Hypothalamic and hippocampal transcriptome changes in App mice as a function of metabolic and inflammatory dysfunction.

The progression of Alzheimer's disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer's disease.

Functional Characterization of 21 Rare Allelic Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin -Deethylation.

Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin -deethylation.

Functional Assessment of 12 Rare Allelic Variants Identified in a Population of 4773 Japanese Individuals.

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.

Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6-Hydroxylation.

CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone).

Heterologous expression of high-activity cytochrome P450 in mammalian cells.

The evaluation of Cytochrome P450 (CYP) enzymatic activity is essential to estimate drug pharmacokinetics. Numerous CYP allelic variants have been identified; the functional characterisation of these variants is required for their application in precision medicine. Results from heterologous expression systems using mammalian cells can be integrated in in vivo studies; however, other systems such as E.

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase.

Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified.

CYP2D6 genotyping analysis and functional characterization of novel allelic variants in a Ni-Vanuatu and Kenyan population by assessing dextromethorphan O-demethylation activity.

While CYP2D6 allele and phenotype frequencies have been extensively studied, currently, very little ethnically specific data is available regarding the East African and South Pacific region, including Kenya and Vanuatu. The absence of information regarding gene polymorphisms and their resulting clinical effects in these populations may hinder treatment strategies and patient outcome. Given the scarceness of CYP2D6 related data in these populations, the purpose of this study was to perform a pharmacogenomic analysis of the Kenyan and Ni-Vanuatu population and ultimately characterize the enzymatic properties of eight novel CYP2D6 variant proteins expressed in 293FT cells in vitro using dextromethorphan as a substrate.

Functional characterization of 50 CYP2D6 allelic variants by assessing primaquine 5-hydroxylation.

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolic activation of primaquine, an antimalarial drug. CYP2D6 is genetically polymorphic, and these polymorphisms are associated with interindividual variations observed in the therapeutic efficacy of primaquine. To further understand this association, we performed in vitro enzymatic analyses of the wild-type CYP2D6.

Tyrosine hydroxylase gene expression is facilitated by alcohol followed by the degradation of the protein by ubiquitin proteasome system.

Objectives: Alcohol intake induces brief periods of euphoria; however, its continuous consumption can lead the development of alcohol tolerance. The euphoria, an intense feeling of wellbeing, is deeply associated with dopamine. Dopamine biosynthesis is strictly regulated by tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine.