgerald; Patrick Fanelli; Elisa Passini; Blanca Rodriguez; Frederick Sannajust; Christopher Regan

    Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use.

    更新日期:2020-01-23
  • 更新日期:2020-01-23
  • Next-generation drug repurposing using human genetics and network biology
    Curr. Opin. Pharmacol. (IF 5.203) Pub Date : 2020-01-22
    Serguei Nabirotchkin; Alex E Peluffo; Philippe Rinaudo; Jinchao Yu; Rodolphe Hajj; Daniel Cohen

    Drug repurposing has attracted increased attention, especially in the context of drug discovery rates that remain too low despite a recent wave of approvals for biological therapeutics (e.g. gene therapy). These new biological entities-based treatments have high costs that are difficult to justify for small markets that include rare diseases. Drug repurposing, involving the identification of single or combinations of existing drugs based on human genetics data and network biology approaches represents a next-generation approach that has the potential to increase the speed of drug discovery at a lower cost. This Pharmacological Perspective reviews progress and perspectives in combining human genetics, especially genome-wide association studies, with network biology to drive drug repurposing for rare and common diseases with monogenic or polygenic etiologies. Also, highlighted here are important features of this next generation approach to drug repurposing, which can be combined with machine learning methods to meet the challenges of personalized medicine.

    更新日期:2020-01-23
  • Injectable biodegradable bi-layered capsule for sustained delivery of bevacizumab in treating wet age-related macular degeneration
    J. Control. Release (IF 7.901) Pub Date : 2020-01-23
    Pengfei Jiang; Francisco J. Chaparro; Clayton T. Cuddington; Andre F. Palmer; Matthew P. Ohr; John J. Lannutti; Katelyn E. Swindle-Reilly
    更新日期:2020-01-23
  • Synthesis, in‐vitro and in‐silico study of novel thiazoles as potent antibacterial agents and MurB inhibitors
    Arch. Pharm. (IF 2.145) Pub Date : 2020-01-22
    Sherif M. H. Sanad; Ahmed A. M. Ahmed; Ahmed E. M. Mekky
    更新日期:2020-01-23
  • Targeting iNOS As a Valuable Strategy for the Therapy of Glioma
    ChemMedChem (IF 3.016) Pub Date : 2020-01-22
    Cristina Maccallini; Marialucia Gallorini; Amelia Cataldi; Rosa Amoroso
    更新日期:2020-01-23
  • Physiologically based pharmacokinetic–pharmacodynamic modeling for prediction of vonoprazan pharmacokinetics and its inhibition on gastric acid secretion following intravenous/oral administration to rats, dogs and humans
    Acta Pharmacol. Sin. (IF 4.010) Pub Date : 2020-01-22
    Wei-min Kong; Bin-bin Sun; Zhong-jian Wang; Xiao-ke Zheng; Kai-jing Zhao; Yang Chen; Jia-xin Zhang; Pei-hua Liu; Liang Zhu; Ru-jun Xu; Ping Li; Li Liu; Xiao-dong Liu
    更新日期:2020-01-23
  • ASPI: a public–private partnership to develop treatments for autism
    Nat. Rev. Drug. Disc. (IF 57.618) Pub Date : 2020-01-22
    Seth Ness; Gahan Pandina; Shyla Jagannatha; Kyle Wathen; Abigail Bangerter; Nikolay V. Manyakov; Robert Hendren; Bennett Leventhal; Declan Murphy; Geraldine Dawson; Wayne C. Drevets; Husseini K. Manji

    Numerous potential therapeutic targets are being investigated in autism spectrum disorder (ASD). Here, we discuss a platform trial approach for designing proof-of-concept (POC) clinical studies of ASD — via the Autism Spectrum POC Initiative (ASPI) — that can be conducted through a public–private partnership with the aim of finding effective treatments in the most expeditious manner.

    更新日期:2020-01-23
  • Neutrophils as emerging therapeutic targets
    Nat. Rev. Drug. Disc. (IF 57.618) Pub Date : 2020-01-22
    Tamás Németh; Markus Sperandio; Attila Mócsai
    更新日期:2020-01-23
  • Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors
    ACS Med. Chem. Lett. (IF 3.737) Pub Date : 2020-01-22
    Baljinder Singh; Jean A. Bernatchez; Laura-Isobel McCall; Claudia M. Calvet; Jasmin Ackermann; Julia M. Souza; Diane Thomas; Everton M. Silva; Kelly A. Bachovchin; Dana M. Klug; Hitesh B. Jalani; Seema Bag; Melissa J. Buskes; Susan E. Leed; Norma E. Roncal; Erica C. Penn; Jessey Erath; Ana Rodriguez; Richard J. Sciotti; Robert F. Campbell; James McKerrow; Jair L. Siqueira-Neto; Lori Ferrins; Michael P. Pollastri
    更新日期:2020-01-23
  • Structure–Bioactivity Relationships of Lapatinib Derived Analogs against Schistosoma mansoni
    ACS Med. Chem. Lett. (IF 3.737) Pub Date : 2020-01-22
    Melissa J. Buskes; Monica Clements; Kelly A. Bachovchin; Hitesh B. Jalani; Allison Leonard; Seema Bag; Dana M. Klug; Baljinder Singh; Robert F. Campbell; Richard J. Sciotti; Nelly El-Sakkary; Conor R. Caffrey; Michael P. Pollastri; Lori Ferrins
    更新日期:2020-01-23
  • Do We Build Similar Molecules for Comorbid Diseases? Tevarud in Drug Design, an Analysis for Depression and Inflammation
    ACS Med. Chem. Lett. (IF 3.737) Pub Date : 2020-01-22
    F. Esra Önen Bayram; Sarah A. A. Alradhwani; Gulcin Tugcu; Hande Sipahi
    更新日期:2020-01-23
  • Drug Annotations for a New Decade
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-22
    Wendy B. Young; Gunda I. Georg; Shaomeng Wang

    The Drug Annotations Series was launched in 2014 to share in case study form the story of a new drug from laboratory to clinical development. In Drug Annotations, readers follow the medicinal chemistry journey of an important drug that impacts human health. Our aim is to identify and publish these stories to instruct and support members of the chemistry and drug discovery communities in the pursuit of ground-breaking medicine for patients. Since its inception, the Drug Annotations Series has become the premier venue to showcase such case studies. As of this writing, 55 manuscripts have been published and the manuscripts have spanned a range of modalities including small molecules, proteins, and antibody drug conjugates, just to name a few. We would like to take this opportunity to thank the previous editors Drs. Jeff Zablocki and Carlos Garcia-Echeverria for their leadership in launching and defining this series. The high quality and range of contributions over the past 6 years have set a high bar and made this series a must-read section of the journal today. As a new decade launches, we are delighted to announce that Dr. Wendy B. Young, Senior Vice President, Genentech, will serve as the new Associate Editor for Drug Annotations. Dr. Young is the Senior Vice President for Small Molecule Drug Discovery at Genentech, where she leads a team of roughly 400 scientists (chemistry, biochemical pharmacology, drug metabolism and pharmacokinetics, pharmaceutical sciences) engaged in oncology, immunology, neuroscience, and infectious disease drug discovery and development. She has served as Chair of ACS MEDI, is an ACS Fellow, and is the recipient of the 2020 Earle B. Barnes Award for Leadership in Chemical Research. For Drug Annotations, a successful submission will highlight the full journey traveled by one discrete compound from its inception to progression into human clinical trials or approval. The manuscript should include information regarding target selection; hit identification; structure–activity relationships, including target potency, drug metabolism, and pharmacokinetics; pharmacology; and ideally, safety data. For compounds in early clinical development, human pharmacokinetic (PK) and initial clinical efficacy data are desirable but not essential to being accepted for publication. For compounds that are in pivotal trials or approved for marketing, clinical trial data and/or appropriate references should be included. Additionally, the author(s) should describe the goal of the program and the potential benefit to patients (e.g., first-in-class, best-in-class, and improvements over previous compounds). Please note that it is acceptable for pieces of the story to have been published previously, as the goal of Drug Annotations is to capture the complete story in one setting. From these stories, the medicinal chemistry community will have insights into the challenges overcome and the fine-tuning required to ensure a successful drug. For additional information on submissions, please refer to the guidelines for authors: http://pubsapp.acs.org/paragonplus/submission/jmcmar/jmcmar_authguide.pdf? We look forward to continuing growth of this truly exciting manuscript type under the leadership of Dr. Wendy Young. We also welcome any suggestions on stories you would like to read or how to make the Drug Annotations Series even more impactful and beneficial to our scientific community and the general public at large. Please send any suggestions for Drug Annotations to Dr. Wendy Young at [email protected]. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. This article has not yet been cited by other publications.

    更新日期:2020-01-23
  • Development of Novel N-hydroxypyridone Derivatives as Potential Anti-Ischemic Stroke Agents
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-22
    Linghao Hu; Hongxuan Feng; Hongguang Zhang; Songda Yu; Qinyuan Zhao; Wei Wang; Fengxia Bao; Xun Ding; Jiajing Hu; Manjiong Wang; Yixiang Xu; Zengrui Wu; Xiaokang Li; Yun Tang; Fei Mao; Xiaoyan Chen; Haiyan Zhang; Jian Li
    更新日期:2020-01-23
  • Dose Predictions for Drug Design
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-22
    Tristan S. Maurer; Dennis Smith; Kevin Beaumont; Li Di
    更新日期:2020-01-23
  • Breaking the Glass Ceiling in Simulation and Modeling: Women in Pharmaceutical Discovery
    J. Med. Chem. (IF 6.054) Pub Date : 2020-01-22
    Kelly L. Damm-Ganamet; Renee L. DesJarlais; Tami Marrone; Amy Y. Shih; Jamie M. Schiffer; Laura Perez-Benito; Taraneh Mirzadegan
    更新日期:2020-01-23
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
加州大学洛杉矶分校
上海纽约大学William Glover
南开大学化学院周其林
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug