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Insulin resistance AND mtor

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https://www.readbyqxmd.com/read/27865874/bromodomain-containing-protein-2-induces-insulin-resistance-via-the-mtor-akt-signaling-pathway-and-an-inflammatory-response-in-adipose-tissue
#1
Ruixin Sun, Yi Wu, Weihua Hou, Zujun Sun, Yuxiong Wang, Huanhuan Wei, Wei Mo, Min Yu
Insulin resistance is a major metabolic abnormality in a large majority of patients with type II diabetes. Bromodomain-containing protein 2 (Brd2), a transcriptional co-activator/co-repressor with switch mating type/sucrose non-fermenting (SWI/SNF)-like functions that regulates chromatin, suppresses adipocyte differentiation and regulates pancreatic β-cell biology. However, the effects of Brd2 on insulin resistance remain unknown. Here, overexpression of Brd2 in white adipose tissue of wild-type (WT) mice led to insulin resistance...
November 16, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27847319/transcriptional-profiles-of-type-2-diabetes-in-human-skeletal-muscle-reveal-insulin-resistance-metabolic-defects-apoptosis-and-molecular-signatures-of-immune-activation-in-response-to-infections
#2
Chun Wu, Gang Xu, Shang-Yi A Tsai, William J Freed, Chun-Ting Lee
Skeletal muscle insulin resistance is considered to be the primary defect involved in type 2 diabetes mellitus (T2DM). Despite transcriptome studies in limited T2DM human subjects suggesting an association of T2DM with impaired oxidative phosphorylation in muscle, its molecular pathogenesis remains largely unknown. To identify dysregulated genes and gene networks that are associated with T2DM in human skeletal muscle, we examined expression patterns of 56,318 transcribed genes on 92 T2DM cases and 184 gender-, age- and race-matched non-diabetic controls from the Genotype-Tissue Expression (GTEx) database...
November 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27826244/judicious-toggling-of-mtor-activity-to-combat-insulin-resistance-and-cancer-current-evidence-and-perspectives
#3
REVIEW
Pei Shi Ong, Louis Z Wang, Xiaoyun Dai, Sheng Hsuan Tseng, Shang Jun Loo, Gautam Sethi
The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27816546/anhydroicaritin-improves-diet-induced-obesity-and-hyperlipidemia-and-alleviates-insulin-resistance-by-suppressing-srebps-activation
#4
Zu-Guo Zheng, Ya-Ping Zhou, Xin Zhang, Pyone Myat Thu, Zhi-Shen Xie, Chong Lu, Tao Pang, Bin Xue, Da-Qian Xu, Yan Chen, Xiao-Wei Chen, Hui-Jun Li, Xiaojun Xu
SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs...
December 15, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27791467/identification-of-natural-products-with-neuronal-and-metabolic-benefits-through-autophagy-induction
#5
Yuying Fan, Nan Wang, Altea Rocchi, Weiran Zhang, Robert Vassar, Yifa Zhou, Congcong He
Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies...
October 28, 2016: Autophagy
https://www.readbyqxmd.com/read/27765027/ridaforolimus-mk-8669-synergizes-with-dalotuzumab-mk-0646-in-hormone-sensitive-breast-cancer
#6
Marc A Becker, Xiaonan Hou, Piyawan Tienchaianada, Brian B Haines, Sean C Harrington, S John Weroha, Sriram Sathyanarayanan, Paul Haluska
BACKGROUND: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years...
October 20, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27753529/cyclin-g2-promotes-cell-cycle-arrest-in-breast-cancer-cells-responding-to-fulvestrant-and-metformin-and-correlates-with-patient-survival
#7
Maike Zimmermann, Aruni P S Arachchige-Don, Michaela S Donaldson, Tommaso Patriarchi, Mary C Horne
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest...
October 18, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27698829/microrna-486-5p-enhances-hepatocellular-carcinoma-tumor-suppression-through-repression-of-igf-1r-and-its-downstream-mtor-stat3-and-c-myc
#8
Rana Ahmed Youness, Hend Mohamed El-Tayebi, Reem Amr Assal, Karim Hosny, Gamal Esmat, Ahmed Ihab Abdelaziz
The insulin-like growth factor (IGF)-axis has been paradigmatically involved in hepatocellular carcinoma (HCC) tumor initiation, progression and drug resistance. Consequently, members of the IGF-axis and most importantly, IGF-1 receptor (IGF-1R) have been considered as intriguing targets for HCC therapy. Few miRNAs have been recently reported to be associated with IGF-1R regulation. The present study aimed to investigate the role of microRNA (miRNA/miR)-486-5p in the regulation of IGF-1R and its downstream signaling cascades...
October 2016: Oncology Letters
https://www.readbyqxmd.com/read/27659519/profiles-of-mirnas-matched-to-biology-in-aromatase-inhibitor-resistant-breast-cancer
#9
Reiner Hoppe, Ping Fan, Florian Büttner, Stefan Winter, Amit K Tyagi, Heather Cunliffe, V Craig Jordan, Hiltrud Brauch
Aromatase inhibitor (AI) resistance during breast cancer treatment is mimicked by MCF-7:5C (5C) and MCF-7:2A (2A) cell lines that grow spontaneously. Survival signaling is reconfigured but cells are vulnerable to estradiol (E2)-inducible apoptosis. These model systems have alterations of stress related pathways including the accumulation of endoplasmic reticulum, oxidative, and inflammatory stress that occur prior to E2-induced apoptosis. We investigated miRNA expression profiles of 5C and 2A to characterize their AI resistance phenotypes...
September 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27659301/anti-ageing-active-ingredients-from-herbs-and-nutraceuticals-used-in-traditional-chinese-medicine-pharmacological-mechanisms-and-implications-for-drug-discovery
#10
REVIEW
Chun-Yan Shen, Jian-Guo Jiang, Li Yang, Da-Wei Wang, Wei Zhu
Ageing, an unanswered question in the medical field, is a multifactorial process that results in a progressive functional decline in cells, tissues and organisms. Although it is impossible to prevent ageing, slowing down the rate of ageing is entirely possible to achieve. Traditional Chinese medicine (TCM) is characterized by the nourishing of life and its role in anti-ageing is getting more and more attention. This article summarizes the work done on the natural products from TCM that are reported to have anti-ageing effects, in the past two decades...
September 23, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27626216/the-triangle-of-death-in-alzheimer-disease-brain-the-aberrant-cross-talk-among-energy-metabolism-mtor-signaling-and-protein-homeostasis-revealed-by-redox-proteomics
#11
Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D Allan Butterfield
SIGNIFICANCE: Alzheimer disease (AD), a multifactorial neurodegenerative disorder that represents the most disabling condition in the aged, shares many features of insulin resistance diseases, suggesting AD can be considered a metabolic disease, characterized by reduced insulin signaling, increased oxidative stress, pro-inflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. RECENT ADVANCES: Reduced glucose utilization and energy metabolism in AD has been associated with accumulation of Aβ and hyperphosphorylated tau, increased oxidative stress, and accumulation of unfolded/misfolded proteins...
September 14, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27613445/a-comprehensive-approach-to-the-molecular-determinants-of-lifespan-using-a-boolean-model-of-geroconversion
#12
Loic Verlingue, Aurélien Dugourd, Gautier Stoll, Emmanuel Barillot, Laurence Calzone, Arturo Londoño-Vallejo
Altered molecular responses to insulin and growth factors (GF) are responsible for late-life shortening diseases such as type-2 diabetes mellitus (T2DM) and cancers. We have built a network of the signaling pathways that control S-phase entry and a specific type of senescence called geroconversion. We have translated this network into a Boolean model to study possible cell phenotype outcomes under diverse molecular signaling conditions. In the context of insulin resistance, the model was able to reproduce the variations of the senescence level observed in tissues related to T2DM's main morbidity and mortality...
September 9, 2016: Aging Cell
https://www.readbyqxmd.com/read/27609771/insulin-promotes-proliferation-and-fibrosing-responses-in-activated-pancreatic-stellate-cells
#13
Jiayue Yang, Richard T Waldron, Hsin-Yuan Su, Aune Moro, Hui-Hua Chang, Guido Eibl, Kevin Ferreri, Fouad R Kandeel, Aurelia Lugea, Ling Li, Stephen J Pandol
Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27576731/igf-1r-and-mtor-blockade-novel-resistance-mechanisms-and-synergistic-drug-combinations-for-ewing-sarcoma
#14
Salah-Eddine Lamhamedi-Cherradi, Brian A Menegaz, Vandhana Ramamoorthy, Deeksha Vishwamitra, Ying Wang, Rebecca L Maywald, Adriana S Buford, Izabela Fokt, Stanislaw Skora, Jing Wang, Aung Naing, Alexander J Lazar, Eric M Rohren, Najat C Daw, Vivek Subbiah, Robert S Benjamin, Ravin Ratan, Waldemar Priebe, Antonios G Mikos, Hesham M Amin, Joseph A Ludwig
BACKGROUND: Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined. METHODS: To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy...
December 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27534530/the-role-of-amino-acid-induced-mammalian-target-of-rapamycin-complex-1-mtorc1-signaling-in-insulin-resistance
#15
REVIEW
Mee-Sup Yoon, Cheol Soo Choi
Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance...
2016: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/27508151/exercise-and-dietary-change-ameliorate-high-fat-diet-induced-obesity-and-insulin-resistance-via-mtor-signaling-pathway
#16
Ju Yong Bae, Ki Ok Shin, Jinhee Woo, Sang Heon Woo, Ki Soeng Jang, Yul Hyo Lee, Sunghwun Kang
PURPOSE: The purpose of this study was to investigate the effect of exercise and dietary change on obesity and insulin resistance and mTOR signaling protein levels in skeletal muscles of obese rats. METHODS: Sixty male Sprague-Dawley rats were divided into CO (Normal diet) and HF (High Fat diet) groups in order to induce obesity for 15 weeks. The rats were then subdivided into CO, COT (CO + Training), HF, HFT (HF + Training), HFND (Dietary change), and HFNDT (HFND + Training) groups (10 rats / group)...
June 2016: Journal of Exercise Nutrition & Biochemistry
https://www.readbyqxmd.com/read/27500257/mtor-inhibition-reduced-insulin-secretion-and-sensitivity-in-a-rat-model-of-metabolic-syndrome
#17
Jordi Rovira, María Jose Ramírez-Bajo, Elisenda Banon-Maneus, Daniel Moya-Rull, Pedro Ventura-Aguiar, Natalia Hierro-Garcia, Marta Lazo-Rodriguez, Ignacio Revuelta, Armando Torres, Federico Oppenheimer, Josep M Campistol, Fritz Diekmann
BACKGROUND: Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β -cell toxicity. METHODS: Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days...
February 2016: Transplantation Direct
https://www.readbyqxmd.com/read/27461402/lkb1-controls-brown-adipose-tissue-growth-and-thermogenesis-by-regulating-the-intracellular-localization-of-crtc3
#18
Tizhong Shan, Yan Xiong, Pengpeng Zhang, Zhiguo Li, Qingyang Jiang, Pengpeng Bi, Feng Yue, Gongshe Yang, Yizhen Wang, Xiaoqi Liu, Shihuan Kuang
Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity...
2016: Nature Communications
https://www.readbyqxmd.com/read/27445979/myomirs-as-markers-of-insulin-resistance-and-decreased-myogenesis-in-skeletal-muscle-of-diet-induced-obese-mice
#19
Flávia de Toledo Frias, Mariana de Mendonça, Amanda Roque Martins, Ana Flávia Gindro, Bruno Cogliati, Rui Curi, Alice Cristina Rodrigues
High-fat diet (HFD) feeding causes insulin resistance (IR) in skeletal muscle of mice, which affects skeletal muscle metabolism and function. The involvement of muscle-specific microRNAs in the evolution of skeletal muscle IR during 4, 8, and 12 weeks in HFD-induced obese mice was investigated. After 4 weeks in HFD, mice were obese, hyperglycemic, and hyperinsulinemic; however, their muscles were responsive to insulin stimuli. Expressions of MyomiRs (miR-1, miR-133a, and miR-206) measured in soleus muscles were not different from those found in control mice...
2016: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/27411383/increased-skeletal-muscle-glut4-expression-in-obese-mice-after-voluntary-wheel-running-exercise-is-posttranscriptional
#20
Jami M Gurley, Beth A Griesel, Ann Louise Olson
Exercise promotes glucose clearance by increasing skeletal muscle GLUT4-mediated glucose uptake. Importantly, exercise upregulates muscle GLUT4 expression in an insulin-independent manner under conditions of insulin resistance, such as with type 2 diabetes. However, the insulin-independent mechanism responsible for rescued muscle GLUT4 expression is poorly understood. We used voluntary wheel running (VWR) in mice to test the prevailing hypothesis that insulin-independent upregulation of skeletal muscle GLUT4 protein expression with exercise is through increased Glut4 transcription...
October 2016: Diabetes
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