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Wohn-Jenn Leu, Sharada Prasanna Swain, She-Hung Chan, Jui-Ling Hsu, Shih-Ping Liu, Mei-Ling Chan, Chia-Chun Yu, Lih-Ching Hsu, Yen-Lin Chou, Wei-Ling Chang, Duen-Ren Hou, Jih-Hwa Guh
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation...
October 19, 2016: Oncotarget
Alan J Simmons, Cherié R Scurrah, Eliot T McKinley, Charles A Herring, Jonathan M Irish, M Kay Washington, Robert J Coffey, Ken S Lau
Cellular heterogeneity poses a substantial challenge to understanding tissue-level phenotypes and confounds conventional bulk analyses. To analyze signaling at the single-cell level in human tissues, we applied mass cytometry using cytometry time of flight to formalin-fixed, paraffin-embedded (FFPE) normal and diseased intestinal specimens. This technique, called FFPE-DISSECT (disaggregation for intracellular signaling in single epithelial cells from tissue), is a single-cell approach to characterizing signaling states in embedded tissue samples...
October 11, 2016: Science Signaling
Yuka Hirashita, Yoshiyuki Tsukamoto, Kazuyoshi Yanagihara, Shoichi Fumoto, Naoki Hijiya, Chisato Nakada, Tomohisa Uchida, Keiko Matsuura, Masaaki Kodama, Tadayoshi Okimoto, Tsutomu Daa, Masataka Seike, Hidekatsu Iha, Kuniaki Shirao, Kazunari Murakami, Masatsugu Moriyama
Since gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, targeting of the RTK/KRAS-downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. Here, we assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS-downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition...
October 3, 2016: Cancer Science
Gabriel Nasri Marzuca-Nassr, Kaio Fernando Vitzel, Luís Gustavo De Sousa, Gilson M Murata, Amanda Rabello Crisma, Carlos Flores Rodrigues Junior, Phablo Abreu, Rosângela Pavan Torres, Jorge Mancini-Filho, Sandro M Hirabara, Philip Newsholme, Rui Curi
The effects of either eicosapentaenoic (EPA)- or docosahexaenoic (DHA)-rich fish oils on hindlimb suspension (HS)-induced muscle disuse atrophy were compared. Daily oral supplementations (0.3 mL/100 g b.w.) with mineral oil (MO) or high EPA or high DHA fish oils were performed in adult rats. After 2 weeks, the animals were subjected to HS for further 2 weeks. The treatments were maintained alongside HS At the end of 4 weeks, we evaluated: body weight gain, muscle mass and fat depots, composition of fatty acids, cross-sectional areas (CSA) of the soleus muscle and soleus muscle fibers, activities of cathepsin L and 26S proteasome, and content of carbonylated proteins in the soleus muscle...
September 2016: Physiological Reports
Adriana D Hernandez-García, Daniel A Columbus, Rodrigo Manjarín, Hanh V Nguyen, Agus Suryawan, Renán A Orellana, Teresa A Davis
Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight-fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps...
October 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
Nisebita Sahu, Darlene Dela Cruz, Min Gao, Wendy Sandoval, Peter M Haverty, Jinfeng Liu, Jean-Philippe Stephan, Benjamin Haley, Marie Classon, Georgia Hatzivassiliou, Jeff Settleman
The role of essential amino acids in metabolic reprogramming of cancer cells is now well established, whereas the role of non-essential amino acids (NEAAs) in malignancy remains less clear. Here, we have identified an important role for the NEAA proline in the tumorigenic potential of a subset of cancer cells. By profiling a large panel of cancer cell lines, we observed that proline consumption and expression of proline biosynthesis enzymes were well correlated with clonogenic and tumorigenic potential. Moreover, proline starvation or inhibition of proline biosynthesis enzymes impaired clonogenic/tumorigenic potential...
September 3, 2016: Cell Metabolism
Kevin M Mazor, Martha H Stipanuk
Amino-acid deprivation is sensed by the eIF2α kinase GCN2. Under conditions of essential amino-acid limitation, GCN2 phosphorylates eIF2α, inhibiting the formation of a new ternary complex and hence mRNA translation initiation. While decreasing global mRNA translation, eIF2α phosphorylation also increases the translation of the integrated stress response (ISR) transcription factor ATF4, which increases the expression of many stress response genes that contain a C/EBP-ATF response element (CARE), including Atf4, 4Ebp1, Asns, and Chop...
September 10, 2016: Amino Acids
Camilo Mejia, Josh Lewis, Clinton Jordan, Juan Mejia, Connor Ogden, Troy Monson, Duane Winden, Marc Watson, Paul R Reynolds, Juan A Arroyo
Cigarette smoke is known to be a risk for the development of intrauterine growth restriction (IUGR). Our objective was to assess the effects of secondhand smoke (SHS) during pregnancy and to what extent it regulates the activation of mTOR family members and murine trophoblast invasion. Mice were treated to SHS for 4 days. Placental and fetal weights were recorded at the time of necropsy. Immunohistochemistry was used to determine the level of placental trophoblast invasion. Western blots were utilized to assess the activation of caspase 3, XIAP, mTOR, p70 and 4EBP1 in treated and control placental lysates...
September 9, 2016: Cell and Tissue Research
Aanchal Kakkar, Atreye Majumdar, Anupam Kumar, Manjari Tripathi, Pankaj Pathak, Mehar C Sharma, Vaishali Suri, Vivek Tandon, Sarat P Chandra, Chitra Sarkar
OBJECTIVE: Recently, BRAF V600E mutation, and activation of mTOR and MAPK pathways have been identified in various glial/glioneuronal tumors. Dysembryoplastic neuroepithelial tumors (DNTs) are epilepsy-associated glioneuronal neoplasms which have not been analyzed extensively in this respect. METHODS: Sequencing for BRAF V600E mutation, analysis of BRAF copy number by qRT-PCR, and immunohistochemistry for mTOR (p-S6, p-4EBP1) and MAPK (p-MAPK) pathways were performed...
August 28, 2016: Epilepsy Research
Chuan Shen, Chenghong Peng, Baiyong Shen, Zhecheng Zhu, Ning Xu, Tao Li, Junjie Xie
Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM)...
August 25, 2016: Oncotarget
J X Zhao, X D Liu, K Li, W Z Liu, Y S Ren, J X Zhang
The objective of this experiment was to investigate the mechanisms through which different levels of dietary energy affect postnatal skeletal muscle development in ewe lambs. Twelve Dorper × Small Thin-Tailed crossbred ewe lambs (100 d of age; 20 ± 0.5 kg BW) were selected randomly and divided into 2 groups in a completely randomized design. Animals were offered identical diets at 100% or 65% of ad libitum intake. Lambs were euthanized when BW in the ad libitum group reached 35 kg and the semitendinosus muscle was sampled...
October 2016: Domestic Animal Endocrinology
YanHong Wang, JunQiang Liu, Hui Wu, XingTang Fang, Hong Chen, ChunLei Zhang
PURPOSE: The mechanism of dietary amino acids in regulating milk protein synthesis at the translational level is not well understood. Numerous studies have shown that the amino acid signal is transferred through the mammalian target of rapamycin (mTOR) pathway; however, the extracellular amino acid-sensing mechanism that activates mTOR complex 1 is unknown. We tested the hypotheses that the T1R1/T1R3 heterodimer functions as a direct sensor of the fed state and amino acid availability preceding the mTOR pathway and affects milk protein synthesis in mammary epithelial cells...
August 18, 2016: European Journal of Nutrition
W L Zhang, W J Ma, S Chen, X Z Wu, H R Zhang, J H Zhang
OBJECTIVE: To explore the molecular mechanisms of resistance to phosphatidyl inositol 3-kinase (PI3K) inhibitors in triple-negative breast cancer (TNBC) cells. METHODS: HCC70 cells (TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β-catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF-7 (ER-positive) and SK-BR3 (HER2-positive) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations (IC50) were calculated...
August 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
Moni Nader, Nathalie Chahine, Charelle Salem, Ramez Chahine
Restoration of blood flow to the ischemic myocardium is imperative to avoid demise of cardiomyocytes, but is paradoxically associated with irreversible damage to cardiac tissues due to the excessive generation of reactive oxygen species (ROS). We have previously reported that saffron, a natural antioxidant, attenuated ischemia-reperfusion (IR) injuries in vitro; however, its role in a meaningful cardiac recovery remains unknown. Here, we show that saffron supplement (oral administration for 6 weeks) reduced myocardial damage and restored cardiac function in an IR model of rabbit hearts...
August 10, 2016: Journal of Physiology and Biochemistry
Si Hyoung Kim, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Seong Jin Lee
The effec.t of BIIB021, a novel heat shock protein 90 (hsp90) inhibitor, on survival of thyroid carcinoma cells has not been evaluated. In this study, the impact of BIIB021 alone or in combination with the histone acetyltransferase inhibitor triptolide on survival of thyroid carcinoma cells was identified. In 8505C and TPC-1 thyroid carcinoma cells, BIIB021 caused cell death in conjunction with alterations in expression of hsp90 client proteins. Cotreatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, decreased cell viability, and increased the percentage of dead cells and cytotoxic activity...
June 18, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Kai Hu, Hai-Bo Dai, Zhi-Long Qiu
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that belongs to the phosphoinositide-3-kinase (PI3K)-related kinase family. Oncogenic activation of mTOR signaling significantly contributes to the progression of different types of cancers including osteosarcoma (OS; the most common primary malignant tumor of bone). In the present study, we review the association of the mTOR signaling pathway with OS, and the possible effective treatment strategies by targeting this pathway. In the metastatic behavior of OS, one of the most common actionable aberrations was found in the PI3K/Akt/mTOR pathway...
September 2016: Oncology Reports
Hiromi Ito, Osamu Ichiyanagi, Sei Naito, Vladimir N Bilim, Yoshihiko Tomita, Tomoyuki Kato, Akira Nagaoka, Norihiko Tsuchiya
BACKGROUND: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin 1 (mTORC1) signaling pathway is aberrantly activated in renal cell carcinoma (RCC). We previously demonstrated glycogen synthase kinase-3β (GSK-3β) positively regulated RCC proliferation. The aim of this study was to evaluate the role of GSK-3 in the PI3K/Akt/mTORC1 pathway and regulation of the downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), ribosomal protein S6 kinase (S6K), and ribosomal protein S6 (S6RP)...
2016: BMC Cancer
Fuzhi Zhuang, Mei Li, Xin Gao, Yun Wang, Dongdong Wang, Xing Ma, Tengfei Ma, Shuling Gu
Alarin is a newly derived neuropeptide from a splice variant of the galanin-like peptide gene. We previously showed that alarin has an antidepressant-like effect by increasing the activity of the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways, mediated by the tropomyosin-related kinase B receptor in the unpredictable chronic mild stress (UCMS) mouse model. Administration of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents the rapid antidepressant-like effect induced by ketamine in animal models, indicating a vital role of mTOR in depression pathophysiology...
October 15, 2016: Behavioural Brain Research
David Barras, Edoardo Missiaglia, Pratyaksha Wirapati, Oliver M Sieber, Robert N Jorissen, Christopher Love, Peter L Molloy, Ian T Jones, Stephen McLaughlin, Peter Gibbs, Justin Guinney, Iris M Simon, Arnaud Roth, Fred T Bosman, Sabine Tejpar, Mauro Delorenzi
PURPOSE: Mutation of BRAF at the valine 600 residue occurs in ~10% of colorectal cancers (CRC), a group with particularly poor prognosis. The response of BRAF mutant CRC to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains minimal and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E CRC and potential subgroups within this population. EXPERIMENTAL DESIGN: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data, we performed unsupervised clustering using non-negative matrix factorization to identify gene expression based subgroups and characterized pathway activation...
June 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Matthew H Sharp, Ryan P Lowery, C Brooks Mobley, Carlton D Fox, Eduardo O de Souza, Kevin A Shields, James C Healy, Ned Q Arick, Richard M Thompson, Michael D Roberts, Jacob M Wilson
OBJECTIVE: The purpose of this study was to investigate the effects of Fortetropin on skeletal muscle growth and strength in resistance-trained individuals and to investigate the anabolic and catabolic signaling effects using human and rodent models. METHODS: In the rodent model, male Wistar rats (250 g) were gavage fed with either 1.2 ml of tap water control (CTL) or 0.26 g Fortetropin for 8 days. Then rats participated in a unilateral plantarflexion exercise bout...
June 22, 2016: Journal of the American College of Nutrition
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