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mTOR inhibition

Adam C Labonte, Sun-Sang J Sung, Lucas T Jennelle, Aditya P Dandekar, Young S Hahn
: The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Michael L Schulte, Matthew R Hight, Gregory D Ayers, Qi Liu, Yu Shyr, M Kay Washington, H Charles Manning
PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF (V600E) , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting...
October 21, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Ruinan Gu, Fali Zhang, Gang Chen, Chaojun Han, Jay Liu, Zhaoxiang Ren, Yi Zhu, John L Waddington, Long Tai Zheng, Xuechu Zhen
Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis...
October 18, 2016: Brain, Behavior, and Immunity
Chao-Ming Hung, Ying-Chao Lin, Liang-Chih Liu, Sheng-Chu Kuo, Chi-Tang Ho, Tzong-Der Way
CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU-145 and LNCap. It had a very low IC50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin at the colchicine-binding site then disrupted microtubule polymerization...
October 18, 2016: Chemico-biological Interactions
Cheng-Fu Chang, Yi-Chao Lee, Kuen-Haur Lee, Hui-Ching Lin, Chia-Ling Chen, Che-Kun James Shen, Chi-Chen Huang
BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS...
October 21, 2016: Journal of Biomedical Science
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
Oznur Bayraktar, Ozlem Oral, Nur Mehpare Kocaturk, Yunus Akkoc, Karin Eberhart, Ali Kosar, Devrim Gozuacik
The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone...
2016: PloS One
Chihua Wu, Jing Luo
BACKGROUND Long non-coding RNA (lncRNA) UCA1 is an oncogene in breast cancer. The purpose of this study was to investigate the role of UCA1 in tamoxifen resistance of estrogen receptor positive breast cancer cells. MATERIAL AND METHODS Tamoxifen sensitive MCF-7 cells were transfected for UCA1 overexpression, while tamoxifen resistant LCC2 and LCC9 cells were transfected with UCA siRNA for UCA1 knockdown. qRT-PCR was performed to analyze UCA1 expression. CCK-8 assay, immunofluorescence staining of cleaved caspase-9, and flow cytometric analysis of Annexin V/PI staining were used to assess tamoxifen sensitivity...
October 21, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Susan Heavey, Sinead Cuffe, Stephen Finn, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Niall McVeigh, Martin Barr, Kenneth O'Byrne, Kathy Gately
Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression...
October 19, 2016: Oncotarget
Xin-Shuang Yu, Juan Du, Yu-Jun Fan, Feng-Jun Liu, Li-Li Cao, Ning Liang, De-Guo Xu, Jian-Dong Zhang
OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h...
October 18, 2016: Oncotarget
Marco Tucci, Stefania Stucci, Anna Passarelli, Stella D'Oronzo, Franco Silvestris
Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM), and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, EVR significantly abrogated the in vitro OC-like activity of DCs from 12 MM patients. Exploring the EVR effects, we found that the inhibition of the osteo-erosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward CEBPbeta/MAFB axis Therefore, MM patients with MBD would probably benefit from mTOR inhibition...
October 17, 2016: Experimental Hematology
Mª Carmen Herrero-Sánchez, Concepción Rodríguez-Serrano, Julia Almeida, Laura San Segundo, Susana Inogés, Ángel Santos-Briz, Jesús García-Briñón, Luis Antonio Corchete, Jesús F San Miguel, Consuelo Del Cañizo, Belén Blanco
BACKGROUND: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect...
October 20, 2016: Journal of Hematology & Oncology
Marc A Becker, Xiaonan Hou, Piyawan Tienchaianada, Brian B Haines, Sean C Harrington, S John Weroha, Sriram Sathyanarayanan, Paul Haluska
BACKGROUND: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years...
October 20, 2016: BMC Cancer
Anil Prasad, Nagina Khudaynazar, Ramana V Tantravahi, Amanda M Gillum, Benjamin S Hoffman
Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC...
October 15, 2016: Oncotarget
Kosuke Toda, Kenji Kawada, Masayoshi Iwamoto, Susumu Inamoto, Takehiko Sasazuki, Senji Shirasawa, Suguru Hasegawa, Yoshiharu Sakai
A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor-based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC...
October 17, 2016: Neoplasia: An International Journal for Oncology Research
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
Lu Cao, Mingui Fu, Santosh Kumar, Anil Kumar
Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity...
October 20, 2016: Cell Death & Disease
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
Jing Zhang, Ya-Qin Tan, Ming-Hui Wei, Xiao-Jing Ye, Guan-Ying Chen, Rui Lu, Ge-Fei Du, Gang Zhou
Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4(+) T cells and CD8(+) T cells. B7-H1 induced by Toll-like receptors (TLRs), can suppress T cell immune reaction, thereby resulting in immune tolerance. However, the role of TLRs-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway down-regulated B7-H1 transcriptional expression...
October 20, 2016: Experimental Dermatology
K R Vogel, G R Ainslie, E E W Jansen, G S Salomons, K M Gibson
Aldehyde dehydrogenase 5a1-deficient (aldh5a1(-/-)) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1(-/-) mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR...
October 16, 2016: Biochimica et Biophysica Acta
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