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Biochemical Pharmacology Sep 2023Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged... (Review)
Review
Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, and response to therapy in various types of cancer. Cancer cells exhibit remarkable adaptability by modulating glucose, lipids, amino acids, and nucleotide metabolism to survive in nutrient- and oxygen-deprived environments. Although medulloblastoma has been extensively studied from a genomic perspective, leading to the identification of four subgroups and their respective subcategories, the investigation of its metabolic phenotype has remained relatively understudied. This review focus on the available literature, aiming to summarize the current knowledge about the main metabolic pathways that are deregulated in medulloblastoma tumors, while emphasizing the controversial aspects and the progress that is yet to be made. Furthermore, we underscored the insights gained so far regarding the impact of metabolism on the development of drug resistance in medulloblastoma and the therapeutic strategies employed to target specific metabolic pathways.
Topics: Humans; Medulloblastoma; Cerebellar Neoplasms; Hunger; Brain Neoplasms; Metabolic Networks and Pathways
PubMed: 37481140
DOI: 10.1016/j.bcp.2023.115697 -
Drug Metabolism and Disposition: the... Oct 2023We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and...
We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and activity in human liver cytosol (HLC) and five recombinant human AO preparations (rAO) were determined using targeted proteomics and carbazeran oxidation assay, respectively. AO content was highly variable as indicated by the relative expression factor (REF; i.e., HLC to rAO content) ranging from 0.001 to 1.7 across different in vitro systems. The activity of AO in HLC degrades at a 10-fold higher rate in the presence of the substrate as compared with the activity performed after preincubation without substrate. To scale the metabolic activity from rAO to HLC, a protein-normalized activity factor (pnAF) was proposed wherein the activity was corrected by AO content, which revealed up to sixfold higher AO activity in HLC versus rAO systems. A similar value of pnAF was observed for another substrate, ripasudil. Physiologically based pharmacokinetic (PBPK) modeling revealed a significant additional clearance (CL; 66%), which allowed for the successful prediction of in vivo CL of four other substrates, i.e., O-benzyl guanine, BIBX1382, zaleplon, and zoniporide. For carbazeran, the metabolite identification study showed that the direct glucuronidation may be contributing to around 12% elimination. Taken together, this study identified differential protein content, instability of in vitro activity, role of additional AO clearance, and unaccounted metabolic pathways as plausible reasons for the underprediction of AO-mediated drug metabolism. Consideration of these factors and integration of REF and pnAF in PBPK models will allow better prediction of AO metabolism. SIGNIFICANCE STATEMENT: This study elucidated the plausible reasons for the underprediction of aldehyde oxidase (AO)-mediated drug metabolism and provided recommendations to address them. It demonstrated that integrating protein content and activity differences and accounting for the loss of AO activity, as well as consideration of extrahepatic clearance and additional pathways, would improve the in vitro to in vivo extrapolation of AO-mediated drug metabolism using physiologically based pharmacokinetic modeling.
Topics: Humans; Aldehyde Oxidase; Carbamates; Kinetics; Metabolic Clearance Rate; Liver
PubMed: 37429730
DOI: 10.1124/dmd.123.001379 -
Chemico-biological Interactions Aug 2023Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the cellular antioxidant defense system at the posttranscriptional level.... (Review)
Review
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the cellular antioxidant defense system at the posttranscriptional level. During oxidative stress, Nrf2 is released from its negative regulator Kelch-like ECH-associated protein 1 (Keap1) and binds to antioxidant response element (ARE) to transcribe antioxidative metabolizing/detoxifying genes. Various transcription factors like aryl hydrocarbon receptor (AhR) and nuclear factor kappa light chain enhancer of activated B cells (NF-kB) and epigenetic modification including DNA methylation and histone methylation might also regulate the expression of Nrf2. Despite its protective role, Keap1/Nrf2/ARE signaling is considered as a pharmacological target due to its involvement in various pathophysiological conditions such as diabetes, cardiovascular diseases, cancers, neurodegenerative diseases, hepatotoxicity and kidney disorders. Recently, nanomaterials have received a lot of attention due to their unique physiochemical properties and are also used in various biological applications, for example, biosensors, drug delivery systems, cancer therapy, etc. In this review, we will be discussing the functions of nanoparticles and Nrf2 as a combined therapy or sensitizing agent and their significance in various diseases such as diabetes, cancers and oxidative stress-mediated diseases.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Antioxidants; Neoplasms; Nanoparticles
PubMed: 37187268
DOI: 10.1016/j.cbi.2023.110535 -
Clinical & Translational Oncology :... Feb 2024Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development.... (Review)
Review
Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer.
Topics: Humans; Stomach Neoplasms; Energy Metabolism; Neoplasms; Glycolysis; Citric Acid Cycle; Oxidative Phosphorylation
PubMed: 37477784
DOI: 10.1007/s12094-023-03278-3 -
Journal of Drug Targeting Dec 2023Therapy on lipid metabolism is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases.... (Review)
Review
Therapy on lipid metabolism is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases. Tumorigenesis is inextricably linked to lipid metabolism. In this regard, the features of lipid metabolism include lipid synthesis, decomposition, metabolism and lipid storage and mobilisation from intracellular lipid droplets. Most importantly, the regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects. Different cancers and immune cells have different dependence on lipid metabolism, playing a pivotal role in differentiation and function of immune cells. However, what lies before the immunotherapy targeting lipid metabolism is side effects of systemic toxicity and defects of individual drugs, which strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies. This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells and their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.HighlightsThe regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects.Preparations of focusing lipid metabolism have side effects of systemic toxicity and defects of individual drugs. It strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies.This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells as well as their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.
Topics: Humans; Lipid Metabolism; Nanomedicine; Neoplasms; Immunotherapy; Lipids; Drug-Related Side Effects and Adverse Reactions; Tumor Microenvironment
PubMed: 37962291
DOI: 10.1080/1061186X.2023.2283829 -
Molecular Biology Reports Dec 2023Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune... (Review)
Review
Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune tolerance. Accumulating evidence also demonstrates cytoprotective and immunomodulatory properties of kynurenine pathway in conditions affecting either central or peripheral nervous system as well as other conditions such as inflammatory bowel disease (IBD). Although multilevel association exists between the inflammatory bowel disease (IBD) and various neurologic (e.g., neurodegenerative) disorders, it is believed that the kynurenine pathway plays a pivotal role in the development of both IBD and neurodegenerative disorders. In this setting, there is strong evidence linking the gut-brain axis with intestinal dysfunctions including IBD which is consistent with the fact that the risk of neurodegenerative diseases is higher in IBD patients. This review aims to highlight the role of kynurenine metabolic pathway in various neurologic and psychiatric diseases as well as relationship between IBD and neurodegenerative disorders in the light of the kynurenine metabolic pathway.
Topics: Humans; Kynurenine; Inflammatory Bowel Diseases; Mental Disorders; Neurodegenerative Diseases; Metabolic Networks and Pathways
PubMed: 37848760
DOI: 10.1007/s11033-023-08859-7 -
Annual Review of Pharmacology and... Jan 2024Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the... (Review)
Review
Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations.
Topics: Humans; Artificial Intelligence; Genotype; Biomarkers; Phenotype; Drug-Related Side Effects and Adverse Reactions
PubMed: 37585662
DOI: 10.1146/annurev-pharmtox-032023-121106 -
Mini Reviews in Medicinal Chemistry 2024Oxidative stress has been reported to be involved in the onset and development of several diseases, including neurodegenerative and cardiovascular disorders, some types... (Review)
Review
Oxidative stress has been reported to be involved in the onset and development of several diseases, including neurodegenerative and cardiovascular disorders, some types of cancer, and diabetes. Therefore, finding strategies to detoxify free radicals is an active area of research. One of these strategies is the use of natural or synthetic antioxidants. In this context, melatonin (MLT) has been proven to possess most of the required characteristics of an efficient antioxidant. In addition, its protection against oxidative stress continues after being metabolized, since its metabolites also exhibit antioxidant capacity. Based on the appealing properties of MLT and its metabolites, various synthetic analogues have been developed to obtain compounds with higher activity and lower side effects. This review addresses recent studies with MLT and related compounds as potential antioxidants.
Topics: Melatonin; Antioxidants; Humans; Oxidative Stress; Animals
PubMed: 37366352
DOI: 10.2174/1389557523666230627140816 -
Biochemical Society Transactions Apr 2024Pathological breakdown of membrane lipids through excessive lipid peroxidation (LPO) was first described in the mid-20th century and is now recognized as a form of... (Review)
Review
Pathological breakdown of membrane lipids through excessive lipid peroxidation (LPO) was first described in the mid-20th century and is now recognized as a form of regulated cell death, dubbed ferroptosis. Accumulating evidence unveils how metabolic regulation restrains peroxidation of phospholipids within cellular membranes, thereby impeding ferroptosis execution. Unleashing these metabolic breaks is currently therapeutically explored to sensitize cancers to ferroptosis inducing anti-cancer therapies. Reversely, these natural ferroptotic defense mechanisms can fail resulting in pathological conditions or diseases such as ischemia-reperfusion injury, multi-organ dysfunction, stroke, infarction, or neurodegenerative diseases. This minireview outlines current ferroptosis-inducing anti-cancer strategies and highlights the detection as well as the therapeutic targeting of ferroptosis in preclinical experimental settings. Herein, we also briefly summarize observations related to LPO, iron and redox deregulation in patients that might hint towards ferroptosis as a contributing factor.
Topics: Ferroptosis; Humans; Lipid Peroxidation; Neoplasms; Animals; Iron; Oxidation-Reduction; Antineoplastic Agents; Reperfusion Injury; Neurodegenerative Diseases
PubMed: 38629629
DOI: 10.1042/BST20230550 -
ACS Nano Aug 2023Ferroptosis, a type of regulated cell death driven by iron-dependent phospholipid peroxidation, has captured much attention in the field of nanomedicine since it was... (Review)
Review
Ferroptosis, a type of regulated cell death driven by iron-dependent phospholipid peroxidation, has captured much attention in the field of nanomedicine since it was coined in 2012. Compared with other regulated cell death modes such as apoptosis and pyroptosis, ferroptosis has many distinct features in the molecular mechanisms and cellular morphology, representing a promising strategy for treating cancers that are resistant to conventional therapeutic modalities. Moreover, recent insights collectively reveal that ferroptosis is tightly connected to the maintenance of the tumor immune microenvironment (TIME), suggesting the potential application of ferroptosis therapies for evoking robust antitumor immunity. From a biochemical perspective, ferroptosis is intricately regulated by multiple cellular metabolic pathways, including iron metabolism, lipid metabolism, redox metabolism, , highlighting the importance to elucidate the relationship between tumor metabolism and ferroptosis for developing antitumor therapies. In this review, we provide a comprehensive discussion on the current understanding of ferroptosis-inducing mechanisms and thoroughly discuss the relationship between ferroptosis and various metabolic traits of tumors, which offer promising opportunities for direct tumor inhibition through a nanointegrated approach. Extending from the complex impact of ferroptosis on TIME, we also discussed those important considerations in the development of ferroptosis-based immunotherapy, highlighting the challenges and strategies to enhance the ferroptosis-enabled immunostimulatory effects while avoiding potential side effects. We envision that the insights in this study may facilitate the development and translation of ferroptosis-based nanomedicines for tumor treatment.
Topics: Humans; Ferroptosis; Nanomedicine; Lipid Metabolism; Neoplasms; Iron; Tumor Microenvironment
PubMed: 37573530
DOI: 10.1021/acsnano.3c04632