-
Biomedicine & Pharmacotherapy =... Jun 2024The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular... (Review)
Review
The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular homeostasis is disrupted, ER quality control (ERQC) system is activated effectively to remove misfolded and unfolded proteins through ER-phagy, ER-related degradation (ERAD), and molecular chaperones. When unfolded protein response (UPR) and ER stress are activated, the cell may be suffering a huge blow, and the most probable consequence is apoptosis. The membrane contact points between the ER and sub-organelles contribute to communication between the organelles. The decrease in oxygen concentration affects the morphology and structure of the ER, thereby affecting its function and further disrupting the stable state of cells, leading to the occurrence of disease. In this study, we describe the functions of ER-, ERQC-, and ER-related membrane contact points and their changes under hypoxia, which will help us further understand ER and treat ER-related diseases.
Topics: Endoplasmic Reticulum; Humans; Animals; Endoplasmic Reticulum Stress; Unfolded Protein Response; Hypoxia; Apoptosis; Cell Hypoxia; Endoplasmic Reticulum-Associated Degradation
PubMed: 38781866
DOI: 10.1016/j.biopha.2024.116812 -
The Journal of Clinical Investigation Oct 2023Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a...
Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.
Topics: Humans; Peroxisomes; Lipid Metabolism; Melanoma; Ceramides
PubMed: 37616051
DOI: 10.1172/JCI166644 -
Journal of Experimental & Clinical... Nov 2023Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the... (Review)
Review
Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.
Topics: Humans; T-Lymphocytes; Tumor Microenvironment; Neoplasms; Energy Metabolism; Immunotherapy; Amino Acids
PubMed: 37924140
DOI: 10.1186/s13046-023-02845-4 -
Disease Models & Mechanisms Nov 2023By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic... (Review)
Review
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
Topics: Humans; Membrane Transport Proteins; Solute Carrier Proteins; Biological Transport; Neoplasms; Cell Physiological Phenomena; Tumor Microenvironment
PubMed: 38037877
DOI: 10.1242/dmm.050404 -
Cells Dec 2023Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress... (Review)
Review
Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.
Topics: Animals; Lipid Metabolism; Glucose; Sirtuin 1; Diabetes Mellitus, Type 2; Hydrolases; Sirtuins; Mammals
PubMed: 38201252
DOI: 10.3390/cells13010048 -
Neurobiology of Disease Sep 2023Brain metabolic pathways relating to bioenergetic and redox homeostasis are closely linked, and deficits in these pathways are thought to occur in many neurodegenerative... (Review)
Review
Brain metabolic pathways relating to bioenergetic and redox homeostasis are closely linked, and deficits in these pathways are thought to occur in many neurodegenerative diseases. Astrocytes play important roles in both processes, and growing evidence suggests that neuron-astrocyte intercellular signalling ensures brain bioenergetic and redox homeostasis in health. Moreover, alterations to this crosstalk have been observed in the context of neurodegenerative pathology. In this review, we summarise the current understanding of how neuron-astrocyte interactions influence brain metabolism and antioxidant functions in health as well as during neurodegeneration. It is apparent that deleterious and adaptive protective responses alter brain metabolism in disease, and that knowledge of both may illuminate targets for future therapeutic interventions.
Topics: Humans; Neurodegenerative Diseases; Astrocytes; Oxidation-Reduction; Brain; Neurons
PubMed: 37558170
DOI: 10.1016/j.nbd.2023.106255 -
Clinical and Translational Medicine Jan 2024One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic... (Review)
Review
BACKGROUND
One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune-related adverse events in patients.
METHODS
We collected numerous literatures to explain the roles of one-carbon metabolism in cancer immunotherapy.
RESULTS
In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future.
CONCLUSION
Targeting one-carbon metabolism is useful for cancer immunotherapy.
Topics: Humans; Neoplasms; Antineoplastic Agents; Metabolic Networks and Pathways; Carbon
PubMed: 38279895
DOI: 10.1002/ctm2.1521 -
Concepts of Lactate Metabolic Clearance Rate and Lactate Clamp for Metabolic Inquiry: A Mini-Review.Nutrients Jul 2023Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor.... (Review)
Review
Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor. Blood lactate concentration is sensitive to the metabolic state of tissues and organs as lactate rates of appearance and disposal/disappearance in the circulation rise and fall in response to physical exercise and other metabolic disturbances. The highest lactate flux rates have been measured during moderate intensity exercise in endurance-trained individuals who exhibit muscular and metabolic adaptations lending to superior oxidative capacity. In contrast, a diminished ability to utilize lactate is associated with poor metabolic fitness. Given these widespread implications in exercise performance and health, we discuss the concept of lactate metabolic clearance rate, which increases at the onset of exercise and, unlike flux rates, reaches a peak just below the power output associated with the maximal lactate steady state. The metabolic clearance rate is determined by both disposal rate and blood concentration, two parameters that are mutually interdependent and thus difficult to parse during steady state exercise studies. We review the evolution of the in vivo lactate clamp methodology to control blood lactate concentration and discuss its application in the investigation of whole-body lactate disposal capacities. In conclusion, we assert that the lactate clamp is a useful research methodology for examining lactate flux, in particular the factors that drive metabolic clearance rate.
Topics: Humans; Lactic Acid; Oxygen Consumption; Metabolic Clearance Rate; Anaerobic Threshold; Exercise; Exercise Test; Physical Endurance
PubMed: 37513631
DOI: 10.3390/nu15143213 -
Nutrients Oct 2023Studies have examined the possible utility of epigenetic phenomena (DNA methylation changes, covalent histone modifications, and miRNA expression patterns) in predicting... (Review)
Review
Studies have examined the possible utility of epigenetic phenomena (DNA methylation changes, covalent histone modifications, and miRNA expression patterns) in predicting individual responses to different lifestyle programs. Nonetheless, most available evidence is focused on identifying epigenetic marks eventually associated with body composition and adiposity outcomes, whereas their roles in metabolic endings remain less explored. This document comprehensively reviewed the evidence regarding the use of epigenetic signatures as putative biomarkers of metabolic outcomes (glycemic, lipid, blood pressure, and inflammatory/oxidative stress features) in response to different lifestyle interventions in humans. Although more investigation is still necessary in order to translate this knowledge in clinical practice, these scientific insights are contributing to the design of advanced strategies for the precise management of cardiometabolic risk, gaining understanding on metabolic heterogeneity, allowing for the prediction of metabolic outcomes, and facilitating the design of epigenome-based nutritional strategies for a more customized approach for metabolic alterations treatment under the scope of precision nutrition.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Biomarkers; Obesity; Life Style
PubMed: 37836535
DOI: 10.3390/nu15194251 -
Biotechnology Advances Oct 2023Temperature affects cellular processes at different spatiotemporal scales, and identifying the genetic and molecular mechanisms underlying temperature responses paves... (Review)
Review
Temperature affects cellular processes at different spatiotemporal scales, and identifying the genetic and molecular mechanisms underlying temperature responses paves the way to develop approaches for mitigating the effects of future climate scenarios. A systems view of the effects of temperature on cellular physiology can be obtained by focusing on metabolism since: (i) its functions depend on transcription and translation and (ii) its outcomes support organisms' development, growth, and reproduction. Here we provide a systematic review of modelling efforts directed at investigating temperature effects on properties of single biochemical reactions, system-level traits, metabolic subsystems, and whole-cell metabolism across different prokaryotes and eukaryotes. We compare and contrast computational approaches and theories that facilitate modelling of temperature effects on key properties of enzymes and their consideration in constraint-based as well as kinetic models of metabolism. In addition, we provide a summary of insights from computational approaches, facilitating integration of omics data from temperature-modulated experiments with models of metabolic networks, and review the resulting biotechnological applications. Lastly, we provide a perspective on how different types of metabolic modelling can profit from developments in machine learning and models of different cellular layers to improve model-driven insights into the effects of temperature relevant for biotechnological applications.
Topics: Temperature; Metabolic Networks and Pathways; Phenotype; Models, Biological
PubMed: 37348662
DOI: 10.1016/j.biotechadv.2023.108203