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International Journal of Molecular... Dec 2023Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we... (Review)
Review
Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development.
Topics: Humans; Sphingolipids; Virus Diseases; Signal Transduction; Lipid Metabolism; Metabolic Networks and Pathways; Sphingosine
PubMed: 38139132
DOI: 10.3390/ijms242417303 -
Seminars in Cancer Biology Aug 2019In the past half century, our version on cancer, from tumor initiation, growth, to metastasis, is dominated by genetic mutation. The importance of metabolism and... (Review)
Review
In the past half century, our version on cancer, from tumor initiation, growth, to metastasis, is dominated by genetic mutation. The importance of metabolism and epigenetics was not recognized until most recently. Extensive cell proliferation is one of the hallmarks of cancers. To support the energetic and anabolic demands of enhanced proliferation, tumors reprogram the pathways of nutrient procurement and metabolism. In this context, a new link between metabolic alterations and cancer progression has been unraveled over the last decade by the studies conducted in the area of cancer cell metabolism. Cancer cells are known to alter their metabolic profile during the course of tumorigenesis and metastasis thereby exhibiting a tightly regulated program of metabolic plasticity. Noteworthy, certain metabolic alteration are known to occur at the epigenetic level, thus making epigenetics and metabolism highly interwoven in a reciprocal manner. Metabolites that are generated during metabolic pathways, such as in glycolytic cycle and oxidative phosphorylation, serve as cofactors or substrates for the enzymatic reactions that catalyze the epigenetic modifications and transcriptional regulation. Several studies also indicate that the epigenome is sensitive to cellular metabolism. Since many of the metabolic alterations and consequently aberrated epigenetic regulation are common to a wide range of cancer types, they serve as promising targets for anti-cancer therapies. Here we discuss the latest findings in cancer cell metabolism, elucidating the major anabolic, catabolic and energetic demands required for sustaining cancer growth, and the influence of altered metabolism on epigenetics and vice versa. A comprehensive research pertaining to metabolomic profiling and epigenome interactors/mediators in malignant neoplasias is imperative in deciphering the potential targets that can be exploited for the development of robust anti-cancer therapies.
Topics: Animals; DNA Methylation; Disease Susceptibility; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 31185282
DOI: 10.1016/j.semcancer.2019.06.006 -
Current Opinion in Pediatrics Feb 2020In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although... (Review)
Review
PURPOSE OF REVIEW
In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although current standard of care regimens for several pediatric malignancies incorporate agents that target tumor metabolism, these drugs have been part of the therapeutic landscape for decades. More recent research has focused on the identification and targeting of new metabolic vulnerabilities in pediatric cancers. The purpose of this review is to describe the most recent translational findings in the metabolic targeting of pediatric malignancies.
RECENT FINDINGS
Across multiple pediatric cancer types, dependencies on a number of key metabolic pathways have emerged through study of patient tissue samples and preclinical modeling. Among the potentially targetable vulnerabilities are glucose metabolism via glycolysis, oxidative phosphorylation, amino acid and polyamine metabolism, and NAD metabolism. Although few agents have yet to move forward into clinical trials for pediatric cancer patients, the robust and promising preclinical data that have been generated suggest that future clinical trials should rationally test metabolically targeted agents for relevant disease populations.
SUMMARY
Recent advances in our understanding of the metabolic dependencies of pediatric cancers represent a source of potential new therapeutic opportunities for these diseases.
Topics: Amino Acids; Antineoplastic Agents; Child; Folic Acid; Glycolysis; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; NAD; Neoplasms; Oxidative Phosphorylation; Polyamines
PubMed: 31789976
DOI: 10.1097/MOP.0000000000000853 -
Immunological Reviews May 2020The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the... (Review)
Review
The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4 T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues.
Topics: Amino Acids; Animals; Autoimmunity; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Cholesterol; Disease Susceptibility; Energy Metabolism; Fatty Acids; Homeostasis; Humans; Lipid Metabolism; Lupus Erythematosus, Systemic; Oxidation-Reduction; Oxidative Phosphorylation; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 32162304
DOI: 10.1111/imr.12847 -
Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
Pharmacology Research & Perspectives Feb 2022Opicapone (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide) is a selective catechol-O-methyltransferase inhibitor that...
Opicapone (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide) is a selective catechol-O-methyltransferase inhibitor that has been granted marketing authorization in Europe, Japan, and United States. The present work describes the metabolism and disposition of opicapone in the rat obtained in support to its development and regulatory filling. Plasma levels and elimination of total radioactivity were determined after oral and intravenous administration of [ C]-opicapone. The maximum plasma concentrations of opicapone-related radioactivity were reached at early time points followed by a gradual return to baseline with a biphasic elimination. Fecal excretion was the primary route of elimination of total radioactivity. Quantitative distribution of drug-related radioactivity demonstrated that opicapone and related metabolites did not distribute to the central nervous system. Opicapone was extensively metabolized in rats resulting in more than 20 phase I and phase II metabolites. Although O-glucuronidation, -sulfation, and -methylation of the nitrocatechol moiety were the principal metabolic pathways, small amount of the N-acetyl derivative was detected, as a result of reduction of the nitro group and subsequent conjugation. Other metabolic transformations included N-oxide reduction to the pyridine derivative and reductive cleavage of 1,2,4-oxadiazole ring followed by further conjugative reactions. Reaction phenotyping studies suggested that SULT 1A1*1 and *2 and UGT1A7, UGT1A8, UGT1A9, and UGT1A10 may be involved in opicapone sulfation and glucuronidation, respectively. However, the reductive metabolic pathways mediated by gut microflora cannot be excluded. Opicapone, in the rat, was found to be rapidly absorbed, widely distributed to peripheric tissues, metabolized mainly via conjugative pathways at the nitro catechol ring, and primarily excreted via feces.
Topics: Administration, Intravenous; Administration, Oral; Animals; Arylsulfotransferase; Catechol O-Methyltransferase Inhibitors; Glucuronosyltransferase; Male; Oxadiazoles; Phenotype; Rats; Rats, Wistar; Tissue Distribution
PubMed: 34939338
DOI: 10.1002/prp2.891 -
ChemistryOpen Dec 2022Drugs are metabolized within the liver (pH 7.4) by phase I and phase II metabolism. During the process, reactive metabolites can be formed that react covalently with... (Review)
Review
Drugs are metabolized within the liver (pH 7.4) by phase I and phase II metabolism. During the process, reactive metabolites can be formed that react covalently with biomolecules and induce toxicity. Identifying and detecting reactive metabolites is an important part of drug development. Preclinical and clinical investigations are conducted to assess the toxicity and safety of a new drug candidate. Electrochemistry coupled to mass spectrometry is an ideal complementary technique to the current preclinical studies, a pure instrumental approach without any purification steps and tedious protocols. The combination of microfluidics with electrochemistry towards the mimicry of drug metabolism offers portability, low volume of reagents and faster reaction times. This review explores the development of microfluidic electrochemical cells for mimicking drug metabolism.
Topics: Electrochemistry; Microfluidics; Oxidation-Reduction; Mass Spectrometry
PubMed: 36166688
DOI: 10.1002/open.202200100 -
The FEBS Journal Apr 2020Detoxication, or 'drug-metabolizing', enzymes and drug transporters exhibit remarkable substrate promiscuity and catalytic promiscuity. In contrast to substrate-specific... (Review)
Review
Detoxication, or 'drug-metabolizing', enzymes and drug transporters exhibit remarkable substrate promiscuity and catalytic promiscuity. In contrast to substrate-specific enzymes that participate in defined metabolic pathways, individual detoxication enzymes must cope with substrates of vast structural diversity, including previously unencountered environmental toxins. Presumably, evolution selects for a balance of 'adequate' k /K values for a wide range of substrates, rather than optimizing k /K for any individual substrate. However, the structural, energetic, and metabolic properties that achieve this balance, and hence optimize detoxication, are not well understood. Two features of detoxication enzymes that are frequently cited as contributions to promiscuity include the exploitation of highly reactive versatile cofactors, or cosubstrates, and a high degree of flexibility within the protein structure. This review examines these intuitive mechanisms in detail and clarifies the contributions of the classic ligand binding models 'induced fit' (IF) and 'conformational selection' (CS) to substrate promiscuity. The available literature data for drug metabolizing enzymes and transporters suggest that IF is exploited by these promiscuous detoxication enzymes, as it is with substrate-specific enzymes, but the detoxication enzymes uniquely exploit 'IFs' to retain a wide range of substrates at their active sites. In contrast, whereas CS provides no catalytic advantage to substrate-specific enzymes, promiscuous enzymes may uniquely exploit it to recruit a wide range of substrates. The combination of CS and IF, for recruitment and retention of substrates, can potentially optimize the promiscuity of drug metabolizing enzymes and drug transporters.
Topics: Aldehyde Oxidase; Biological Transport; Carrier Proteins; Epoxide Hydrolases; Humans; Oxygenases; Pharmaceutical Preparations; Substrate Specificity; Transferases
PubMed: 31663687
DOI: 10.1111/febs.15116 -
The AAPS Journal Sep 2019The emergence and continued evolution of the transporter field has caused re-evaluation and refinement of the original principles surrounding drug disposition. In this... (Review)
Review
The emergence and continued evolution of the transporter field has caused re-evaluation and refinement of the original principles surrounding drug disposition. In this paper, we emphasize the impact that transporters can have on volume of distribution and how this can affect the other major pharmacokinetic parameters. When metabolic drug-drug interactions or pharmacogenomic variance changes the metabolism of a drug, the volume of distribution appears to be unchanged while clearance, bioavailability, and half-life are changed. When transporters are involved in the drug-drug interactions or pharmacogenomic variance, the volume of distribution can be markedly affected causing counterintuitive changes in half-life. Cases are examined where a volume of distribution change is significant enough that although clearance decreases, half-life decreases. Thus, drug dosing decisions must be made based on CL/F changes, not half-life changes, as such volume of distribution alterations will also influence the half-life results.
Topics: Animals; Biological Availability; Drug Interactions; Humans; Membrane Transport Proteins; Metabolic Clearance Rate; Models, Biological; Pharmaceutical Preparations; Tissue Distribution
PubMed: 31482335
DOI: 10.1208/s12248-019-0373-3