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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
X H Sun, M S Yin, Y L Mu
Objective: To investigate the alterations of mTOR signaling pathway and autophagy in the development of type 2 diabetes and early diabetic cardiomyopathy and to study their roles in pathogenesis of diabetic myocardium. Methods: A type 2 diabetes rat model was established by injection of streptozocin after five-week of high fat diet. The rats were randomly divided into control group, experiment group of 2 weeks and experiment group of 4 weeks. Alterations of mTOR, p-mTOR, S6K1, Beclin-1 and LC3-Ⅱ expression in myocardium were determined by Western blot and immunohistochemistry...
October 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Kristen T Crowell, David I Soybel, Charles H Lang
Muscle deconditioning is commonly observed in patients surviving sepsis. Little is known regarding the molecular mechanisms regulating muscle protein homeostasis during the recovery or convalescence phase. We adapted a sepsis-recovery mouse model that uses cecal ligation and puncture (CLP), followed 24 h later by cecal resection and antibiotic treatment, to identify putative cellular pathways regulating protein synthesis and breakdown in skeletal muscle. Ten days after CLP, body weight and food consumption did not differ between control and sepsis-recovery mice, but gastrocnemius weight was reduced...
October 5, 2016: Shock
Dong Xue, Cuixing Zhou, Hao Lu, Renfang Xu, Xianlin Xu, Xiaozhou He
In prior research, evidence has been found for a relation between low exposure of long non-coding RNAs (lncRNAs) and prostate tumor genesis. This study aims to clarify the underlying mechanisms of lncRNA GAS5 in prostate cancer (PCa). In total, 118 pairs of PCa tissues and matched adjacent non-tumor tissues were collected. Additionally, lncRNA GAS5 exposure levels were determined using RT-PCR and in situ hybridization. In addition, dual-luciferase report assay was performed to verify the target effect of lncRNA GAS5 on miR-103...
October 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Manuela Marabita, Martina Baraldo, Francesca Solagna, Judith Johanna Maria Ceelen, Roberta Sartori, Hendrik Nolte, Ivan Nemazanyy, Stéphane Pyronnet, Marcus Kruger, Mario Pende, Bert Blaauw
Loss of skeletal muscle mass and force aggravates age-related sarcopenia and numerous pathologies, such as cancer and diabetes. The AKT-mTORC1 pathway plays a major role in stimulating adult muscle growth; however, the functional role of its downstream mediators in vivo is unknown. Here, we show that simultaneous inhibition of mTOR signaling to both S6K1 and 4E-BP1 is sufficient to reduce AKT-induced muscle growth and render it insensitive to the mTORC1-inhibitor rapamycin. Surprisingly, lack of mTOR signaling to 4E-BP1 only, or deletion of S6K1 alone, is not sufficient to reduce muscle hypertrophy or alter its sensitivity to rapamycin...
October 4, 2016: Cell Reports
Zahra Taherian-Esfahani, Atieh Abedin-Do, Zahra Nouri, Reza Mirfakhraie, Soudeh Ghafouri-Fard, Elahe Motevaseli
BACKGROUND: Lactobacilli are a group of beneficial bacteria whose anti cancer effects have been evaluated in different cancer cell lines as well as animal models and human subjects. Such anti cancer effects can be exerted via different mechanisms such as modulation of immune response as well as inhibition of pathogens colonization. In addition, lactobacilli have direct cytotoxic effects against cancer cells which may be exerted through modulation of expression cancer related pathways...
June 2016: Iranian Journal of Cancer Prevention
Klaudyna Fidyt, Anna Fiedorowicz, Leon Strządała, Antoni Szumny
Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. Nevertheless, their antineoplastic effects have hardly been investigated in vivo. In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells. The mechanisms underlying the anticancer activities of these sesquiterpenes are poorly described...
September 30, 2016: Cancer Medicine
Alisson L da Rocha, Ana P Pinto, Giovana R Teixeira, Bruno C Pereira, Luciana C Oliveira, Adriana C Silva, Gustavo P Morais, Dennys E Cintra, José R Pauli, Adelino S R da Silva
Recently, we demonstrated that an overtraining (OT) protocol for mice based on downhill running sessions increased the hepatic phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (S6K1; Thr389), a downstream target of the mammalian target of rapamycin complex 1 (mTORC1). In liver, the overactivation of the Akt/mTORC1 pathway induces lipogenesis via regulation of the action of sterol regulatory element binding protein-1 (SREBP-1) at multiple steps. Herein, we verified the effects of three running OT models with same external load (i...
September 29, 2016: Journal of Cellular Physiology
Lili Wang, Jingang Yang, Changling Li, Sining Xing, Ying Yu, Shuo Liu, Song Zhao, Dongchu Ma
Objective To investigate regulatory role of ribosomal protein S6 kinase 1 (S6K1) in the polyploidization of different megakaryocytic leukemia cell lines at the different differentiation stages. Methods Megakaryocytic leukemia cell lines (Dami, Meg-01 and HEL cells) were induced towards polyploidization by SP600125, a c-Jun N-terminal kinase (JNK) inhibitor. The SP600125-inducing process was blocked by H-89, a cAMP-dependent protein kinase (PKA) inhibitor. The phenotype (CD41a, CD42a and CD42b) and DNA ploidy were detected by flow cytometry...
October 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Song Zhao, Jingang Yang, Changling Li, Sining Xing, Ying Yu, Shuo Liu, Feifei Pu, Dongchu Ma
Objective To investigate the regulatory effect of post-translation modification of ribosomal protein S6 kinase 1 (S6K1) on the polyploidization of megakaryocytes. Methods SP600125, a c-Jun N-terminal kinase (JNK) inhibitor, and H-89, a cAMP-dependent protein kinase (PKA) inhibitor, were used to treat CMK cells separately or in combination. With propidium iodide (PI) to dye DNA in the treated cells, the relative DNA content was detected by flow cytometry, and then the DNA polyploidy was analyzed. The change of expression and phosphorylation of ribosomal protein S6 kinase 1 (S6K1), an important mammalian target of rapamycin (mTOR) downstream target molecule, was analyzed by Western blotting...
October 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
İsmet Gün, Özkan Özdamar, Zafer Küçükodacı, Murat Muhçu, Dilaver Demirel
OBJECTIVE: To assess whether the immunopositivity of S6K1, a crucial effector of the mTOR signaling pathway, varies between early-stage low-grade and advanced-stage high-grade endometrial endometrioid adenocarcinoma (EEA) as well as to discuss its prognostic significance. MATERIAL AND METHODS: A total of 22 normal endometrial tissue samples (Control group) and 41 EEA specimens (Study group) were enrolled in the study, and all the samples underwent immunohistochemical staining for S6 kinase alpha (S6K1)...
2016: Journal of the Turkish German Gynecological Association
Jisoo Park, Quangdon Tran, Kisun Mun, Kouhei Masuda, So Hee Kwon, Seon-Hwan Kim, Dong-Hoon Kim, George Thomas, Jongsun Park
The major biological function of mitochondria is to generate cellular energy through oxidative phosphorylation. Apart from cellular respiration, mitochondria also play a key role in signaling processes, including aging and cancer metabolism. It has been shown that S6K1-knockout mice are resistant to obesity due to enhanced beta-oxidation, with an increased number of large mitochondria. Therefore, in this report, the possible involvement of S6K1 in regulating mitochondria dynamics and function has been investigated in stable lenti-shS6K1-HeLa cells...
December 2016: Cellular Signalling
Yuan Feng, Jihong Zhou, Zhanhua Li, Ying Jiang, Ying Zhou
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation...
2016: PloS One
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
Pan Tan, Yan-Jiao Wang, Shuang Li, Yi Wang, Je-Yu He, Yi-Yin Chen, Hui-Qian Deng, Wu Huang, Jun-Kun Zhan, You-Shuo Liu
Replicative senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related cardiovascular diseases. Rapamycin can delay the onset of aging-related diseases via inhibition of the mammalian target of rapamycin (mTOR), but its role in vascular aging remains elusive. This study investigated the involvement of mTOR signaling in replicative senescence of VSMCs. Replicative senescence was induced by the extended passages of human VSMCs. Aging-related cell morphology was observed. The aging-related proteins and enzyme activity, and oxidative stress were measured...
November 2016: Molecular and Cellular Biochemistry
Zhe-Zhu Jin, Wei Wang, Di-Long Fang, Yong-Jun Jin
We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment...
September 30, 2016: Biochemical and Biophysical Research Communications
Jinghui Liu, Beilei Wang, Pu Huang, Hanying Wang, Kailun Xu, Xiaofeng Wang, Lihong Xu, Zonglou Guo
Microcystin-LR (MC-LR), a heptapeptide produced by blue-green algae, is shown to induce cytotoxicity by inhibiting protein phosphatase 2A (PP2A) activity. Our previous study revealed that MC-LR promoted cell proliferation in vitro by activating the Akt/mTORC1/S6K1 pathway. This study aims to further investigate the effects of MC-LR on cell proliferation and the correlated mechanisms in vivo. Mice were injected intraperitoneally with 20-80 μg/kg/d MC-LR from 2 h (hours) to 4 d (days). The results showed that the associations of MC-LR with PP2A/C (PP2A C subunit) were concentration-dependent but not time-dependent in the liver, whereas the total PP2A activity was inhibited in both concentration and time dependent manners...
November 2016: Chemosphere
Isadora C B Pavan, Sami Yokoo, Daniela C Granato, Letícia Meneguello, Carolina M Carnielli, Mariana R Tavares, Camila L do Amaral, Lidia B de Freitas, Adriana F Paes Leme, Augusto D Luchessi, Fernando M Simabuco
S6Ks are major effectors of the mTOR (mammalian target of rapamycin) pathway, signaling for increased protein synthesis and cell growth in response to insulin, AMP/ATP levels, and amino acids. Deregulation of this pathway has been related to disorders and diseases associated with metabolism, such as obesity, diabetes, and cancer. S6K family is composed of two main members, S6K1 and S6K2, which comprise different isoforms resulted from alternative splicing or alternative start codon use. Although important molecular functions have been associated with p70-S6K1, the most extensively studied isoform, the S6K2 counterpart lacks information...
October 2016: Proteomics
Yu-Hsuan Hsiao, Yu-Ting Huang, Chia-Yu Hung, Tzu-Chien Kuo, Fuh-Jinn Luo, Ta-Chun Yuan
Androgen receptor (AR) is a steroid hormone receptor that functions as a transcription factor for regulating cell growth and survival. Aberrant AR function becomes a risk factor for promoting the progression of prostate cancer (PCa). In this study, we examined the roles of proline-rich tyrosine kinase 2 (PYK2) and ribosomal S6 kinase 1 (S6K1) in regulating AR expression and activity and growth properties in PCa cells. Compared with normal prostate tissues, PCa tumors exhibited high levels of PYK2 and S6K1 expression...
August 2016: Endocrine-related Cancer
Camila L Amaral, Lidia B Freitas, Rodrigo E Tamura, Mariana R Tavares, Isadora C B Pavan, Marcio C Bajgelman, Fernando M Simabuco
BACKGROUND: The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms-p70-S6K1, p85-S6K1 and p54-S6K2-in prostate cancer, as well as their potential as therapeutic targets...
2016: BMC Cancer
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