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Journal of Hematology & Oncology Jul 2023Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by... (Review)
Review
Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.
Topics: Humans; Macrophages; Neoplasms; Tumor-Associated Macrophages; Metabolic Networks and Pathways; Tumor Microenvironment
PubMed: 37491279
DOI: 10.1186/s13045-023-01478-6 -
The Journal of Pharmacology and... Jan 2024Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be...
Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR), and nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.
Topics: Mice; Animals; Metabolic Syndrome; Obesity; Energy Metabolism; Insulin Resistance; Receptors, Cytoplasmic and Nuclear; ERRalpha Estrogen-Related Receptor; Estrogens
PubMed: 37739806
DOI: 10.1124/jpet.123.001733 -
Journal of Molecular Medicine (Berlin,... Aug 2023Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible interstitial lung disease characterized by a progressive decline in lung function. The etiology of IPF is... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible interstitial lung disease characterized by a progressive decline in lung function. The etiology of IPF is unknown, which poses a significant challenge to the treatment of IPF. Recent studies have identified a strong association between lipid metabolism and the development of IPF. Qualitative and quantitative analysis of small molecule metabolites using lipidomics reveals that lipid metabolic reprogramming plays a role in the pathogenesis of IPF. Lipids such as fatty acids, cholesterol, arachidonic acid metabolites, and phospholipids are involved in the onset and progression of IPF by inducing endoplasmic reticulum stress, promoting cell apoptosis, and enhancing the expression of pro-fibrotic biomarkers. Therefore, targeting lipid metabolism can provide a promising therapeutic strategy for pulmonary fibrosis. This review focuses on lipid metabolism in the pathogenesis of pulmonary fibrosis.
Topics: Humans; Lipid Metabolism; Idiopathic Pulmonary Fibrosis; Endoplasmic Reticulum Stress
PubMed: 37289208
DOI: 10.1007/s00109-023-02336-1 -
Nutrients Oct 2023Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost.... (Review)
Review
Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
Topics: Humans; Neoplasms; Glycolysis; Energy Metabolism; Treatment Outcome
PubMed: 37836529
DOI: 10.3390/nu15194245 -
The Journal of Clinical Investigation Jan 2024Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal... (Review)
Review
Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.
Topics: Humans; Macrophages; Oxidative Phosphorylation; Myeloid Cells; Immunotherapy; Neoplasms
PubMed: 38226622
DOI: 10.1172/JCI175445 -
Nature Reviews. Nephrology Jan 2024Metabolic homeostasis operates differently in men and women. This sex asymmetry is the result of evolutionary adaptations that enable women to resist loss of energy... (Review)
Review
Metabolic homeostasis operates differently in men and women. This sex asymmetry is the result of evolutionary adaptations that enable women to resist loss of energy stores and protein mass while remaining fertile in times of energy deficit. During starvation or prolonged exercise, women rely on oxidation of lipids, which are a more efficient energy source than carbohydrates, to preserve glucose for neuronal and placental function and spare proteins necessary for organ function. Carbohydrate reliance in men could be an evolutionary adaptation related to defence and hunting, as glucose, unlike lipids, can be used as a fuel for anaerobic high-exertion muscle activity. The larger subcutaneous adipose tissue depots in healthy women than in healthy men provide a mechanism for lipid storage. As female mitochondria have higher functional capacity and greater resistance to oxidative damage than male mitochondria, uniparental inheritance of female mitochondria may reduce the transmission of metabolic disorders. However, in women, starvation resistance and propensity to obesity have evolved in tandem, and the current prevalence of obesity is greater in women than in men. The combination of genetic sex, programming by developmental testosterone in males, and pubertal sex hormones defines sex-specific biological systems in adults that produce phenotypic sex differences in energy homeostasis, metabolic disease and drug responses.
Topics: Pregnancy; Adult; Humans; Female; Male; Sex Characteristics; Placenta; Energy Metabolism; Obesity; Glucose; Selection, Genetic; Lipids
PubMed: 37923858
DOI: 10.1038/s41581-023-00781-2 -
Nature Chemical Biology Dec 2023Hyperactivated glycolysis is a metabolic hallmark of most cancer cells. Although sporadic information has revealed that glycolytic metabolites possess nonmetabolic...
Hyperactivated glycolysis is a metabolic hallmark of most cancer cells. Although sporadic information has revealed that glycolytic metabolites possess nonmetabolic functions as signaling molecules, how these metabolites interact with and functionally regulate their binding targets remains largely elusive. Here, we introduce a target-responsive accessibility profiling (TRAP) approach that measures changes in ligand binding-induced accessibility for target identification by globally labeling reactive proteinaceous lysines. With TRAP, we mapped 913 responsive target candidates and 2,487 interactions for 10 major glycolytic metabolites in a model cancer cell line. The wide targetome depicted by TRAP unveils diverse regulatory modalities of glycolytic metabolites, and these modalities involve direct perturbation of enzymes in carbohydrate metabolism, intervention of an orphan transcriptional protein's activity and modulation of targetome-level acetylation. These results further our knowledge of how glycolysis orchestrates signaling pathways in cancer cells to support their survival, and inspire exploitation of the glycolytic targetome for cancer therapy.
Topics: Humans; Glycolysis; Neoplasms; Signal Transduction; Biochemical Phenomena; Cell Line
PubMed: 37322158
DOI: 10.1038/s41589-023-01355-w -
European Journal of Internal Medicine Dec 2023Products containing cannabidiol(CBD) are easily accessible. CBD is reported to inhibit the drug-metabolizing proteins(DMP) Cytochrome P450(CYP)3A4/5, CYP2C9, CYP2B6,... (Review)
Review
IMPORTANCE
Products containing cannabidiol(CBD) are easily accessible. CBD is reported to inhibit the drug-metabolizing proteins(DMP) Cytochrome P450(CYP)3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, carboxylesterase 1(CES1), uridine 5'diphospho-glucoronosyltransferase(UGT)1A9, UGT2B7, P-glycoprotein(P-gp) and Breast Cancer Resistance Protein(BCRP). The relevance of CBD-drug interactions is largely unknown. Aim of the study was to identify drugs, potentially interacting with orally ingested CBD, to assess whether CBD-drug interactions have been reported, and if substrates of DMP are frequently prescribed drugs.
OBSERVATIONS
Identified were 403 drugs as substrates of DMP. CBD-drug interactions were reported for 53/403 substrates in humans (n = 25), in vivo (n = 13) or in vitro (n = 15). In 31/53 substrates, CBD induced an increase, in 1/53 a decrease, in 4/53 no change in the substrate level. For 5/53 substrates, the results were controversial, and in 12/53 no substrate levels were reported. Among the 30 most frequently prescribed drugs in Germany were 67% substrates of DMP and among the 50 most frequently prescribed drugs in the USA 68%.
RELEVANCE AND CONCLUSIONS
There is an urgent need for pharmacologic studies on CBD-drug interactions. Patients should be educated on the potential risk and awareness should be increased among physicians. Regulatory authorities should become aware of the problem and start an initiative on an international level to increase the safety of CBD.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cannabidiol; Neoplasm Proteins; Cytochrome P-450 Enzyme System; Drug Interactions
PubMed: 37541924
DOI: 10.1016/j.ejim.2023.07.029 -
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