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Jing Qiu, Min Wang, Jun Zhang, Qing Cai, Dan Lu, Yansong Li, Yushu Dong, Tianzhi Zhao, Huisheng Chen
Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro...
October 18, 2016: International Immunopharmacology
Xia Chen, Hua Guo, Fuxia Li, Di Fan
BACKGROUND: The present study is designed to explore the metastasis-inhibitory effect of physcion 8-O-β-glucopyranoside (PG) in human breast cancer, and the mechanisms underlying its role in tumor metastasis. METHODS: Both in vitro and in vivo studies were conducted. Cell migration and invasion were analyzed by transwell assay. The translocation of β-catenin from the nucleus to cytoplasm membrane was demonstrated by immunofluorescent staining. The expression of signaling molecules was determined by Western blot or qRT-PCR...
September 13, 2016: Pharmacological Reports: PR
Chae Lim Jung, Hyemin Mun, Se-Young Jo, Ju-Hee Oh, ChuHee Lee, Eun-Kyung Choi, Se Jin Jang, Young-Ah Suh
Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process...
October 19, 2016: Oncotarget
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
Soojong Park, Ahmad Fudhaili, Sang-Seok Oh, Ki Won Lee, Hamadi Madhi, Dong-Hee Kim, Jiyun Yoo, Hyung Won Ryu, Ki-Hun Park, Kwang Dong Kim
BACKGROUND: Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified. PURPOSE: We identified a candidate metabolite for anti-human bladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin-resistant T24R2 human bladder cancer cells...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Ruijie Zhang, Nana Zhang, Hai Zhang, Chunxiao Liu, Xiaoqing Dong, Xiaoxue Wang, Yu Zhu, Chong Xu, Lei Liu, Sijun Yang, Shile Huang, Long Chen
BACKGROUND AND PURPOSE: Increasing evidence has suggested cadmium (Cd), as an inducer of reactive oxygen species (ROS), is a potential pathogenic factor in human neurodegenerative diseases. Thus, it is important to find effective interventions for Cd-induced oxidative stress in the central nervous system. The purpose of this study was to determine whether and how celastrol, a plant-derived triterpene, could mitigate Cd-induced ROS and cell death in neuronal cells. EXPERIMENTAL APPROACH: PC12, SH-SY5Y cells and primary murine neurons were chosen as a model to study celastrol neuroprotection against Cd-poisoning...
October 20, 2016: British Journal of Pharmacology
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
Xiangbin Song, Zifa Li, Fei Liu, Zhenyong Wang, Lin Wang
Previous study has demonstrated that puerarin (PU) exerts nephroprotective effect against Pb-induced cytotoxicity in primary rat proximal tubular (rPT) cells. Autophagy can protect cells from various cytotoxic stimuli, but its role in the process of PU against Pb-induced nephrotoxicity is still unknown. This study aims to investigate whether PU can alleviate Pb-induced renal damage by recovering autophagy. Data showed that Pb inhibited the autophagic flux, as evidenced by the accumulation of LC3-II and p62 as well as the confocal microscopy analysis of GFP-LC3 puncta and punctate spots of monodansylcadaverine staining, whereas coadministration of PU could restore Pb-induced autophagy inhibition...
October 20, 2016: Journal of Biochemical and Molecular Toxicology
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
Zhong'e Zhou, Yong Tang, Xian Jin, Chengjun Chen, Yi Lu, Liang Liu, Chengxing Shen
Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects...
2016: Journal of Diabetes Research
Michael B Lazarus, Rebecca S Levin, Kevan M Shokat
Elongation Factor-2 Kinase (eEF2K) in an unusual mammalian enzyme that has one known substrate, elongation factor-2. It belongs to a class of kinases, called alpha kinases, that has little sequence identity to the >500 conventional protein kinases, but performs the same reaction and has similar catalytic residues. The phosphorylation of eEF2 blocks translation elongation, which is thought to be critical to regulating cellular energy usage. Here we report a system for discovering new substrates of alpha kinases and identify the first new substrates of eEF2K including AMPK and alpha4, and determine a sequence motif for the kinase that shows a requirement for threonine residues as the target of phosphorylation...
October 17, 2016: Cellular Signalling
Aurore Woller, Hélène Duez, Bart Staels, Marc Lefranc
To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet...
October 18, 2016: Cell Reports
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
Yang Sun, Dajun Zhao, Yang Yang, Chao Gao, Xing Zhang, Zhiqiang Ma, Shuai Jiang, Lin Zhao, Wenhao Chen, Kai Ren, Wei Yi, Feng Gao
The underlying mechanisms of cardioprotection of adiponectin (APN) against ischemia/reperfusion (I/R) injury remain largely unknown. The present study aimed to investigate whether calreticulin (CRT) mediated APN's cardioprotection against I/R injury. We inhibited mice cardiac CRT expression via intra-myocardial injection of CRT SiRNA, performed transient LAD ligation, measured the cardiac function, apoptosis and oxidative stress to identify CRT's effects on cardioprotective actions of APN against I/R injury in vivo...
October 18, 2016: Apoptosis: An International Journal on Programmed Cell Death
Prashant Trikha, Robert L Plews, Andrew Stiff, Shalini Gautam, Vincent Hsu, David Abood, Robert Wesolowski, Ian Landi, Xiaokui Mo, John Phay, Ching-Shih Chen, John Byrd, Michael Caligiuri, Susheela Tridandapani, William Carson
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored...
2016: Oncoimmunology
Huafeng Wang, Huan Zhang, Yuqing Zhang, Dan Wang, Xixi Cheng, Fengrui Yang, Qi Zhang, Zhenyi Xue, Yan Li, Lijuan Zhang, Luhong Yang, Guolin Miao, Daiqing Li, Zhiyu Guan, Yurong Da, Zhi Yao, Fei Gao, Liang Qiao, Li Kong, Rongxin Zhang
Plumbagin is a quinonoid constituent extracted from Plumbago genus, and it exhibits diverse pharmacological effects. This study thoroughly investigated the effects of plumbagin on thioacetamide-induced acute and chronic liver injury. Results shown that plumbagin increased survival rate, reduced liver congestion and inflammation, and decreased macrophages and neutrophils in the fulminant hepatic failure model, and remarkably diminished liver fibrosis and inflammation in the chronic liver injury model. Furthermore, plumbagin significantly suppress the HSCs/myofibroblasts activation by reduced expression of markers α-SMA and COL-1/3, and reduced macrophage in liver...
October 14, 2016: Oncotarget
Haleh Vaez, Moslem Najafi, Maryam Rameshrad, Negisa Seyed Toutounchi, Mehraveh Garjani, Jaleh Barar, Alireza Garjani
Toll like receptors (TLRs) are key players in the innate immune responses. The energy sensing enzyme, AMPK, has been implicated in the modulation of immunity. The present study investigated whether AMPK activation by metformin could contribute to the regulation of immune responses in the isolated heart via suppression of TLR4 activity, independent of circulatory immunity. Isolated Wistar rat hearts were perfused with Krebs-Henseleit buffer in the absence or presence of lipopolysaccharide (LPS; 0.2μM), LPS+metformin (10mM), and LPS+metformin+compound C (10μM)...
October 14, 2016: International Immunopharmacology
Kalina Biernacka, Raj A Persad, Amit Bahl, David Gillatt, Jeff M P Holly, Claire M Perks
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes via targeting this pathway...
October 17, 2016: Endocrine-related Cancer
Mihwa Kim, Ji-Yeon Jung, Seungho Choi, Hyunseung Lee, Liza D Morales, Jeong-Tae Koh, Sun Hun Kim, Yoo-Duk Choi, Chan Choi, Thomas J Slaga, Won Jae Kim, Dae Joon Kim
Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family receptor alpha 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy...
October 18, 2016: Autophagy
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