An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition

Objective: Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy. Methods: We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids (EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixture designed on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells. Results: The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells. Conclusion: Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells’ death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers

An original amino acid formula favours in vitro corneal epithelial wound healing by promoting Fn1, ITGB1, and PGC-1α expression

Corneal disorders are frequent, involving most diabetic patients; among its manifestations, they include delayed wound healing. Since maintenance of mitochondrial homeostasis is fundamental for the cell, stimulation of mitochondrial biogenesis represents a unique therapeutic tool for preventing and treating disorders with a deficit in energy metabolism. We have recently demonstrated that a branched-chain amino acid (BCAA)-enriched mixture (BCAAem) supported mitochondrial biogenesis in cardiac and skeletal muscle, reduced liver damage caused by alcohol, and prevented the doxorubicin-dependent mitochondrial damage in cardiomyocytes. The present study aimed to investigate a new amino acid mixture, named six amino acids (6AA), to promote corneal epithelial wound healing by regulating mitochondrial biogenesis. A murine epithelium cell line (TKE2) exposed to this mixture showed increased mitochondrial biogenesis markers, fibronectin 1 (Fn1) and integrin beta 1 (ITGB1) involved in extracellular matrix synthesis and cell migration. Most importantly, the 6AA mixture completely restored the wound in scratch assays, confirming the potential of this new formula in eye disorders like keratopathy. Moreover, our results demonstrate for the first time that peroxisome proliferator-receptor γ coactivator 1 α (PGC-1α) is expressed in TKE2 cells, which controls mitochondrial function and corneal repair process. These results could be relevant for the treatment mainly focused on corneal re-epithelialisation

Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging

Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes − controlling adipokines, microRNAs, extracellular vesicles, and metabolites − and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor − with never before seen weight loss and insulin-sensitizing efficacy − promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat

Sex steroids, carcinogenesis, and cancer progression

The relationship between sex steroids and cancer has been studied for more than a century. Using an original intact cell analysis, we investigated sex steroid metabolism in a panel of human cancer cell lines, either hormone responsive or unresponsive, originating from human breast, endometrium, and prostate. We found that highly divergent patterns of steroid metabolism exist and that the catalytic preference (predominantly reductive or oxidative) is strictly associated with the steroid receptor status of cells. We explored intra-tissue concentrations and profiles of estrogens in a set of human breast tumors as compared to normal mammary tissues, also in relation to their estrogen receptor status. In particular, we showed that, with hydroxyestrogens representing the majority of all tissue estrogens, concentrations of individual metabolites, as well as their ratios, significantly differ when comparing normal tissue with cancer tissues or when they are related to the overall survival of cancer patients. © 2004 New York Academy of Sciences

A peculiar formula of essential amino acids prevents rosuvastatin myopathy in mice

Aims: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Results: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy

Role of Portion Size in the Context of a Healthy, Balanced Diet: A Case Study of European Countries

Over the past decades, a generalised increase in food portion sizes has probably contributed to the growing global obesity epidemic. Increasing awareness of appropriate portion sizes could contribute to reversing this trend through better control of calorie intake. In this study, a comparison of standard portion sizes in European countries for various food categories shows a wide variability of their importance for food, nutrient, and energy consumption according to government and institutional websites. On the other hand, the overall averages appear to be largely in line with the values indicated by the Italian Society of Human Nutrition, which is the most comprehensive and detailed document among those evaluated. The exceptions are milk and yoghurt, for which the reference portions in Europe are generally higher, and vegetables and legumes, for which portions are smaller than those reported in the Italian document. Moreover, the portion sizes of staple foods (e.g., pasta and potatoes) vary according to different food traditions. It is reasonable to consider that the creation of harmonised standard reference portions common to the European countries, based on international guidelines and scientific evidence, would significantly contribute to consumers' nutritional education and ability to make informed choices for a healthy diet

Cannabinoid Receptor Stimulation Impairs Mitochondrial Biogenesis in Mouse White Adipose Tissue, Muscle, and Liver: The Role of eNOS, p38 MAPK, and AMPK Pathways

OBJECTIVE - Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice. RESEARCH DESIGN AND METHODS - The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS-/- and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA. RESULTS - ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS-/- mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD. CONCLUSIONS - CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mic

Main belt asteroids taxonomical information from dark energy survey data

While proper orbital elements are currently available for more than 1 million asteroids, taxonomical information is still lagging behind. Surveys like SDSS-MOC4 provided preliminary information for more than 100 000 objects, but many asteroids still lack even a basic taxonomy. In this study, we use Dark Energy Survey (DES) data to provide new information on asteroid physical properties. By cross-correlating the new DES data base with other data bases, we investigate how asteroid taxonomy is reflected in DES data. While the resolution of DES data is not sufficient to distinguish between different asteroid taxonomies within the complexes, except for V-type objects, it can provide information on whether an asteroid belongs to the C- or S-complex. Here, machine learning methods optimized through the use of genetic algorithms were used to predict the labels of more than 68 000 asteroids with no prior taxonomic information. Using a high-quality, limited set of asteroids with data on gri slopes and i - z colours, we detected 409 new possible V-type asteroids. Their orbital distribution is highly consistent with that of other known V-type objects

Exploring the Bimodal Solar System via Sample Return from the Main Asteroid Belt: The Case for Revisiting Ceres

Abstract: Sample return from a main-belt asteroid has not yet been attempted, but appears technologically feasible. While the cost implications are significant, the scientific case for such a mission appears overwhelming. As suggested by the “Grand Tack” model, the structure of the main belt was likely forged during the earliest stages of Solar System evolution in response to migration of the giant planets. Returning samples from the main belt has the potential to test such planet migration models and the related geochemical and isotopic concept of a bimodal Solar System. Isotopic studies demonstrate distinct compositional differences between samples believed to be derived from the outer Solar System (CC or carbonaceous chondrite group) and those that are thought to be derived from the inner Solar System (NC or non-carbonaceous group). These two groups are separated on relevant isotopic variation diagrams by a clear compositional gap. The interface between these two regions appears to be broadly coincident with the present location of the asteroid belt, which contains material derived from both groups. The Hayabusa mission to near-Earth asteroid (NEA) (25143) Itokawa has shown what can be learned from a sample-return mission to an asteroid, even with a very small amount of sample. One scenario for main-belt sample return involves a spacecraft launching a projectile that strikes an object and flying through the debris cloud, which would potentially allow multiple bodies to be sampled if a number of projectiles are used on different asteroids. Another scenario is the more traditional method of landing on an asteroid to obtain the sample. A significant range of main-belt asteroids are available as targets for a sample-return mission and such a mission would represent a first step in mineralogically and isotopically mapping the asteroid belt. We argue that a sample-return mission to the asteroid belt does not necessarily have to return material from both the NC and CC groups to viably test the bimodal Solar System paradigm, as material from the NC group is already abundantly available for study. Instead, there is overwhelming evidence that we have a very incomplete suite of CC-related samples. Based on our analysis, we advocate a dedicated sample-return mission to the dwarf planet (1) Ceres as the best means of further exploring inherent Solar System variation. Ceres is an ice-rich world that may be a displaced trans-Neptunian object. We almost certainly do not have any meteorites that closely resemble material that would be brought back from Ceres. The rich heritage of data acquired by the Dawn mission makes a sample-return mission from Ceres logistically feasible at a realistic cost. No other potential main-belt target is capable of providing as much insight into the early Solar System as Ceres. Such a mission should be given the highest priority by the international scientific community