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AMP activated kinase

Michael Christensen, Jonas B Jensen, Steen Jakobsen, Niels Jessen, Jørgen Frøkiær, Bruce E Kemp, Allison L Marciszyn, Hui Li, Núria M Pastor-Soler, Kenneth R Hallows, Rikke Nørregaard
The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs)...
October 26, 2016: Scientific Reports
Stephanie M Cossette, Vijesh J Bhute, Xiaoping Bao, Leanne M Harmann, Mark A Horswill, Indranil Sinha, Adam Gastonguay, Shabnam Pooya, Michelle Bordas, Suresh N Kumar, Shama P Mirza, Sean Palecek, Jennifer Strande, Ramani Ramchandran
BACKGROUND: -Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our lab has previously shown that sucrose non-fermenting related kinase (SNRK) enzyme, which belongs to the AMP-activated kinase (AMPK) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure, and death by 8-10 months...
October 25, 2016: Circulation. Cardiovascular Genetics
Hua-Qiang Zhu, Jin-Ben Ma, Xie Song, Heng-Jun Gao, Chao-Qun Ma, Hong Chang, Hong-Guang Li, Fang-Feng Liu, Jun Lu, Xu Zhou
Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways...
October 20, 2016: Oncology Reports
Wenjie Li, Fei Cao, Juan Li, Zhixin Wang, Yu Ren, Zheyong Liang, Peijun Liu
Simvastatin (SIM), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to inhibit the activity of hepatitis B virus (HBV), however, the mechanism underlying its antiviral function remains unknown. Minichromosome maintenance (MCM) 7, a component of the MCM complex, has been reported to act as an important host factor aiding virus genome replication in host cells. The present study demonstrated that downregulation of MCM7 inhibited the expression of proteins transferred by adenoviral vectors...
October 20, 2016: Molecular Medicine Reports
Randa Abdel Malik, Nina Zippel, Timo Frömel, Juliana Heidler, Sven Zukunft, Barbara Walzog, Nariman Ansari, Francesco Pampaloni, Susanne Wingert, Michael A Rieger, Ilka Wittig, Beate Fisslthaler, Ingrid Fleming
RATIONALE: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia and while the AMPKα1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKα2 subunit in vascular repair. OBJECTIVE: To determine the role of the AMPKα2 subunit in vascular repair. METHODS AND RESULTS: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKα2(-/-) versus wild-type mice, a phenotype reproduced in mice lacking AMPKα2 in myeloid cells (AMPKα2(ΔMC))...
October 24, 2016: Circulation Research
A Blomme, B Costanza, P de Tullio, M Thiry, G Van Simaeys, S Boutry, G Doumont, E Di Valentin, T Hirano, T Yokobori, S Gofflot, O Peulen, A Bellahcène, F Sherer, C Le Goff, E Cavalier, A Mouithys-Mickalad, F Jouret, P G Cusumano, E Lifrange, R N Muller, S Goldman, P Delvenne, E De Pauw, M Nishiyama, V Castronovo, A Turtoi
Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes...
October 24, 2016: Oncogene
Liliana F Iannucci, Jingfeng Sun, Brijesh K Singh, Jin Zhou, Vincent A Kaddai, Antonia Lanni, Paul M Yen, Rohit A Sinha
Short-chain fatty acids (SCFAs) are gut microbial fermentation products derived from dietary fiber sources. Although depletion of gut microflora has been linked to the development of liver disease, the direct effects of SCFAs on intracellular hepatic processes are not well understood. In this study, we demonstrated that the SCFAs, propionate and butyrate, regulated autophagic flux in hepatic cells in a cell-autonomous manner. Induction of autophagy by SCFAs required PPARγ stimulation of Uncoupling Protein 2 (UCP2) expression that was associated with reduced intracellular ATP levels and activation of PRKAA1/AMPK (protein kinase, AMP-activated, alpha 1 catalytic subunit)...
October 20, 2016: Biochemical and Biophysical Research Communications
Chatchai Muanprasat, Varanuj Chatsudthipong
Chitosan oligosaccharide (COS) is an oligomer of β-(1➔4)-linked D-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti-hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement...
October 20, 2016: Pharmacology & Therapeutics
Wanxing Duan, Ke Chen, Zhengdong Jiang, Xin Chen, Liankang Sun, Jiahui Li, Jianjun Lei, Qinhong Xu, Jiguang Ma, Xuqi Li, Liang Han, Zheng Wang, Zheng Wu, Fengfei Wang, Erxi Wu, Qingyong Ma, Zhenhua Ma
Emerging evidence suggests that metformin, as an activator of AMP-activated protein kinase (AMPK), may be useful in preventing and treating PDAC. However, whether metformin has an effect on the stromal reaction of PDAC remains unknown. In this study, we first evaluated the expression of AMPK and phosphorylated-AMPK (P-AMPK) in normal and PDAC tissues, our data indicate that reduced P-AMPK expression is a frequent event in PDAC and correlated with poor prognosis and the dense stromal reaction. We then determined the efficacy of metformin on PDAC growth in vitro and in vivo...
October 20, 2016: Cancer Letters
Yufeng Li, Zheng Li, Dan Wang, Xiang Zhang, Jia Li, Sher Ali, Jingze Lu, Hao Zong, Xiaolan Xu
Insulin-stimulated GLUT4 translocation from GLUT4 storage vesicles (GSVs) to the plasma membrane (PM) constitutes a key process for blood glucose control. Therefore, compounds that could promote GLUT4 translocation into the PM represent potential drugs for the treatment of diabetes. In this research, we screened for agonists that induce GLUT4 translocation by using a novel pH-sensitive fluorescent probe, insulin-regulated aminopeptidase (IRAP)-mOrange2. We identified as well as validated one agonist, staurosporine, from a 64,000 compound library...
October 18, 2016: Biochemical and Biophysical Research Communications
John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
Jin Kyung Kim, Hye-Mi Lee, Ki-Sun Park, Dong-Min Shin, Tae Sung Kim, Yi Sak Kim, Hyun-Woo Suh, Soo Yeon Kim, In Soo Kim, Jin-Man Kim, Ji-Woong Son, Kyung Mok Sohn, Sung Soo Jung, Chaeuk Chung, Sang-Bae Han, Chul-Su Yang, Eun-Kyeong Jo
Autophagy is an important antimicrobial effector process that defends against Mycobacterium tuberculosis (Mtb), the human pathogen causing tuberculosis (TB). MicroRNAs (miRNAs), endogenous noncoding RNAs, are involved in various biological functions and act as post-transcriptional regulators to target mRNAs. The process by which miRNAs affect antibacterial autophagy and host defense mechanisms against Mtb infections in human monocytes and macrophages is largely uncharacterized. In this study, we show that Mtb significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3'-untranslated region of DRAM2 (DNA damage regulated autophagy modulator 2) in human monocytes and macrophages...
October 20, 2016: Autophagy
Demin Cai, Mengjie Yuan, Haoyu Liu, Shifeng Pan, Wenqiang Ma, Jian Hong, Ruqian Zhao
Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets...
October 18, 2016: Nutrients
Bonglee Kim, Moon-Jea Woo, Chul-Soo Park, Sang-Hun Lee, Jin-Soo Kim, Boim Kim, Seho An, Sung-Hoon Kim
Hovenia dulcis Thunb. (HDT) was known to have anti-fatigue, anti-diabetes, neuroprotective, and hepatoprotective effects. In the present study, the anti-fatty liver mechanism of HDT was elucidated in oleic acid (OA)-treated Hep G2 cells and acute hyperlipidemia mouse model using Triton WR-1339. Here, HDT activated p-AMP-activated protein kinase (p-AMPK), proliferator activated receptor-α, carnitine palmitoyltransferase and also inhibited the expression of lipogenesis and cholesterol synthesis proteins, such as 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element binding protein-1c, SREBP-2, and fatty acid synthase in OA-treated Hep G2 cells...
October 20, 2016: Phytotherapy Research: PTR
Z Q Lu, Y Ren, X H Zhou, X F Yu, J Huang, D Y Yu, X X Wang, Y Z Wang
As meat quality is basically dependent on muscle fibre characteristics, it is important to know how muscle fibres are regulated and transformed. This study aimed to investigate the effect of maternal dietary supplementation on muscle fibre types using 3% saturated fatty acid (palmitic acid, PA) or 3% unsaturated fatty acid (linoleic acid, LA) from 80 days of gestation to the weaning of offspring (25 days post-natal). The results indicated that higher mRNA levels of MyHCI type genes were found in the soleus muscles of piglets that suckled from LA-supplemented sows than from PA-supplemented sows...
October 20, 2016: Journal of Animal Physiology and Animal Nutrition
Ning Xia, Huige Li
Under physiological conditions, perivascular adipose tissue (PVAT) attenuates agonist-induced vasoconstriction by releasing vasoactive molecules including hydrogen peroxide, angiotensin 1-7, adiponectin, methyl palmitate, hydrogen sulfide, nitric oxide (NO) and leptin. This anticontractile function of PVAT is lost under conditions of obesity. The central mechanism underlying PVAT dysfunction in obesity is likely to be an "obesity triad" (consisting of PVAT hypoxia, inflammation and oxidative stress) that leads to dysregulation of PVAT-derived vasoregulators...
October 20, 2016: British Journal of Pharmacology
Pushpa Raj Joshi, Thekla Apitz, Stephan Zierz
During physical activity in McArdle patients, little or no lactate is released in the skeletal muscle. However, excessive ammonia production has frequently been reported in these patients. Production of ammonia is catalysed by AMP deaminase (AMPD) and adenylate kinase (AK). The activities of AMPD and AK along with housekeeping enzyme phosphoglucoisomerase (PGI) were measured in 11 genetically confirmed McArdle patients and compared with 27 healthy controls. The AMPD and AK activities were not significantly different in patients and controls...
October 20, 2016: Neurological Research
Gargi Mahapatra, Ashwathy Varughese, Qinqin Ji, Icksoo Lee, Jenney Liu, Asmita Vaishnav, Christopher Sinkler, Alexandr A Kapralov, Carlos T Moraes, Thomas H Sanderson, Timothy L Stemmler, Lawrence I Grossman, Valerian E Kagan, Joseph S Brunzelle, Arthur R Salomon, Brian F P Edwards, Maik Hüttemann
Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain (ETC) and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr28, leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated Thr28Glu phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared to wild-type unphosphorylated Cytc...
October 7, 2016: Journal of Biological Chemistry
Tzu-Pin Shentu, Ming He, Xiaoli Sun, Jianlin Zhang, Fan Zhang, Brendan Gongol, Traci L Marin, Jiao Zhang, Liang Wen, Yinsheng Wang, Gregory G Geary, Yi Zhu, David A Johnson, John Y-J Shyy
OBJECTIVE: Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress. APPROACH AND RESULTS: Analysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation...
October 6, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Jeffrey D Cooney, Ricardo C T Aguiar
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of cyclic-AMP in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases SYK and PI3K, inhibits VEGFA secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets...
October 18, 2016: Blood
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