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International Journal of Molecular... Feb 2021The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell... (Review)
Review
The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented.
Topics: Gluconeogenesis; Humans; Metabolic Networks and Pathways; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 33540663
DOI: 10.3390/ijms22031476 -
Physiology & Behavior Dec 2015Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic... (Review)
Review
Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic effects. However, data from several epidemiological studies have found that consumption of NNSs, mainly in diet sodas, is associated with increased risk to develop obesity, metabolic syndrome, and type 2 diabetes. The main purpose of this article is to review recent scientific evidence supporting potential mechanisms that explain how "metabolically inactive" NNSs, which have few, if any, calories, might promote metabolic dysregulation. Three potential mechanisms, which are not mutually exclusive, are presented: 1) NNSs interfere with learned responses that contribute to control glucose and energy homeostasis, 2) NNSs interfere with gut microbiota and induce glucose intolerance, and 3) NNSs interact with sweet-taste receptors expressed throughout the digestive system that play a role in glucose absorption and trigger insulin secretion. In addition, recent findings from our laboratory showing an association between individual taste sensitivity to detect sucralose and sucralose's acute effects on metabolic response to an oral glucose load are reported. Taken as a whole, data support the notion that NNSs have metabolic effects. More research is needed to elucidate the mechanisms by which NNSs may drive metabolic dysregulation and better understand potential effects of these commonly used food additives.
Topics: Animals; Energy Metabolism; Enteroendocrine Cells; Humans; Non-Nutritive Sweeteners
PubMed: 26095119
DOI: 10.1016/j.physbeh.2015.06.024 -
Phytochemistry Sep 2022Microalgae are important primary producers and form the basis for the marine food web. As global climate changes, so do salinity levels that algae are exposed to. A...
Microalgae are important primary producers and form the basis for the marine food web. As global climate changes, so do salinity levels that algae are exposed to. A metabolic response of algal cells partly alleviates the resulting osmotic stress. Some metabolites involved in the response are well studied, but the full metabolic implications of adaptation remain unclear. Improved analytical methodology provides an opportunity for additional insight. We can now follow responses to stress in major parts of the metabolome and derive comprehensive charts of the resulting metabolic re-wiring. In this study, we subjected three species of diatoms to high salinity conditions and compared their metabolome to controls in an untargeted manner. The three well-investigated species with sequenced genomes Phaeodactylum tricornutum, Thalassiosira pseudonana, and Skeletonema marinoi were selected for our survey. The microalgae react to salinity stress with common adaptations in the metabolome by amino acid up-regulation, production of saccharides, and inositols. But also species-specific dysregulation of metabolites is common. Several metabolites previously not connected with osmotic stress reactions are identified, including 4-hydroxyproline, pipecolinic acid, myo-inositol, threonic acid, and acylcarnitines. This expands our knowledge about osmoadaptation and calls for further functional characterization of metabolites and pathways in algal stress physiology.
Topics: Acclimatization; Diatoms; Metabolome; Microalgae; Salinity
PubMed: 35671808
DOI: 10.1016/j.phytochem.2022.113267 -
International Review of Cell and... 2013The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness.... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Proteolysis; Unfolded Protein Response
PubMed: 23317820
DOI: 10.1016/B978-0-12-407704-1.00005-1 -
Seminars in Radiation Oncology Jan 2019The aberrant vasculature in the tumor microenvironment creates hypoxic zones, poor perfusion, and high interstitial fluid pressure. Also, the tumor cell metabolic... (Review)
Review
The aberrant vasculature in the tumor microenvironment creates hypoxic zones, poor perfusion, and high interstitial fluid pressure. Also, the tumor cell metabolic phenotype utilizes the aerobic glycolytic pathways for energy source and generation of cell mass. These physiologic and metabolic phenotypes in solid tumors are amenable for molecular imaging techniques to extract imaging biomarkers such as pO and enzyme kinetics reflecting glycolysis. The imaging biomarkers have value in diagnostic and prognostic purposes. Additionally, they can be used to guide choices for tailored treatment regimens. Electron paramagnetic resonance imaging for pO imaging and C magnetic resonance imaging with hyperpolarized C probes such as C-labeled pyruvate have shown significant potential in characterizing the tumor microenvironment physiologically and metabolically.
Topics: Animals; Biomarkers, Tumor; Glycolysis; Humans; Molecular Imaging; Neoplasms; Tumor Microenvironment
PubMed: 30573188
DOI: 10.1016/j.semradonc.2018.10.004 -
Genes Feb 2022Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms... (Review)
Review
Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms underlying variable drug responses. The identification of DNA variants which markedly contribute to inter-individual variations in drug responses would improve the efficacy of treatments and decrease the rate of the adverse side effects of drugs. This review focuses only on the impact of polymorphisms within drug-metabolizing enzymes on drug responses. Anticancer drugs usually have a very narrow therapeutic index; therefore, it is very important to use appropriate doses in order to achieve the maximum benefits without putting the patient at risk of life-threatening toxicities. However, the adjustment of the appropriate dose is not so easy, due to the inheritance of specific polymorphisms in the genes encoding the target proteins and drug-metabolizing enzymes. This review presents just a few examples of such polymorphisms and their impact on the response to therapy.
Topics: Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Pharmacogenetics; Polymorphism, Genetic
PubMed: 35205356
DOI: 10.3390/genes13020311 -
Molecular Metabolism Aug 2020ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as... (Review)
Review
BACKGROUND
ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.
SCOPE OF REVIEW
This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.
MAJOR CONCLUSIONS
INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Gene Expression; Gene Expression Regulation; Metabolic Networks and Pathways; Metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcriptional Activation
PubMed: 32251664
DOI: 10.1016/j.molmet.2020.100973 -
Experimental & Molecular Medicine Mar 2022It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes... (Review)
Review
It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response.
Topics: Cell Differentiation; Humans; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Sirtuins; T-Lymphocytes
PubMed: 35296782
DOI: 10.1038/s12276-022-00739-7 -
Accounts of Chemical Research Nov 2022Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological... (Review)
Review
Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.
Topics: Animals; Mice; Endocannabinoids; Lipid Metabolism; Brain; Neurons; Synaptic Transmission
PubMed: 36283077
DOI: 10.1021/acs.accounts.2c00521