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Scientific Reports Jan 2021Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet...
Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet the cellular and metabolic processes within the biological component of this system are still elusive. Here we dissect the biohybrid composed of the anaerobic acetogenic bacterium Moorella thermoacetica and cadmium sulphide nanoparticles (CdS) in terms of physiology, metabolism, enzymatics and transcriptomic profiling. Our analyses show that while the organism does not grow on L-cysteine, it is metabolized to acetate in the biohybrid system and this metabolism is independent of CdS or light. CdS cells have higher metabolic activity, despite an inhibitory effect of Cd on key enzymes, because of an intracellular storage compound linked to arginine metabolism. We identify different routes how cysteine and its oxidized form can be innately metabolized by the model acetogen and what intracellular mechanisms are triggered by cysteine, cadmium or blue light.
Topics: Acetates; Biological Transport; Cadmium; Carbon; Carbon Isotopes; Complex Mixtures; Cysteine; Energy Metabolism; Gene Expression Regulation, Bacterial; Light; Magnetic Resonance Spectroscopy; Moorella; Oxidation-Reduction; Transcriptome
PubMed: 33495538
DOI: 10.1038/s41598-021-81103-z -
Drug Delivery and Translational Research Apr 2021For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven...
For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven difficult to quantify because drug clearance from the viable cutaneous tissue is not well characterised. Without such knowledge, of course, it is difficult-if not impossible-to predict a priori whether and over what time frame a topical formulation will permit an effective concentration of drug within the skin 'compartment' to be achieved. Here, we test the hypothesis that valuable information about drug disposition, and specifically its clearance, in this experimentally difficult-to-access compartment (at least, in vivo) can be derived from available systemic pharmacokinetic data for drugs administered via transdermal delivery systems. A multiple regression analysis was undertaken to determine the best-fit empirical correlation relating clearance from the skin to known or easily calculable drug properties. It was possible, in this way, to demonstrate a clear relationship between drug clearance from the skin and key physical chemical properties of the drug (molecular weight, log P and topological polar surface area). It was further demonstrated that values predicted by the model correlated well with those derived from in vitro skin experiments.
Topics: Administration, Cutaneous; Drug Delivery Systems; Drug Elimination Routes; Metabolic Clearance Rate; Skin; Skin Absorption
PubMed: 33164164
DOI: 10.1007/s13346-020-00864-8 -
Frontiers in Pharmacology 2023Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an...
Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an integrated metabolomics, culturomics, and bionics framework for systematically studying probiotics-driven drug metabolism. We discovered that 75% (27/36 of the assayed drugs) were metabolized by five selected probiotics, and drugs containing nitro or azo groups were more readily metabolized. As proof-of-principle experiments, we showed that Zhang (LCZ) could metabolize racecadotril to its active products, S-acetylthiorphan and thiorphan, in monoculture, in a near-real simulated human digestion system, and in an fecal co-culture system. However, a personalized effect was observed in the racecadotril-metabolizing activity of Zhang, depending on the individual's host gut microbiome composition. Based on data generated by our workflow, we proposed a possible mechanism of interactions among Zhang, racecadotril, and host gut microbiome, providing practical guidance for probiotic-drug co-treatment and novel insights into precision probiotics.
PubMed: 36778014
DOI: 10.3389/fphar.2023.1047863 -
Clinical Pharmacology and Therapeutics Jul 2020Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological... (Review)
Review
Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME) of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies-including systems biology analyses of "omics" data as well as metabolomics studies-indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME proteins in a large multiorgan remote sensing and signaling network. We use the Remote Sensing and Signaling Theory (RSST) to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST-based view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME proteins with key pathways in metabolism and signaling. The RSST-based view should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.
Topics: Animals; Biological Transport; Drug Development; Enzymes; Humans; Membrane Transport Proteins; Metabolomics; Models, Biological; Pharmaceutical Preparations; Systems Biology
PubMed: 32119114
DOI: 10.1002/cpt.1818 -
International Journal of Molecular... Jan 2022The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which... (Review)
Review
The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial-mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal-epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer.
Topics: Animals; Biomarkers; Biomarkers, Tumor; Disease Management; Disease Progression; Disease Susceptibility; Drug Resistance, Neoplasm; Energy Metabolism; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Organ Specificity; Oxidative Stress; RNA Interference; RNA, Long Noncoding; Signal Transduction; Transcription Factors; Tumor Microenvironment
PubMed: 35054987
DOI: 10.3390/ijms23020800 -
Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics.International Journal of Molecular... Apr 2020Reactive Oxygen Species or "ROS" encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species.... (Review)
Review
Reactive Oxygen Species or "ROS" encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Homeostasis; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 32354000
DOI: 10.3390/ijms21093100 -
Biochimica Et Biophysica Acta.... Jun 2021Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by... (Review)
Review
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.
Topics: Animals; Constitutive Androstane Receptor; Humans; Inactivation, Metabolic; Liver Diseases; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Xenobiotics
PubMed: 33600998
DOI: 10.1016/j.bbadis.2021.166101 -
Archives of Toxicology May 2021The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both... (Review)
Review
The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 (P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug-drug or drug-toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Cells, Cultured; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Hydroxylation; Insecticides; Ivermectin; Membrane Transport Proteins; Microsomes, Liver; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Pharmaceutical Preparations
PubMed: 33719007
DOI: 10.1007/s00204-021-03025-z -
Frontiers in Immunology 2024Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past... (Review)
Review
Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
Topics: Humans; Fructose; Neoplasms; Tumor Microenvironment; Animals; Cellular Reprogramming; Energy Metabolism; Metabolic Reprogramming
PubMed: 38711514
DOI: 10.3389/fimmu.2024.1375461 -
Accounts of Chemical Research Nov 2022Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological... (Review)
Review
Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.
Topics: Animals; Mice; Endocannabinoids; Lipid Metabolism; Brain; Neurons; Synaptic Transmission
PubMed: 36283077
DOI: 10.1021/acs.accounts.2c00521