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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Structurally, mTOR is the catalytic subunit of two molecular complexes, mTORC1 and mTORC2. mTORC1 (mTOR Complex 1) is composed of mTOR itself, Raptor (the Regulatory-Associated Protein of mTOR), mLST8/GβL (Mammalian Lst8/G-Protein Β-Subunit-Like Protein), and the partner proteins PRAS40 and DEPTOR. This whole complex functions as the nutrient/energy/redox sensor and controls protein synthesis. The activity of the mTORC1complex is stimulated by nutrients including glucose and amino acids (particularly leucine), insulin, growth factors, serum, phosphatidic acid, and oxidative stress. It is inhibited by low nutrient levels, growth factor deprivation, and reductive stress, and also by certain compounds such as rapamycin and farnesylthiosalicylic acid (FTS). The mTOR pathway can become dysregulated in some human diseases, especially some cancers, and so inhibition of the pathway can lead to a beneficial therapeutic effect. This works because inhibition of mTOR delivers the false signal that the cell is starved of nutrients and lacks growth factor stimulation. This initiates a cellular starvation response which includes metabolic reprogramming, prevention of cell growth and arrest of cell division. mTORC2 appears to be insensitive to nutrients and energy signals. Also, mTOR is a crucial component of the transmission of signals mediated by the phosphatidylinositol 3-kinase (PI3K) pathway, a signaling cascade that is aberrant in more than 70% of tumors. Activation of PI3K by growth factors signals through AKT (PKB) to stimulate growth and proliferation.
Functional Omics and Big Data Analysis in Microalgae
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
Chetan Paliwal, Tonmoy Ghosh, Asha A. Nesamma, Pavan P. Jutur
Transcriptomics analysis of C. reinhardtii under phosphorus (P) starvation showed that transcriptional factor Pi starvation response 1 (PSR1) leads all the responses during P starvation and regulates the lipid and starch metabolism (Bajhaiya et al. 2017). Comparative analysis of de novo transcriptome and gene expression of Scenedesmus acutus TISTR8540 during N stress identified certain lipase genes which were down-regulated specifically along with glycolysis and starch synthesis, whereas gluconeogenesis, photosynthesis, TAG degradation and starch synthesis were up-regulated, confirming the channelling of carbon flux towards fatty acid and TAG synthesis (Sirikhachornkit et al. 2018). Therefore, transcriptome studies help in unraveling the molecular response during stress, thereby developing genetic manipulation strategies for the production of desired products.
The obesity epidemic and American culture
Published in Anna Bellisari, The Anthropology Of Obesity in the United States, 2016
It is definitely not for lack of trying that so many Americans have been unable to lose excess weight. The problem is that human energy-sparing physiology which evolved over millions of years is vigorously opposed to voluntary restriction of energy intake. It shifts into over-drive to preserve energy stores and increase the appetite for high-energy foods. The diet industry has become a booming, highly profitable business because many Americans are “on a diet.” Millions of dieters have lost literally tons of weight at a cost of billions of dollars – $60.5 billion in 2013 alone (marketdataenterprises.com/studies/#FS45). Yet obesity rates have continued to rise, and, in fact, there is a direct connection between constant efforts to lose weight and increasing obesity (Farley and Cohen 2001; Pietilainen et al. 2012; Macpherson-Sanchez 2015). That dieting may actually promote obesity is not as paradoxical as it may seem, since the human body counters any type of energy deprivation, be it via famine or dieting, with metabolic adaptation, the “starvation response” of increased energy efficiency inherited from Paleolithic ancestors. With each bout of food restriction, the metabolic system reduces energy requirements by lowering basal metabolic rate and physical activity. Carbohydrate oxidation increases to provide warmth and quick energy while fat oxidation decreases, shifting more fat to storage in adipose tissue. After the diet has ended, appetite and food intake increase to compensate for the loss and to maintain the stable energy state. In fact, after repeated dieting, food preferences change to sweeter and fattier items such as ice cream (Drewnowski and Holden-Wiltse 1992). Even though the effort to lose weight may be temporarily successful, maintaining the lower weight is compromised by persistent hormonal changes that raise levels of appetite-stimulating ghrelin and lower levels of satiety-promoting leptin (Sumithran et al. 2011). The diet industry is so very profitable not only because more and more individuals with obesity are trying to lose weight, but also because they repeat the effort several times in “yo-yo” dieting. In 2007 alone Americans spent $55 billion on weight loss programs (Downs and Lowenstein 2011).
Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver
Published in Nutritional Neuroscience, 2022
Lisanne E. Wisse, Denise Visser, Timo J. ter Braak, Abdellatif Bakkali, Eduard A. Struys, Christopher D. Morrison, Marjo S. van der Knaap, Truus E. M. Abbink
The current study aimed to investigate if amino acid restriction modulates expression of the ATF4-regulated transcriptome in brain, resulting in episodic deterioration of the clinical phenotype in VWM mice. These mice are homozygous for a pathogenic mutation in eIF2B associated with an early onset disease course in humans.9 If the diet would cause rapid and evident decline in the mouse motor behavior or induce a coma, this phenotype could model the episodic neurological deterioration in VWM patients. We subjected wild type (wt) and early-symptomatic mutant eIF2B (2b5ho) mice to an isocaloric diet with protein levels reduced to 5% (normal protein levels are 15–20%). The diet is isocaloric to prevent a general starvation response instead of a shortage of amino acids and has been shown to induce an ISR in mice.15 We assessed the dietary effects on body weight and walking behavior and euthanized the mice after three weeks to assess ISR markers in several organs, including the central nervous system (CNS). We did not find diet-induced reductions in amino acid concentrations and ISR modulation in wt nor 2b5ho brain. Strikingly, we found evidence for differential ISR activation by the low protein diet in liver in wt versus 2b5ho mice, with 2b5ho mice being unresponsive. The latter may be a result from a subtle ISR deregulation in 2b5ho mouse liver.
A single cell survey of the microbial impacts on the mouse small intestinal epithelium
Published in Gut Microbes, 2022
Derek K.L. Tsang, Ryan J. Wang, Oliver De Sa, Arshad Ayyaz, Elisabeth G. Foerster, Giuliano Bayer, Shawn Goyal, Daniel Trcka, Bibaswan Ghoshal, Jeffrey L. Wrana, Stephen E. Girardin, Dana J. Philpott
Further GSEA analysis in GF intestinal epithelium revealed several metabolism-associated gene sets. In tandem, the increased expression of starvation response transcription factors36 and decreased mTOR signaling by pS6 levels suggest that the absence of microbes fosters a nutritionally deficient environment for the epithelium. As such, we hypothesized that microbiota-dependent mTOR signaling was induced by the production of key microbial metabolites. Interestingly, mTOR signaling plays an important role in regulating the activity of the intestinal crypt. Chronic intestinal epithelial mTOR hyperactivation in young mice (two-month-old) induces intestinal crypt expansion and proliferation, while chronic long-term intestinal epithelial (six-month-old) mTOR hyperactivation accelerates epithelium aging and functionally decreases villus length, glucose absorption, and suppresses ISC proliferation.48 However, suppression of mTOR in PCs by caloric restriction has been shown to promote ISC self-renewal.38 In connection to these observations, our data suggest that microbiota-dependent changes in the epithelium may be driven by increased basal mTOR signaling. While we observed an increase in mTOR signaling in the SPF intestinal crypt base and PCs, we did not see a concurrent increase in ISC self-renewal as marked by significant differences in Olfm4+ ISCs or BrdU+ TA cells. This discrepancy may be attributed to the diverse mechanisms by which the microbiota and/or species-specific microbes may regulate the proliferative potential of ISCs. For instance, microbes have been shown to induce the expression of MHC class II in the intestinal epithelium2,49 and this may promote T helper cell cytokine interactions that directly facilitate ISC self-renewal and differentiation.50 Moreover, individual microbial species, such as L. rhamnosus and L. reuteri induce intestinal proliferation through NADPH oxidase 1-dependent ROS generation51 and dietary fructose production,52 respectively. While our data highlight that microbiota impact mTOR signaling in the small intestinal crypts, additional studies investigating mTOR signaling in the context of microbial metabolites will provide greater insight in leveraging microbes as drivers of epithelial restitution.