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Psychiatry Research Jan 2022Schizophrenia has a large disease burden globally. Early intervention in psychosis, and therefore a decreased duration of untreated psychosis, has a positive clinical... (Review)
Review
BACKGROUND
Schizophrenia has a large disease burden globally. Early intervention in psychosis, and therefore a decreased duration of untreated psychosis, has a positive clinical impact. There are several recognized risk factors for psychosis, including trauma history and substance use. This systematic review examined the literature for studies related to epigenetic changes in first-episode psychosis, with the goal of identifying future research directions.
METHODS
A literature review was conducted from inception to October 3, 2021 using MedLine/PubMed, Web of Science, and PsycInfo searches with the keywords ("first-episode schizophrenia" OR "first-episode psychosis" OR "drug-naive schizophrenia" OR "drug-naive psychosis") AND (epigenetic OR methylation OR hydroxymethylation OR "histone modification" OR "miRNA") as well as a search of the bibliography of the identified papers.
RESULTS
Seventeen studies that examined various portions of the genome were included in this systematic review. There were two studies that showed hypomethylation at the LINE-1 portion of the genome and two that showed hypermethylation at LINE-1. Additionally, two studies showed hypomethylation specifically at the GRIN2B promoter (part of LINE-1).
CONCLUSIONS
Although sample sizes were small, these studies provide evidence for epigenetic alterations in early psychosis. Further research in this area is warranted for more definitive epigenetic correlations.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Promoter Regions, Genetic; Psychotic Disorders; Schizophrenia
PubMed: 34896847
DOI: 10.1016/j.psychres.2021.114325 -
Biomedicine & Pharmacotherapy =... Sep 2022Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary... (Review)
Review
Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
Topics: Azetidines; Benzyl Compounds; Cytochrome P-450 CYP2C9; Genotype; Pharmacogenetics
PubMed: 36076616
DOI: 10.1016/j.biopha.2022.113536 -
Obesity Reviews : An Official Journal... Aug 2023Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP-1 analog effects on AT distribution are unclear.
OBJECTIVES
To investigate GLP1-analog effects on adiposity distribution.
SEARCH METHODS
PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre-defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist-to-hip ratio (W:H). Search was conducted until May 17, 2022.
DATA COLLECTION AND ANALYSIS
Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3.
MAIN RESULTS
Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta-analysis. GLP-1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non-significant effects on W:H. Overall bias risk was low.
CONCLUSIONS
GLP-1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP-1 analogs may have significant roles in combating metabolic, obesity-associated diseases via reductions of key AT depot volumes.
Topics: Humans; Adiposity; Glucagon-Like Peptide 1; Obesity; Body Weight; Liver
PubMed: 37191219
DOI: 10.1111/obr.13574 -
Metabolites Dec 2022Gliomas are highly lethal tumours characterised by heterogeneous molecular features, producing various metabolic phenotypes leading to therapeutic resistance. Lipid... (Review)
Review
Gliomas are highly lethal tumours characterised by heterogeneous molecular features, producing various metabolic phenotypes leading to therapeutic resistance. Lipid metabolism reprogramming is predominant and has contributed to the metabolic plasticity in glioma. This systematic review aims to discover lipids alteration and their biological roles in glioma and the identification of potential lipids biomarker. This systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Extensive research articles search for the last 10 years, from 2011 to 2021, were conducted using four electronic databases, including PubMed, Web of Science, CINAHL and ScienceDirect. A total of 158 research articles were included in this study. All studies reported significant lipid alteration between glioma and control groups, impacting glioma cell growth, proliferation, drug resistance, patients' survival and metastasis. Different lipids demonstrated different biological roles, either beneficial or detrimental effects on glioma. Notably, prostaglandin (PGE2), triacylglycerol (TG), phosphatidylcholine (PC), and sphingosine-1-phosphate play significant roles in glioma development. Conversely, the most prominent anti-carcinogenic lipids include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and vitamin D3 have been reported to have detrimental effects on glioma cells. Furthermore, high lipid signals were detected at 0.9 and 1.3 ppm in high-grade glioma relative to low-grade glioma. This evidence shows that lipid metabolisms were significantly dysregulated in glioma. Concurrent with this knowledge, the discovery of specific lipid classes altered in glioma will accelerate the development of potential lipid biomarkers and enhance future glioma therapeutics.
PubMed: 36557318
DOI: 10.3390/metabo12121280 -
Drug Metabolism Reviews Nov 2023Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated... (Review)
Review
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (C) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher C, AUC and half-life (t) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.
Topics: Male; Humans; Nebivolol; Hypertension; Fluvoxamine; Lansoprazole; Drug Interactions
PubMed: 37849071
DOI: 10.1080/03602532.2023.2271195 -
European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
Nutrients Nov 2020A number of previous investigations have been designed to determine the effect of acute caffeine intake on the rate of fat oxidation during exercise. However, these... (Meta-Analysis)
Meta-Analysis
A number of previous investigations have been designed to determine the effect of acute caffeine intake on the rate of fat oxidation during exercise. However, these investigations have shown contradictory results due to the differences in the exercise protocols used or the co-ingestion of caffeine with other substances. Hence, to date, there is no consensus about the effect of caffeine on fat oxidation during exercise. The purpose of this study was to conduct a systematic review followed by a meta-analysis to establish the effect of acute intake of caffeine (ranging from 2 to 7 mg/kg of body mass) on the rate of fat oxidation during exercise. A total of 19 studies published between 1978 and 2020 were included, all of which employed crossover experimental designs in which the ingestion of caffeine was compared to a placebo. Studies were selected if the exercise intensity was consistent in the caffeine and placebo trials and if these were preceded by a fasting protocol. A subsequent meta-analysis was performed using the random effects model to calculate the standardized mean difference (SMD). The meta-analysis revealed that caffeine significantly ( = 0.008) increased the fat oxidation rate (SMD = 0.73; 95% CI = 0.19 to 1.27). This increment was consistent with a significant ( = 0.04) reduction of the respiratory exchange ratio (SMD = -0.33; 95% CI = -0.65 to -0.01) and a significant ( = 0.049) increase in the oxygen uptake (SMD = 0.23; 95% CI = 0.01 to 0.44). The results also showed that there was a dose-response effect of caffeine on the fat oxidation rate, indicating that more than 3.0 mg/kg is necessary to obtain a statistically significant effect of this stimulant on fat oxidation during exercise. Additionally, the ability of caffeine to enhance fat oxidation during exercise was higher in sedentary or untrained individuals than in trained and recreational athletes. In conclusion, pre-exercise intake of a moderate dose of caffeine may effectively increase fat utilization during aerobic exercise of submaximal intensity performed after a fasting period. However, the fitness level of the participant may modulate the magnitude of the effect of caffeine on fat oxidation during exercise.
Topics: Adipose Tissue; Caffeine; Central Nervous System Stimulants; Exercise; Humans; Lipid Metabolism
PubMed: 33255240
DOI: 10.3390/nu12123603 -
Phytotherapy Research : PTR Nov 2023Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid... (Review)
Review
Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid metabolism are crucial contributors in the development of cardiovascular diseases. The abnormal cardiac fatty acid metabolism usually leads to energy deficit, oxidative stress, excessive apoptosis, and inflammation. Targeting fatty acid metabolism has been regarded as a novel approach to the treatment of cardiovascular diseases. However, there are currently no specific drugs that regulate fatty acid metabolism to treat cardiovascular diseases. Many traditional Chinese medicines have been widely used to treat cardiovascular diseases in clinics. And modern studies have shown that they exert a cardioprotective effect by regulating the expression of key proteins involved in fatty acid metabolism, such as peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase 1. Hence, we systematically reviewed the relationship between fatty acid metabolism disorders and four types of cardiovascular diseases including heart failure, coronary artery disease, cardiac hypertrophy, and diabetic cardiomyopathy. In addition, 18 extracts and eight monomer components from traditional Chinese medicines showed cardioprotective effects by restoring cardiac fatty acid metabolism. This work aims to provide a reference for the finding of novel cardioprotective agents targeting fatty acid metabolism.
Topics: Humans; Cardiovascular Diseases; Heart; Medicine, Chinese Traditional; PPAR alpha; Fatty Acids; Energy Metabolism
PubMed: 37533230
DOI: 10.1002/ptr.7965 -
Frontiers in Medicine 2021Many putative uremic toxins-like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF-are organic anions. Both inter-organ and inter-organismal...
Many putative uremic toxins-like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF-are organic anions. Both inter-organ and inter-organismal communication are involved. For example, the gut microbiome is the main source of indole, which, after modification by liver drug metabolizing enzymes (DMEs), becomes indoxyl sulfate. Various organic anion transporters (organic anion transporters, OATs; organic anion-transporting polypeptides, OATPs; multidrug resistance-associated proteins, MRPs, and other ABC transporters like ABCG2)-often termed "drug transporters"-mediate movement of uremic toxins through cells and organs. In the kidney proximal tubule, critical roles for OAT1 and OAT3 in regulating levels of protein-bound uremic toxins have been established using knock-out mice. OATs are important in maintaining residual tubular function in chronic kidney disease (CKD); as CKD progresses, intestinal transporters like ABCG2, which extrude urate and other organic anions into the gut lumen, seem to help restore homeostasis. Uremic toxins like indoxyl sulfate also regulate signaling and metabolism, potentially affecting gene expression in extra-renal tissues as well as the kidney. Focusing on the history and evolving story of indoxyl sulfate, we discuss how uremic toxins appear to be part of an extensive "remote sensing and signaling" network-involving so-called drug transporters and drug metabolizing enzymes which modulate metabolism and signaling. This systems biology view of uremic toxins is leading to a new appreciation of uremia as partly due to disordered remote sensing and signaling mechanisms-resulting from, and causing, aberrant inter-organ (e.g., gut-liver- kidney-CNS) and inter-organismal (e.g., gut microbiome-host) communication.
PubMed: 33937275
DOI: 10.3389/fmed.2021.592602 -
Briefings in Bioinformatics Sep 2021Individual variations in drug efficacy, side effects and adverse drug reactions are still challenging that cannot be ignored in drug research and development. The aim of...
Individual variations in drug efficacy, side effects and adverse drug reactions are still challenging that cannot be ignored in drug research and development. The aim of pharmacometabonomics is to better understand the pharmacokinetic properties of drugs and monitor the drug effects on specific metabolic pathways. Here, we systematically reviewed the recent technological advances in pharmacometabonomics for better understanding the pathophysiological mechanisms of diseases as well as the metabolic effects of drugs on bodies. First, the advantages and disadvantages of all mainstream analytical techniques were compared. Second, many data processing strategies including filtering, missing value imputation, quality control-based correction, transformation, normalization together with the methods implemented in each step were discussed. Third, various feature selection and feature extraction algorithms commonly applied in pharmacometabonomics were described. Finally, the databases that facilitate current pharmacometabonomics were collected and discussed. All in all, this review provided guidance for researchers engaged in pharmacometabonomics and metabolomics, and it would promote the wide application of metabolomics in drug research and personalized medicine.
Topics: Chromatography, Liquid; Databases, Factual; Gas Chromatography-Mass Spectrometry; Humans; Mass Spectrometry; Metabolome; Metabolomics; Pharmaceutical Preparations; Pharmacokinetics; Precision Medicine
PubMed: 33866355
DOI: 10.1093/bib/bbab138