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https://www.readbyqxmd.com/read/28811599/histone-deacetylase-6-hdac6-is-an-essential-factor-for-oocyte-maturation-and-asymmetric-division-in-mice
#1
Dongjie Zhou, Yun-Jung Choi, Jin-Hoi Kim
Tubastatin A (Tub-A), a highly selective histone deacetylase 6 (HDAC6) inhibitor, has been widely used as a cytotoxic anticancer agent, or for the treatment of patients with asthma. However, the potential toxicity of Tub-A on oocyte maturation and asymmetric division is still unclear. Therefore, the present study was designed to examine the effect and potential regulatory role of Tub-A on the meiotic maturation of oocytes. We observed that Tub-A treatment induced an increased level of the acetylation of α-tubulin, and a failure of spindle migration and actin cap formation...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811537/prognostic-significance-and-function-of-mammalian-target-of-rapamycin-in-tongue-squamous-cell-carcinoma
#2
Shau-Hsuan Li, Chih-Yen Chien, Wan-Ting Huang, Sheng-Dean Luo, Yan-Ye Su, Wan-Yu Tien, Ya-Chun Lan, Chang-Han Chen
Despite improvement in preoperative imaging, surgical technique, and adjuvant therapy, the prognosis of patients with tongue squamous cell carcinoma (SCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) play a key role in the regulation of tumor cell proliferation and survival. However, the significance of mTOR on the prognosis of tongue SCC remains largely undefined. In the present study, immunohistochemistry was performed to evaluate the expression of phosphorylated mTOR (p-mTOR) in 160 surgically resected tongue SCC, and correlated with survival...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28810557/role-of-mammalian-target-of-rapamycin-signaling-in-autophagy-and-the-neurodegenerative-process-using-a-senescence-accelerated-mouse-prone-8-model
#3
Yanyong Wang, Qinying Ma, Xiaowei Ma, Zhongxia Zhang, Na Liu, Mingwei Wang
The mammalian target of rapamycin (mTOR) kinase is an inhibitor of autophagy, which is an intracellular system involved in the degradation of long-lived proteins and organelles in lysosomes. Recent evidence suggests that the steady incline in mTOR function during aging may be associated with the cognitive decline related to aging and may also promote development of Tau pathology. At present, the senescence accelerated mouse prone 8 (SAMP8) is an experimental model that has been proposed for the study of age-related neurodegenerative changes associated with aging...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28807764/staphylococcal-enterotoxin-c2-mutant-drives-t-lymphocyte-activation-through-pi3k-mtor-and-nf-%C3%A4-b-signaling-pathways
#4
Xuanhe Fu, Mingkai Xu, Songyuan Yao, Huiwen Zhang, Chenggang Zhang, Jinghai Zhang
Staphylococcal enterotoxin C2 (SEC2), a superantigen, causes rapid clonal expansion of lymphocytes and secretion of T cell growth factors, leading to a severe inflammatory response within tissues. Although previous studies have shown that ST-4, a SEC2 mutant with enhanced recognition of Vβ regions of T-cell receptors (TCRVβ), can activate an increased number of T cells and produce more cytokines than SEC2. However, the signaling mechanisms of SEC2/ST-4-mediated immune activation have not been addressed. In this study, we showed that the phosphatidylinositide-3-kinase (PI-3K) inhibitor LY294002, mammalian target of rapamycin (mTOR) inhibitor rapamycin, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor Bay11-7085 could suppress SEC2/ST-4-induced proliferation, CD69/CD25 expression, cell-cycle progression, and IL-2 production in BALB/c mouse splenocytes...
August 11, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28806782/the-use-of-18f-fluoro-deoxy-glucose-positron-emission-tomography-18f-fdg-pet-as-a-non-invasive-pharmacodynamic-biomarker-to-determine-the-minimally-pharmacologically-active-dose-of-azd8835-a-novel-pi3k%C3%AE-inhibitor
#5
Juliana Maynard, Sally-Ann Emmas, Francois-Xavier Ble, Herve Barjat, Emily Lawrie, Urs Hancox, Urszula M Polanska, Alison Pritchard, Kevin Hudson
BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development...
2017: PloS One
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#6
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28805979/effects-of-mtor-inhibition-on-cardiac-and-adipose-tissue-pathology-and-glucose-metabolism-in-rats-with-metabolic-syndrome
#7
Ayako Uchinaka, Mamoru Yoneda, Yuichiro Yamada, Toyoaki Murohara, Kohzo Nagata
The mammalian target of rapamycin (mTOR) is a regulator of metabolism and is implicated in pathological conditions such as obesity and diabetes. We aimed to investigate the role of mTOR in obesity. A new animal model of metabolic syndrome (MetS), named DahlS.Z-Lepr(fa) /Lepr(fa) (DS/obese) rats was established previously in our laboratory. In this study, we used this model to evaluate the effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism. DS/obese rats were treated with the mTOR inhibitor, everolimus, (0...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28802652/an-autophagic-mechanism-is-involved-in-the-6-hydroxydopamine-induced-neurotoxicity-in-vivo
#8
Xin He, Wei Yuan, Zijian Li, Juan Feng
6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied...
August 9, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28802252/exploiting-radiation-induced-signaling-to-increase-the-susceptibility-of-resistant-cancer-cells-to-targeted-drugs-akt-and-mtor-inhibitors-as-an-example
#9
Iris Eke, Adeola Y Makinde, Molykutty J Aryankalayil, Veit Sandfort, Sanjeewani T Palayoor, Barbara H Rath, Lance Liotta, Mariaelena Pierobon, Emanuel F Petricoin, Matthew F Brown, Jayne M Stommel, Mansoor M Ahmed, C Norman Coleman
Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate pro-survival pathways which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28801605/luteolin-a-natural-flavonoid-inhibits-methylglyoxal-induced-apoptosis-via-the-mtor-4e-bp1-signaling-pathway
#10
Yi Liu, Jie Huang, Xian Zheng, Xia Yang, Yan Ding, Tongyong Fang, Yuyun Zhang, Shuaishuai Wang, Xiaofei Zhang, Xuan Luo, Anlei Guo, Kelly A Newell, Yinghua Yu, Xu-Feng Huang
Methylglyoxal (MG) accumulation has been observed in human cerebrospinal fluid and body tissues under hyperglycaemic conditions. Recent research has demonstrated that MG-induces neuronal cell apoptosis, which promotes the development of diabetic encephalopathy. Our previous animal study has shown that luteolin, a natural flavonoid, attenuates diabetes-associated cognitive dysfunction. To further explore the neuroprotective properties of luteolin, we investigated the inhibitive effect of luteolin on MG-induced apoptosis in PC12 neuronal cells...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#11
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28796163/hypertension-caused-by-lenvatinib-and-everolimus-in-the-treatment-of-metastatic-renal-cell-carcinoma
#12
REVIEW
Mathias Alrø Fichtner Bendtsen, Daniela Grimm, Johann Bauer, Markus Wehland, Petra Wise, Nils E Magnusson, Manfred Infanger, Marcus Krüger
Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC...
August 10, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28795288/novel-agents-in-the-treatment-of-thymic-malignancies
#13
REVIEW
Claire Merveilleux du Vignaux, Jean-Michel Maury, Nicolas Girard
The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed...
August 10, 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28794469/targeting-the-pi3k-akt-mtor-signalling-pathway-in-cystic-fibrosis
#14
R Reilly, M S Mroz, E Dempsey, K Wynne, S J Keely, E F McKone, C Hiebel, C Behl, J A Coppinger
Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28794108/plk1-regulates-spindle-association-of-phosphorylated-eukaryotic-translation-initiation-factor-4e-binding-protein-and-spindle-function-in-mouse-oocytes
#15
Ashley L Severance, Keith E Latham
Oocyte meiotic spindles are associated with spindle-enriched mRNAs, phosphorylated ribosome protein S6, and phosphorylated variants of the key translational regulator EIF4EBP1, consistent with translational control of localized mRNAs by EIF4EBP1 in facilitating spindle formation and stability. Using specific kinase inhibitors, we determined which kinases regulate phosphorylation status of EIF4EBP1 associated with meiotic spindles in mouse oocytes, and effects of kinase inhibition on chromosome congression and spindle formation...
August 9, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28793293/triggering-of-eryptosis-the-suicidal-erythrocyte-death-by-mammalian-target-of-rapamycin-mtor-inhibitor-temsirolimus
#16
Abdulla Al Mamun Bhuyan, Hang Cao, Florian Lang
BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is utilized for the treatment of malignancy. Temsirolimus is at least in part effective by triggering suicidal tumor cell death. The most common side effect of temsirolimus treatment is anemia. At least in theory, the anemia following temsirolimus treatment could result from stimulation of eryptosis, the suicidal erythrocyte death. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface...
July 24, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28790887/mir-16-and-fluoxetine-both-reverse-autophagic-and-apoptotic-change-in-chronic-unpredictable-mild-stress-model-rats
#17
Yang Yang, Zhiying Hu, Xiaoxue Du, Henry Davies, Xue Huo, Marong Fang
In the clinic selective serotonin reuptake inhibitors (SSRIs), like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT) via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS) depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28790340/verteporfin-inhibits-growth-of-human-glioma-in-vitro-without-light-activation
#18
Ahmad Al-Moujahed, Katarzyna Brodowska, Tomasz P Stryjewski, Nikolaos E Efstathiou, Ioannis Vasilikos, Joanna Cichy, Joan W Miller, Evangelos Gragoudas, Demetrios G Vavvas
Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19)...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28789624/hedgehog-inhibitor-sonidegib-potentiates-177-lu-octreotate-therapy-of-got1-human-small-intestine-neuroendocrine-tumors-in-nude-mice
#19
Johan Spetz, Britta Langen, Nils Rudqvist, Toshima Z Parris, Khalil Helou, Ola Nilsson, Eva Forssell-Aronsson
BACKGROUND: (177)Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of (177)Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using (177)Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib...
August 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28781084/crystal-structure-and-regulation-of-the-citrus-pol-iii-repressor-maf1-by-auxin-and-phosphorylation
#20
Adriana Santos Soprano, Priscila Oliveira de Giuseppe, Hugo Massayoshi Shimo, Tatiani Brenelli Lima, Fernanda Aparecida Heleno Batista, Germanna Lima Righetto, José Geraldo de Carvalho Pereira, Daniela Campos Granato, Andrey Fabricio Ziem Nascimento, Fabio Cesar Gozzo, Paulo Sérgio Lopes de Oliveira, Ana Carolina Migliorini Figueira, Juliana Helena Costa Smetana, Adriana Franco Paes Leme, Mario Tyago Murakami, Celso Eduardo Benedetti
MAF1 is the main RNA polymerase (Pol) III repressor that controls cell growth in eukaryotes. The Citrus ortholog, CsMAF1, was shown to restrict cell growth in citrus canker disease but its role in plant development and disease is still unclear. We solved the crystal structure of the globular core of CsMAF1, which reveals additional structural elements compared with the previously available structure of hMAF1, and explored the dynamics of its flexible regions not present in the structure. CsMAF1 accumulated in the nucleolus upon leaf excision, and this translocation was inhibited by auxin and by mutation of the PKA phosphorylation site, S45, to aspartate...
July 24, 2017: Structure
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