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https://www.readbyqxmd.com/read/28550180/a-novel-de-novo-mutation-in-prkag2-gene-infantile-onset-phenotype-and-signaling-pathway-involved
#1
Yanchun Xu, Alex Gray, David Grahame Hardie, Alper Uzun, Sunil Shaw, James F Padbury, Chanika Phornphutkul, Yi-Tang Tseng
PRKAG2 encodes the γ2-subunit isoform of the 5' AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved and therapeutic options for K475E mutation using cells stably expressing human wild type (WT) or the K475E mutant...
May 26, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28549860/crude-terpene-glycoside-component-from-radix-paeoniae-rubra-protects-against-isoproterenol-induced-myocardial-ischemic-injury-via-activation-of-the-pi3k-akt-mtor-signaling-pathway
#2
Zhongcheng Ke, Gang Wang, Lei Yang, Huihui Qiu, Hao Wu, Mei Du, Juan Chen, Jie Song, Xiaobin Jia, Liang Feng
ETHNOPHARMACOLOGICAL RELEVANCE: Radix paeoniae rubra, also known as chishao (CS), is a frequently used traditional Chinese medicine that can promote blood circulation to remove blood stasis. It has been widely used for the prevention and treatment of cardiovascular diseases in China. Although terpene glycoside (TG), the major component in CS, has been shown to possess cardioprotective properties, the mechanism underlying CS-TG's preventive effect against myocardial ischemia injury is unknown...
May 23, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28549345/a-novel-synthetic-derivative-of-quercetin-8-trifluoromethyl-3-5-7-3-4-o-pentamethyl-quercetin-inhibits-bladder-cancer-growth-by-targeting-the-ampk-mtor-signaling-pathway
#3
Ting Tao, Caimei He, Jun Deng, Yanjun Huang, Qiongli Su, Mei Peng, Meiling Yi, Kwame Oteng Darko, Hui Zou, Xiaoping Yang
Quercetin is a naturally existing compound and shows attractive anticancer properties for a variety of solid tumors including glioma, bladder cancer, hepatocellular carcinoma, breast cancer, hematological malignancies and prostate carcinoma. However, these anticancer properties have not been clinically approved due to unclear mechanistic information and its low bioactivity. In our previous study, we elucidated that quercetin activates AMPK pathway which is the major mechanism for its unique anticancer effect in bladder cancer...
May 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28549178/rhoa-rock-inhibition-improves-the-beneficial-effects-of-glucocorticoid-treatment-in-dystrophic-muscle-implications-for-stem-cell-depletion
#4
Xiaodong Mu, Ying Tang, Koji Takayama, Wanqun Chen, Aiping Lu, Bing Wang, Kurt Weiss, Johnny Huard
Glucocorticoid treatment represents a standard palliative treatment for Duchenne muscular dystrophy (DMD) patients, but various adverse effects have limited this treatment. In an effort to understand the mechanism(s) by which glucocorticoids impart their effects on the dystrophic muscle, and potentially reduce the adverse effects, we have studied the effect of prednisolone treatment in dystrophin/utrophin double knockout (dKO) mice, which exhibit a severe dystrophic phenotype due to rapid muscle stem cell depletion...
May 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28548968/aldose-reductase-interacts-with-akt1-to-augment-hepatic-akt-mtor-signaling-and-promote-hepatocarcinogenesis
#5
Jia-Xing Zhao, Ya-Wei Yuan, Cheng-Fu Cai, Dong-Yan Shen, Mao-Li Chen, Feng Ye, Yan-Jun Mi, Qi-Cong Luo, Wang-Yu Cai, Wei Zhang, Ying Long, Yong Zeng, Guo-Dong Ye, Shu-Yu Yang
Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548933/kir2dl5-mutation-and-loss-underlies-sporadic-dermal-neurofibroma-pathogenesis-and-growth
#6
Corina Anastasaki, Sonika Dahiya, David H Gutmann
Dermal neurofibromas (DNFs) are benign peripheral nerve sheath tumors thought to originate from Schwann cell progenitors. These tumors represent one of the hallmarks of the neurofibromatosis type 1 (NF1) tumor predisposition syndrome, where they can number in the thousands. While NF1-DNFs arise due to mutations in the NF1 gene, the vast majority of DNFs occur sporadically (sp-DNFs), where the genetic etiology is currently unknown. Herein, we employed whole-exome sequencing of sp-DNFs to identify a recurrent mutation in the KIR2DL5 gene, which codes for a protein suppressor of natural killer (NK) cell activity...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548926/preclinical-study-of-cc223-as-a-potential-anti-ovarian-cancer-agent
#7
Zhenzhen Jin, Huanfu Niu, Xuenan Wang, Lei Zhang, Qin Wang, Aijun Yang
Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548030/everolimus-inhibited-multiple-isoforms-of-udp-glucuronosyltransferases-ugts
#8
Zuo Du, Guang Wang, Yun-Feng Cao, Cui-Min Hu, Kun Yang, Yong-Zhe Liu, Chun-Ze Zhang, Wei-Hua Zhang, Zhi-Tu Zhu, Hong-Zhi Sun, Xiao-Yu Sun, Mo Hong, Zhong-Ze Fang
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 uM of everolimus exerted more than 80% inhibition towards UGT1A1, -1A3, and -2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus towards the activity cavity of UGT1A3 and UGT2B7...
May 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28544747/k-ras-mutation-and-amplification-status-is-predictive-of-resistance-and-high-basal-pakt-is-predictive-of-sensitivity-to-everolimus-in-biliary-tract-cancer-cell-lines
#9
Yvonne Yeung, David K Lau, Fiona Chionh, Hoanh Tran, Janson W T Tse, Andrew J Weickhardt, Mehrdad Nikfarjam, Andrew M Scott, Niall C Tebbutt, John M Mariadason
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signaling pathway is hyperactivated in a subset of BTCs and clinical activity to the mTOR inhibitor everolimus has been observed in some BTC patients. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways...
May 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28542590/the-mth1-inhibitor-th588-demonstrates-anti-tumoral-effects-alone-and-in-combination-with-everolimus-5-fu-and-gamma-irradiation-in-neuroendocrine-tumor-cells
#10
Elke Tatjana Aristizabal Prada, Michael Orth, Svenja Nölting, Gerald Spöttl, Julian Maurer, Christoph Auernhammer
Modulation of the redox system in cancer cells has been considered a promising target for anti-cancer therapy. The novel MTH1 inhibitor TH588 proved tremendous potential in terms of cancer cell eradication, yet its specificity has been questioned by recent reports, indicating that TH588 may also induce cancer cell death by alternative mechanisms than MTH1 inhibition. Here we used a panel of heterogeneous neuroendocrine tumor cells in order to assess cellular mechanisms and molecular signaling pathways implicated in the effects of TH588 alone as well as dual-targeting approaches combining TH588 with everolimus, cytotoxic 5-fluorouracil or γ-irradiation...
2017: PloS One
https://www.readbyqxmd.com/read/28542038/hypoxia-as-a-target-for-drug-combination-therapy-of-liver-cancer
#11
Cressida Bowyer, Andrew L Lewis, Andrew W Lloyd, Gary J Phillips, Wendy M Macfarlane
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment...
May 24, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28539264/op16-a-novel-ent-kaurene-diterpenoid-potentiates-the-antitumor-effect-of-rapamycin-by-inhibiting-rapamycin-induced-feedback-activation-of-akt-signaling-in-esophageal-squamous-cell-carcinoma
#12
Ke-Zheng Peng, Yu Ke, Qi Zhao, Fei Tian, Hong-Min Liu, Guiqin Hou, Zhaoming Lu
Hyperactivation of mTOR signaling pathway has been viewed as a significant molecular pathogenesis of cancer. However, inhibition of mTOR by rapamycin and its analogs could induce numerous negative feedback loops to attenuate their therapeutic efficacy. As a traditional Chinese herbal medicine, Rabdosia rubescens has been used to treat esophageal squamous cell carcinoma (ESCC) for hundreds of years, and its major effective component is oridonin. Here we reported that OP16, a novel analog of oridonin, showed potent inhibition of cell proliferation and Akt phosphorylation in ESCC cells...
May 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28537902/endoplasmic-reticulum-stress-promotes-autophagy-and-apoptosis-and-reverses-chemoresistance-in-human-ovarian-cancer-cells
#13
Jin-Long Hu, Xin-Long Hu, Ai-Ye Guo, Chao-Jie Wang, Yi-Yang Wen, Shun-Dong Cang
Ovarian cancer presents the highest mortality rate among gynecological tumors. Here, we measured cell viability, proliferation, apoptosis, autophagy, and expression of endoplasmic reticulum stress (ERS)-related proteins, PI3K/AKT/mTOR pathway-related proteins, and apoptosis- and autophagy-related proteins in SKOV3 and SKOV3/CDDP cells treated with combinations of CDDP, tunicamycin, and BEZ235 (blank control, CDDP, CDDP + tunicamycin, CDDP + BEZ235, and CDDP + tunicamycin + BEZ235). Increasing concentrations of tunicamycin and CDDP activated ERS in SKOV3 cells, reduced cell viability and proliferation, increased apoptosis and autophagy, enhanced expression of ERS-related proteins, and inhibited expression of PI3K/AKT/mTOR pathway-related proteins...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537878/biological-characterization-of-sn32976-a-selective-inhibitor-of-pi3k-and-mtor-with-preferential-activity-to-pi3k%C3%AE-in-comparison-to-established-pan-pi3k-inhibitors
#14
Gordon W Rewcastle, Sharada Kolekar, Christina M Buchanan, Swarna A Gamage, Anna C Giddens, Kit Y Tsang, Jackie D Kendall, Ripudaman Singh, Woo-Jeong Lee, Greg C Smith, Weiping Han, David J Matthews, William A Denny, Peter R Shepherd, Stephen M F Jamieson
Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537457/inhibition-of-mtor-kinase-as-a-therapeutic-target-for-acute-myeloid-leukemia
#15
Yoko Tabe, Agostino Tafuri, Kazumasa Sekihara, Haeun Yang, Marina Konopleva
Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML. Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival...
May 24, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28536634/microrna-210-induces-endothelial-cell-apoptosis-by-directly-targeting-pdk1-in-the-setting-of-atherosclerosis
#16
Ying Li, Chunyan Yang, Lili Zhang, Ping Yang
BACKGROUND: Atherosclerosis is a chronically inflammatory disease and one of the leading causes of deaths worldwide. Endothelial cell apoptosis plays a crucial role in its development. Several microRNAs (miRNAs) are reportedly involved in atherosclerotic plaque formation, including miRNA-210 (miR-210). However, the underlying mechanism of its role in endothelial cell apoptosis during atherosclerosis is still largely unknown. METHODS: A mouse model with atherosclerosis induced by a high-fat diet (HFD) was built in ApoE (-/-) mice...
2017: Cellular & Molecular Biology Letters
https://www.readbyqxmd.com/read/28534996/ginsenoside-rd-regulates-the-akt-mtor-p70s6k-signaling-cascade-and-suppresses-angiogenesis-and-breast-tumor-growth
#17
Eryun Zhang, Hailian Shi, Li Yang, Xiaojun Wu, Zhengtao Wang
Blockade of angiogenesis is an important approach for cancer treatment and prevention. In the present study, we investigated the effect of ginsenoside Rd (Rd) on angiogenesis in vitro and in vivo. Our results demonstrated that Rd inhibited vascular endothelial growth factor (VEGF)-induced migration, tube formation and proliferation of primary cultured human umbilical vascular endothelial cells (HUVECs) dose‑dependently. Furthermore, Rd abrogated VEGF-induced sprouting of the vessels from aortic rings, and inhibited vascular formation in the Matrigel plug assay in vivo...
May 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28534368/study-on-the-molecular-mechanism-of-rac3-on-regulating-autophagy-in-human-lung-cancer-cells
#18
Xuyang Xiao, Gebang Wang, Hongxu Liu
PURPOSE: Rac3 plays an important role in regulating tumorigenesis. Autophagy plays a vital role in tumorigenesis and tumor progression. The relationship between the two remains unclear. The objective of the present study was to determine the specific molecular mechanism of intracellular Rac3 in regulating autophagy and reveal the relationship between tumor cell autophagy and apoptosis. METHODS: A laser confocal microscope was used to photograph the accumulated EGFP-MAP1LC3 spots for investigating the relationship between Rac3 and autophagy at the cellular level...
March 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#19
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28532580/sirt1-ameliorates-systemic-sclerosis-by-targeting-the-mtor-pathway
#20
Xiaoxia Zhu, Haiyan Chu, Shuai Jiang, Qingmei Liu, Lei Liu, Yu Xue, Shucong Zheng, Weiguo Wan, Jianhua Qiu, Jiucun Wang, Hejian Zou
BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation and fibrosis. Our previous research has indicated that Sirtuin1 (Sirt1) plays a role in the regulation of TNF-α-induced inflammation; however, whether Sirt1 may inhibit the progress of SSc by blocking inflammation remains unknown. OBJECTIVE: We aimed to investigate the function of Sirt1 in SSc. METHODS: The function and its mechanism of Sirt1 were evaluated in fibroblasts or scleroderma mice...
May 3, 2017: Journal of Dermatological Science
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