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Peng Zou, Longhua Liu, Louise D Zheng, Kyle K Payne, Masoud H Manjili, Michael O Idowu, Jinfeng Zhang, Eva M Schmelz, Zhiyong Cheng
Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1), was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam) in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells...
2016: Oxidative Medicine and Cellular Longevity
Shasha Liu, Qidi Ai, Kai Feng, Yubing Li, Xiang Liu
Reperfusion therapy is widely used to treat acute myocardial infarction (AMI). However, further injury to the heart induced by rapidly initiating reperfusion is often encountered in clinical practice. A lack of pharmacological strategies in clinics limits the prognosis of patients with myocardial ischemia-reperfusion injury (MIRI). Dihydromyricetin (DMY) is one of the most abundant components in vine tea, commonly known as the tender stems and leaves of Ampelopsis grossedentata. The aim of this study was to evaluate the cardioprotection of DMY against myocardial ischemia-reperfusion (I/R) injury and to further investigate the underlying mechanism...
October 13, 2016: Apoptosis: An International Journal on Programmed Cell Death
Antoine Heni Chaanine, Erik Kohlbrenner, Scott I Gamb, Adam J Guenzel, Katherine A Klaus, Ahmed U Fayyaz, K Sreekumaran Nair, Roger J Hajjar, Margaret M Redfield
The Forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy and cell death in post-mitotic cells. Its role in regulating mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BNIP3, modulates mitochondrial morphology and function in HF. We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE) stressed adult cardiac myocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9...
September 30, 2016: American Journal of Physiology. Heart and Circulatory Physiology
William J Smiles, Evelyn B Parr, Vernon G Coffey, Orly Lacham-Kaplan, John A Hawley, Donny M Camera
Alcohol ingestion decreases post-exercise rates of muscle protein synthesis, but the mechanism(s) (e.g., increased protein breakdown) underlying this observation are unknown. Autophagy is an intracellular "recycling" system required for homeostatic substrate and organelle turnover; its dysregulation may provoke apoptosis and lead to muscle atrophy. We investigated the acute effects of alcohol ingestion on autophagic cell signaling responses to a bout of concurrent (combined resistance- and endurance-based) exercise...
September 27, 2016: American Journal of Physiology. Endocrinology and Metabolism
Jianfei Lu, Zhao Jiang, Yingyu Chen, Changman Zhou, Chunhua Chen
Loss of von Hippel-Lindau tumor suppressor protein (VHL) or hypoxia results in nuclear relocalization of PDCD5 and subsequent mouse double minute 2 homolog (Mdm2) degradation. Thus, VHL may involved in the PDCD5 mediated apoptosis and autophagy after MCAO. In the present study, using PDCD5 knockout (PDCD5(-/-)) mice, we aimed to demonstrate that knockout of PDCD5 gene could protect the brain from ischemic injury by inhibiting the PDCD5-VHL pathway. 24h post MCAO surgery, PDCD5 gene knockout mice presented obvious improved brain blood flow, improved neurological behavior and decreased cerebral infarction compared with wild type mice...
November 1, 2016: Brain Research
Hui-Mei Wu, Li-Jie Shao, Zi-Feng Jiang, Rong-Yu Liu
PURPOSE: Gemcitabine has been used as a therapeutic drug combined with cisplatin for the treatment of lung cancer patients. However, the prognosis is poor due to acquired resistance. Accumulating studies have revealed that autophagy may contribute to the drug resistance. Therefore, the present study is aimed to clarify the mechanisms underlying gemcitabine-acquired resistance. METHODS: SPC-A1 and A549 cells were incubated with gemcitabine followed by assessment of cell viability with MTT assays...
September 7, 2016: Lung
Wen-Han Chang, Huey-Lan Huang, Wei-Pang Huang, Chien-Chih Chen, Yu-Jen Chen
Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92...
September 3, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Terri D McBride, U Andrew, Nicko Ly, Julio G Soto
RNA sequencing of untreated and r-Moj-DM treated SK-Mel-28 cells was performed after 6 h, to begin unraveling the apoptotic pathway induced by r-Moj-DM. Bioinformatic analyses of RNA sequencing data yielded 40 genes that were differentially expressed. Nine genes were upregulated and 31 were downregulated. qRT-PCR was used to validate differential expression of 13 genes with known survival or apoptotic-inducing activities. Expression of BNiP3, IGFBP3, PTPSF, Prune 2, TGF-ß, and TXNIP were compared from cells treated with r-Moj-DN (a strong apoptotic inducer) or r-Moj-DA (a non-apoptotic inducer) for 1 h, 2 h, 4 h, and 6 h after treatment...
October 2016: Toxicon: Official Journal of the International Society on Toxinology
Zhengtang Qi, Jie Xia, Xiangli Xue, Qiang He, Liu Ji, Shuzhe Ding
Nicotinamide (NAM), or vitamin B3, is an essential coenzyme for ATP synthesis and an inhibitor of sirtuin 1. Recently, conflicting results were reported regarding the treatment of NAM in type 2 diabetes and obesity. The aim of this study was to determine whether and how long-term treatment with NAM at lower dose would affect insulin sensitivity in mice fed chow diet. We treated mice with NAM (100 mg/kg/day) and normal chow for 8 weeks. Strikingly, NAM induced glucose intolerance and skeletal muscle lipid accumulation in nonobese mice...
October 2016: Journal of Nutritional Biochemistry
Xiaolong Gu, Dandan Han, Wei Chen, Limei Zhang, Qianyun Lin, Jian Gao, Séamus Fanning, Bo Han
Fluorine may result in damage to teeth, bones and other body tissues, and is a serious public health problem. SIRT1 deacetylates FOXOs, which brings about apoptosis and autophagy promotion or suppression. Fluorine may induce cell apoptosis, however, the role of autophagy in apoptosis induced by fluorine is still poorly understood, and the interaction between SIRT1 and FOXOs should be further illustrated. Therefore, this study investigated the mechanisms underlying the NaF- induced apoptosis and autophagy in osteoblast-like MC3T3-E1 cells in vitro through activating or inhibiting SIRT1...
August 24, 2016: Oncotarget
Evanka Madan, Bhawana Dikshit, Srinivas H Gowda, Chitrangda Srivastava, Chitra Sarkar, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol
The hypoxic microenvironment is an important contributor of glioblastoma (GBM) aggressiveness via HIF1α, while tumour inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study was designed to explore the functional interaction and significance of FAT1 and HIF1α under severe hypoxia-mimicking tumour microenvironment in primary human tumours. We first identified a positive correlation of FAT1 with HIF1α and its target genes in GBM tumour specimens, revealing the significance of the FAT1-HIF1α axis in glioma cells...
December 1, 2016: International Journal of Cancer. Journal International du Cancer
Tongmei Zhang, Liang Xue, Li Li, Chengyuan Tang, Zhengqing Wan, Ruoxi Wang, Jieqiong Tan, Ya Tan, Hailong Han, Runyi Tian, Timothy R Billiar, W Andy Tao, Zhuohua Zhang
Mutations in PINK1 (PTEN-induced putative kinase 1) cause early onset familial Parkinson's disease (PD). PINK1 accumulates on the outer membrane of damaged mitochondria followed by recruiting parkin to promote mitophagy. Here, we demonstrate that BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3), a mitochondrial BH3-only protein, interacts with PINK1 to promote accumulation of full-length PINK1 on outer membrane of mitochondria and this facilitates parkin recruitment and PINK1/parkin-mediated mitophagy...
August 15, 2016: Journal of Biological Chemistry
Gábor Koncsos, Zoltán V Varga, Tamás Baranyai, Kerstin Boengler, Susanne Rohrbach, Ling Li, Klaus-Dieter Schlüter, Rolf Schreckenberg, Tamás Radovits, Attila Oláh, Csaba Mátyás, Árpád Lux, Mahmoud Al-Khrasani, Tímea Komlódi, Nóra Bukosza, Domokos Máthé, László Deres, Monika Barteková, Tomáš Rajtík, Adriana Adameová, Krisztián Szigeti, Péter Hamar, Zsuzsanna Helyes, László Tretter, Pál Pacher, Béla Merkely, Zoltán Giricz, Rainer Schulz, Péter Ferdinandy
Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy...
October 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Federica Rizzo, Dario Ronchi, Sabrina Salani, Monica Nizzardo, Francesco Fortunato, Andreina Bordoni, Giulia Stuppia, Roberto Del Bo, Daniela Piga, Romana Fato, Nereo Bresolin, Giacomo P Comi, Stefania Corti
Charcot-Marie-Tooth 2A (CMT2A) is an inherited peripheral neuropathy caused by mutations in MFN2, which encodes a mitochondrial membrane protein involved in mitochondrial network homeostasis. Because MFN2 is expressed ubiquitously, the reason for selective motor neuron (MN) involvement in CMT2A is unclear. To address this question, we generated MNs from induced pluripotent stem cells (iPSCs) obtained from CMT2A patients as an in vitro disease model. CMT2A iPSC-derived MNs (CMT2A-MNs) exhibited a global reduction in mitochondrial content and altered mitochondrial positioning without significant differences in survival and axon elongation...
August 9, 2016: Human Molecular Genetics
Victoria E Pedanou, Stéphane Gobeil, Sébastien Tabariès, Tessa M Simone, Lihua Julie Zhu, Peter M Siegel, Michael R Green
Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells...
2016: ELife
Zaira Aversa, Fabrizio Pin, Simone Lucia, Fabio Penna, Roberto Verzaro, Maurizio Fazi, Giuseppina Colasante, Andrea Tirone, Filippo Rossi Fanelli, Cesarina Ramaccini, Paola Costelli, Maurizio Muscaritoli
Basal rates of autophagy can be markedly accelerated by environmental stresses. Recently, autophagy has been involved in cancer-induced muscle wasting. Aim of this study has been to evaluate if autophagy is induced in the skeletal muscle of cancer patients. The expression (mRNA and protein) of autophagic markers has been evaluated in intraoperative muscle biopsies. Beclin-1 protein levels were increased in cachectic cancer patients, suggesting autophagy induction. LC3B-I protein levels were not significantly modified...
2016: Scientific Reports
Maya Z Springer, Kay F Macleod
Mitophagy is a selective form of macro-autophagy in which mitochondria are specifically targeted for autophagic degradation. Mitophagy plays an important role in cellular homeostasis by eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to stress. Cells execute mitophagy through several non-redundant mechanisms, including the PINK1/Parkin partnership that modulates turnover of depolarized mitochondria and stress-induced BNIP3, NIX and FUNDC1 molecular adaptors that interact directly with LC3 to promote mitophagy...
July 25, 2016: Journal of Pathology
Guan Gui, Shan-shan Meng, Lu-juan Li, Bin Liu, Hong-xia Liang, Chao-shen Huangfu
Nitrites play multiple characteristic functions in invasion and metastasis of hepatic cancer cells, but the exact mechanism is not yet known. Cancer cells can maintain the malignant characteristics via clearance of excess mitochondria by mitophagy. The purpose of this article was to determine the roles of nitrite, reactive oxygen species (ROS) and hypoxia inducing factor 1 alpha (HIF-1 α) in mitophagy of hepatic cancer cells. After exposure of human hepatocellular carcinoma SMMC-7721 cells to a serial concentrations of sodium nitrite for 24 h under normal oxygen, the maximal cell vitality was increased by 16 mg x (-1) sodium nitrite...
January 2016: Yao Xue Xue Bao, Acta Pharmaceutica Sinica
Chunling Huang, Yuan Zhang, Darren J Kelly, Christina Y R Tan, Anthony Gill, Delfine Cheng, Filip Braet, Jin-Sung Park, Carolyn M Sue, Carol A Pollock, Xin-Ming Chen
Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys...
2016: Scientific Reports
M Gugnoni, V Sancisi, G Gandolfi, G Manzotti, M Ragazzi, D Giordano, I Tamagnini, M Tigano, A Frasoldati, S Piana, A Ciarrocchi
The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer...
July 4, 2016: Oncogene
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