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https://www.readbyqxmd.com/read/29788890/inhibition-of-pyruvate-dehydrogenase-kinase-as-a-therapeutic-strategy-against-cancer
#1
Swatishree Sradhanjali, Mamatha M Reddy
Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate dehydrogenase kinase (PDK) is a gatekeeper enzyme involved in altered glucose metabolism in tumors. There are four isoforms of PDK (1 to 4) in humans. PDK phosphorylates E1α subunit of pyruvate dehydrogenase complex (PDC) and inactivates it...
May 22, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29764240/ferrous-glycinate-regulates-cell-energy-metabolism-by-restricting-hypoxia-induced-factor-1%C3%AE-expression-in-human-a549-cells
#2
Yung-Ting Kuo, Jhong-Huei Jheng, Mei-Chen Lo, Wei-Lu Chen, Shyang-Guang Wang, Horng-Mo Lee
Iron or oxygen regulates the stability of hypoxia inducible factor-1α (HIF-1α). We investigated whether ferrous glycinate would affect HIF-1α accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. Addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells...
May 15, 2018: Free Radical Research
https://www.readbyqxmd.com/read/29535262/skp2-dependent-reactivation-of-akt-drives-resistance-to-pi3k-inhibitors
#3
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
https://www.readbyqxmd.com/read/29459421/igf-1-protects-sh-sy5y-cells-against-mpp-induced-apoptosis-via-pi3k-pdk-1-akt-pathway
#4
Chanyang Kim, Seungjoon Park
Insulin-like growth factor (IGF)-1 is a well-known anti-apoptotic pro-survival factor and phosphatidylinositol-3-kinase (PI3K)/Akt pathway is linked to cell survival induced by IGF-1. It is also reported that Akt signaling is modulated by 3-phosphoinositide-dependent kinase-1 (PDK1). In the current study, we investigated whether the anti-apoptotic effect of IGF-1 in SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+ ) is associated with the activity of PI3K/PDK1/Akt pathway. Treatment of cells with IGF-1 inhibited MPP+ -induced apoptotic cell death...
March 2018: Endocrine Connections
https://www.readbyqxmd.com/read/29456710/mechanism-of-apoptosis-induction-associated-with-erk1-2-upregulation-via-goniothalamin-in-melanoma-cells
#5
Suphakorn Tangchirakhaphan, Sukanda Innajak, Sirinun Nilwarangkoon, Nudjaree Tanjapatkul, Wilawan Mahabusrakum, Ramida Watanapokasin
The present study aimed to investigate the effect of goniothalamin on apoptosis induction in the A375 melanoma cell line. Melanoma is a type of skin cancer with increased prevalence and no potential standard treatment. Goniothalamin is a plant, bioactive styrly-lactone, which has various bioactivities including anti-microbial, anti-inflammatory and anti-cancer. Apoptosis induction by goniothalamin has been studied in numerous cancer cell lines, however not in the melanoma cell line A375. The results of the MTT assay demonstrated that goniothalamin induced anti-proliferation in a dose dependent manner...
March 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28990055/defective-insulin-signaling-and-the-protective-effects-of-dimethyldiguanide-during-follicular-development-in-the-ovaries-of-polycystic-ovary-syndrome
#6
Fan Wang, Shaobing Wang, Zhenghong Zhang, Qingqiang Lin, Yiping Liu, Yijun Xiao, Kaizhuan Xiao, Zhengchao Wang
It is established that the physiological effects of insulin are primarily mediated by the insulin signaling pathway. However, a defective insulin signaling is closely associated with the clinical manifestations of polycystic ovary syndrome (PCOS), which include excess androgen levels, insulin resistance and anovulation, and is involved in the pathophysiology of PCOS at the molecular level. Dimethyldiguanide (DMBG) has been widely employed to alleviate reproduction dysfunction in women with PCOS, however, the exact mechanism of this effect remains unclear...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28987868/impairment-of-akt-activity-by-cyp2e1-mediated-oxidative-stress-is-involved-in-chronic-ethanol-induced-fatty-liver
#7
Tao Zeng, Cui-Li Zhang, Ning Zhao, Min-Jie Guan, Mo Xiao, Rui Yang, Xiu-Lan Zhao, Li-Hua Yu, Zhen-Ping Zhu, Ke-Qin Xie
Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver...
April 2018: Redox Biology
https://www.readbyqxmd.com/read/28839175/oxygen-nanobubbles-revert-hypoxia-by-methylation-programming
#8
Pushpak N Bhandari, Yi Cui, Bennett D Elzey, Craig J Goergen, Christopher M Long, Joseph Irudayaraj
Targeting the hypoxic tumor microenvironment has a broad impact in cancer epigenetics and therapeutics. Oxygen encapsulated nanosize carboxymethyl cellulosic nanobubbles were developed for mitigating the hypoxic regions of tumors to weaken the hypoxia-driven pathways and inhibit tumor growth. We show that 5-methylcytosine (5mC) hypomethylation in hypoxic regions of a tumor can be reverted to enhance cancer treatment by epigenetic regulation, using oxygen nanobubbles in the sub-100 nm size range, both, in vitro and in vivo...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28689265/aerobic-glycolysis-hypothesis-through-wnt-beta-catenin-pathway-in-exudative-age-related-macular-degeneration
#9
REVIEW
Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-Noël Vallée
Exudative age-related macular degeneration (AMD) is characterized by molecular mechanisms responsible for the initiation of choroidal neovascularization (CNV). Inflammatory processes are associated with upregulation of the canonical WNT/beta-catenin pathway in exudative AMD. We focus this review on the link between WNT/beta-catenin pathway activation and neovascular progression in exudative AMD through activation of aerobic glycolysis for production of angiogenic factors. Increased WNT/beta-catenin pathway involves hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2)...
August 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28634229/akt-activation-by-ca-2-calmodulin-dependent-protein-kinase-kinase-2-camkk2-in-ovarian-cancer-cells
#10
Angela M Gocher, Gissou Azabdaftari, Lindsey M Euscher, Shuhang Dai, Loukia G Karacosta, Thomas F Franke, Arthur M Edelman
Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide-dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (β) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3)...
August 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28632756/identification-of-atf-7-and-the-insulin-signaling-pathway-in-the-regulation-of-metallothionein-in-c-elegans-suggests-roles-in-aging-and-reactive-oxygen-species
#11
Julie A Hall, Matthew K McElwee, Jonathan H Freedman
It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens...
2017: PloS One
https://www.readbyqxmd.com/read/28620312/thermodynamics-in-gliomas-interactions-between-the-canonical-wnt-beta-catenin-pathway-and-ppar-gamma
#12
REVIEW
Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-Noël Vallée
Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28556776/-hif-1%C3%AE-is-required-for-disturbed-flow-induced-metabolic-reprogramming-in-human-and-porcine-vascular-endothelium
#13
David Wu, Ru-Ting Huang, Robert B Hamanaka, Matt Krause, Myung-Jin Oh, Cheng-Hsiang Kuo, Recep Nigdelioglu, Angelo Y Meliton, Leah Witt, Guohao Dai, Mete Civelek, Nanduri R Prabhakar, Yun Fang, Gökhan M Mutlu
Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α ( HIF-1α ), downstream of NAD(P)H oxidase-4 ( NOX4 )-derived reactive oxygen species (ROS)...
May 30, 2017: ELife
https://www.readbyqxmd.com/read/28423362/trop2-promotes-proliferation-migration-and-metastasis-of-gallbladder-cancer-cells-by-regulating-pi3k-akt-pathway-and-inducing-emt
#14
Xinxing Li, Shifeng Teng, Yanyan Zhang, Weigang Zhang, Xianwen Zhang, Kai Xu, Houshan Yao, Jun Yao, Haolu Wang, Xiaowen Liang, Zhiqian Hu
The human trophoblast cell surface antigen 2 (TROP2) is overexpressed in many cancers. However, its effect on proliferation, migration and metastasis of gallbladder cancer remains unclear. In this study, we found that TROP2 was highly expressed in gallbladder cancer. Overexpression of TROP2 was associated with poor prognosis. Knockdown of TROP2 in gallbladder cancer cell lines strongly inhibited the cell proliferation, clone formation, invasion and migration in vitro, while TROP2 overexpression had opposite effects...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405929/thermodynamics-in-cancers-opposing-interactions-between-ppar-gamma-and-the-canonical-wnt-beta-catenin-pathway
#15
REVIEW
Yves Lecarpentier, Victor Claes, Alexandre Vallée, Jean-Louis Hébert
Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated...
December 2017: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/28395173/particular-phosphorylation-of-pi3k-akt-on-thr308-via-pdk-1-and-pten-mediates-melatonin-s-neuroprotective-activity-after-focal-cerebral-ischemia-in-mice
#16
Ulkan Kilic, Ahmet Burak Caglayan, Mustafa Caglar Beker, Mehmet Yalcin Gunal, Berrak Caglayan, Esra Yalcin, Taha Kelestemur, Reyhan Zeynep Gundogdu, Burak Yulug, Bayram Yılmaz, Bilal Ersen Kerman, Ertugrul Kilic
Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonin's neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI...
August 2017: Redox Biology
https://www.readbyqxmd.com/read/28371849/therapeutic-inhibition-of-mir-375-attenuates-post-myocardial-infarction-inflammatory-response-and-left-ventricular-dysfunction-via-pdk-1-akt-signalling-axis
#17
Venkata N S Garikipati, Suresh K Verma, Darukeshwara Jolardarashi, Zhongjian Cheng, Jessica Ibetti, Maria Cimini, Yan Tang, Mohsin Khan, Yujia Yue, Cindy Benedict, Emily Nickoloff, May M Truongcao, Erhe Gao, Prasanna Krishnamurthy, David A Goukassian, Walter J Koch, Raj Kishore
Aims: Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whether inhibition of MI-induced miR-375 by LNA anti-miR-375 can improve recovery after acute MI. Methods and results: Ten weeks old mice were treated with either control or LNA anti miR-375 after induction of MI by LAD ligation...
July 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28366735/regulator-of-g-protein-signaling-1-modulates-paraquat-induced-oxidative-stress-and-longevity-via-the-insulin-like-signaling-pathway-in-caenorhabditis-elegans
#18
Mingyu Wu, Xin Kang, Qiang Wang, Chunyu Zhou, Chandra Mohan, Ai Peng
Insulin or insulin like signaling (IIS) pathway is a crucial pathway in Caenorhabditis elegans associated with mediating longevity, and stress resistance. Regulators of G protein signaling (RGS) also modulate stress resistance and longevity in multiple in vitro and in vivo models. However, the mechanism underlying RGS mediating stress resistance and longevity remains largely unclear. Here we report that rgs-1, an important member of rgs family, is a novel modulator of IIS pathway in C. elegans. We found that the loss of rgs-1 dramatically promoted paraquat resistance in C...
May 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28238857/asiaticoside-attenuation-of-rotenone-induced-oxidative-burden-in-a-rat-model-of-hemiparkinsonism-by-maintaining-the-phosphoinositide-mediated-synaptic-integrity
#19
Margabandhu Gopi, Vanisree Arambakkam Janardhanam
Asiaticoside (AS), a triterpenoid saponin isolated from the Indian medicinal herb Centella asiatica is known to exert a neuroprotective effect by attenuating the neurobehavioral, neurochemical and pathological changes in animal models. However, its potential neuroprotection in rotenone-induced hemiparkinsonism which implicates phospholipid-mediated neurotransmission remains unclear. Therefore, we have investigated the neuroprotective effects of AS in rat model of ROT-infused hemiparkinsonism with respect to phosphoinositides-assisted cytodynamics and synaptic function...
April 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28163304/predominant-contribution-of-dgk%C3%AE-over-dgk%C3%AE-in-the-control-of-pkc-pdk-1-regulated-functions-in-t-cells
#20
Antonia Ávila-Flores, Javier Arranz-Nicolás, Elena Andrada, Denise Soutar, Isabel Mérida
Diacylglycerol kinase (DGK)-mediated consumption of the diacylglycerol (DAG) generated in response to antigen recognition is an important mechanism to limit T-cell function. Targeting DGK activity presents new opportunities for therapeutic manipulation of the immune response, but assessment of individual DGK functions is complex. T cells express two DGK isoforms, DGKα and DGKζ, and there are no isoform-specific inhibitors. Here we used short interfering RNA-mediated gene silencing in human T cells and DGKα- and DGKζ-deficient mice to define DGK isoform-specific regulation of key signaling pathways during T-cell activation...
July 2017: Immunology and Cell Biology
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