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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/29428730/targeting-sphingosine-kinase-2-by-abc294640-inhibits-human-skin-squamous-cell-carcinoma-cell-growth
#3
Jianbo Zhou, Jin Chen, Huanmiao Yu
The activity of ABC294640, a small-molecular sphingosine kinase 2 (SphK2) inhibitor, in human skin squamous cell carcinoma (SCC) cells was tested in this study. SphK2 mRNA and protein are expressed in established (A431 cell line) and primary human skin SCC cells. ABC294640 dose-dependently inhibited survival, cell cycle progression and proliferation of skin SCC cells. Furthermore, ABC294640 induced caspase-3/-9 and apoptosis activation in skin SCC cells. The SphK2 inhibitor was however non-cytotoxic to SphK2-null skin melanocytes, keratinocytes and fibroblasts...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29418022/acute-antiobesity-effects-of-intracerebroventricular-11%C3%AE-hsd1-inhibitor-administration-in-diet-induced-obese-mice
#4
Minchul Seo, S K M Azizul Islam, Seong-Su Moon
Hypothalamus is the regulatory center of both appetite and energy balance, and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, link between the role of 11β-HSD1 in hypothalamus and obesity has yet to be elucidated. In this study, embryonal primary hypothalamic neurons and high fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors in in vitro and in vivo...
February 8, 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29416044/a-small-molecule-inhibitor-of-rheb-selectively-targets-mtorc1-signaling
#5
Sarah J Mahoney, Sridhar Narayan, Lisa Molz, Lauren A Berstler, Seong A Kang, George P Vlasuk, Eddine Saiah
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29414598/combination-of-hindlimb-suspension-and-immobilization-by-casting-exaggerates-sarcopenia-by-stimulating-autophagy-but-does-not-worsen-osteopenia
#6
Toni L Speacht, Andrew R Krause, Jennifer L Steiner, Charles H Lang, Henry J Donahue
Astronauts in space experience a unique environment that causes the concomitant loss of bone and muscle. However, the interaction between these tissues and how osteopenia and sarcopenia affect each other is unclear. We explored this relationship by exaggerating unloading-induced muscle loss using a unilateral casting model in conjunction with hindlimb suspension (HLS). Five-month-old, male C57Bl/6J mice subjected to HLS for 2 weeks displayed a significant decrease in gastrocnemius and quadriceps weight (-9-10%), with a two-fold greater decrease in muscle mass observed in the HLS + casted limb...
February 2, 2018: Bone
https://www.readbyqxmd.com/read/29408091/aspirin-induces-beclin-1-dependent-autophagy-of-human-hepatocellular-carcinoma-cell
#7
Zhenjun Huang, Weilun Fang, Weihua Liu, Li Wang, Bin Liu, Shiming Liu, Shaojun Liu
Aspirin not only reduces the incidence of hepatocellular carcinoma (HCC) but also plays a synergistic role with chemotherapy for HCC treatment. However, the underlying mechanisms remain incompletely elucidated. Given that autophagy triggers cancer cell death, the present study examined the autophagic effect of aspirin on HCC cells. Results showed that aspirin increased LC3II/LC3I ratio, decreased p62 expression, and enhanced autophagic flux (autophagosome and autolysosome puncta) in Hep3B, HepG2, or SMMC-7721 cells, reflecting the autophagy of HCC cells...
January 31, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29399144/two-novel-stk11-missense-mutations-induce-phosphorylation-of-s6k-and-promote-cell-proliferation-in-peutz-jeghers-syndrome
#8
Ran Li, Zhiqing Wang, Shu Liu, Baoping Wu, Di Zeng, Yali Zhang, Lanbo Gong, Feihong Deng, Haoxuan Zheng, Yadong Wang, Chudi Chen, Junsheng Chen, Bo Jiang
Peutz-Jeghers syndrome (PJS) is a rare hereditary disease caused by mutations in serine threonine kinase 11 (STK11) and characterized by an increased risk of developing cancer. Inactivation of STK11 has been associated with the mammalian target of rapamycin (mTOR) pathway. Hyperactivation and phosphorylation of the key downstream target genes ribosomal protein S6 kinase 1 (S6K1) and S6 promote protein synthesis and cell proliferation. To better understand the effects of STK11 dysfunction in the pathogenesis of PJS, genomic DNA samples from 21 patients with PJS from 11 unrelated families were investigated for STK11 mutations in the present study...
January 2018: Oncology Letters
https://www.readbyqxmd.com/read/29367005/the-impaired-immune-function-and-structural-integrity-by-dietary-iron-deficiency-or-excess-in-gill-of-fish-after-infection-with-flavobacterium-columnare-regulation-of-nf-%C3%AE%C2%BAb-tor-jnk-p38mapk-nrf2-and-mlck-signalling
#9
Yan-Lin Guo, Pei Wu, Wei-Dan Jiang, Yang Liu, Sheng-Yao Kuang, Jun Jiang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
The aim of this study was to investigate the effects and potential mechanisms of dietary iron on immune function and structural integrity in gill of young grass carp (Ctenopharyngodon idella). A total of 630 grass carp (242.32 ± 0.58 g) were fed diets containing graded levels of iron at 12.15 (basal diet), 35.38, 63.47, 86.43, 111.09, 136.37 and 73.50 mg/kg for 60 days. Subsequently, a challenge test was conducted by infection with Flavobacterium columnare to investigate the effects of dietary iron on gill immune function and structural integrity in young grass carp...
January 20, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29357370/parallel-pi3k-akt-and-mtor-inhibition-is-required-to-control-feedback-loops-that-limit-tumor-therapy
#10
Anuja Sathe, Géraldine Chalaud, Immanuel Oppolzer, Kit Yeng Wong, Margarita von Busch, Sebastian C Schmid, Zhichao Tong, Margitta Retz, Juergen E Gschwend, Wolfgang A Schulz, Roman Nawroth
Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences...
2018: PloS One
https://www.readbyqxmd.com/read/29334873/nobiletin-prevents-cadmium-induced-neuronal-apoptosis-by-inhibiting-reactive-oxygen-species-and-modulating-jnk-erk1-2-and-akt-mtor-networks-in-rats
#11
Youyang Qu, Yu Liu, Li Chen, Yanmei Zhu, Xingjun Xiao, Di Wang, Yulan Zhu
Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b...
January 16, 2018: Neurological Research
https://www.readbyqxmd.com/read/29326164/the-glutamine-transporter-asct2-slc1a5-promotes-tumor-growth-independently-of-the-amino-acid-transporter-lat1-slc7a5
#12
Yann Cormerais, Pierre André Massard, Milica Vucetic, Sandy Giuliano, Eric Tambutté, Jerome Durivault, Valérie Vial, Hitoshi Endou, Michael F Wempe, Scott K Parks, Jacques Pouyssegur
The transporters for glutamine and essential amino acids (EAA), ASCT2 (solute carrier family 1 member 5, SLC1A5), and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers EAA entry via the LAT1 exchanger, thus activating mechanistic target of rapamycin complex 1 (mTORC1) and stimulating growth. Here, to further investigate whether these two transporters are functionally coupled, we compared the respective knockout (KO) of either LAT1 or ASCT2 in colon (LS174T) and lung (A549) adenocarcinoma cell lines...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29285026/corrigendum-hepatic-s6k1-partially-regulates-lifespan-of-mice-with-mitochondrial-complex-i-deficiency
#13
Takashi K Ito, Chenhao Lu, Jacob Khan, Quy Nguyen, Heather Z Huang, Dayae Kim, James J Phillips, Jo Tan, Yenna Lee, Tuyet Nguyen, Samy Khessib, Natalie Lim, Surapat Mekvanich, Joshua Oh, Victor V Pineda, Weirong Wang, Alessandro Bitto, Jonathan Y An, John F Morton, Mitsutoshi Setou, Warren C Ladiges, Matt Kaeberlein
[This corrects the article on p. 113 in vol. 8, PMID: 28919908.].
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/29278652/parp1-induces-cardiac-fibrosis-by-mediating-mtor-activity
#14
Shuya Sun, Yuehuai Hu, Qiyao Zheng, Zhen Guo, Duanping Sun, Shaorui Chen, Yiqiang Zhang, Peiqing Liu, Jing Lu, Jianmin Jiang
Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis...
December 26, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29258409/effect-of-dj-1-downregulation-on-the-functions-of-the-first-trimester-extravillous-trophoblasts
#15
Han-Sung Kwon, Ji Hyun Park, Han-Sung Hwang, In-Sook Sohn, Young-Han Kim, SiHyun Cho
DJ-1 ( PARK7) has been reported to be causative gene of Parkinson disease and also an oncogene. A loss in DJ-1 function can lead to cell death in neurodegenerative disease, or a gain of it can cause unregulated cell survival in cancer, respectively. DJ-1 protein is known to be expressed mainly in trophoblastic cells in the placenta with increased expression in the first trimester compared to later in term. However, its role in trophoblast regulation remains unknown. This study aimed to investigate the effect of DJ-1 regulation on a first trimester extravillous trophoblast cell line, HTR-8/SVneo...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/29250185/inhibition-of-gli1-mediated-prostate-cancer-cell-proliferation-by-inhibiting-the-mtor-s6k1-signaling-pathway
#16
Hong Yang, Libing Hu, Zhimin Liu, Yang Qin, Ruiqian Li, Guoying Zhang, Bin Zhao, Chengwei Bi, Yonghong Lei, Yu Bai
Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer-associated mortality in males worldwide. However, the role of the non-canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma-associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen-independent prostate cancer cell lines PC3 and DU145, but not in the androgen-dependent cancer cell line LNCaP...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29248227/d-glucose-and-amino-acid-deficiency-inhibits-casein-synthesis-through-jak2-stat5-and-ampk-mtor-signaling-pathways-in-mammary-epithelial-cells-of-dairy-cows
#17
M C Zhang, S G Zhao, S S Wang, C C Luo, H N Gao, N Zheng, J Q Wang
Amino acids and energy deficiency lead to lower milk protein content in dairy cows. However, the known mechanisms involved in this process do not adequately explain the variability of milk protein concentration in the mammary gland. We hypothesized that a deficiency in d-glucose (d-Glc) or AA would inhibit casein synthesis by regulating signaling pathways in mammary epithelial cells. Cow mammary epithelial cells (CMEC) were subjected to combinations of 1 of 3 concentrations of d-Glc (0, 2.50, or 17.5 mM) and 1 of 3 concentrations of AA (0, 1...
December 13, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/29247557/combination-of-melatonin-and-rapamycin-for-head-and-neck-cancer-therapy-suppression-of-akt-mtor-pathway-activation-and-activation-of-mitophagy-and-apoptosis-via-mitochondrial-function-regulation
#18
Ying-Qiang Shen, Ana Guerra-Librero, Beatriz I Fernandez-Gil, Javier Florido, Sergio García-López, Laura Martinez-Ruiz, Miguel Mendivil-Perez, Viviana Soto-Mercado, Darío Acuña-Castroviejo, Hector Ortega-Arellano, Victor Carriel, María E Diaz-Casado, Russel J Reiter, Iryna Rusanova, Ana Nieto, Luis C López, Germaine Escames
Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In the present study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death, and to identify potential cross-talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin-treated HNSCC cell lines (Cal-27 and SCC-9)...
December 16, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/29240643/temporally-distinct-regulation-of-pathways-contributing-to-cardiac-proteostasis-during-the-acute-and-recovery-phases-of-sepsis
#19
Kristen T Crowell, Samantha Moreno, Jennifer L Steiner, Catherine S Coleman, David I Soybel, Charles H Lang
BACKGROUND: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation. METHODS: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture (CLP) as well as long-term changes that manifest during the chronic (10 d) recovery phase...
December 13, 2017: Shock
https://www.readbyqxmd.com/read/29221131/hoxa5-increases-mitochondrial-apoptosis-by-inhibiting-akt-mtorc1-s6k1-pathway-in-mice-white-adipocytes
#20
Fei Feng, Qian Ren, Song Wu, Muhammad Saeed, Chao Sun
Homeobox A5(Hoxa5), a member of the Hox family, plays a important role in the regulation of proliferation and apoptosis in cancer cells. The dysregulation of the adipocyte apoptosis in vivo leads to obesity and metabolic disorders. However, the effects of Hoxa5 on adipocyte apoptosis are still unknown. In this study, palmitic acid (PA) significantly increased the mRNA level of Hoxa5 and triggered white adipocyte apoptosis in vivo and in vitro. Further analysis revealed that Hoxa5 enhanced the early and late apoptotic cells and fragmentation of genomic DNA in adipocytes from inguinal white adipose tissue (iWAT) of mice...
November 10, 2017: Oncotarget
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