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Maria Mrakovcic, Leopold F Fröhlich
Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell's energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis...
March 21, 2018: Biomolecules
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
Minako Nagatome, Yuki Kondo, Daisuke Kadowaki, Yusuke Saishyo, Mitsuru Irikura, Tetsumi Irie, Yoichi Ishitsuka
Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity...
February 2018: Heliyon
Emilie Bahne, Andreas Brønden, Tina Vilsbøll, Filip Krag Knop
Metformin is an oral anti-hyperglycaemic drug used as first-line treatment of Type 2 diabetes. It is more effective when administered orally than when administered intravenously, and metformin formulations, which prolong the time residing in the gut are the most potent. This indicates that the intestine plays an essential role in metformin's mode of action. Metformin also increases plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1). This metformin-induced GLP-1 increment may constitute an important link between the gut and the glucose-lowering effect of metformin...
March 19, 2018: Ugeskrift for Laeger
Jiawei Liu, Mian Zu, Kaotan Chen, Li Gao, Huan Min, Weiling Zhuo, Weiwen Chen, Ailin Liu
BACKGROUND: Neuraminidase (NA) is one of the key surface protein of the influenza virus, and has been established as a primary drug target for anti-influenza therapies. This study aimed to screen bioactive herbal extracts from some medicinal plants traditionally used in Lingnan Chinese Medicines by NA activity high-throughput screening assay. METHODS: One hundred ninety herbal extracts from 95 medicinal plants collected in Guangzhou were screened for their potential inhibitory activities against A (H1N1) influenza neuraminidase, and the most active extracts were further evaluated for their anti-influenza virus activities using virus-induced cytopathic effect (CPE)...
March 20, 2018: BMC Complementary and Alternative Medicine
Maëlle Duffey, Cecilia P Sanchez, Michael Lanzer
BACKGROUND: The increased resistance of the human malaria parasite Plasmodium falciparum to currently employed drugs creates an urgent call for novel anti-malarial drugs. Particularly, efforts should be devoted to developing fast-acting anti-malarial compounds in case clinical resistance increases to the first-line artemisinin-based combination therapy. SC83288, an amicarbalide derivative, is a clinical development candidate for the treatment of severe malaria. SC83288 is fast-acting and able to clear P...
March 20, 2018: Malaria Journal
Beena Negi, Prija Poonan, Mohammad Fawad Ansari, Deepak Kumar, Sakshi Aggarwal, Ramandeep Singh, Amir Azam, Diwan S Rawat
A series of 22 novel metronidazole-triazole-styryl hybrids were synthesized and evaluated for their in vitro antiamoebic activity against HM1: IMSS strain of Entamoeba histolytica. Some of the hybrids were found to be more active (IC50  = 0.12-0.35 μM) than the reference drug metronidazole (IC50  = 1.79 μM). The most active compounds were found to be non-toxic (up to 50 μM) against the Vero cells showing a good safety profile of these hybrids. The docking and ADMET studies were also conducted to investigate the probable mode of action...
March 13, 2018: European Journal of Medicinal Chemistry
Jacqueline M Zaengle-Barone, Abigail C Jackson, David M Besse, Bradford Becken, Mehreen Arshad, Patrick C Seed, Katherine J Franz
The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a non-toxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms...
March 20, 2018: ACS Infectious Diseases
Juan Ramón Avilés-Moreno, Giel Berden, Jos Oomens, Bruno Martínez-Haya
Proton bonding drives the supramolecular chemistry of a broad range of materials with polar moieties. Proton delocalization and electronic charge redistribution have a profound impact on the structure of proton-bound molecular frameworks, and pose fundamental challenges to quantum chemical modelling. This study provides insights into the structural and spectral signatures of the intramolecular proton bond formed in a benchmark polyazamacrocycle anionophore (cyclen, 1,4,7,10-tetraazacyclododecane). Infrared action spectroscopy is employed to characterize the macrocycle, isolated in protonated form...
March 20, 2018: Physical Chemistry Chemical Physics: PCCP
S M Plummer, J Wright, R A Currie
An increased incidence of liver tumours in the long term rodent bioassay is not an uncommon finding, invariably as a result of a non-genotoxic mode of action. Non-genotoxic liver carcinogenesis has been found to involve activation of certain nuclear hormone receptors (NHR) including the constitutive androstane receptor (CAR), peroxisome proliferator activated receptor alpha (PPARalpha) and arylhydrocarbon receptor (AHR) and more recently the induction of specific microRNAs (miRs), has also been demonstrated following CAR activation in studies up to 90 days (Koufaris et al...
2018: Toxicology Reports
DanRong Hu, LiJuan Chen, Ying Qu, JinRong Peng, BingYang Chu, Kun Shi, Ying Hao, Lin Zhong, MengYao Wang, ZhiYong Qian
The combination of chemotherapy with photodynamic therapy (PDT) has attracted broad attention as it can overcome limitations of conventional chemo-treatment by using different modes of action. However, the efficacy of PDT to treat solid tumors is severely affected by hypoxia in tumors. Methods : In this study, we developed oxygen-generating theranostic nanoparticles (CDM NPs) by hierarchically assembling doxorubicin (DOX), chlorin e6 (Ce6) and colloidal manganese dioxide (MnO2 ) with poly (ε-caprolactone-co-lactide)-b-poly (ethylene glycol)-b-poly (ε-caprolactone-co-lactide) for treating breast cancer...
2018: Theranostics
Klara Habartova, Radim Havelek, Martina Seifrtova, Karel Kralovec, Lucie Cahlikova, Jakub Chlebek, Eva Cermakova, Nadezda Mazankova, Jana Marikova, Jiri Kunes, Lucie Novakova, Martina Rezacova
Scoulerine is an isoquinoline alkaloid, which indicated promising suppression of cancer cells growth. However, the mode of action (MOA) remained unclear. Cytotoxic and antiproliferative properties were determined in this study. Scoulerine reduces the mitochondrial dehydrogenases activity of the evaluated leukemic cells with IC50 values ranging from 2.7 to 6.5 µM. The xCELLigence system revealed that scoulerine exerted potent antiproliferative activity in lung, ovarian and breast carcinoma cell lines. Jurkat and MOLT-4 leukemic cells treated with scoulerine were decreased in proliferation and viability...
March 19, 2018: Scientific Reports
Mahendra Shukla, Femi M Francis, Jawahar Lal
Conessine, a steroidal alkaloid obtained from the bark and seeds of the plant species of Apocynaceae family, elicits a histamine antagonistic action, selectively for the H3 histaminergic receptors. This alkaloid is used mainly for the treatment of dysentery and helminthic disorders. For the quantification of conessine in serum, a liquid chromatography-tandem mass spectrometry method was developed. Chromatographic separation was achieved on a Zorbax SB-CN column (100 × 4.6 mm, 3.5 µm), and a mobile phase consisting of 90% methanol in aqueous ammonium acetate buffer (pH 3...
January 1, 2018: European Journal of Mass Spectrometry
Yi Zhou, Qingqing Chang, Wenjie Wang, Xiaofang Zhang, Fang Zhou, Jianguo Sun, Guangji Wang, Ying Peng
FY363 is a new chemical entity of gemcitabine analog, which has been shown to have a significant inhibitory effect on cell proliferation in a variety of tumor cell lines in vitro. As a carbamate derivative, FY363 would be converted to the active metabolite gemcitabine through enzyme action in vivo. In order to clarify the exposure of FY363 prototype and its metabolite gemcitabine in vivo after administration of FY363, a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated to simultaneously determine FY363 and gemcitabine in rat plasma after liquid-liquid extraction with ethyl acetate...
March 14, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Sandrine Charles, Stéphane Jomini, Valérie Fessard, Emilie Bigorgne-Vizade, Christophe Rousselle, Cécile Michel
A review of in vitro genotoxicity studies on titanium dioxide nanoparticles (TiO2 -NPs) published between 2010 and 2016 was performed by France in the framework of the CLP Regulation 1272/2008/EC. Neither the few in vivo studies of low quality nor the larger number of acceptable in vitro studies available for genotoxicity allowed France to conclude on the genotoxicity of TiO2 -NPs. Based on this work, it was decided to compare the acceptable in vitro studies to understand the reasons for the diverging results observed, such as the materials tested or of the protocols used and their inherent interferences...
March 19, 2018: Nanotoxicology
Gembu Maryu, Haruko Miura, Yoichi Uda, Akira T Komatsubara, Michiyuki Matsuda, Kazuhiro Aoki
Protein kinases play pivotal roles in intracellular signal transduction, and dysregulation of kinases leads to pathological results such as malignant tumors. Kinase activity has hitherto been measured by biochemical methods such as in vitro phosphorylation assay and western blotting. However, these methods are less useful to explore spatial and temporal changes in kinase activity and its cell-to-cell variation. Recent advances in fluorescent proteins and live-cell imaging techniques enable us to visualize kinase activity in living cells with high spatial and temporal resolutions...
March 17, 2018: Cell Structure and Function
Mikhail M Savitski, Nico Zinn, Maria Faelth-Savitski, Daniel Poeckel, Stephan Gade, Isabelle Becher, Marcel Muelbaier, Anne J Wagner, Katrin Strohmer, Thilo Werner, Stephanie Melchert, Massimo Petretich, Anna Rutkowska, Johanna Vappiani, Holger Franken, Michael Steidel, Gavain M Sweetman, Omer Gilan, Enid Y N Lam, Mark A Dawson, Rab K Prinjha, Paola Grandi, Giovanna Bergamini, Marcus Bantscheff
Protein degradation plays important roles in biological processes and is tightly regulated. Further, targeted proteolysis is an emerging research tool and therapeutic strategy. However, proteome-wide technologies to investigate the causes and consequences of protein degradation in biological systems are lacking. We developed "multiplexed proteome dynamics profiling" (mPDP), a mass-spectrometry-based approach combining dynamic-SILAC labeling with isobaric mass tagging for multiplexed analysis of protein degradation and synthesis...
March 3, 2018: Cell
Larisa V Lysenko, Jeesun Kim, Francisco Madamba, Anna A Tyrtyshnaia, Aarti Ruparelia, Alexander M Kleschevnikov
Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications...
March 14, 2018: Neurobiology of Disease
Fiona Sewell, Nichola Gellatly, Maria Beaumont, Natalie Burden, Richard Currie, Lolke de Haan, Thomas H Hutchinson, Miriam Jacobs, Catherine Mahony, Ian Malcomber, Jyotigna Mehta, Graham Whale, Ian Kimber
The advent of adverse outcome pathways (AOPs) has provided a new lexicon for description of mechanistic toxicology, and a renewed enthusiasm for exploring modes of action resulting in adverse health and environmental effects. In addition, AOPs have been used successfully as a framework for the design and development of non-animal approaches to toxicity testing. Although the value of AOPs is widely recognised, there remain challenges and opportunities associated with their use in practise. The purpose of this article is to consider specifically how the future trajectory of AOPs may provide a basis for addressing some of those challenges and opportunities...
March 16, 2018: Archives of Toxicology
Mairi M Littleson, Christopher M Baker, Anne J Dalençon, Elizabeth C Frye, Craig Jamieson, Alan R Kennedy, Kenneth B Ling, Matthew M McLachlan, Mark G Montgomery, Claire J Russell, Allan J B Watson
Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target...
March 16, 2018: Nature Communications
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