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Yang Zou, Jiang-Yan Zhou, Jiu-Bai Guo, Li-Qun Wang, Yong Luo, Zi-Yu Zhang, Fa-Ying Liu, Jun Tan, Feng Wang, Ou-Ping Huang
Endometriosis is a potential premalignant disorder. The underlying molecular aberrations, however, are not fully understood. A recent exome sequencing study found that 25% (10/39) of deep infiltrating endometriosis harbored cancer driver gene mutations. However, it is unclear whether these mutations also exist in ovarian endometriosis. Here, a total of 101 ovarian endometriosis samples were analyzed for the presence of these gene mutations, including KRAS, PPP2R1A, PIK3CA and ARID1A. In addition, 6 other cancer-associated genes (BRAF, NRAS, HRAS, ERK1, ERK2 and PTEN) were also analyzed...
March 9, 2018: Mutation Research
Shingo Matsuda, Daisuke Matsuzawa, Daisuke Ishii, Haruna Tomizawa, Eiji Shimizu
Onset of fear-related disorders such as post-traumatic stress disorder is enhanced from adolescence until adulthood. However, the biological mechanisms underlying this vulnerability remain unclear. Therefore, we investigated contextual fear memory and extinction in 4-, 6-, 8-, 10-, and 15-week-old female mice. We also measured phosphorylation of ERK2 in the medial prefrontal cortex (mPFC) and the dorsal hippocampus in the mPFC following fear conditioning or extinction in 6- and 15-week-old mice. We found that 10- and 15-week-old mice showed stronger fear memory and more resistance to fear extinction than 6-week-old mice...
March 10, 2018: Neurobiology of Learning and Memory
Xuelian Li, GuoYuan Wang, MuGe QiLi, HaiHai Liang, TianShi Li, XiaoQiang E, Ying Feng, Ying Zhang, Xiao Liu, Ming Qian, BoZhi Xu, ZhiHang Shen, Samuel Chege Gitau, DanDan Zhao, HongLi Shan
BACKGROUND/AIMS: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload-induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment...
March 2, 2018: Cellular Physiology and Biochemistry
Satoru Nagatoishi, Sou Yamaguchi, Etsuko Katoh, Keita Kajita, Takane Yokotagawa, Satoru Kanai, Toshio Furuya, Kouhei Tsumoto
19 F NMR has recently emerged as an efficient, sensitive tool for analyzing protein binding to small molecules, and surface plasmon resonance (SPR) is also a popular tool for this purpose. Herein a combination of19 F NMR and SPR was used to find novel binders to the ATP-binding pocket of MAP kinase extracellular regulated kinase 2 (ERK2) by fragment screening with an original fluorinated-fragment library. The19 F NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening...
February 22, 2018: Bioorganic & Medicinal Chemistry
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
March 5, 2018: Nature Medicine
Katia E Helfenberger, Nerina M Villalba, Bruno Buchholz, Alberto Boveris, Juan José Poderoso, Ricardo J Gelpi, Cecilia Poderoso
Activation of ERK1/2 implies the phosphorylation of tyrosine (pTyr) and threonine (pThr) by MEK1/2; both reactions were thought to be cytoplasmic, promoting ERK to reach the nucleus where it activates several transcription factors. In addition, H2O2 concentrations are known to modulate ERK intracellular translocation, which impacts on cellular proliferation. In this context, the objective of this work was to study the sequence of ERK phosphorylation under two redox conditions and to analyze a putative mitochondrial contribution to this process, in LP07 murine lung cells...
2018: PloS One
Tao-Tao Liu, Qian Hao, Yan Zhang, Zhao-Hui Li, Zhi-Hua Cui, Wei Yang
PURPOSE: This study aimed to explore the effects of microRNA-133b (miR-133b) on diabetic retinopathy (DR) by targeting angiotensinogen (AGT) through the angiotensin-II (AngII) extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway in rats. METHODS: The DR rat model was established using retinal tissues of DR rats and normal rats. Immunohistochemistry was performed to detect the protein expressions of AGT and CD34 in retinal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were applied to detect miR-133b expression, AGT, AngII, ERK1/2 mRNA, and protein expressions in tissues and cells after transfection...
February 28, 2018: Acta Ophthalmologica
Ponnayyan Sulochana Suresh, Ravi Kumar Jairam, Devaraj V Chandrasekhar, Anera Balakrishna Vinod, Rakesh A Hiremath, Anusha Raj, Mohd Zainuddin, Ravi Kanth Bhamidipati, Ramesh Mullangi
BACKGROUND AND OBJECTIVES: Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. METHODS: Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (Vss ) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]...
February 22, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Dandan Li, Winifred Lo, Udo Rudloff
Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an estimated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer...
February 22, 2018: Clinical and Translational Medicine
Jian-Jun Xie, Yan-Yi Jiang, Yuan Jiang, Chun-Quan Li, Lim-Mei Chee, Omer An, Anand Mayakonda, Ling-Wen Ding, Lin Long, Chun Sun, Le-Hang Lin, Li Chen, Jian-Yi Wu, Zhi-Yong Wu, Qi Cao, Wang-Kai Fang, Wei Yang, Stephen J Meltzer, Henry Yang, Melissa Fullwood, Li-Yan Xu, En-Min Li, De-Chen Lin, H Phillip Koeffler
BACKGROUND & AIMS: Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription PCR assays to measure expression levels of LINC01503...
February 15, 2018: Gastroenterology
Mingjie Xu, Jiangfeng Li, Xiao Wang, Shuai Meng, Jiaying Shen, Song Wang, Xin Xu, Bo Xie, Ben Liu, Liping Xie
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of bladder cancer (BCa). MiR-22 was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in BCa remain unclear. Here, we find that miR-22 is frequently downregulated in BCa tissues compared with adjacent non-cancerous tissues. Overexpression of miR-22 significantly inhibits proliferation, migration, and invasion of BCa cells both in vitro and in vivo...
February 12, 2018: Cell Death & Disease
Xuzhu Lin, Lewan Parker, Emma Mclennan, Xinmei Zhang, Alan Hayes, Glenn McConell, Tara C Brennan-Speranza, Itamar Levinger
Uncarboxylated osteocalcin (ucOC) stimulates muscle glucose uptake in mice EDL and soleus muscles. However, whether ucOC also exerts a similar effect in insulin-stimulated muscles in a muscle type-specific manner is currently unclear. We aimed to test the hypothesis that, with insulin stimulation, ucOC per se has a greater effect on oxidative muscle compared with glycolytic muscle, and to explore the underlying mechanisms. Mouse (C57BL6, male 9-12 weeks) extensor digitorum longus (EDL) and soleus muscles were isolated and longitudinally split into halves...
February 9, 2018: Calcified Tissue International
Xiao-Xue Li, Zhi-Jing Wang, Yu Zheng, Yun-Feng Guan, Peng-Bo Yang, Xiang Chen, Cong Peng, Jian-Ping He, Yuan-Li Ai, Sheng-Fu Wu, Kun-Yi Chien, Qiao Wu, Hang-Zi Chen
Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation...
February 1, 2018: Molecular Cell
Matthew G Annis, Veronique Ouellet, Jonathan P Rennhack, Sylvain L'Esperance, Claudine Rancourt, Anne-Marie Mes-Masson, Eran R Andrechek, Peter M Siegel
BACKGROUND: The Fos-related antigen 1 (FRA-1) transcription factor promotes tumor cell growth, invasion and metastasis. Phosphorylation of FRA-1 increases protein stability and function. We identify a novel signaling axis that leads to increased phosphorylation of FRA-1, increased extracellular matrix (ECM)-induced breast cancer cell invasion and is prognostic of poor outcome in patients with breast cancer. METHODS: While characterizing five breast cancer cell lines derived from primary human breast tumors, we identified BRC-31 as a novel basal-like cell model that expresses elevated FRA-1 levels...
January 30, 2018: Breast Cancer Research: BCR
Zhongchi Li, Kang Xu, Nannan Zhang, Gabriel Amador, Yanying Wang, Sen Zhao, Liyuan Li, Ying Qiu, Zhao Wang
Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase associated with numerous aspects of health and physiology. Overexpression of SIRT6 has emerged as a protector in cardiac tissues against pathologic cardiac hypertrophy. However, the mechanism of this protective effect is not fully understood. Here, both in vivo and in vitro results demonstrated that SIRT6 overexpression can attenuate cisplatin-induced kidney injury in terms of renal dysfunction, inflammation and apoptosis. In addition, SIRT6 knockout aggravated kidney injury caused by cisplatin...
January 16, 2018: Kidney International
Nadia Hanafy Metwally, Emad Abdallah Deeb
The key intermediate 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) is considered as a precursor for some novel pyrazolo[4,3-c]pyridines 4a-c, arylhydrazopyrazolo[4,3-c]pyridines 8a-e, pyrazolo[4,5,1-ij][1,6]naphthyridines 11a-e and pyrido[4',3':3,4]pyrazolo[1,5-a]-pyrimidines 15a-d through Knovenegal condensation, coupling reaction and Michael addition. Some of the newly synthesized pyrazolo[4,3-c]pyridine derivatives were investigated for anticancer activity. The results of the cytotoxic activity revealed that compound 6b was the most active compound against the breast and liver carcinoma cell lines which gives IC50 values of 1...
January 10, 2018: Bioorganic Chemistry
Zhengzheng Su, Mengni Zhang, Miao Xu, Xinglan Li, Junya Tan, Yunyi Xu, Xiuyi Pan, Ni Chen, Xueqin Chen, Qiao Zhou
BACKGROUND: The ERK signaling pathway is frequently deregulated in tumorigenesis, mostly by classical mechanisms such as gene mutation of its components (eg, RAS and RAF). However, whether and how multiple key components of ERK pathway are regulated by microRNAs are not clear. METHODS: We firstly predicted post-transcriptional regulation of multiple key components of the ERK signaling pathway by miR181c through bioinformatics analysis, and then confirmed the post-transcriptional regulation by dual luciferase reporter gene assays and Western blot analysis...
January 16, 2018: Prostate
Dongjie Li, Yutao Wei, Shangzhi Xu, Qiang Niu, Mei Zhang, Shugang Li, Mingxia Jing
Arsenic is a toxic metal, which ultimately leads to cell apoptosis. ERK is considered a key transcriptional regulator of arsenic‑induced apoptosis. Due to a few controversial issues about arsenic‑mediated extracellular signal‑regulated MAP kinases (ERK) signaling, a meta‑analysis was performed. Subgroup analyses demonstrated that high doses (≥2 µmol/l) of arsenic increased the expression of Ras, ERK, ERK1, ERK2, phosphorylated (p)‑ERK, p‑ERK1, and p‑ERK2, while low doses (<2 µmol/l) decreased the expression of Ras, ERK1, p‑ERK, and p‑ERK2 when compared to control groups...
January 5, 2018: Molecular Medicine Reports
Paul Denver, Victor A Gault, Paula L McClean
AIMS: Metabolic disease increases risk of Alzheimer's disease and cognitive dysfunction. Chronic high fat diet (HFD) feeding leads to cognitive impairment and neuroinflammation. This study demarcated pathological events in brain as a result of short-term to chronic HFD feeding. Efficacy of Xenin-25[Lys(13)PAL] was assessed in chronic HFD-fed mice. METHODS: C57BL/6 mice were fed HFD or normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and Morris water maze...
January 5, 2018: Diabetes, Obesity & Metabolism
Jessica L Brown, Jianjun Xie, Miguel Brieno Enriquez, Jennifer Sones, Cynthia N Angulo, Ulrich Boehm, Andrew Miller, Chirine Toufaily, Ying Wang, Daniel J Bernard, Mark S Roberson
Extracellular signal-regulated kinase (ERK) signaling regulates hormone action in the reproductive axis, but specific mechanisms have yet to be completely elucidated. In the present study, ERK1 null and ERK2 floxed mice were combined with a gonadotrope-specific Cre (GRIC) driver. Female ERK double knockout (ERKdko) animals were hypogonadotropic, resulting in anovulation and complete infertility. Transcript levels of four gonadotrope-specific genes (GnRHR and the three gonadotropin subunits) were reduced in pituitaries at estrus in ERKdko females and the post-castration response to endogenous GnRH hyper-stimulation was blunted...
January 3, 2018: Endocrinology
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