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European Journal of Cancer Prevention :... Nov 2023Ferroptosis is a unique cell death modality triggered by iron-dependent lipid peroxidation, with cysteine metabolism and glutathione-dependent antioxidant defence... (Review)
Review
Ferroptosis is a unique cell death modality triggered by iron-dependent lipid peroxidation, with cysteine metabolism and glutathione-dependent antioxidant defence responses as the primary triggering mechanisms. Ferroptosis is an independent tumour suppression mechanism and has been implicated in various disorders. In tumourigenesis, ferroptosis plays a dual role in promoting and inhibiting tumours. P53, NFE2L2, BAP1, HIF, and other tumour suppressor genes regulate ferroptosis, releasing damage-associated molecular patterns or lipid metabolites to influence cellular immune responses. Ferroptosis is also involved in tumour suppression and metabolism. The combination of amino acid, lipid, and iron metabolism is involved in the initiation and execution of ferroptosis, and metabolic regulatory mechanisms also play roles in malignancies. Most investigations into ferroptosis in gastric cancer are concentrated on predictive models, not the underlying processes. This review investigates the underlying mechanisms of ferroptosis, tumour suppressor genes, and the tumour microenvironment.
Topics: Humans; Stomach Neoplasms; Ferroptosis; Cell Death; Lipid Peroxidation; Iron; Lipids; Tumor Microenvironment
PubMed: 37318883
DOI: 10.1097/CEJ.0000000000000817 -
International Journal of Molecular... Aug 2023Reactive oxygen species (ROS) are important regulating factors that play a dual role in plant and human cells. As the first messenger response in organisms, ROS... (Review)
Review
Reactive oxygen species (ROS) are important regulating factors that play a dual role in plant and human cells. As the first messenger response in organisms, ROS coordinate signals in growth, development, and metabolic activity pathways. They also can act as an alarm mechanism, triggering cellular responses to harmful stimuli. However, excess ROS cause oxidative stress-related damage and oxidize organic substances, leading to cellular malfunctions. This review summarizes the current research status and mechanisms of ROS in plant and human eukaryotic cells, highlighting the differences and similarities between the two and elucidating their interactions with other reactive substances and ROS. Based on the similar regulatory and metabolic ROS pathways in the two kingdoms, this review proposes future developments that can provide opportunities to develop novel strategies for treating human diseases or creating greater agricultural value.
Topics: Humans; Eukaryotic Cells; Reactive Oxygen Species; Oxidative Stress
PubMed: 37685857
DOI: 10.3390/ijms241713052 -
Toxicology Dec 2023Human lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or...
Human lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or pancreas but also adipose tissue. Recently, population-based studies revealed the association between arsenic exposure and the development of metabolic diseases such as obesity and type 2 diabetes. To shed light on the molecular bases of such association, we determined the concentration that inhibited 17% of cell viability and investigated the effects of arsenic acute exposure on adipose-derived human mesenchymal stem cells differentiated in vitro into mature adipocytes and treated with sodium arsenite (NaAsO, 10 nM to 10 µM). Untargeted metabolomics and gene expression analyses revealed a strong dose-dependent inhibition of lipogenesis and lipolysis induction, reducing the cellular ability to store lipids. These dysregulations were emphasized by the inhibition of the cellular response to insulin, as shown by the perturbation of several genes and metabolites involved in the mentioned biological pathways. Our study highlighted the activation of an adaptive oxidative stress response with the strong induction of metallothioneins and increased glutathione levels in response to arsenic accumulation that could exacerbate the decreased insulin sensitivity of the adipocytes. Arsenic exposure strongly affected the expression of arsenic transporters, responsible for arsenic influx and efflux, and induced a pro-inflammatory state in adipocytes by enhancing the expression of the inflammatory interleukin 6 (IL6). Collectively, our data showed that an acute exposure to low levels of arsenic concentrations alters key adipocyte functions, highlighting its contribution to the development of insulin resistance and the pathogenesis of metabolic disorders.
Topics: Humans; Arsenic; Diabetes Mellitus, Type 2; Adipose Tissue; Adipocytes; Insulin; Insulin Resistance; Metabolome
PubMed: 37956786
DOI: 10.1016/j.tox.2023.153672 -
La Clinica Terapeutica 2023Nutrigenomics - the study of the interactions between genetics and nutrition - has emerged as a pivotal field in personalized nutrition. Among various genetic... (Review)
Review
BACKGROUND
Nutrigenomics - the study of the interactions between genetics and nutrition - has emerged as a pivotal field in personalized nutrition. Among various genetic variations, single-nucleotide polymorphisms (SNPs) have been extensively studied for their probable relationship with metabolic traits.
METHODS
Throughout this review, we have employed a targeted research approach, carefully handpicking the most representative and relevant articles on the subject. Our methodology involved a systematic review of the scientific literature to ensure a comprehensive and accurate overview of the available sources.
RESULTS
SNPs have demonstrated a significant influence on lipid metabolism, by impacting genes that encode for enzymes involved in lipid synthesis, transport, and storage. Furthermore, they have the ability to affect enzymes in glycolysis and insulin signaling pathways: in a way, they can influence the risk of type 2 diabetes. Thanks to recent advances in genotyping technologies, we now know numerous SNPs linked to lipid and carbohydrate metabolism. The large-scale studies on this topic have unveiled the potential of personalized dietary recommendations based on an individual's genetic makeup. Personalized nutritional interventions hold promise to mitigate the risk of various chronic diseases; however, translating these scientific insights into actionable dietary guidelines is still challenging.
CONCLUSIONS
As the field of nutrigenomics continues to evolve, collaborations between geneticists, nutritionists, and healthcare providers are essential to harness the power of genetic information for improving metabolic health. By unraveling the genetic basis of metabolic responses to diet, this field holds the potential to revolutionize how we approach dietary recommendations and preventive healthcare practices.
Topics: Humans; Nutrigenomics; Polymorphism, Single Nucleotide; Diabetes Mellitus, Type 2; Diet; Lipids; Carbohydrate Metabolism
PubMed: 37994765
DOI: 10.7417/CT.2023.2488 -
Drug Metabolism and Disposition: the... Oct 2023Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual's drug... (Review)
Review
Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual's drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, nongenetic factors are also known to influence drug metabolism phenotypes. This minireview discusses approaches beyond pharmacogenetic testing to phenotype DMEs-particularly the cytochrome P450 enzymes-in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating noncoding RNAs and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity, 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies, and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. SIGNIFICANCE STATEMENT: This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. It highlights the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic strategy for patient characterization and precision dosing.
Topics: Humans; Precision Medicine; Cytochrome P-450 Enzyme System; Metabolic Clearance Rate; Biomarkers
PubMed: 37419681
DOI: 10.1124/dmd.122.001066 -
Annual Review of Pharmacology and... Jan 2024Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the... (Review)
Review
Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations.
Topics: Humans; Artificial Intelligence; Genotype; Biomarkers; Phenotype; Drug-Related Side Effects and Adverse Reactions
PubMed: 37585662
DOI: 10.1146/annurev-pharmtox-032023-121106 -
EMBO Reports Oct 2023Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to...
Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell-specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady-state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions.
Topics: Animals; Smegmamorpha; Mitochondria; Energy Metabolism; Glycolysis; Oxidative Phosphorylation; Adenosine Triphosphate; Mammals
PubMed: 37548091
DOI: 10.15252/embr.202256380 -
Cell Reports Dec 2023The dysfunction and clonal constriction of tumor-infiltrating CD8 T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic...
The dysfunction and clonal constriction of tumor-infiltrating CD8 T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8 T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8 T cell metabolic and functional fitness. De novo NAD synthesis is involved in CD8 T cell metabolism and antitumor function. KP-derived NAD promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD synthesis limits CD8 T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD regulates the CD8 T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD synthesis could restore CD8 T cell metabolic fitness and antitumor function.
Topics: Humans; NAD; CD8-Positive T-Lymphocytes; Kynurenine; Metabolic Networks and Pathways
PubMed: 38041812
DOI: 10.1016/j.celrep.2023.113518 -
Cell Death & Disease Jul 2023DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways...
DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways have been correlated with cellular response to DNA damage. Here, we show that fatty acid oxidation (FAO) is a crucial regulator of DNA double-strand break repair, particularly homologous recombination repair. Mechanistically, FAO contributes to DNA repair by activating poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that detects DNA breaks and promotes DNA repair pathway. Upon DNA damage, FAO facilitates PARP1 acetylation by providing acetyl-CoA, which is required for proper PARP1 activity. Indeed, cells reconstituted with PARP1 acetylation mutants display impaired DNA repair and enhanced sensitivity to DNA damage. Consequently, FAO inhibition reduces PARP1 activity, leading to increased genomic instability and decreased cell viability upon DNA damage. Finally, our data indicate that FAO serves as an important participant of cellular response to DNA damage, supporting DNA repair and genome stability.
Topics: Humans; Acetylation; DNA Repair; DNA; Poly (ADP-Ribose) Polymerase-1; DNA Breaks, Double-Stranded; DNA Damage; Fatty Acids
PubMed: 37454129
DOI: 10.1038/s41419-023-05968-w -
Clinical Nutrition (Edinburgh, Scotland) Feb 2024Short-term intensive fasting (STIF), known as beego in Chinese phonetic articulation, has been practiced for more than two thousand years. However, the potential risk of...
BACKGROUND & AIMS
Short-term intensive fasting (STIF), known as beego in Chinese phonetic articulation, has been practiced for more than two thousand years. However, the potential risk of STIF and the body's response to the risk have not been adequately evaluated. This study aims to address this issue, focusing on the STIF-triggered metabolic response of the liver and kidney.
METHODS
The STIF procedure in the clinical trial includes a 7-day water-only intensive fasting phase and a 7-day gradual refeeding phase followed by a regular diet. The intensive fasting in humans was assisted with psychological induction. To gain insights not available in the clinical trial, we designed a STIF program for mice that resulted in similar phenotypes seen in humans. Plasma metabolic profiling and examination of gene expression as well as liver and kidney function were performed by omics, molecular, biochemical and flow cytometric analyses. A human cell line model was also used for mechanistic study.
RESULTS
Clinically significant metabolites of fat and protein were found to accumulate during the fasting phase, but they were relieved after gradual refeeding. Metabolomics profiling revealed a universal pattern in the consumption of metabolic intermediates, in which pyruvate and succinate are the two key metabolites during STIF. In the STIF mouse model, the accumulation of metabolites was mostly counteracted by the upregulation of catabolic enzymes in the liver, which was validated in a human cell model. Kidney filtration function was partially affected by STIF but could be recovered by refeeding. STIF also reduced oxidative and inflammatory levels in the liver and kidney. Moreover, STIF improved lipid metabolism in mice with fatty liver without causing accumulation of metabolites after STIF.
CONCLUSIONS
The accumulation of metabolites induced by STIF can be relieved by spontaneous upregulation of catabolic enzymes, suggesting an adaptive and protective metabolic response to STIF stress in the mammalian body.
Topics: Mice; Humans; Animals; Fasting; Diet; Liver; Lipid Metabolism; Mammals
PubMed: 38181523
DOI: 10.1016/j.clnu.2023.12.020