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Nutrients Oct 2019Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent... (Review)
Review
Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid-hydroxy-fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines.
Topics: Adipose Tissue; Cold Temperature; Diet; Exercise; Humans; Lipid Metabolism
PubMed: 31614481
DOI: 10.3390/nu11102422 -
Cellular and Molecular Life Sciences :... Apr 2021Multiple sclerosis (MS) is an inflammatory demyelinating disease of the nervous system that primarily affects young adults. Although the exact etiology of the disease... (Review)
Review
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the nervous system that primarily affects young adults. Although the exact etiology of the disease remains obscure, it is clear that alterations in the metabolome contribute to this process. As such, defining a reliable and disease-specific metabolome has tremendous potential as a diagnostic and therapeutic strategy for MS. Here, we provide an overview of studies aimed at identifying the role of metabolomics in MS. These offer new insights into disease pathophysiology and the contributions of metabolic pathways to this process, identify unique markers indicative of treatment responses, and demonstrate the therapeutic effects of drug-like metabolites in cellular and animal models of MS. By and large, the commonly perturbed pathways in MS and its preclinical model include lipid metabolism involving alpha-linoleic acid pathway, nucleotide metabolism, amino acid metabolism, tricarboxylic acid cycle, D-ornithine and D-arginine pathways with collective role in signaling and energy supply. The metabolomics studies suggest that metabolic profiling of MS patient samples may uncover biomarkers that will advance our understanding of disease pathogenesis and progression, reduce delays and mistakes in diagnosis, monitor the course of disease, and detect better drug targets, all of which will improve early therapeutic interventions and improve evaluation of response to these treatments.
Topics: Animals; Biomarkers; Humans; Metabolic Networks and Pathways; Metabolome; Multiple Sclerosis
PubMed: 33449145
DOI: 10.1007/s00018-020-03733-2 -
International Journal of Molecular... Jun 2021As sphingolipids are constituents of the cell and vacuole membranes of eukaryotic cells, they are a critical component acquired from our daily diets. In the present... (Review)
Review
As sphingolipids are constituents of the cell and vacuole membranes of eukaryotic cells, they are a critical component acquired from our daily diets. In the present review, we highlight the knowledge regarding how dietary sphingolipids affect our health, particularly our intestinal health. Animal- and plant-derived foods contain, respectively, sphingomyelin (SM) and glucosylceramide (GlcCer) as their representative sphingolipids, and the sphingoid base as a specific structure of sphingolipids also differs depending upon the source and class. For example, sphingosine is predominant among animal sphingolipids, and tri-hydroxy bases are present in free ceramide (Cer) from plants and fungi. Dietary sphingolipids exhibit low absorption ratios; however, they possess various functions. GlcCer facilitates improvements in intestinal impairments, lipid metabolisms, and skin disorders, and SM can exert both similar and different effects compared to those elicited by GlcCer. We discuss the digestion, absorption, metabolism, and function of sphingolipids while focused on the structure. Additionally, we also review old and new classes in the context of current advancements in analytical instruments.
Topics: Animals; Healthy Lifestyle; Humans; Intestines; Lipid Metabolism; Plants; Sphingolipids
PubMed: 34208952
DOI: 10.3390/ijms22137052 -
Seminars in Perinatology Apr 2020Hepatic drug metabolism is a major route of drug elimination, mediated by multiple drug-metabolizing enzymes. Any changes in the rate and extent of hepatic drug... (Review)
Review
Hepatic drug metabolism is a major route of drug elimination, mediated by multiple drug-metabolizing enzymes. Any changes in the rate and extent of hepatic drug metabolism can lead to altered drug efficacy or toxicity. Accumulating clinical evidence indicates that pregnancy is accompanied by changes in hepatic drug metabolism. In this article, we discuss in vitro and in vivo tools used to study the mechanisms underlying the altered drug metabolism during pregnancy, focusing on primary hepatocyte culture, transgenic animal models, and use of probe drugs to assess change in enzymatic activity. The information obtained from these studies has enabled prediction of clinical PK changes for a given drug in pregnant women.
Topics: Animals; Biomedical Research; Cytochrome P-450 Enzyme System; Female; Hepatobiliary Elimination; Hepatocytes; Humans; Liver; Mice; Mice, Transgenic; Models, Animal; Pharmaceutical Preparations; Pharmacokinetics; Pregnancy; Primary Cell Culture
PubMed: 32122644
DOI: 10.1016/j.semperi.2020.151228 -
Cells Nov 2021Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in... (Review)
Review
Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity.
Topics: Animals; Humans; Models, Biological; Pregnane X Receptor; Protein Processing, Post-Translational; Signal Transduction
PubMed: 34831484
DOI: 10.3390/cells10113262 -
Cell Research Jan 2021Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells....
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.
Topics: Animals; Cell Line; Citric Acid Cycle; G1 Phase; Glucose; Glycolysis; Humans; Isocitrate Dehydrogenase; Mice; Mutagenesis, Site-Directed; Nocodazole; Protein Isoforms; RNA Interference; RNA, Small Interfering; S Phase; S-Phase Kinase-Associated Proteins; Ubiquitination
PubMed: 32669607
DOI: 10.1038/s41422-020-0372-z -
Cells Oct 2020Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated... (Review)
Review
Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on and expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.
Topics: Alternative Splicing; Animals; Biological Clocks; Constitutive Androstane Receptor; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Hepatocytes; Humans; Inactivation, Metabolic; Mice; Pregnane X Receptor; Protein Isoforms; Receptors, Cytoplasmic and Nuclear; Tissue Distribution; Transcription Factors
PubMed: 33142929
DOI: 10.3390/cells9112395 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183 -
Expert Opinion on Drug Metabolism &... Apr 2021Precision drug therapy requires accounting for pertinent factors in pharmacokinetic (PK) inter-individual variability (., pharmacogenetics, diseases, polypharmacy, and... (Review)
Review
Precision drug therapy requires accounting for pertinent factors in pharmacokinetic (PK) inter-individual variability (., pharmacogenetics, diseases, polypharmacy, and natural product use) that can cause sub-therapeutic or adverse effects. Although each of these individual factors can alter victim drug PK, multi-factorial interactions can cause additive, synergistic, or opposing effects. Determining the magnitude and direction of these complex multi-factorial effects requires understanding the rate-limiting redundant and/or sequential PK processes for each drug. Perturbations in drug-metabolizing enzymes and/or transporters are integral to single- and multi-factorial PK interactions. Examples of single factor PK interactions presented include gene-drug (pharmacogenetic), disease-drug, drug-drug, and natural product-drug interactions. Examples of multi-factorial PK interactions presented include drug-gene-drug, natural product-gene-drug, gene-gene-drug, disease-natural product-drug, and disease-gene-drug interactions. Clear interpretation of multi-factorial interactions can be complicated by study design, complexity in victim drug PK, and incomplete mechanistic understanding of victim drug PK. Incorporation of complex multi-factorial PK interactions into precision drug therapy requires advances in clinical decision tools, intentional PK study designs, drug-metabolizing enzyme and transporter fractional contribution determinations, systems and computational approaches (., physiologically-based pharmacokinetic modeling), and PK phenotyping of progressive diseases.
Topics: Animals; Drug Interactions; Humans; Membrane Transport Proteins; Models, Biological; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Precision Medicine; Research Design
PubMed: 33339463
DOI: 10.1080/17425255.2021.1867105 -
European Journal of Pharmaceutical... Apr 2023A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized...
A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized by high inter- and intraindividual differences, but their impact on drug distribution and efficacy remains incompletely understood. This research gap is pressing, as, e.g., inflammatory disorders of the colon are on the rise globally. In an effort to help close this gap, we provide considerations on determining colonic epithelial and microbial cellular parameters, and their impact on drug bioavailability. First, we cover the major cell types found in vivo within the epithelium and microbiota, and discuss how they can be modeled in vitro. We then draw attention to their structural similarities and differences with regard to determinants of drug distribution. Once a drug is solubilized in the luminal fluids, there are two main classes of such determinants: 1) binding processes, and 2) transporters and drug-metabolizing enzymes. Binding lowers the unbound intracellular fraction (f), which will, in turn, limit the amount of drug available for transport to desired sites. Transporters and drug metabolizing enzymes are ADME proteins impacting intracellular accumulation (Kp). Across cell types, we point out which processes are likely particularly impactful. Together, f and Kp can be used to describe intracellular bioavailability (F), which is a measure of local drug distribution, with consequences for efficacy. Determining these cellular parameters will be beneficial in understanding colonic drug distribution and will advance the field of drug delivery.
Topics: Epithelial Cells; Colon; Epithelium; Biological Availability; Pharmaceutical Preparations; Membrane Transport Proteins
PubMed: 36690119
DOI: 10.1016/j.ejps.2023.106389