RESUMEN
Non-alcoholic fatty liver disease (NAFLD) is considered the most common chronic liver disease worldwide, affecting nearly 25% of the global adult population. Increasing evidence suggests that functional and compositional changes in the gut microbiota may contribute to the development and promote the progression of NAFLD. 16S rRNA gene next-generation sequencing is widely used to determine specific features of the NAFLD microbiome, but a complex system such as the gut microbiota requires a comprehensive approach. We used three different approaches: MALDI-TOF-MS of bacterial cultures, qPCR, and 16S NGS sequencing, as well as a wide variety of statistical methods to assess the differences in gut microbiota composition between NAFLD patients without significant fibrosis and the control group. The listed methods showed enrichment in Collinsella sp. and Oscillospiraceae for the control samples and enrichment in Lachnospiraceae (and in particular Dorea sp.) and Veillonellaceae in NAFLD. The families, Bifidobacteriaceae, Lactobacillaceae, and Enterococcaceae (particularly Enterococcus faecium and Enterococcus faecalis), were also found to be important taxa for NAFLD microbiome evaluation. Considering individual method observations, an increase in Candida krusei and a decrease in Bacteroides uniformis for NAFLD patients were detected using MALDI-TOF-MS. An increase in Gracilibacteraceae, Chitinophagaceae, Pirellulaceae, Erysipelatoclostridiaceae, Muribaculaceae, and Comamonadaceae, and a decrease in Acidaminococcaceae in NAFLD were observed with 16S NGS, and enrichment in Fusobacterium nucleatum was shown using qPCR analysis. These findings confirm that NAFLD is associated with changes in gut microbiota composition. Further investigations are required to determine the cause-and-effect relationships and the impact of microbiota-derived compounds on the development and progression of NAFLD.
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Microbioma Gastrointestinal , Microbiota , Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Microbioma Gastrointestinal/genética , ARN Ribosómico 16S/genética , Fibrosis , Bacteroidetes , Hígado/patologíaRESUMEN
Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.
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Antipsicóticos , Síndrome de QT Prolongado , Esquizofrenia , Humanos , Antipsicóticos/efectos adversos , Predisposición Genética a la Enfermedad , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genética , Electrocardiografía , Marcadores GenéticosRESUMEN
Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically "non-dopamine" Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of "non-dopamine" Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS.
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Antipsicóticos , Trastornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapéutico , Biomarcadores , Citocinas/uso terapéutico , Dopamina/uso terapéutico , Humanos , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/diagnóstico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia Resistente al TratamientoRESUMEN
Characterization of the within-host genetic diversity of viral pathogens is required for selection of effective treatment of some important viral infections, e.g. HIV, HBV and HCV. Despite the technical ability of detection, there are conflicting data regarding the clinical significance of low-frequency variants, partially because of the difficulty of their distinguishing from experimental artifacts. The issue of cross-contamination is relevant for all highly sensitive techniques, including deep sequencing: even trace contamination leads to a significant increase of false positives in identified SNVs. Determination of infections by multiple genotypes of some viruses, the incidence of which can be considerable, especially in risk groups, is also clinically significant in some cases. We developed a new viral reference-guided assembler, VirGenA, that can separate mixtures of strains of different intraspecies genetic groups (genotypes, subtypes, clades, etc.) and assemble a separate consensus sequence for each group in a mixture. It produced long assemblies for mixture components of extremely low frequencies (<1%) allowing detection of cross-contamination of samples by divergent genotypes. We tested VirGenA on both clinical and simulated data. On both types of data, VirGenA shows better or similar results than the existing de novo assemblers. Cross-platform implementation (including source code) is freely available at https://github.com/gFedonin/VirGenA/releases.
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Algoritmos , Genoma Viral , Secuenciación de Nucleótidos de Alto Rendimiento/estadística & datos numéricos , Análisis de Secuencia de ADN/estadística & datos numéricos , Biología Computacional , Simulación por Computador , Bases de Datos Genéticas/estadística & datos numéricos , Variación Genética , Genotipo , VIH-1/clasificación , VIH-1/genética , Hepacivirus/clasificación , Hepacivirus/genética , Humanos , Programas InformáticosRESUMEN
BACKGROUND: The genus Borrelia comprises spirochaetal bacteria maintained in natural transmission cycles by tick vectors and vertebrate reservoir hosts. The main groups are represented by a species complex including the causative agents of Lyme borreliosis and relapsing fever group Borrelia. Borrelia miyamotoi belongs to the relapsing fever group of spirochetes and forms distinct populations in North America, Asia, and Europe. As all Borrelia species B. miyamotoi possess an unusual and complex genome consisting of a linear chromosome and a number of linear and circular plasmids. The species is considered an emerging human pathogen and an increasing number of human cases are being described in the Northern hemisphere. The aim of this study was to produce a high quality reference genome that will facilitate future studies into genetic differences between different populations and the genome plasticity of B. miyamotoi. RESULTS: We used multiple available sequencing methods, including Pacific Bioscience single-molecule real-time technology (SMRT) and Oxford Nanopore technology (ONT) supplemented with highly accurate Illumina sequences, to explore the suitability for whole genome assembly of the Russian B. miyamotoi isolate, Izh-4. Plasmids were typed according to their potential plasmid partitioning genes (PF32, 49, 50, 57/62). Comparing and combining results of both long-read (SMRT and ONT) and short-read methods (Illumina), we determined that the genome of the isolate Izh-4 consisted of one linear chromosome, 12 linear and two circular plasmids. Whilst the majority of plasmids had corresponding contigs in the Asian B. miyamotoi isolate FR64b, there were only four that matched plasmids of the North American isolate CT13-2396, indicating differences between B. miyamotoi populations. Several plasmids, e.g. lp41, lp29, lp23, and lp24, were found to carry variable major proteins. Amongst those were variable large proteins (Vlp) subtype Vlp-α, Vlp-γ, Vlp-δ and also Vlp-ß. Phylogenetic analysis of common plasmids types showed the uniqueness in Russian/Asian isolates of B. miyamotoi compared to other isolates. CONCLUSIONS: We here describe the genome of a Russian B. miyamotoi clinical isolate, providing a solid basis for future comparative genomics of B. miyamotoi isolates. This will be a great impetus for further basic, molecular and epidemiological research on this emerging tick-borne pathogen.
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Borrelia/genética , Genoma Bacteriano/genética , Genómica/métodos , Plásmidos/genética , Secuenciación Completa del Genoma/métodos , Animales , Proteínas Bacterianas/genética , Secuencia de Bases , Borrelia/clasificación , Borrelia/patogenicidad , Cromosomas Bacterianos/genética , ADN Bacteriano/genética , Humanos , Ixodes/microbiología , Enfermedad de Lyme/microbiología , Filogenia , Fiebre Recurrente/microbiología , Especificidad de la EspecieRESUMEN
In 2018, a previously unknown Ebola virus, Bombali virus, was discovered in Sierra Leone. We describe detection of Bombali virus in Guinea. We found viral RNA in internal organs of 3 Angolan free-tailed bats (Mops condylurus) trapped in the city of N'Zerekore and in a nearby village.
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Quirópteros/virología , Brotes de Enfermedades/prevención & control , Reservorios de Enfermedades , Ebolavirus/aislamiento & purificación , Fiebre Hemorrágica Ebola/epidemiología , Animales , Guinea/epidemiología , Fiebre Hemorrágica Ebola/transmisión , Humanos , Liberia/epidemiología , ZoonosisRESUMEN
We studied minor variants within two tick-borne encephalitis virus (TBEV) populations with a common ancestor: the mouse brain-adapted variant EK-328c and the tick-adapted variant M. High-throughput sequencing with custom amplicons from RT-PCR viral RNA was performed on Illumina MiSeq 2*250 paired-end v2 chemistry. Using the LowFreq program (default settings) and Sanger-sequenced consensus as a reference, variants with an abundance of 1â% and above within the studied populations were identified. Using the obtained data in the context of our previous studies, we concluded that TBEV variants, which are different from the major population phenotype and can become a major part of the viral population under favourable environmental conditions, can exist at abundances of less than 1â% in the long-term. The comparison of our data with the literature allowed us to conclude that the laboratory variant EK-328c and variant M have similar SNV counts to TBEV variants from natural populations and some fast-evolving RNA viruses.
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Virus de la Encefalitis Transmitidos por Garrapatas/genética , Encefalitis Transmitida por Garrapatas/virología , Animales , Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Ratones , ARN Viral/genética , Análisis de Secuencia de ARNRESUMEN
Capnocytophaga canimorsus is a part of healthy oral flora of dogs and cats. However, when it is transmitted to human subjects via animal bites or scratches, it can cause severe complications like endocarditis or even lethal septic shock, especially in immunocompromised persons. In this study, we performed the first whole-genome sequencing on Illumina HiSeq platform of Russian isolate of C. canimorsus that have caused lethal sepsis in 51-old male from Moscow. We believe that the availability of genomic sequence and annotation for the given strain could be useful for future epidemiological surveillance studies in Russia and other countries.
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Capnocytophaga/genética , Infecciones por Bacterias Gramnegativas/microbiología , Sepsis/microbiología , Secuenciación Completa del Genoma , Capnocytophaga/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Moscú , Análisis de Secuencia de ADNRESUMEN
We developed a novel technique for the efficient conjugation of oligonucleotides with various alkyl azides such as fluorescent dyes, biotin, cholesterol, N-acetylgalactosamine (GalNAc), etc. using copper-catalysed alkyne-azide cycloaddition on the solid phase and CuI·P(OEt)3 as a catalyst. Conjugation is carried out in an oligonucleotide synthesizer in fully automated mode and is coupled to oligonucleotide synthesis and on-column deprotection. We also suggest a set of reagents for the construction of diverse conjugates. The sequential double-click procedure using a pentaerythritol-derived tetraazide followed by the addition of a GalNAc or Tris-GalNAc alkyne gives oligonucleotide-GalNAc dendrimer conjugates in good yields with minimal excess of sophisticated alkyne reagents. The approach is suitable for high-throughput synthesis of oligonucleotide conjugates ranging from fluorescent DNA probes to various multi-GalNAc derivatives of 2'-modified siRNA.
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Acetilgalactosamina/química , Oligonucleótidos/química , Oligonucleótidos/síntesis química , Alquinos/química , Automatización , Azidas/química , Química Clic , Reacción de Cicloadición , Técnicas de Síntesis en Fase SólidaRESUMEN
Molecular beacons (MBs) are valuable tools in molecular biology, clinical diagnostics and analytical chemistry. Here we describe a novel approach for the design of MBs with nucleotide or non-nucleotide linkers between the stem and loop regions. Such modified MBs have significantly improved specificity and performance for single nucleotide polymorphism (SNP) detection. These advantages are especially distinct, when compared to the classic MBs, in the case of possible interactions between the stem and loop regions. We demonstrated the applicability of such modified MBs for the discrimination of common Factor V, NOS3 and ADRB2 SNPs in model plasmids and in clinical samples. The developed approach could be applicable not only to fluorescently labeled MBs, but also to other biosensors based on nucleic acids with stem-loop structures.
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Ácidos Nucleicos/química , Sondas de Oligonucleótidos/química , Polimorfismo de Nucleótido Simple , Técnicas Biosensibles , Sensibilidad y EspecificidadRESUMEN
Nowadays modified oligonucleotides are widely used in diagnostics and as novel therapeutics. Introduction of modified or unnatural residues into oligonucleotides allows fine tuning of their binding properties to complementary nucleic acids and leads to improved stability both in vitro and in vivo. Previously it was demonstrated that insertion of phenoxazine nucleotides with various groups in C9-position into oligonucleotides leads to a significant increase of duplex stability with complementary DNA and RNA. Here the synthesis of a novel G-clamp nucleoside analogue (G8AE-clamp) bearing 2-aminoethyl tether at C8-atom is presented. Introduction of such modified residues into oligonucleotides lead to enhanced specificity of duplex formation towards complementary DNA and RNA targets with increased thermal and 3'-exonuclease stability. According to CD-spectroscopy studies G8AE-clamp does not substantially disrupt helix geometry. Primers containing G8AE-clamp demonstrated superior sensitivity in qPCR detection of dsRNA of Kemerovo virus in comparison to native oligonucleotides.
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Guanosina/análogos & derivados , Oligonucleótidos/síntesis química , Orbivirus/genética , Oxazinas/química , ARN Viral/metabolismo , Dicroismo Circular , Exonucleasas/metabolismo , Guanosina/metabolismo , Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Oligonucleótidos/química , ARN Bicatenario/análisis , ARN Bicatenario/genética , ARN Bicatenario/metabolismo , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
An alkyl azide derivative of 1-phenylethynylpyrene (PEPy) dye was prepared and used in the functionalization of oligonucleotides via click chemistry. Spectral and photo-physical properties of the PEPy-modified oligonucleotides as a single strand, and in perfect or mismatched duplexes, have been studied. A series of PEPy-Dabcyl fluorogenic TaqMan probes were synthesized and tested in qPCR. PEPy proved to be a superior substitute for AMCA as a short wavelength fluorescent dye for qPCR probes. PEPy probes were shown to significantly reduce Cq (a fractional PCR cycle used for quantification) vs. AMCA labeled probes, thus improving on the reliability of detection. Moreover, a larger increase of fluorescence during amplification was observed in the case of PEPy probes that makes this dye very suitable for an end-point PCR technique. This study broadens the panel of fluorescent dyes suitable for the use in probes for quantitative real-time PCR.
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Colorantes Fluorescentes/química , Pirenos/química , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Alquinos/química , Azidas/química , Catálisis , Química Clic , Color , Cobre/química , Cumarinas/química , Colorantes Fluorescentes/síntesis química , Oligonucleótidos/química , Oligonucleótidos/genética , Pirenos/síntesis químicaRESUMEN
A novel N-TFA-protected carboxyrhodamine 6G (R6G) phosphoramidite was synthesized for use in an automated DNA synthesis to prepare 5'-labeled oligonucleotides. Deprotection and purification conditions were optimized for 5'-labeled and dual-labeled oligonucleotide probes. As an alternative we synthesized an azide derivative of R6G for CuAAC post-synthetic oligonucleotide labeling. Dual-labeled probes obtained by both methods showed the same efficacy in a quantitative PCR assay. R6G-labeled probes demonstrated superior properties in a qPCR assay in comparison with alternative HEX, JOE and SIMA dyes due to more efficient fluorescence quenching by BHQ-1. We successfully used R6G dual-labeled probes for rotavirus genotyping.
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Sondas de Oligonucleótidos/química , Sondas de Oligonucleótidos/síntesis química , Rodaminas/química , Fluorescencia , Colorantes Fluorescentes/química , Genotipo , Rotavirus/genética , SolucionesRESUMEN
OBJECTIVE: The aim of the study was to evaluate the diagnostic value of Nugent score, wet mount microscopy, and polymerase chain reaction (PCR) test developed in Russia for bacterial vaginosis (BV) diagnosis. MATERIALS AND METHODS: One hundred Caucasian women were enrolled in this study. Three vaginal samples were taken from each participant: 1 for PCR analysis, 1 for Nugent score evaluation, and 1 for wet mount microscopy. The smears for microscopy were air-dried and sent to Femicare, Tienen, Belgium, for blinded analysis by microscopy. Multiplex real-time PCR was performed using primers and probes targeting Gardnerella vaginalis, Atopobium vaginae, Lactobacillus species, and total quantity of bacterial DNA (16SrRNA gene). RESULTS: Agreement among the 3 methods was 72 (73.5%) of 98 samples. Agreement between Nugent score and PCR results was 77 (78.6%) of 98 samples; between wet mount microscopy and PCR, 81 (82.65%) of 98 samples; between wet mount microscopy and Nugent score, 84 (85.7%) of 98 samples. The sensitivity and specificity of the methods studied were as follows: 75% (21/28) and 97.1% (68/70) for Nugent score, 96.4% (27/28) and 94.3% (66/70) for wet mount microscopy, 92.8% (26/28) and 85.7% (60/70) for PCR, respectively. CONCLUSIONS: This study demonstrated that wet mount microscopy is a superior method for BV diagnosis. The PCR test under study showed a high sensitivity and can be used for discrimination between normal flora and BV.
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Microscopía/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Vagina/microbiología , Vaginosis Bacteriana/diagnóstico , Adulto , Bélgica , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Sensibilidad y Especificidad , Población Blanca , Adulto JovenRESUMEN
Anti-human immunodeficiency virus (HIV) broadly neutralizing antibodies (bNAbs) offer a promising approach for the treatment of HIV-1. The current paradigm for antibody therapy involves passive antibody transfer, requiring regular delivery of bNAbs in treating chronic diseases such as HIV-1. An alternative strategy is to use AAV-mediated gene transfer to enable in vivo production of desirable anti-HIV-1 antibodies. In this study, we investigated two sets of triple combinations of AAV9-vectors encoding different bNAbs: N6, 10E8, 10-1074 (CombiMab1), and VRC07-523, PGDM1400, 10-1074 (CombiMab2). We used CBAxC57Bl and C57BL/6 mouse models to characterize rAAV-induced antibody expression and to evaluate the neutralization capacity of mouse sera against a global panel of HIV-1 viral strains. rAAV9-mediated IgG expression varied between bNAb clones and mouse strains, with C57BL/6 mice exhibiting higher bNAb titers following rAAV delivery. Although CombiMab2 treatment elicited a higher IgG titer than CombiMab1, both combinations resulted in neutralization of all the viral strains from the global HIV-1 panel. Our data highlight the potential of AAV vectors as a long-term option for HIV-1 therapy.
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Anticuerpos Neutralizantes , Dependovirus , Vectores Genéticos , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Inmunoglobulina G , Ratones Endogámicos C57BL , Animales , Dependovirus/genética , Dependovirus/inmunología , VIH-1/inmunología , VIH-1/genética , Humanos , Ratones , Anticuerpos Anti-VIH/inmunología , Anticuerpos Neutralizantes/inmunología , Vectores Genéticos/genética , Inmunoglobulina G/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/terapia , Femenino , Células HEK293RESUMEN
The development of effective diagnostic kits for HIV-1 remains a pressing concern. We designed diagnostic oligonucleotides for HIV-1 real-time PCR to target the most conserved region of the HIV-1 genome and assessed the mutation frequency at annealing sites. Two databases of nucleotide sequences, Los Alamos and NCBI, were analyzed, revealing that more than 99% of the sequences either lack mutations or contain 1-2 mutations at the binding site of the forward and reverse primers. Additionally, 98.5% of the sequences either lack mutations or contain 1-2 mutations at the binding site of the TaqMan probe. To evaluate the efficiency of primers and the probe in real-time PCR in the case of mutations at their binding sites, we constructed several plasmids containing the most common mutations and, in a model experiment, showed how different mutations affect the efficiency of PCR. Our analysis demonstrated that about 98.5% of HIV-1 strains can be efficiently detected using a single pair of selected primers. For the remaining 1.5% of strains, a more careful selection of the second target is needed.
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One of the main challenges for the mass introduction of the molecular diagnostics of soil-transmitted helminths (STHs) into clinical practice is the lack of a generally recognized effective method for isolating parasitic DNA from fecal samples. In the present study, we assessed the effects of various pretreatment procedures on the efficiency of removing PCR inhibitors and extracting Toxocara canis DNA from feces. We evaluated the effectiveness of four destructive methods (bead beating, the action of temperature-dependent enzymes, freeze-heat cycles, and incubation in a lysis buffer) on the integrity of T. canis eggs and the efficiency of DNA extraction. Also, we evaluated the effects of prewashes and the use of commercial concentrators on DNA extraction from fecal samples contaminated with T. canis eggs. A bead beating procedure was sufficient to destroy the T. canis eggs, while the effects of enzymes and freeze-heat cycles did not lead to a significant destruction of the eggs or the release of Toxocara DNA. Helminth DNA isolation protocols that do not include a bead beating step are not preferred. The preconcentration of STH eggs from feces using a commercial concentrator and subsequent washing can significantly increase the yield of DNA from STHs and reduce PCR inhibition.
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Dengue fever, an infectious disease that affects more than 100 million people every year, is a global health problem. Vaccination may be the most effective prevention strategy for the disease. However, the development of vaccines against dengue fever is complicated by the high risk of developing an antibody-dependent increase in infection. This article describes the development of an MVA-d34 vaccine against the dengue virus based on a safe and effective MVA viral vector. The DIII domains of the envelope protein (E) of the dengue virus are used as vaccine antigens, as antibodies against these domains do not cause an enhancement of infection. The use of the DIII domains of each of the four dengue virus serotypes made it possible to generate a humoral response against all four dengue virus serotypes in immunized mice. We also showed that the sera of vaccinated mice present virus-neutralizing activity against dengue serotype 2. Thus, the developed MVA-d34 vaccine is a promising candidate vaccine against dengue fever.
RESUMEN
Antipsychotic-induced akathisia (AIA) is a movement disorder characterized by a subjective feeling of inner restlessness or nervousness with an irresistible urge to move, resulting in repetitive movements of the limbs and torso, while taking antipsychotics (APs). In recent years, there have been some associative genetic studies of the predisposition to the development of AIA. Objective: The goal of our study was to review the results of associative genetic and genome-wide studies and to systematize and update the knowledge on the genetic predictors of AIA in patients with schizophrenia (Sch). Methods: We searched full-text publications in PubMed, Web of Science, Springer, Google Scholar, and e-Library databases from 1977 to 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) quality scale was used for the critical selection of the studies. Results: We identified 37 articles, of which 3 were included in the review. Thus, the C allele of rs1800498 (59414 C>T) and the A allele of rs1800497 (17316 G>A) (TaqIA) from the DRD2 gene as well as the TT genotype rs13212041 (77461407 C>T) from the HTR1B gene were found to be associated with AIA. Conclusions: Uncovering the genetic biomarkers of AIA may provide a key to developing a strategy for the personalized prevention and treatment of this adverse neurological drug reaction of APs in patients with Sch in real clinical practice.
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/efectos adversos , Agitación Psicomotora/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , BiomarcadoresRESUMEN
Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington's disease, Parkinson's disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: ß-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient's pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine).