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Nanoparticle–Based RNA (siRNA) Combination Therapy Toward Overcoming Drug Resistance in Cancer
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Autophagy is considered to be a cytoprotective process involved in the normal turnover of long-lived proteins and whole organelles to maintain a healthy cellular status [157]. However, recent data strongly demonstrate that autophagy is intimately linked to apoptosis or necrosis and serves both pro-survival and pro-death functions. Autophagy regulation requires an orchestrated interplay between many signaling molecules, including mammalian target of rapamycin (mTOR) kinase, which has the most potent impact on autophagy [158,159]. Once activated, mTOR inhibits autophagy via the phosphorylation of autophagy-related proteins. AMP activated protein kinase (AMPK) activation can lead to autophagy by negatively regulating mTOR [160,161]. The tumor suppressor protein p53 can trigger autophagy by phosphorylating AMPK and further inhibiting the mTOR signaling pathway [160]. Beclin-1 also plays a critical role in autophagosome formation and crosstalk between autophagy and apoptosis [161]. The BH3 domain-mediated binding of Beclin-1 to B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL) inhibits autophagy. However, the c-Jun N-terminal kinase (JNK) 1- or extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Bcl-2 or death-associated protein kinase-mediated phosphorylation of Beclin-1 induces the dissociation of the Beclin-1–Bcl-2/Bcl-XL complex, thus inhibiting autophagy [161–165]. Intracellular calcium ions (Ca2+) can regulate the activation of JNK and the apoptotic signaling pathway [166].
Assessment of Quercetin Isolated from Enicostemma Littorale Against Few Cancer Targets: An in Silico Approach
Published in A. K. Haghi, Ana Cristina Faria Ribeiro, Lionello Pogliani, Devrim Balköse, Francisco Torrens, Omari V. Mukbaniani, Applied Chemistry and Chemical Engineering, 2017
The mammalian target of rapamycin (mTOR) also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) is a protein encoded by FRAP1 gene. mTOR is a serine/ threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient and energy levels and redox status. The mTOR pathway is dysregulated in human diseases, especially in certain cancers. Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12. The FKBP12-rapamycin complex binds directly to the FKBP12-rapamycin binding (FRB) domain of mTOR. mTOR is the catalytic subunit of two molecular complexes.4
Treatment Options for Chemical Sensitivity
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 5, 2017
William J. Rea, Kalpana D. Patel
This process of autophagy involves a series of protein complexes composed of atg gene products coordinate the formation of autophagosomes. The Atg1/ULK1 complex (Atg1 in yeast and ULK1 in mammals) is an essential positive regulator of autophagosome formation.183 When nutrients are abundant, binding of the ULK1 complex by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) inhibits autophagy. mTORC1 is an important regulator of cell growth and metabolism. It is composed of five subunits that include Raptor, which binds ULK1, and mTOR, a serine-threonine kinase. By phosphorylating ULK1 and another complex member (the mammalian homolog of yeast Atg13), mTOR inhibits autophagy initiation. In starvation, mTORC1 dissociates from the ULK1 complex, freeing it to trigger autophagosome nucleation and elongation.
The effects of phosphatidic acid on performance and body composition - a scoping review
Published in Journal of Sports Sciences, 2022
Filipe J. Teixeira, Nelson Tavares, Catarina N. Matias, Stuart M. Phillips
Phospholipid supplements have been gaining prominence due to their possible effect on sports performance (Jager et al., 2007). Phosphatidic acid (PA) is a structural phospholipid of cell membranes and an intracellular messenger that regulates several signalling proteins (Lim et al., 2003). Phospholipids contain two fatty acids and a phosphate group linked by a covalent bond to a glycerol molecule (Lim et al., 2003). Several studies have indicated that PA may be a signalling molecule that stimulates activation of the mechanistic target of rapamycin complex-1 (mTORC1) (Goodman, 2019; You et al., 2012, 2014). Stimulation of mTORC1 increases protein synthesis in response to RE (Dickinson et al., 2011). One could hypothesize that enhancing mTORC1 activity by the performance of RE and ingestion of PA may lead to a greater increase in muscle protein synthesis (MPS), which may lead to greater hypertrophic adaptations versus RE training without supplementation, especially if maintained at long term (> 10 weeks) (Damas et al., 2016). How PA activates mTORC1 and increases MPS is not yet fully understood.
MicroRNA expression profiling involved in MC-LR-induced hepatotoxicity using high-throughput sequencing analysis
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Shu Yang, Lv Chen, Cong Wen, Xian Zhang, Xiangling Feng, Fei Yang
To pinpoint the target genes affected by miRNAs, GO enrichment analyses revealed that the processes significantly altered by MC-LR involved systems development, metabolism, and protein binding. Further, KEGG pathway enrichment analysis showed that the target genes of differentially expressed miRNAs in normal liver cell line predominantly participated in mTOR signaling pathway, Ras signaling pathway, Rap1 signaling pathway, HIF-1 signaling pathway, and pathways in cancer development. mTOR is a highly conserved serine/threonine kinase that regulates cell growth, cell cycle progression, and metabolism (Laplante and Sabatini 2012). mTOR signaling was found to be activated in many types of cancers (Menon and Manning 2008). It was suggested that activation of mTOR signaling was associated with advanced tumor stages and poor survival outcomes in various types of cancers, including human hepatocellular carcinoma (HCC) (Hayashi et al. 2017; Matter et al. 2014). It is of interest that in MC-LR-induced thyroid dysfunction the mTOR signaling pathway was activated in mice (Zhao et al. 2015). Similarly MC-LR was found to activate mTOR in our hepatic cell line.
Adverse cardiovascular effects of exposure to cadmium and mercury alone and in combination on the cardiac tissue and aorta of Sprague–Dawley rats
Published in Journal of Environmental Science and Health, Part A, 2021
Sandra Arbi, Megan Jean Bester, Liselle Pretorius, Hester Magdalena Oberholzer
Some characteristics of autophagy were present in the exposed groups and these are the presence of probably lipid vacuoles and mitochondrial swelling. This protective mechanism occurs via the inhibition of the rapamycin complex 1 (mTORC1) pathway that prevents endoplasmic reticulum stress. A study investigating Cd and As toxicity as autophagy inducing agents showed that exposure to CdCl2 for up to 18 h at doses lower than 10 µM causes autophagy, whereas exposure for 24 h to 1 µM CdCl2, caused apoptosis. Cadmium has been shown to induce autophagy via ROS dependant pathways.[45]