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https://www.readbyqxmd.com/read/29457836/deptor-suppresses-lipogenesis-and-ameliorates-hepatic-steatosis-and-acute-on-chronic-liver-injury-in-alcoholic-liver-disease
#1
Hanqing Chen, Feng Shen, Alex Sherban, Allison Nocon, Yu Li, Hua Wang, Ming-Jiang Xu, Xianliang Rui, Jinyan Han, Bingbing Jiang, Donghwan Lee, Na Li, Farnaz Keyhani-Nejad, Jian-Gao Fan, Feng Liu, Amrita Kamat, Nicolas Musi, Leonard Guarente, Pal Pacher, Bin Gao, Mengwei Zang
Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6K1 in hepatocytes...
February 19, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29457786/intracellular-lipid-metabolism-impairs-%C3%AE-cell-compensation-during-diet-induced-obesity
#2
Risheng Ye, Ruth Gordillo, Mengle Shao, Toshiharu Onodera, Zhe Chen, Shiuhwei Chen, Xiaoli Lin, Jeffrey A SoRelle, Xiaohong Li, Miao Tang, Mark P Keller, Regina Kuliawat, Alan D Attie, Rana K Gupta, William L Holland, Bruce Beutler, Joachim Herz, Philipp E Scherer
The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells...
February 19, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29457340/key-role-of-tfeb-nucleus-translocation-for-silver-nanoparticle-induced-cytoprotective-autophagy
#3
Jun Lin, Yiming Liu, Hao Wu, Zhihai Huang, Jingfan Ma, Chang Guo, Feng Gao, Peipei Jin, Pengfei Wei, Yunjiao Zhang, Liu Liu, Rui Zhang, Longxin Qiu, Ning Gu, Longping Wen
Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Here, silver nanoparticles (Ag NPs)-induced cytoprotective autophagy required TFEB is shown. Ag NPs-induced nucleus translocation of TFEB through a well-established mechanism involving dephosphorylation of TFEB at serine-142 and serine-211 but independent of both the mTORC1 and ERK1/2 pathways. TFEB nucleus translocation precedes autophagy induced by Ag NPs and leads to enhanced expression of autophagy-essential genes...
February 19, 2018: Small
https://www.readbyqxmd.com/read/29455584/hepes-activates-a-mit-tfe-dependent-lysosomal-autophagic-gene-network-in-cultured-cells-a-call-for-caution
#4
Marc J Tol, Martijn J C van der Lienden, Tanit L Gabriel, Jacob J Hagen, Saskia Scheij, Tineke Veenendaal, Judith Klumperman, Wilma E Donker-Koopman, Arthur J Verhoeven, Hermen Overkleeft, Johannes M Aerts, Carmen A Argmann, Marco van Eijk
In recent years, the lysosome has emerged as a highly dynamic, transcriptionally regulated organelle that is integral to nutrient-sensing and metabolic rewiring. This is coordinated by a lysosome-to-nucleus signaling nexus in which MTORC1 controls the subcellular distribution of the microphthalmia-transcription factor E (MiT/TFE) family of "master lysosomal regulators". Yet, despite the importance of the lysosome in cellular metabolism, the impact of traditional in vitro culture media on lysosomal dynamics and/or MiT/TFE localization has not been fully appreciated...
February 17, 2018: Autophagy
https://www.readbyqxmd.com/read/29449635/purkinje-cells-derived-from-tsc-patients-display-hypoexcitability-and-synaptic-deficits-associated-with-reduced-fmrp-levels-and-reversed-by-rapamycin
#5
Maria Sundberg, Ivan Tochitsky, David E Buchholz, Kellen Winden, Ville Kujala, Kush Kapur, Deniz Cataltepe, Daria Turner, Min-Joon Han, Clifford J Woolf, Mary E Hatten, Mustafa Sahin
Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC...
February 15, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29449538/downregulation-of-perk-activity-and-eif2%C3%AE-serine-51-phosphorylation-by-mtor-complex-1-elicits-pro-oxidant-and-pro-death-effects-in-tuberous-sclerosis-deficient-cells
#6
Jothilatha Krishnamoorthy, Clara Tenkerian, Jyotsana Gupta, Nour Ghaddar, Shuo Wang, Cedric Darini, Kirk A Staschke, Abhishek Ghosh, Valentina Gandin, Ivan Topisirovic, Arnold S Kristof, Maria Hatzoglou, George Simos, Antonis E Koromilas
Oxidative stress determines cell fate through several mechanisms, among which regulation of mRNA translation by the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2α at serine 51 (eIF2αP) plays a prominent role. Increased eIF2αP can contribute to tumor progression as well as tumor suppression. While eIF2αP is increased in most cells to promote survival and adaptation to different forms of stress, we demonstrate that eIF2αP is reduced in tuberous sclerosis complex 2 (TSC2)-deficient cells subjected to oxidative insults...
February 15, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29449374/-time-resolved-analysis-of-amino-acid-stress-identifies-eif2-phosphorylation-as-necessary-to-inhibit-mtorc1-activity-in-liver
#7
Inna A Nikonorova, Emily T Mirek, Christina C Signore, Michael P Goudie, Ronald C Wek, Tracy G Anthony
Amino acid availability is sensed by general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal transduction events remains mysterious. In this study we utilized mouse genetic models to investigate the role of GCN2 in hepatic mTORC1 regulation upon amino acid stress induced by a single injection of asparaginase. We found that deletion of Gcn2 prevented hepatic phosphorylation of eukaryotic initiation factor 2 alpha (eIF2) to asparaginase and instead unleashed mTORC1 activity...
February 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29448247/knockdown-of-magea6-activates-amp-activated-protein-kinase-ampk-signaling-to-inhibit-human-renal-cell-carcinoma-cells
#8
Xueting Ye, Jing Xie, Hang Huang, Zhexian Deng
BACKGROUND/AIMS: Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). METHODS: MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29445291/raptor-mediates-the-antiproliferation-of-cardamonin-by-mtorc1-inhibition-in-skov3-cells
#9
Daohua Shi, Yanting Zhu, Peiguang Niu, Jintuo Zhou, Huajiao Chen
Purpose: Cardamonin inhibits the proliferation of SKOV3 cells by suppressing the mammalian target of rapamycin complex 1 (mTORC1). However, the mechanism of cardamonin on mTORC1 inhibition has not been well demonstrated. The regulatory-associated protein of TOR (Raptor) is an essential component of mTORC1. Here, we investigated the role of Raptor in the mTORC1 inhibition effect of cardamonin in SKOV3 cells. Methods: The expression of Raptor was knockdown by small interfering RNA (siRNA)...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29443392/spatial-aspects-of-oncogenic-signaling-determine-response-to-combination-therapy-in-slice-explants-from-kras-driven-lung-tumors
#10
Katja Närhi, Ashwini S Nagaraj, Elina Parri, Riku Turkki, Petra W van Duijn, Annabrita Hemmes, Jenni Lahtela, Virva Uotinen, Mikko I Mäyränpää, Kaisa Salmenkivi, Jari Räsänen, Nina Linder, Jan Trapman, Antti Rannikko, Olli Kallioniemi, Taija Af Hällström, Johan Lundin, Wolfgang Sommergruber, Simon Anders, Emmy W Verschuren
A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision-cut slices from Kras-driven non-small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC)...
February 14, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29436695/inhibition-of-mammalian-target-of-rapamycin-complex-1-signaling-by-n-3-polyunsaturated-fatty-acids-promotes-locomotor-recovery-after-spinal-cord-injury
#11
Jiping Nie, Jian Chen, Jianguo Yang, Qinqin Pei, Jing Li, Jia Liu, Lixin Xu, Nan Li, Youhao Chen, Xiaohua Chen, Hao Luo, Tiansheng Sun
The present study aimed to explore the effects of n‑3 polyunsaturated fatty acids (PUFAs) on autophagy and their potential for promoting locomotor recovery after spinal cord injury (SCI). Primary neurons were isolated and cultured. Sprague‑Dawley rats were randomly divided into three groups and fed diets with different amounts of n‑3 PUFAs. A model of spinal cord contusion was created at the T10 spinal segment and the composition of PUFAs was analyzed using gas chromatography. Spinal repair and motor function were evaluated postoperatively...
February 8, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29436393/therapeutically-targeting-tumor-microenvironment-mediated-drug-resistance-in-estrogen-receptor-positive-breast-cancer
#12
Kevin Shee, Wei Yang, John W Hinds, Riley A Hampsch, Frederick S Varn, Nicole A Traphagen, Kishan Patel, Chao Cheng, Nicole P Jenkins, Arminja N Kettenbach, Eugene Demidenko, Philip Owens, Anthony C Faber, Todd R Golub, Ravid Straussman, Todd W Miller
Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29435158/osteopontin-integrin-engagement-induces-hif-1%C3%AE-tcf12-mediated-endothelial-mesenchymal-transition-to-exacerbate-colorectal-cancer
#13
Chi-Shuan Fan, Wei-Shone Chen, Li-Li Chen, Chia-Chi Chen, Yu-Ting Hsu, Kee Voon Chua, Horng-Dar Wang, Tze-Sing Huang
Osteopontin (OPN) is a multi-functional phospho-glycoprotein that can stimulate angiogenesis through acting on endothelial cells. As angiogenic sprouting involves endothelial-to-mesenchymal transition (EndoMT), we are intrigued to know whether OPN exerts an effect on EndoMT. Clinically, we indeed detected EndoMT-derived cells next to OPN-expressing cells in colorectal cancer tissues. Furthermore, we treated OPN to primary cultures of endothelial cells to investigate the EndoMT-inducing activity and the underlying mechanisms...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29434241/streptomyces-sp-metabolite-s-promotes-bax-mediated-intrinsic-apoptosis-and-autophagy-involving-inhibition-of-mtor-pathway-in-cervical-cancer-cell-lines
#14
Vipin Mohan Dan, Balaji Muralikrishnan, Rahul Sanawar, Vinodh J S, Bhushan Bapusaheb Burkul, Kalanghad Puthankalam Srinivas, Asha Lekshmi, N S Pradeep, Syed G Dastager, B Santhakumari, Thankayyan R Santhoshkumar, R Ajay Kumar, Madhavan Radhakrishna Pillai
In cervical cancer, the association between HPV infection and dysregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) places mTOR as an attractive therapeutic target. The failure of current treatment modalities in advanced stages of this cancer and drawbacks of already available mTOR inhibitors demand for novel drug candidates. In the present study we identified the presence of a mTOR inhibitor in an active fraction of the ethyl acetate extract of Streptomyces sp OA293...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29432734/the-anti-osteosarcoma-cell-activity-by-a-mtorc1-2-dual-inhibitor-res-529
#15
Xujun Hu, Zirui Wang, Meikai Chen, Xuerong Chen, Wenqing Liang
mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation...
February 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428729/downregulated-cdkn1c-p57kip2-drives-tumorigenesis-and-associates-with-poor-overall-survival-in-breast-cancer
#16
Zhu Qiu, Yunhai Li, Beilei Zeng, Xiaoqin Guan, Hongzhong Li
CDKN1C, also known as p57kip2, is considered to be a potential tumor suppressor implicated in several kinds of human cancers. However, the current knowledge of CDKN1C in breast cancer remains obscure. In the present study, we demonstrated that CDKN1C was dramatically downregulated in breast cancer compared with normal tissues by using real-time quantitative polymerase chain reaction, western blot and two public data portals: The Cancer Genome Atlas (TCGA) and Oncomine datasets. Moreover, the expression of CDKN1C was correlated with age and tumor size in the TCGA cohort containing 708 cases of breast cancer...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428724/dual-inhibition-of-mtorc1-and-mtorc2-perturbs-cytoskeletal-organization-and-impairs-endothelial-cell-elongation
#17
Kiyomi Tsuji-Tamura, Minetaro Ogawa
Elongation of endothelial cells is an important process in vascular formation and is expected to be a therapeutic target for inhibiting tumor angiogenesis. We have previously demonstrated that inhibition of mTORC1 and mTORC2 impaired endothelial cell elongation, although the mechanism has not been well defined. In this study, we analyzed the effects of the mTORC1-specific inhibitor everolimus and the mTORC1/mTORC2 dual inhibitor KU0063794 on the cytoskeletal organization and morphology of endothelial cell lines...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428642/dual-inhibition-of-mtorc1-2-by-dcz0358-induces-cytotoxicity-in-multiple-myeloma-and-overcomes-the-protective-effect-of-the-bone-marrow-microenvironment
#18
Lu Gao, Bo Li, Guang Yang, Peng Liu, Xiucai Lan, Shuaikang Chang, Yi Tao, Zhijian Xu, Bingqian Xie, Xi Sun, Yingcong Wang, Liangning Hu, Dandan Yu, Yongsheng Xie, Wenxuan Bu, Xiaosong Wu, Weiliang Zhu, Jumei Shi
Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment-mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti-MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment...
February 8, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29427611/imaging-pathological-activities-of-human-brain-tissue-in-organotypic-culture
#19
Caroline Le Duigou, Etienne Savary, Mélanie Morin-Brureau, Daniel Gomez-Dominguez, André Sobczyk, Farah Chali, Giampaolo Milior, Larissa Kraus, Jochen C Meier, Dimitri M Kullmann, Bertrand Mathon, Liset Menendez de la Prida, Georg Dorfmuller, Johan Pallud, Emmanuel Eugène, Stéphane Clemenceau, Richard Miles
BACKGROUND: Insights into human brain diseases may emerge from tissue obtained after operations on patients. However techniques requiring transduction of transgenes carried by viral vectors cannot be applied to acute human tissue. NEW METHOD: We show that organotypic culture techniques can be used to maintain tissue from patients with three different neurological syndromes for several weeks in vitro. Optimized viral vector techniques and promoters for transgene expression are described...
February 7, 2018: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/29424687/architecture-of-the-human-mtorc2-core-complex
#20
Edward Stuttfeld, Christopher H S Aylett, Stefan Imseng, Daniel Boehringer, Alain Scaiola, Evelyn Sauer, Michael N Hall, Timm Maier, Nenad Ban
The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex.
February 9, 2018: ELife
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