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Yarong Song, Peng Zhang, Yadong Sun, Xuechao Li, Lifeng Chen, Yajun Xiao, Yifei Xing
Autophagy is an evolutionarily conserved catabolic process in eukaryotic cells, which allows cells to overcome a wide array of of stresses and has recently been shown to result in drug resistance. This study examined the effect of autophagy on oleanolic acid (OA)-induced cytotoxicity against bladder cancer cells. Our study demonstrated that OA inhibited cell viability, proliferation, and induced apoptosis in bladder cancer lines T24 and EJ. Furthermore, OA induced autophagy in both cell lines by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR) and promoting unc-51 like autophagy activating kinase 1 (ULK1)...
July 4, 2017: Oncotarget
Haijian Sun, Xuexue Zhu, Wei Lin, Yuetao Zhou, Weiwei Cai, Liying Qiu
Background /Aims: Accumulating evidence indicates that endothelial inflammation is one of the critical determinants in pathogenesis of atherosclerotic cardiovascular disease. Our previous studies had demonstrated that Vaccariae prevented high glucose or oxidative stress-triggered endothelial dysfunction in vitro. Very little is known about the potential effects of hypaphorine from Vaccariae seed on inflammatory response in endothelial cells. METHODS: In the present study, we evaluated the anti-inflammatory effects of Vaccariae hypaphorine (VH) on lipopolysaccharide (LPS)-challenged endothelial EA...
July 3, 2017: Cellular Physiology and Biochemistry
Tian-Guang Zhang, Takashi Ikejima, Toshihiko Hayashi, Jun Zhao, Yi-Mei Wang, Shuang-Qing Peng
Isoniazid (INH) is a first-line antituberculosis drug that is adversely associated with hepatotoxicity. Recently, impairment of mitochondrial homeostasis involved in this side effect has been noticed. Mitochondrial homeostasis is achieved by the balance between the generation of functional mitochondria by biogenesis and elimination of dysfunctional mitochondria by autophagy. AMP-activated protein kinase (AMPK) can maintain mitochondrial stability through positive control of these two processes. In this study, we showed that AMPK activator acadesine (AICAR) alleviated INH-caused impairment of mitochondrial biogenesis by activation of silent information regulator two ortholog 1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1 α) pathway in HepG2 cells...
May 29, 2017: Journal of Applied Toxicology: JAT
Jenny K Y Wong, Wai Him Kwok, George H M Chan, Timmy L S Choi, Emmie N M Ho, Murielle Jaubert, Ludovic Bailly-Chouriberry, Yves Bonnaire, Adam Cawley, H Ming Williams, John Keledjian, Lydia Brooks, Adam Chambers, Yuanyuan Lin, Terence S M Wan
Acadesine, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, commonly known as AICAR, is a naturally occurring adenosine monophosphate-activated protein kinase (AMPK) activator in many mammals including humans and horses. AICAR has attracted considerable attention recently in the field of doping control due to a study showing enhancement of endurance performance in unexercised or untrained mice, resulting in the term "exercise pill". Its use has been classified as gene doping by the World Anti-Doping Agency (WADA), and since it is endogenous, it may only be possible to control deliberate administration of AICAR to racehorses after establishment of an appropriate threshold...
April 13, 2017: Drug Testing and Analysis
Jifeng Nie, Aidong Liu, Qunya Tan, Kai Zhao, Kui Hu, Yong Li, Bin Yan, Lin Zhou
AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, its activity in human gallbladder cancer cells was evaluated here. We show that AICAR provoked significant apoptosis in human gallbladder cancer cell lines (Mz-ChA-1, QBC939 and GBC-SD) and primary gallbladder cancer cells. AICAR-induced cytotoxicity in gallbladder cancer cells appears independent of AMPK activation. Inhibition of AMPK, via AMPKα shRNA knockdown or dominant negative mutation (T172A), failed to rescue GBC-SD cells from AICAR...
January 8, 2017: Biochemical and Biophysical Research Communications
Feng Guo, Shuang-Qing Liu, Xing-Hua Gao, Long-Yang Zhang
AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, which induces cytotoxic effect to several cancer cells. Its potential activity in prostate cancer cells and the underlying signaling mechanisms have not been extensively studied. Here, we showed that AICAR primarily induced programmed necrosis, but not apoptosis, in prostate cancer cells (LNCaP, PC-3 and PC-82 lines). AICAR's cytotoxicity to prostate cancer cells was largely attenuated by the necrosis inhibitor necrostatin-1...
May 27, 2016: Biochemical and Biophysical Research Communications
Zhang-Feng Zhong, Wen Tan, William W Qiang, Virginia L Scofield, Ke Tian, Chun-Ming Wang, Wen-An Qiang, Yi-Tao Wang
Furanodiene is a bioactive sesquiterpene isolated from the spice-producing Curcuma wenyujin plant (Y. H. Chen and C. Ling) (C. wenyujin), which is a commonly prescribed herb used in clinical cancer therapy by modern practitioners of traditional Chinese medicine. Previously, we have shown that furanodiene inhibits breast cancer cell growth both in vitro and in vivo, however, the mechanism for this effect is not yet known. In this study, therefore, we asked (1) whether cultured breast cancer cells made resistant to the chemotherapeutic agent doxorubicin (DOX) via serial selection protocols are susceptible to furanodiene's anticancer effect, and (2) whether AMP-activated protein kinase (AMPK), which is a regulator of cellular energy homeostasis in eukaryotic cells, participates in this effect...
April 26, 2016: Molecular BioSystems
Jing-Jing Wu, Bin Wei, Yi-Han Ding, Zhi-Kui Deng, Yu-Ye Shi, Yu-Feng Li
OBJECTIVE: To investigate the effects of AMPK agonist Acadesine (AICAR) on growth inhibition of K562 cells and their sensitivity to imatinib (IM). METHODS: K562 cells were cultured with different concentrations of AICAR alone or its combination with IM for 48 hours, the CCK-8 assay was used to detect cell proliferation, the cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression levels of Cyclin D1, Cyclin E1 and Caspase 3 protein were determined by Western blot...
February 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Arnau Montraveta, Sílvia Xargay-Torrent, Laia Rosich, Mònica López-Guerra, Jocabed Roldán, Vanina Rodríguez, Eriong Lee-Vergés, Mercè de Frías, Clara Campàs, Elias Campo, Gaël Roué, Dolors Colomer
Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration...
August 28, 2015: Oncotarget
Richard D Weisel, Nancy Nussmeier, Mark F Newman, Ronald G Pearl, Andrew S Wechsler, Giuseppe Ambrosio, Bertram Pitt, Robert M Clare, Karen S Pieper, Linda Mongero, Tammy L Reece, Terrence M Yau, Stephen Fremes, Philippe Menasché, Armando Lira, Robert A Harrington, T Bruce Ferguson
OBJECTIVES: The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG (RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes. METHODS: The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting...
December 2014: Journal of Thoracic and Cardiovascular Surgery
Yun Sang, Heyin Pei, Liang Ma, Li Huang, Caifeng Xie, Jinying Chen, Xiaolin Liang, Yan Ran, Guangcheng Wang, Zhuang Yang, Dong Cao, Lin He, Yuzhe Wu, Linhong He, Jun Zhu, Jingbo Lan, Lijuan Chen
Triglycerides are the main part of fats and half of the lipids in hepatocytes, and play an important role in metabolism as energy sources and transporters of dietary fat. In this study, 33 derivatives based on 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione were synthesized and evaluated for their lipid-lowering activity. Among them, compound 1i was found to exhibit potent triglyceride-lowering potency in 3T3-L1 adipocytes which was comparable to that of the adenosine monophosphate-activated protein kinase (AMPK) agonist Acadesine (AIACR)...
2014: Chemical & Pharmaceutical Bulletin
Arnau Montraveta, Sílvia Xargay-Torrent, Mónica López-Guerra, Laia Rosich, Patricia Pérez-Galán, Itziar Salaverria, Silvia Beà, Susana G Kalko, Mercè de Frias, Clara Campàs, Gaël Roué, Dolors Colomer
Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL...
February 15, 2014: Oncotarget
V A Glazunova, K V Lobanov, R S Shakulov, A S Mironov, A A Shtil
We studied the cytotoxicity of acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) for tumor and normal cells of various species and tissue origin. In tumor cells, acadesine triggered non-apoptotic death; the potency of the compound to normal cells was substantially lower. Acadesine was toxic for tumor cells with multidrug resistant phenotypes caused by the transmembrane transporter Р-glycoprotein or lack of proapoptotic p53. Activity of adenosine receptors was required for acadesine-induced cell death, whereas functioning of АМР-dependent protein kinase was not required...
July 2013: Acta Naturae
Stefano D'Errico, Giorgia Oliviero, Nicola Borbone, Jussara Amato, Vincenzo Piccialli, Michela Varra, Luciano Mayol, Gennaro Piccialli
The antiviral activity of certain acyclic nucleosides drew our attention to the fact that the replacement of the furanose ring by an alkyl group bearing hydroxyl(s) could be a useful structural modification to modulate the biological properties of those nucleosides. Herein, we report on the synthesis of some novel acadesine analogues, where the ribose moiety is mimicked by a D-ribityl or by a hydroxybutyl chain.
2013: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Edwin K Jackson, Dongmei Cheng, Travis C Jackson, Jonathan D Verrier, Delbert G Gillespie
The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 μmol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) were 0.125 ± 0.020 μmol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) plus guanosine (30 μmol/l) were 1...
March 1, 2013: American Journal of Physiology. Cell Physiology
Eric Van Den Neste, Bruno Cazin, Ann Janssens, Eva González-Barca, María José Terol, Vincent Levy, Jaime Pérez de Oteyza, Pierre Zachee, Andrew Saunders, Mercè de Frias, Clara Campàs
PURPOSE: Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. METHODS: Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen...
March 2013: Cancer Chemotherapy and Pharmacology
Gregory B Lim
No abstract text is available yet for this article.
September 2012: Nature Reviews. Cardiology
Mark F Newman, T Bruce Ferguson, Jennifer A White, Giuseppe Ambrosio, Joerg Koglin, Nancy A Nussmeier, Ronald G Pearl, Bertram Pitt, Andrew S Wechsler, Richard D Weisel, Tammy L Reece, Armando Lira, Robert A Harrington
CONTEXT: Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery. OBJECTIVE: To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days...
July 11, 2012: JAMA: the Journal of the American Medical Association
A J Szentmiklósi, A Cseppento, G Harmati, P P Nánási
This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system...
2011: Current Medicinal Chemistry
K Mullane, D Bullough, D Shapiro
Acadesine is the prototype of a new class of therapeutic compounds termed adenosine-regulating agents (ARAs). The concept of adenosine regulation by acadesine and recognition of its potential therapeutic importance in myocardial ischemia was initiated in academia and led to the founding of a new biopharmaceutical company to develop acadesine and other ARAs. The historical background and preclinical studies that led to the discovery of acadesine and identification of its cardioprotective properties, culminating in international multicenter trials in patients undergoing cardiac surgery, are discussed...
November 1993: Trends in Cardiovascular Medicine
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