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Marzieh Zeinvand-Lorestani, Heibatullah Kalantari, Mohammad Javad Khodayar, Ali Teimoori, Najmaldin Saki, Akram Ahangarpour, Fakher Rahim, Layasadat Khorsandi
Arsenic (As) is a toxic and hazardous metalloid. Unfortunately, its presence in drinking water together with wrong nutritional patterns is associated with an increase in the occurrence of metabolic disorders in young people. Degradation of mitochondria is presented by a specific form of autophagy called mitophagy which is an important landmark leading to apoptosis during lipotoxicity. Lipotoxicity and cellular toxicity due to arsenic intake can lead to changes in mitophagy and apoptosis. The protein derived from SQSTM1 gene, also called p62, plays an important role in energy homeostasis in the liver, and it can contribute to the regulation of autophagic responses given its effect on signaling of mTOR, MAPK, and NF-KB...
October 9, 2018: Environmental Science and Pollution Research International
Meenakshisundaram Balasubramaniam, Srinivas Ayyadevara, Robert J Shmookler Reis
Toxic protein aggregates are key features of progressive neurodegenerative diseases. In addition to "seed" proteins diagnostic for each neuropathy (e.g., Aβ1-42 and tau in Alzheimer's disease), aggregates contain numerous other proteins, many of which are common to aggregates from diverse diseases. We reported that CRAM-1, discovered in insoluble aggregates of C. elegans expressing Q40::YFP, blocks proteasomal degradation of ubiquitinated proteins and thus promotes aggregation. We now show that CRAM-1 contains three α-helical segments forming a UBA-like domain, structurally similar to those of mammalian adaptor proteins (e...
October 5, 2018: Scientific Reports
Do Hoon Kwon, Leehyeon Kim, Hyun Kyu Song
During macroautophagy/autophagy, SQSTM1/p62 plays dual roles as a key mediator of cargo selection and as an autophagic substrate. SQSTM1 links N-degrons and/or ubiquitinated cargoes to the autophagosome by forming homo- or hetero-oligomers, although its N-degron recognition and oligomerization mechanisms are not well characterized. We recently found that SQSTM1 is a novel type of N-recognin whose ZZ domain provides a negatively-charged binding pocket for Arg-charged N-degron (Nt-Arg), a prototype type-1 substrate...
October 5, 2018: Autophagy
Yin Xu, Sheng Zhang, Hui Zheng
Accumulating evidence suggests that misfolded MAPT (microtubule associated protein tau), the main component of neurofibrillary tangles in tauopathies, is subject to degradation by the autophagy-lysosomal pathway. Selective autophagy is a subtype of macroautophagy that requires cargo receptors, such as OPTN (optineurin) or SQSTM1, to recognize specific targets for their sequestration within the autophagosome and their eventual degradation by the lysosome, although their roles in targeting distinct MAPT species have not been fully investigated...
October 5, 2018: Autophagy
Margherita Leonardi, Eluisa Perna, Serena Tronnolone, David Colecchia, Mario Chiariello
Macroautophagy/autophagy is one of the major responses to stress in eukaryotic cells and is implicated in several pathological conditions such as infections, neurodegenerative diseases and cancer. Interestingly, cancer cells take full advantage of autophagy both to support tumor growth in adverse microenvironments and to oppose damages induced by anti-neoplastic therapies. Importantly, different human oncogenes are able to modulate this survival mechanism to support the transformation process, ultimately leading to 'autophagy addiction'...
October 5, 2018: Autophagy
Yanwen Xu, Chuanpeng Liao, Renli Liu, Jing Liu, Zhongping Chen, Huafu Zhao, Zongyang Li, Lei Chen, Changpeng Wu, Hui Tan, Wenlan Liu, Weiping Li
Alternatively activated (M2) macrophage promotes glioma progression and immune escape as the most immunocyte in glioma microenvironment. Finding out the key protein regulating M2 macrophage polarization is necessary for improving treatment. Whether immunity related GTPase M (IRGM) is involved in glioma development and M2 macrophage polarization is unknown. IRGM and M2 macrophage marker CD206 expression were examined using immunohistochemistry among 35 glioma and 11 non-cancerous brain specimens. We found IRGM scores were positively correlated with CD206 scores in glioma specimens and monocyte proportion in blood samples...
October 4, 2018: Cell Biology International
Shahram Darabi, Ali Noori-Zadeh, Farzad Rajaei, Hojjat Allah Abbaszadeh, Salar Bakhtiyari, Navid Ahmady Roozbahany
Parkinson's disease is the second most common neurodegenerative disease that occurs due to cellular autophagy deficiency and the accumulation of alpha-synuclein in the dopaminergic neurons of the substantia nigra pars compacta (SNc) of the brainstem. The SMER28 (also known as 6-Bromo-N-prop-2-enylquinazolin-4-amine) is an autophagy inducer. In this study, the neuroprotective effects of SMER28 were evaluated on autophagy induction, antioxidant system activation, and microgliosis attenuation. The Parkinson's disease model was developed in the male Wistar rats by injection of 6-OHDA into the left striatum...
October 4, 2018: Neurochemical Research
Alberto Danieli, Sascha Martens
The degradation of misfolded proteins is essential for cellular homeostasis. Misfolded proteins are normally degraded by the ubiquitin-proteasome system (UPS), and selective autophagy serves as a backup mechanism when the UPS is overloaded. Selective autophagy mediates the degradation of harmful material by its sequestration within double-membrane organelles called autophagosomes. The selectivity of autophagic processes is mediated by cargo receptors, which link the cargo to the autophagosomal membrane. The p62 cargo receptor (SQSTM1) has a main function during the degradation of misfolded, ubiquitylated proteins by selective autophagy; here it functions to phase separate these proteins into larger condensates and tether them to the autophagosomal membrane...
October 4, 2018: Journal of Cell Science
Hao Zhang, Yanqiu Zhang, Xiaoyun Zhu, Chen Chen, Chao Zhang, Yuanzheng Xia, Yucheng Zhao, Ourania Andrisani, Lingyi Kong
In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in HBV-associated and non-HBV associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection...
October 3, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jia-Shun Wu, Li Li, Sha-Sha Wang, Xin Pang, Jing-Biao Wu, Su-Rui Sheng, Ya-Jie Tang, Ya-Ling Tang, Min Zheng, Xin-Hua Liang
It has previously been demonstrated that autophagy and inflammation act synergistically to promote carcinogenesis. However, the precise roles of autophagy in multistep oral carcinogenesis are still unclear, particularly regarding its association with tumor inflammation. The present study established a 4NQO‑induced oral cancer mouse model and investigated autophagy status in the multistep process of oral carcinogenesis using immunohistochemistry, western blotting and immunofluorescence staining. Furthermore, the number of Gr‑1+CD11b+ myeloid derived suppressor cells (MDSCs) and CD4+ Foxp3+ regulatory T cells (Tregs) during oral carcinogenesis and the association with autophagy status was also examined...
September 28, 2018: Oncology Reports
J J McCormick, T A VanDusseldorp, C G Ulrich, R L Lanphere, K Dokladny, P L Mosely, C M Mermier
Autophagy is a lysosome degradation pathway through which damaged organelles and macromolecules are degraded within the cell. A decrease in activity of the autophagic process has been linked to several age-associated pathologies, including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction. Here, we examined the differences in the autophagic response using autophagy-inducer rapamycin (Rapa) in peripheral blood mononuclear cells (PBMCs) from young (21.8 ± 1...
September 1, 2018: Physiology International
Manas R Biswal, Bradley D Justis, Pingyang Han, Hong Li, Dennis Gierhart, Cheryl K Dorey, Alfred S Lewin
Oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). The dry form of AMD (geographic atrophy) is characterized by loss of RPE, photoreceptors, and macular pigments. The cumulative effects of oxidative stress impact mitochondrial function in RPE. In Sod2flox/floxVMD2-cre mice, the RPE specific deletion of Sod2, the gene for mitochondrial manganese superoxide dismutase (MnSOD), leads to elevated oxidative stress in retina and RPE, and causes changes in the RPE and underlying Bruch's membrane that share some features of AMD...
2018: PloS One
Szabolcs Felszeghy, Johanna Viiri, Jussi J Paterno, Juha M T Hyttinen, Ali Koskela, Mei Chen, Henri Leinonen, Heikki Tanila, Niko Kivinen, Arto Koistinen, Elisa Toropainen, Marialaura Amadio, Adrian Smedowski, Mika Reinisalo, Mateusz Winiarczyk, Jerzy Mackiewicz, Maija Mutikainen, Anna-Kaisa Ruotsalainen, Mikko Kettunen, Kimmo Jokivarsi, Debasish Sinha, Kati Kinnunen, Goran Petrovski, Janusz Blasiak, Geir Bjørkøy, Ari Koskelainen, Heli Skottman, Arto Urtti, Antero Salminen, Ram Kannan, Deborah A Ferrington, Heping Xu, Anna-Liisa Levonen, Pasi Tavi, Anu Kauppinen, Kai Kaarniranta
Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells...
September 14, 2018: Redox Biology
Mengjie Hu, Gulimiran Alitongbieke, Ying Su, Hu Zhou, Xiao-Kun Zhang
Selective clearance of damaged mitochondria can reverse pathological status in chronic inflammatory diseases. We recently identified a critical role of nuclear receptor Nur77 and celastrol in priming inflamed mitochondria for autophagy through its mitochondrial targeting and interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and the autophagic adaptor p62/SQSTM1.
2018: Molecular & Cellular Oncology
Kazuki Ueda, Yuji Okado, Kengo Shigetomi, Makoto Ubukata
(+)-Epogymnolactam (1) was discovered as a novel autophagy inducer from a culture of Gymnopus sp. in our laboratory. To determine structure-activity relationships among (+)-epogymnolactam analogues comparing with cerulenin (2), we synthesized 5 analogues including (-)-epogymnolactam (3) having each different functional group, and 3 analogues with different side-chain lengths. Five analogues, 3, 4, 5, 6, and 7 did not significantly increase the ratio of LC3-II to LC3-I as an autophagy marker in NIH3T3 cells...
September 17, 2018: Bioorganic & Medicinal Chemistry
He Liu, Zhaoyue He, Peter Bode, Holger Moch, Hans-Uwe Simon
Autophagy is a cellular "self-digestion" process known to be essential for various physiological and pathological pathways, including cancer, where its role appears to be context-dependent. In this work, we aimed to investigate the level of autophagy by evaluating the expression of key autophagy-related proteins (ATGs) in testicular germ cell tumors (TGCT) for which autophagy has been rarely investigated. We decided to use an immunohistochemical (IHC) staining approach employing a tissue microarray (TMA)...
2018: Frontiers in Oncology
Yanjun Wu, Yanping Li, Baoya Wang, Xin He, Yunxiao Li, Bo Wu, Ganggang Yu, Haoyan Wang, Bo Xu
AIMS: The aims of this study were to evaluate the effects of p62/SQSTM1 expression levels on lipopolysaccharide (LPS)-induced mucus secretion in BEAS-2B bronchial epithelial cells by measuring expression levels of the MUC5AC gene and the Mucin-5AC (MUC5AC) protein. MATERIALS AND METHODS: Bronchial epithelial cells, BEAS-2B, were treated with LPS at different time points. Rapamycin, an autophagy agonist, was added to the BEAS-2B cells 30 min before LPS treatment...
October 15, 2018: Life Sciences
Sandro Goruppi, Seung-Hee Jo, Csaba Laszlo, Andrea Clocchiatti, Victor Neel, G Paolo Dotto
Cancer-associated fibroblasts (CAFs) are important at all tumor stages. CSL/RBPJκ suppresses the gene expression program leading to CAF activation and associated metabolic reprogramming, as well as autophagy. Little is known about CSL protein turnover, especially in the tumor microenvironment. We report that, in human dermal fibroblasts (HDFs), conditions inducing autophagy-often found in tumor stroma-down-regulate CSL protein levels but do not affect its mRNA levels. Genetic or pharmacologic targeting of the autophagic machinery blocks CSL down-modulation...
September 18, 2018: Cell Reports
Tianyu Han, Meng Guo, Mingxi Gan, Bentong Yu, Xiaoli Tian, Jian-Bin Wang
Macroautophagy/autophagy is a multistep cellular process that sequesters cytoplasmic components for lysosomal degradation. BECN1/Beclin1 is a central protein that assembles cofactors for the formation of a BECN1-PIK3C3-PIK3R4 complex to trigger the autophagy protein cascade. Discovering the regulators of BECN1 is important for understanding the mechanism of autophagy induction. Here, we demonstrate that TRIM59, a tripartite motif protein, plays an important role in autophagy regulation in non-small cell lung cancer (NSCLC)...
September 20, 2018: Autophagy
Susmita Mondal, Debarshi Roy, Sayantani Sarkar Bhattacharya, Ling Jin, Deokbeom Jung, Song Zhang, Eleftheria Kalogera, Julie Staub, Yaxian Wang, Wen Xuyang, Ashwani Khurana, Jeremey Chien, Sucheta Telang, Jason Chesney, Gilles Tapolsky, Dzeja Petras, Viji Shridhar
Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Amongst several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively...
September 18, 2018: International Journal of Cancer. Journal International du Cancer
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