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https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#1
Chun-Han Chen, C Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
PURPOSE: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. EXPERIMENTAL DESIGN: Autophagy flux, morphology and intracellular organelles were evaluated by western blotting, transmission electron microscope and fluorescence microscope. Molecular docking, surface plasmon resonance assay were performed to identify drug-protein interaction...
December 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29203401/skeletal-muscle-from-aged-american-quarter-horses-shows-impairments-in-mitochondrial-biogenesis-and-expression-of-autophagy-markers
#2
Chengcheng Li, Sarah H White, Lori K Warren, Stephanie E Wohlgemuth
Aging is associated with decreased mitochondrial content and function in skeletal muscle, possibly due to compromised biogenesis and autophagic removal of dysfunctional mitochondria. The aim of this study was to compare markers of mitochondrial content and biogenesis and of autophagy between skeletal muscle from young and aged American Quarter Horses. Citrate synthase protein and mtDNA copy number were decreased in triceps brachii (TB) muscle (P<0.05) from aged horses, suggesting an age-related decline in mitochondrial content...
December 1, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/29138276/metabolic-reprogramming-ensures-cancer-cell-survival-despite-oncogenic-signaling-blockade
#3
Hui-Wen Lue, Jennifer Podolak, Kevin Kolahi, Larry Cheng, Soumya Rao, Devin Garg, Chang-Hui Xue, Juha K Rantala, Jeffrey W Tyner, Kent L Thornburg, Ann Martinez-Acevedo, Jen-Jane Liu, Christopher L Amling, Charles Truillet, Sharon M Louie, Kimberly E Anderson, Michael J Evans, Valerie B O'Donnell, Daniel K Nomura, Justin M Drake, Anna Ritz, George V Thomas
There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation...
October 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/29128638/ulk1-regulated-autophagy-a-mechanism-in-cellular-protection-for-aldh2-against-hyperglycemia
#4
Min Liu, Songhe Lu, Wei He, Le Zhang, Ying Ma, Ping Lv, Meijuan Ma, Wenjun Yu, Jiaxing Wang, Mingming Zhang, Yingmei Zhang, Yan Li
Mitochondrial aldehyde dehydrogenase 2 (ALDH2), an important enzyme in the elimination of toxic aldehydes, is involved in cardioprotection against diabetes mellitus. This study was designed to examine the mechanism behind ALDH2-offered protection against high glucose exposure with a focus on autophagy. H9C2 cells were cultured with normal or high glucose medium in the presence or absence of the ALDH2 agonist Alda-1. GFP-LC3 puncta and immunofluorescence were employed to assess autophagosome formation. Western blotting was applied to evaluate autophagy protein markers Atg5, LC3, p62, ULK1 phosphorylation and ALDH2...
November 8, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29076973/blocking-liver-autophagy-accelerates-apoptosis-and-mitochondrial-injury-in-hepatocytes-and-reduces-time-to-mortality-in-a-murine-sepsis-model
#5
Takehiko Oami, Eizo Watanabe, Masahiko Hatano, Youichi Teratake, Lisa Fujimura, Akemi Sakamoto, Chizuru Ito, Kiyotaka Toshimori, Paul E Swanson, Shigeto Oda
Autophagy plays an important role in cell survival, sequestering and degrading a wide variety of substrates. Although an increase of autophagosomes in liver has been reported in sepsis patients as well as septic mice, the influence of autophagy on liver injury, the interaction between autophagy, and other types of cell death in sepsis remains unclear. The aim of this study was to elucidate the contribution of liver autophagy to the pathophysiology of sepsis. We performed a cecal ligation and puncture (CLP) on liver-specific autophagy-deficient (Alb-Cre/Atg5) mice (six to eight-week-old male)...
October 25, 2017: Shock
https://www.readbyqxmd.com/read/29076434/cjk-7-a-novel-flavonoid-from-paulownia-tomentosa-triggers-cell-death-cascades-in-hct-116-human-colon-carcinoma-cells-via-redox-signaling
#6
Mahendra Pal Singh, Ki Hun Park, Sun Chul Kang
BACKGROUND: Colon cancer is the second most common cancer to cause death worldwide. About half of colon cancer patients require adjuvant therapy to control relapse following surgical resection. Therefore, abolition of tumor cell progression using an effective chemotherapeutic agent holds a feasible approach to treat patients suffering from colon cancer. In the present study, we evaluated the effects of geranylated flavonoid CJK-7, isolated from Paulownia tomentosa on HCT-116 human colon carcinoma cells...
October 26, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29056525/ketogenic-diet-attenuates-neuronal-injury-via-autophagy-and-mitochondrial-pathways-in-pentylenetetrazol-kindled-seizures
#7
Bao-Hui Wang, Qun Hou, Yu-Qiang Lu, Meng-Meng Jia, Tao Qiu, Xiao-Hang Wang, Zheng-Xiang Zhang, Yan Jiang
Autophagy alterations have been observed in a variety of neurological disorders, however, very few studies have focused on autophagy alterations in epilepsy. The ketogenic diet (KD) likely ameliorates neuronal loss in several seizure models. However, whether this neuroprotective function occurs via starvation-induced autophagy and its prevalence in chronic kindled seizures remains unknown. The aim of this study was to determine the role of autophagy following seizure under KD, and the potential mechanism involved...
October 19, 2017: Brain Research
https://www.readbyqxmd.com/read/28965951/polydatin-ameliorates-diabetic-cardiomyopathy-via-sirt3-activation
#8
Mingming Zhang, Shanjie Wang, Zheng Cheng, Zhenyu Xiong, Jianjun Lv, Zhi Yang, Tian Li, Shuai Jiang, Jing Gu, Dongdong Sun, Yanhong Fan
BACKGROUND: Diabetic cardiomyopathy is identified as cardiac ventricular dysfunction induced by an insulin shortage in diabetic patients. Our previous studies have shown that Polydatin (PD) alleviates cardiac dysfunction after myocardial infarction (MI) injury. Nevertheless, the mechanism by which PD regulates diabetic cardiomyopathy has not been reported. METHODS: In this study, we demonstrated the effects and described the mechanisms of PD in diabetic cardiomyopathy in both adult mouse hearts and neonatal mouse cardiomyocytes...
November 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28947954/bh3-mimetic-obatoclax-gx15-070-mediates-mitochondrial-stress-predominantly-via-mcl-1-inhibition-and-induces-autophagy-dependent-necroptosis-in-human-oral-cancer-cells
#9
Prasad Sulkshane, Tanuja Teni
We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200-400 nM concentration which correlated with their MCL-1 expression...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28945807/modulating-lysosomal-function-through-lysosome-membrane-permeabilization-or-autophagy-suppression-restores-sensitivity-to-cisplatin-in-refractory-non-small-cell-lung-cancer-cells
#10
Magdalena Circu, James Cardelli, Martin Barr, Kenneth O'Byrne, Glenn Mills, Hazem El-Osta
Lung cancer is the leading cause of cancer-related deaths. Most patients develop resistance to platinum within several months of treatment. We investigated whether triggering lysosomal membrane permeabilization (LMP) or suppressing autophagy can restore cisplatin susceptibility in lung cancer with acquired chemoresistance. Cisplatin IC50 in A549Pt (parental) and A549cisR (cisplatin resistant) cells was 13 μM and 47 μM, respectively. Following cisplatin exposure, A549cisR cells failed to elicit an apoptotic response...
2017: PloS One
https://www.readbyqxmd.com/read/28841353/esrra-estrogen-related-receptor-alpha-is-a-key-coordinator-of-transcriptional-and-post-translational-activation-of-autophagy-to-promote-innate-host-defense
#11
Soo Yeon Kim, Chul-Su Yang, Hye-Mi Lee, Jin Kyung Kim, Yi-Sak Kim, Ye-Ram Kim, Jae-Sung Kim, Tae Sung Kim, Jae-Min Yuk, Catherine Rosa Dufour, Sang-Hee Lee, Jin-Man Kim, Hueng-Sik Choi, Vincent Giguère, Eun-Kyeong Jo
The orphan nuclear receptor ESSRA (estrogen related receptor, alpha) is a key regulator of energy homeostasis and mitochondrial function. Macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. Here, we demonstrate that ESRRA is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. AMP-activated protein kinase pathway and SIRT1 (sirtuin 1) activation led to induction of ESRRA, which is essential for autophagosome formation, in bone marrow-derived macrophages...
August 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28825685/the-effects-of-silica-nanoparticles-on-apoptosis-and-autophagy-of-glioblastoma-cell-lines
#12
Rafał Krętowski, Magdalena Kusaczuk, Monika Naumowicz, Joanna Kotyńska, Beata Szynaka, Marzanna Cechowska-Pasko
Silica nanoparticles (SiNPs) are one of the most commonly used nanomaterials in various medical applications. However, possible mechanisms of the toxicity caused by SiNPs remain unclear. The study presented here provides novel information on molecular and cellular effects of SiNPs in glioblastoma LBC3 and LN-18 cells. It has been demonstrated that SiNPs of 7 nm, 5-15 nm and 10-20 nm induce time- and dose-dependent cytotoxicity in LBC3 and LN-18 cell lines. In contrast to glioblastoma cells, we observed only weak reduction in viability of normal skin fibroblasts treated with SiNPs...
August 21, 2017: Nanomaterials
https://www.readbyqxmd.com/read/28813698/caspase-independent-pathway-is-related-to-nilotinib-cytotoxicity-in-cultured-cardiomyocytes
#13
Qinghui Yang, Chunhui Zhang, Hong Wei, Zenghui Meng, Guangnan Li, Yuanyuan Xu, Yanjun Chen
BACKGROUND/AIMS: Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells. METHODS: Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib-treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28801211/parkin-clearance-of-dysfunctional-mitochondria-regulates-ros-levels-and-increases-survival-of-human-chondrocytes
#14
M Y Ansari, N M Khan, I Ahmad, T M Haqqi
OBJECTIVE: Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions. METHODS: Human chondrocytes were from the unaffected area of knee OA cartilage (n = 12) and were stimulated with IL-1β to mimic pathological conditions...
August 8, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28774732/downregulation-of-tigar-sensitizes-the-antitumor-effect-of-physapubenolide-through-increasing-intracellular-ros-levels-to-trigger-apoptosis-and-autophagosome-formation-in-human-breast-carcinoma-cells
#15
Ting Ma, Yi Zhang, Chao Zhang, Jian-Guang Luo, Ling-Yi Kong
Physapubenolide (PB) is a cytotoxic withanolide isolated from Physalis angulata that was used as a traditional Chinese medicine. In this study, we investigated the role of TIGAR and ROS in PB-induced apoptosis and autophagosome formation in human breast carcinoma MDA-MB-231 and MCF-7 cells. PB induced apoptosis by decreasing mitochondrial membrane potential and elevating the Bax/Bcl-2 protein expression ratio in MDA-MB-231 and MCF-7 cells. Caspase inhibitor Z-VAD-FMK treatment partly blocked PB induced cytotoxicity, suggesting that apoptosis serves as an important role in the anti-proliferative effect of PB...
November 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28729463/dietary-pufas-attenuate-nlrp3-inflammasome-activation-via-enhancing-macrophage-autophagy
#16
Lulu Shen, Yan Yang, Tiantong Ou, Chia-Chi C Key, Sarah H Tong, Russel C Sequeira, Jonathan M Nelson, Yan Nie, Zhan Wang, Elena Boudyguina, Swapnil V Shewale, Xuewei Zhu
Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. We fed Ldlr(-/-) mice diets containing 10% (calories) palm oil (PO) and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, fish oil (FO), echium oil (EO, containing 18:4 n-3), or borage oil (BO, containing 18:3 n-6). Inflammasome activation, autophagic flux, and mitochondrial function were measured in peritoneal macrophages, blood monocytes, or liver from diet-fed mice...
September 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28696570/effects-of-combined-lysosomal-and-mitochondrial-photodamage-in-a-non-small-cell-lung-cancer-cell-line-the-role-of-paraptosis
#17
David Kessel, John J Reiners
We previously reported that a low level of lysosomal photodamage potentiated the phototoxic effect of subsequent mitochondrial photodamage mediated by the benzoporphyrin derivative (BPD) in murine hepatoma 1c1c7 cells. This was attributed to release of Ca(2+) from damaged lysosomes and a calpain-mediated conversion of the autophagy-related protein ATG5 to a pro-apoptotic fragment. We now report a comparison of these results with those obtained with the human non-small-cell lung cancer A549 cell line. A549 cells contained lower levels of ATG5 and were less responsive than 1c1c7 cultures to the PDT combination...
November 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28679997/alternative-autophagy-plays-a-central-role-in-mitochondria-elimination-from-reticulocytes
#18
Shigeomi Shimizu
Mitophagy is a mitochondrial quality control mechanism where damaged and surplus mitochondria are degraded by macroautophagy. Mitophagy is associated with various physiological and pathological events such as mitochondrial clearance during the terminal differentiation of reticulocytes. There are two different mammalian autophagy pathways: the Atg5-dependent conventional pathway and Atg5-independent alternative pathway; the latter is involved in reticulocyte's mitophagy.
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28671312/anti-prostate-cancer-potential-of-gossypetin-via-inducing-apoptotic-and-autophagic-cell-death
#19
Ming-Shih Lee, Chia-Wen Tsai, Chi-Ping Wang, Jing-Hsien Chen, Hui-Hsuan Lin
Gossypetin (GTIN), a naturally occurring hexahydroxy flavone, has been shown to possess antimutagenic, antioxidant, antimicrobial, and antiatherosclerotic effects. Here, we investigated the mechanism(s) underlying the anticancer potential of GTIN. In this study, investigations were showed that GTIN preferentially induces programed cell death of prostate cancer (PCa) cells in vitro and in vivo. MTT data showed that GTIN exhibited the anti-proliferation effect on human PCa cells in a dose- and time-dependent manner...
July 3, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28647341/suppression-of-autophagic-flux-contributes-to-cardiomyocyte-death-by-activation-of-necroptotic-pathways
#20
Makoto Ogasawara, Toshiyuki Yano, Masaya Tanno, Koki Abe, Satoko Ishikawa, Takayuki Miki, Atsushi Kuno, Toshiyuki Tobisawa, Shingo Muratsubaki, Kouhei Ohno, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Tetsuji Miura
BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-α (TNF) and z-VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6±4.3% to 60.6±2.7%, and the LDH release was suppressed by necrostatin-1 (29...
June 21, 2017: Journal of Molecular and Cellular Cardiology
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