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Cell Host & Microbe Aug 2016Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely...
Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.
Topics: Animals; Antibody Formation; B-Lymphocytes; Cell Differentiation; Dietary Fiber; Fatty Acids, Volatile; Fermentation; Gastrointestinal Microbiome; Gastrointestinal Tract; Gene Expression Regulation; Metabolic Networks and Pathways; Mice, Inbred C57BL
PubMed: 27476413
DOI: 10.1016/j.chom.2016.07.001 -
Drug Design, Development and Therapy 2018Cancer is one of the major causes of morbidity and mortality in the world. Carcinogenesis is a multistep process induced by genetic and epigenetic changes that disrupt... (Review)
Review
Cancer is one of the major causes of morbidity and mortality in the world. Carcinogenesis is a multistep process induced by genetic and epigenetic changes that disrupt pathways controlling cell proliferation, apoptosis, differentiation, and senescence. In this context, many bioactive dietary compounds from vegetables and fruits have been demonstrated to be effective in cancer prevention and intervention. Over the years, sulforaphane (SFN), found in cruciferous vegetables, has been shown to have chemopreventive activity in vitro and in vivo. SFN protects cells from environmental carcinogens and also induces growth arrest and/or apoptosis in various cancer cells. In this review, we will discuss several potential mechanisms of the chemopreventive activity of SFN, including regulation of Phase I and Phase II drug-metabolizing enzymes, cell cycle arrest, and induction of apoptosis, especially via regulation of signaling pathways such as Nrf2-Keap1 and NF-κB. Recent studies suggest that SFN can also affect the epigenetic control of key genes and greatly influence the initiation and progression of cancer. This research may provide a basis for the clinical use of SFN for cancer chemoprevention and enable us to design preventive strategies for cancer management, reduce cancer development and recurrence, and thus improve patient survival.
Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Humans; Isothiocyanates; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Neoplasms; Sulfoxides
PubMed: 30254420
DOI: 10.2147/DDDT.S100534 -
Human Genomics May 2021UDP-glucuronosyltransferases (UGTs) are the main phase II drug-metabolizing enzymes mediating the most extensive glucuronidation-binding reaction in the human body. The... (Review)
Review
UDP-glucuronosyltransferases (UGTs) are the main phase II drug-metabolizing enzymes mediating the most extensive glucuronidation-binding reaction in the human body. The UGT1A family is involved in more than half of glucuronidation reactions. However, significant differences exist in the distribution of UGT1As in vivo and the expression of UGT1As among individuals, and these differences are related to the occurrence of disease and differences in metabolism. In addition to genetic polymorphisms, there is now interest in the contribution of epigenetics and noncoding RNAs (especially miRNAs) to this differential change. Epigenetics regulates UGT1As pretranscriptionally through DNA methylation and histone modification, and miRNAs are considered the key mechanism of posttranscriptional regulation of UGT1As. Both epigenetic inheritance and miRNAs are involved in the differences in sex expression and in vivo distribution of UGT1As. Moreover, epigenetic changes early in life have been shown to affect gene expression throughout life. Here, we review and summarize the current regulatory role of epigenetics in the UGT1A family and discuss the relationship among epigenetics and UGT1A-related diseases and treatment, with references for future research.
Topics: Epigenesis, Genetic; Glucuronosyltransferase; Humans; Inactivation, Metabolic; MicroRNAs; Multigene Family
PubMed: 34034810
DOI: 10.1186/s40246-021-00331-6 -
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 -
Cells Oct 2020During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and... (Review)
Review
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.
Topics: Animals; Constitutive Androstane Receptor; Endocrine Disruptors; Humans; Inactivation, Metabolic; Liver; Metabolic Networks and Pathways; Mice; Rats; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Xenobiotics
PubMed: 33076503
DOI: 10.3390/cells9102306 -
Drug Metabolism and Disposition: the... Aug 2018Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome... (Review)
Review
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
Topics: Animals; Cardiotoxicity; Cardiovascular System; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Xenobiotics
PubMed: 29695613
DOI: 10.1124/dmd.117.078964 -
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 -
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