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Basic & Clinical Pharmacology &... Jan 2007Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and... (Comparative Study)
Comparative Study Review
Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride. These agents are subject to drug-drug interactions with other psychotropic agents or with medications used in the treatment of concomitant physical illnesses. Most pharmacokinetic interactions with newer antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug-metabolizing enzymes involved in their biotransformation, i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate-glucuronosyltransferases (UGT). Clozapine is metabolized primarily by CYP1A2, with additional contribution by other CYP isoforms. Risperidone is metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4. Olanzapine undergoes both direct conjugation and CYP1A2-mediated oxidation. Quetiapine is metabolized by CYP3A4, while sertindole and aripiprazole are metabolized by CYP2D6 and CYP3A4. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. Amisulpride is primarily excreted in the urine and undergoes relatively little metabolism. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, co-administration of inhibitors or inducers of the major enzymes responsible for their metabolism may modify their plasma concentrations, leading to potentially significant effects. Most documented metabolic interactions involve antidepressant and anti-epileptic drugs. Of a particular clinical significance is the interaction between fluvoxamine, a potent CYP1A2 inhibitor, and clozapine. Differences in the interaction potential among the novel antipsychotics currently available may be predicted based on their metabolic pathways. The clinical relevance of these interactions should be interpreted in relation to the relative width of their therapeutic index. Avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and, possibly, plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.
Topics: Antipsychotic Agents; Biological Availability; Biotransformation; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans
PubMed: 17214606
DOI: 10.1111/j.1742-7843.2007.00017.x -
The FEBS Journal Oct 2009There is a tightly regulated interaction, which is well-conserved in evolution, between the metabolic and immune systems that is deranged in states of over- or... (Review)
Review
There is a tightly regulated interaction, which is well-conserved in evolution, between the metabolic and immune systems that is deranged in states of over- or under-nutrition. Obesity, an energy-rich condition, is characterized by the activation of an inflammatory process in metabolically active sites such as adipose tissue, liver and immune cells. The consequence of this response is a sharp increase in circulating levels of proinflammatory cytokines, adipokines and other inflammatory markers. Activation of the immune response in obesity is mediated by specific signaling pathways, with Jun N-terminal kinase and IkappaB kinase beta/nuclear factor kappa-light-chain-enhancer of activated B cells being the most well studied. It is known that the above events modify insulin signaling and result in the development of insulin resistance. The nutrient overload characterizing obesity is a metabolic stressor associated with intracellular organelle (e.g. the endoplasmic reticulum) stress. The exact characterization of the series of events and the mechanisms that integrate the inflammatory response with metabolic homeostasis at the cellular and systemic level is a very active research field. In this minireview, we discuss the signaling pathways and molecules associated with the development of obesity-induced inflammation, as well as the evidence that supports a critical role for the stress response in this process.
Topics: Animals; Endoplasmic Reticulum; Humans; I-kappa B Kinase; JNK Mitogen-Activated Protein Kinases; Obesity; Oxidative Stress; Signal Transduction
PubMed: 19754872
DOI: 10.1111/j.1742-4658.2009.07304.x -
Journal of Dairy Science Oct 2023The dairy industry depends upon the cow's successful lactation for economic profitability. Heat stress compromises the economic sustainability of the dairy industry by... (Review)
Review
The dairy industry depends upon the cow's successful lactation for economic profitability. Heat stress compromises the economic sustainability of the dairy industry by reducing milk production and increasing the risk of metabolic and pathogenic disease. Heat stress alters metabolic adaptations, such as nutrient mobilization and partitioning, that support the energetic demands of lactation. Metabolically inflexible cows are unable to enlist the necessary homeorhetic shifts that provide the needed nutrients and energy for milk synthesis, thereby impairing lactation performance. Mitochondria provide the energetic foundation that enable a myriad of metabolically demanding processes, such as lactation. Changes in an animal's energy requirements are met at the cellular level through alterations in mitochondrial density and bioenergetic capacity. Mitochondria also act as central stress modulators and coordinate tissues' energetic responses to stress by integrating endocrine signals, through mito-nuclear communication, into the cellular stress response. In vitro heat insults affect mitochondria through a compromise in mitochondrial integrity, which is linked to a decrease in mitochondrial function. However, limited evidence exists linking the in vivo metabolic effects of heat stress with parameters of mitochondrial behavior and function in lactating animals. This review summarizes the literature describing the cellular and subcellular effects of heat stress, with a focus on the effect of heat stress on mitochondrial bioenergetics and cellular dysfunction in livestock. Implications for lactation performance and metabolic health are also discussed.
Topics: Female; Cattle; Animals; Lactation; Mitochondria; Milk; Energy Metabolism; Heat-Shock Response
PubMed: 37210354
DOI: 10.3168/jds.2023-23340 -
Proceedings of the National Academy of... Nov 2023Microbial communities are fundamental to life on Earth. Different strains within these communities are often connected by a highly connected metabolic network, where the...
Microbial communities are fundamental to life on Earth. Different strains within these communities are often connected by a highly connected metabolic network, where the growth of one strain depends on the metabolic activities of other community members. While distributed metabolic functions allow microbes to reduce costs and optimize metabolic pathways, they make them metabolically dependent. Here, we hypothesize that such dependencies can be detrimental in situations where the external conditions change rapidly, as they often do in natural environments. After a shift in external conditions, microbes need to remodel their metabolism, but they can only resume growth once partners on which they depend have also adapted to the new conditions. It is currently not well understood how microbial communities resolve this dilemma and how metabolic interactions are reestablished after an environmental shift. To address this question, we investigated the dynamical responses to environmental perturbation by microbial consortia with distributed anabolic functions. By measuring the regrowth times at the single-cell level in spatially structured communities, we found that metabolic dependencies lead to a growth delay after an environmental shift. However, a minority of cells-those in the immediate neighborhood of their metabolic partners-can regrow quickly and come to numerically dominate the community after the shift. The spatial arrangement of a microbial community is thus a key factor in determining the communities' ability to maintain metabolic interactions and growth in fluctuating conditions. Our results suggest that environmental fluctuations can limit the emergence of metabolic dependencies between microorganisms.
Topics: Microbiota; Microbial Consortia; Metabolic Networks and Pathways; Microbial Interactions
PubMed: 37903278
DOI: 10.1073/pnas.2301398120 -
Advances in Experimental Medicine and... 2021Triple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells...
Triple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.
Topics: Cell Line, Tumor; Humans; Mitochondria; NAD; Optical Imaging; Oxidation-Reduction; Triple Negative Breast Neoplasms
PubMed: 33966226
DOI: 10.1007/978-3-030-48238-1_40 -
Journal of Cell Science May 2012Since the discovery of AMP-dependent protein kinase (AMPK), its fundamental role in regulating metabolic pathways and the molecular mechanism underlying the regulation... (Review)
Review
Since the discovery of AMP-dependent protein kinase (AMPK), its fundamental role in regulating metabolic pathways and the molecular mechanism underlying the regulation of its activity by adenine nucleotides has been widely studied. AMPK is not only an energy-responsive enzyme, but it also senses redox signals. This review aims at recapitulating the recent lines of evidence that demonstrate the responsiveness of this kinase to metabolic and nitroxidative imbalance, thus providing new insights into the intimate networks of redox-based signals upstream of AMPK. In particular, we discuss its well-recognized activation downstream of mitochondrial dysfunction, debate the recent findings that AMPK is directly targeted by pro-oxidant species, and question alternative redox pathways that allow AMPK to be included into the large class of redox-sensing proteins. The possible therapeutic implications of the role of AMPK in redox-associated pathologies, such as cancer and neurodegeneration, are also discussed in light of recent advances that suggest a role for AMPK in the tuning of redox-dependent processes, such as apoptosis and autophagy.
Topics: AMP-Activated Protein Kinases; Adenosine Monophosphate; Apoptosis; Autophagy; Energy Metabolism; Humans; Mitochondria; Neoplasms; Neurodegenerative Diseases; Oxidation-Reduction; Phosphorylation; Reactive Nitrogen Species; Signal Transduction
PubMed: 22619229
DOI: 10.1242/jcs.095216 -
International Journal of Molecular... Oct 2018The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long... (Review)
Review
The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.
Topics: Animals; Forkhead Box Protein O1; Humans; Lipid Metabolism; MicroRNAs; Non-alcoholic Fatty Liver Disease; Receptors, Estrogen; Thyroid Hormones; ERRalpha Estrogen-Related Receptor
PubMed: 30360449
DOI: 10.3390/ijms19103284 -
Biology Aug 2023Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand...
Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including , , , , and , that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (, , , , and ) and pathogenic genes (, , and ). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.
PubMed: 37759556
DOI: 10.3390/biology12091156 -
Critical Reviews in Oncology/hematology Jun 2017Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this... (Review)
Review
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Energy Metabolism; Humans; Pancreatic Neoplasms
PubMed: 28477742
DOI: 10.1016/j.critrevonc.2017.03.026 -
Molecular Biology of the Cell Jun 2011We studied the steady-state responses to changes in growth rate of yeast when ethanol is the sole source of carbon and energy. Analysis of these data, together with data...
We studied the steady-state responses to changes in growth rate of yeast when ethanol is the sole source of carbon and energy. Analysis of these data, together with data from studies where glucose was the carbon source, allowed us to distinguish a "universal" growth rate response (GRR) common to all media studied from a GRR specific to the carbon source. Genes with positive universal GRR include ribosomal, translation, and mitochondrial genes, and those with negative GRR include autophagy, vacuolar, and stress response genes. The carbon source-specific GRR genes control mitochondrial function, peroxisomes, and synthesis of vitamins and cofactors, suggesting this response may reflect the intensity of oxidative metabolism. All genes with universal GRR, which comprise 25% of the genome, are expressed periodically in the yeast metabolic cycle (YMC). We propose that the universal GRR may be accounted for by changes in the relative durations of the YMC phases. This idea is supported by oxygen consumption data from metabolically synchronized cultures with doubling times ranging from 5 to 14 h. We found that the high oxygen consumption phase of the YMC can coincide exactly with the S phase of the cell division cycle, suggesting that oxidative metabolism and DNA replication are not incompatible.
Topics: Carbon; Cell Cycle; Cell Division; DNA; Energy Metabolism; Ethanol; Gene Expression Regulation, Fungal; Glucose; Mitochondria; Oxygen Consumption; RNA, Messenger; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 21525243
DOI: 10.1091/mbc.E11-02-0132