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Selective autophagy

Claudia Bello, Jianfei Bai, Bartosz K Zambron, Pilar Elías-Rodríguez, Consuelo Gajate, Inmaculada Robina, Irene Caffa, Michele Cea, Fabrizio Montecucco, Alessio Nencioni, Aimable Nahimana, Dominique Aubry, Caroline Breton, Michel A Duchosal, Faustino Mollinedo, Pierre Vogel
We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells...
March 2, 2018: European Journal of Medicinal Chemistry
Naira F Z Schneider, Claudia Cerella, Jin-Young Lee, Aloran Mazumder, Kyung Rok Kim, Annelise de Carvalho, Jennifer Munkert, Rodrigo M Pádua, Wolfgang Kreis, Kyu-Won Kim, Christo Christov, Mario Dicato, Hyun-Jung Kim, Byung Woo Han, Fernão C Braga, Cláudia M O Simões, Marc Diederich
Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+ /K+ -ATPase α subunit, assessed by computational docking...
2018: Frontiers in Pharmacology
Lingfei Shangguan, Xiang Fang, Lide Chen, Liwen Cui, Jinggui Fang
Grapevine autophagy-related genes (ARGs) include 35 members that have unique evolutionary backgrounds and expression patterns, with some of them responding to abiotic stresses, including copper stress. Autophagy is one of the most crucial self-regulating phenomena in livings organisms, including animals, plants, yeasts, etc. In the genomes of plants, like Arabidopsis, rice, tobacco, and barley, more than 30 autophagy-related genes (ARGs) have been found. These ARGs are involved in plant development, programed cell death, and the stress response process...
March 14, 2018: Planta
Junghyun Lim, Aditya Murthy
No abstract text is available yet for this article.
March 14, 2018: Cell Death and Differentiation
Mary G Lin, Johannes Schöneberg, Christopher W Davies, Xuefeng Ren, James H Hurley
Yeast macroautophagy begins with the de novo formation of a double membrane phagophore at the preautophagosomal structure (PAS), followed by its expansion into the autophagosome responsible for cargo engulfment. The kinase Atg1 is recruited to the PAS by Atg13 through interactions between the EAT domain of the former and the tMIM motif of the latter. Mass spectrometry data has shown that in the absence of Atg13, the EAT domain structure is strikingly dynamic, but the function of this Atg13-free dynamic state has been unclear...
March 14, 2018: Molecular Biology of the Cell
Richard S Marshall, Richard D Vierstra
Plants have evolved sophisticated mechanisms to recycle intracellular constituents, which are essential for developmental and metabolic transitions; for efficient nutrient reuse; and for the proper disposal of proteins, protein complexes, and even entire organelles that become obsolete or dysfunctional. One major route is autophagy, which employs specialized vesicles to encapsulate and deliver cytoplasmic material to the vacuole for breakdown. In the past decade, the mechanics of autophagy and the scores of components involved in autophagic vesicle assembly have been documented...
March 14, 2018: Annual Review of Plant Biology
Zhe Sha, Helena M Schnell, Kerstin Ruoff, Alfred Goldberg
Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62 , which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes...
March 13, 2018: Journal of Cell Biology
Stephen Shinsky, David W Christianson
Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well defined, it is only recently that the molecular basis of reversible polyamine acetylation has been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: histone deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine deacetylase...
March 13, 2018: Biochemistry
Alicia Bort, Sergio Quesada, Ágata Ramos-Torres, Marta Gargantilla, Eva María Priego, Sophie Raynal, Franck Lepifre, Jose M Gasalla, Nieves Rodriguez-Henche, Ana Castro, Inés Díaz-Laviada
The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated...
March 12, 2018: Scientific Reports
Damla Tas, Luca Stickley, Federico Miozzo, Rafael Koch, Nicolas Loncle, Virginie Sabado, Bettina Gnägi, Emi Nagoshi
Forkhead box (FOXO) proteins are evolutionarily conserved, stress-responsive transcription factors (TFs) that can promote or counteract cell death. Mutations in FOXO genes are implicated in numerous pathologies, including age-dependent neurodegenerative disorders, such as Parkinson's disease (PD). However, the complex regulation and downstream mechanisms of FOXOs present a challenge in understanding their roles in the pathogenesis of PD. Here, we investigate the involvement of FOXO in the death of dopaminergic (DA) neurons, the key pathological feature of PD, in Drosophila...
March 12, 2018: PLoS Genetics
A J McFarland, A K Davey, C M McDermott, G D Grant, J Lewohl, S Anoopkumar-Dukie
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0-100 μM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration...
March 6, 2018: Toxicology and Applied Pharmacology
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yang Yongji, Changhai Lei, Shi Hu
Post-ischemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischemic heart failure...
March 9, 2018: Journal of Drug Targeting
Megumi Tsuchiya, Hidesato Ogawa, Takako Koujin, Chie Mori, Hiroko Osakada, Shouhei Kobayashi, Yasushi Hiraoka, Tokuko Haraguchi
Autophagy is a bulk degradation pathway, and selective autophagy to remove foreign entities is called xenophagy. The conjugation of ubiquitin to target pathogens is an important process in xenophagy but when and where this ubiquitination occurs remains unclear. Here, we analyzed the temporal sequence and subcellular location of ubiquitination during xenophagy using time-lapse observations, with polystyrene beads mimicking invading pathogens. Results revealed accumulation of a ubiquitination marker around the beads within 3 min after endosome rupture...
March 2018: FEBS Open Bio
Alain Calender, Pierre Antoine Rollat Farnier, Adrien Buisson, Stéphane Pinson, Abderrazzaq Bentaher, Serge Lebecque, Harriet Corvol, Rola Abou Taam, Véronique Houdouin, Claire Bardel, Pascal Roy, Gilles Devouassoux, Vincent Cottin, Pascal Seve, Jean-François Bernaudin, Clarice X Lim, Thomas Weichhart, Dominique Valeyre, Yves Pacheco, Annick Clement, Nadia Nathan
BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr...
March 6, 2018: BMC Medical Genomics
Dagmar E Ehrnhoefer, Dale D O Martin, Mandi E Schmidt, Xiaofan Qiu, Safia Ladha, Nicholas S Caron, Niels H Skotte, Yen T N Nguyen, Kuljeet Vaid, Amber L Southwell, Sabine Engemann, Sonia Franciosi, Michael R Hayden
Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age...
March 6, 2018: Acta Neuropathologica Communications
L Miao, Y Dong, F-B Zhou, Y-L Chang, Z-G Suo, H-Q Ding
OBJECTIVE: To investigate the impact and protective effect of tauroursodeoxycholic acid (TUDCA) on the autophagy of nerve cells in rats with acute spinal cord injury. MATERIALS AND METHODS: Seventy-two 6-8-week-old male Sprague-Dawley (SD) rats were selected and were randomly divided into a sham operation group, a saline control group and a TUDCA treatment group (high and low dose groups). The experimental animals were sacrificed at 24 hours, 5 days and 10 days after spinal cord injury...
February 2018: European Review for Medical and Pharmacological Sciences
H Xia, X-L Qu, L-Y Liu, D-H Qian, H-Y Jing
OBJECTIVE: Lung cancer is one of the most common malignancies worldwide, the morbidity and mortality of which have been on rising in recent years. Moreover, lncRNAs have been implicated in the development of various cancers, as well as cancer treatment and prognosis. In this study, long non-coding RNA (lncRNA) MEG3, an identified tumor suppressor, was explored for its role in the chemotherapy of lung cancer. MATERIALS AND METHODS: All cases were divided into (I+II) group and (III+IV) group according to different stages of tumor node metastasis (TNM), and were divided into sensitive group and insensitive group according to chemotherapy sensitivity...
February 2018: European Review for Medical and Pharmacological Sciences
S-H Zou, X Du, F-D Sun, P-C Wang, M Li
OBJECTIVE: To observe the effect of cisplatin-induced autophagy in human ovarian cancer cell lines and explore the correlation between RP11-135L22.1 with cisplatin-induced autophagy. MATERIALS AND METHODS: Genome-wide expression profile and chemotherapy sensitivity data of ovarian cancer were downloaded from TCGA database. It was found that the expression level of lncRNA RP11-135L22.1 differed between chemotherapy-sensitive group and insensitive group. Besides, RP11-135L22...
February 2018: European Review for Medical and Pharmacological Sciences
Daxiao Sun, Rongbo Wu, Jingxiang Zheng, Pilong Li, Li Yu
Misfolded proteins can be degraded by selective autophagy. The prevailing view is that ubiquitin-tagged misfolded proteins are assembled into aggregates by the scaffold protein p62, and the aggregates are then engulfed and degraded by autophagosomes. Here we report that p62 forms droplets in vivo which have liquid-like properties such as high sphericity, the ability to undergo fusion, and recovery after photobleaching. Recombinant p62 does not undergo phase separation in vitro; however, adding a K63 polyubiquitin chain to p62 induces p62 phase separation, which results in enrichment of high-molecular weight ubiquitin signals in p62 droplets...
March 5, 2018: Cell Research
Yongming Liu, Chen Shen, Xihui Zhang, Huan Yu, Fujun Wang, Yangyun Wang, Leshuai W Zhang
Metal nanoparticles or metal-based compounds have drawn attention in various fields ranging from industry to medicine because of their unique physicochemical properties. Bismuth (Bi) compounds and nanomaterials have been commonly used in alloys, electronic industry, batteries, and as flame retardants as well as for anti- Helicobacter pylori therapy, while the nanomaterial form has great potential for computed tomography imaging and thermotherapy, both of which will be introduced in this review. Although Bi was used for several decades, there is a lack of detailed information concerning their toxicity and mechanisms on human health...
January 1, 2018: Toxicology and Industrial Health
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