Comparison of vestibular function in hereditary hearing loss patients with GJB2, CDH23, and SLC26A4 variants.

To investigate the association between hereditary hearing loss and vestibular function, we compared vestibular function and symptoms among patients with GJB2, SLC26A4, and CDH23 variants. Thirty-nine patients with sensory neural hearing loss (11 males and 28 females) with biallelic pathogenic variants in either GJB2, SLC26A4, or CDH23 were included in this study (13 GJB2, 15 SLC26A4, and 11 CDH23). The patients were examined using caloric testing and cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP). We also compared vestibular function and symptoms between patients with these gene variants and 78 normal-hearing ears without vestibular symptoms as controls. The frequency of semicircular canal hypofunction in caloric testing was higher in patients with SLC26A4 variants (47%) than in those with GJB2 (0%) and CDH23 variants (27%). According to the cVEMP results, 69% of patients with GJB2 variants had saccular hypofunction, a significantly higher proportion than in those carrying other variants (SLC26A4, 20%; CDH23, 18%). In oVEMP, which reflects utricular function, no difference was observed in the frequency of hypofunction among the three genes (GJB2, 15%; SLC26A4, 40%; and CDH23, 36%). Hence, discernable trends indicate vestibular dysfunction associated with each gene.

Insights into Inhalation Drug Disposition: The Roles of Pulmonary Drug-Metabolizing Enzymes and Transporters.

The past five decades have witnessed remarkable advancements in the field of inhaled medicines targeting the lungs for respiratory disease treatment. As a non-invasive drug delivery route, inhalation therapy offers numerous benefits to respiratory patients, including rapid and targeted exposure at specific sites, quick onset of action, bypassing first-pass metabolism, and beyond. Understanding the characteristics of pulmonary drug transporters and metabolizing enzymes is crucial for comprehending efficient drug exposure and clearance processes within the lungs. These processes are intricately linked to both local and systemic pharmacokinetics and pharmacodynamics of drugs. This review aims to provide a comprehensive overview of the literature on lung transporters and metabolizing enzymes while exploring their roles in exogenous and endogenous substance disposition. Additionally, we identify and discuss the principal challenges in this area of research, providing a foundation for future investigations aimed at optimizing inhaled drug administration. Moving forward, it is imperative that future research endeavors to focus on refining and validating in vitro and ex vivo models to more accurately mimic the human respiratory system. Such advancements will enhance our understanding of drug processing in different pathological states and facilitate the discovery of novel approaches for investigating lung-specific drug transporters and metabolizing enzymes. This deeper insight will be crucial in developing more effective and targeted therapies for respiratory diseases, ultimately leading to improved patient outcomes.

Prevalence and molecular characterization of colistin resistance in Pseudomonas aeruginosa isolates: insights from a study in Ardabil hospitals.

BACKGROUND: Pseudomonas aeruginosa is a common cause of nosocomial infections. However, the emergence of multidrug-resistant strains has complicated the treatment of P. aeruginosa infections. While polymyxins have been the mainstay for treatment, there is a global increase in resistance to these antibiotics. Therefore, our study aimed to determine the prevalence and molecular details of colistin resistance in P. aeruginosa clinical isolates collected between June 2019 and May 2023, as well as the genetic linkage of colistin-resistant P. aeruginosa isolates. RESULTS: The resistance rate to colistin was 9% (n = 18) among P. aeruginosa isolates. All 18 colistin-resistant isolates were biofilm producers and carried genes associated with biofilm formation. Furthermore, the presence of genes encoding efflux pumps, TCSs, and outer membrane porin was observed in all colistin-resistant P. aeruginosa strains, while the mcr-1 gene was not detected. Amino acid substitutions were identified only in the PmrB protein of multidrug- and colistin-resistant strains. The expression levels of mexA, mexC, mexE, mexY, phoP, and pmrA genes in the 18 colistin-resistant P. aeruginosa strains were as follows: 88.8%, 94.4%, 11.1%, 83.3%, 83.3%, and 38.8%, respectively. Additionally, down-regulation of the oprD gene was observed in 44.4% of colistin-resistant P. aeruginosa strains. CONCLUSION: This study reports the emergence of colistin resistance with various mechanisms among P. aeruginosa strains in Ardabil hospitals. We recommend avoiding unnecessary use of colistin to prevent potential future increases in colistin resistance.

An update to Kidd blood group system.

Since publication of the original Immunohematology review of the Kidd blood group system in 2015 (Hamilton JR. Kidd blood group system: a review. Immunohematology 2015;31:29-34), knowledge has mushroomed pertaining to gene structure, alleles causing variant and null phenotypes, clinical significance in renal transplant and hemolytic disease of the fetus and newborn, and physiologic functions of urea transporters in non-renal tissues. This review will detail much of this new information.

Control of leaf development in the water fern Ceratopteris richardii by the auxin efflux transporter CrPINMa in the CRISPR/Cas9 analysis.

BACKGROUND: PIN-FORMED genes (PINs) are crucial in plant development as they determine the directionality of auxin flow. They are present in almost all land plants and even in green algae. However, their role in fern development has not yet been determined. This study aims to investigate the function of CrPINMa in the quasi-model water fern Ceratopteris richardii. RESULTS: CrPINMa possessed a long central hydrophilic loop and characteristic motifs within it, which indicated that it belonged to the canonical rather than the non-canonical PINs. CrPINMa was positioned in the lineage leading to Arabidopsis PIN6 but not that to its PIN1, and it had undergone numerous gene duplications. CRISPR/Cas9 genome editing had been performed in ferns for the first time, producing diverse mutations including local frameshifts for CrPINMa. Plants possessing disrupted CrPINMa exhibited retarded leaf emergence and reduced leaf size though they could survive and reproduce at the same time. CrPINMa transcripts were distributed in the shoot apical meristem, leaf primordia and their vasculature. Finally, CrPINMa proteins were localized to the plasma membrane rather than other cell parts. CONCLUSIONS: CRISPR/Cas9 genome editing is feasible in ferns, and that PINs can play a role in fern leaf development.

Voltage-induced calcium release in Caenorhabditis elegans body muscles.

Type 1 voltage-activated calcium channels (CaV1) in the plasma membrane trigger calcium release from the sarcoplasmic reticulum (SR) by two mechanisms. In voltage-induced calcium release (VICR), CaV1 voltage sensing domains are directly coupled to ryanodine receptors (RYRs), an SR calcium channel. In calcium-induced calcium release (CICR), calcium ions flowing through activated CaV1 channels bind and activate RYR channels. VICR is thought to occur exclusively in vertebrate skeletal muscle while CICR occurs in all other muscles (including all invertebrate muscles). Here, we use calcium-activated SLO-2 potassium channels to analyze CaV1-SR coupling in Caenorhabditis elegans body muscles. SLO-2 channels were activated by both VICR and external calcium. VICR-mediated SLO-2 activation requires two SR calcium channels (RYRs and IP3 Receptors), JPH-1/Junctophilin, a PDZ (PSD95, Dlg1, ZO-1 domain) binding domain (PBD) at EGL-19/CaV1's carboxy-terminus, and SHN-1/Shank (a scaffolding protein that binds EGL-19's PBD). Thus, VICR occurs in invertebrate muscles.

CIP1, a CIPK23-interacting transporter, is implicated in Cd tolerance and phytoremediation.

Environmental pollution from cadmium (Cd) presents a serious threat to plant growth and development. Therefore, it's crucial to find out how plants resist this toxic metal to develop strategies for remediating Cd-contaminated soils. In this study, we identified CIP1, a transporter protein, by screening interactors of the protein kinase CIPK23. CIP1 is located in vesicles membranes and can transport Cd2+ when expressed in yeast cells. Cd stress specifically induced the accumulation of CIP1 transcripts and functional proteins, particularly in the epidermal cells of the root tip. CIKP23 could interact directly with the central loop region of CIP1, phosphorylating it, which is essential for the efficient transport of Cd2+. A loss-of-function mutation of CIP1 in wild-type plants led to increased sensitivity to Cd stress. Conversely, tobacco plants overexpressing CIP1 exhibited improved Cd tolerance and increased Cd accumulation capacity. Interestingly, this Cd accumulation was restricted to roots but not shoots, suggesting that manipulating CIP1 does not risk Cd contamination of plants' edible parts. Overall, this study characterizes a novel Cd transporter, CIP1, with potential to enhance plant tolerance to Cd toxicity while effectively eliminating environmental contamination without economic losses.

Small Molecule IITR08367 Potentiates Antibacterial Efficacy of Fosfomycin against Acinetobacter baumannii by Efflux Pump Inhibition.

Fosfomycin is a broad-spectrum single-dose therapy approved for treating lower urinary tract infections. Acinetobacter baumannii, one of the five major UTI-causing pathogens, is intrinsically resistant to fosfomycin. Reduced uptake and active efflux are major reasons for this intrinsic resistance. AbaF, a major facilitator superfamily class of transporter in A. baumannii, is responsible for fosfomycin efflux and biofilm formation. This study describes the identification and validation of a novel small-molecule efflux pump inhibitor that potentiates fosfomycin efficacy against A. baumannii. An AbaF inhibitor screening was performed against Escherichia coli KAM32/pUC18_abaF, using the noninhibitory concentration of 24 putative efflux pump inhibitors. The inhibitory activity of IITR08367 [bis(4-methylbenzyl) disufide] against fosfomycin/H+ antiport was validated using ethidium bromide efflux, quinacrine-based proton-sensitive fluorescence, and membrane depolarization assays. IITR08367 inhibits fosfomycin/H+ antiport activity by perturbing the transmembrane proton gradient. IITR08367 is a nontoxic molecule that potentiates fosfomycin activity against clinical strains of A. baumannii and prevents biofilm formation by inhibiting efflux pump (AbaF). The IITR08367-fosfomycin combination reduced bacterial burden by > 3 log10 in kidney and bladder tissue in the murine UTI model. Overall, fosfomycin, in combination with IITR08367, holds the potential to treat urinary tract infections caused by A. baumannii.

Promoter regulatory mode evolution enhances the high multidrug resistance of tmexCD1-toprJ1.

Antibiotic resistance could rapidly emerge from acquiring the mobile antibiotic resistance genes, which are commonly evolved from an intrinsic gene. The emergence of the plasmid-borne mobilized efflux pump gene cluster tmexCD1-toprJ1 renders the last-resort antibiotic tigecycline ineffective, although its evolutionary mechanism remains unclear. In this study, we investigate the regulatory mechanisms of the progenitor NfxB-MexCD-OprJ, a chromosomally encoded operon that does not mediate antibiotic resistance in the wild-type version, and its homologs, TNfxB1-TMexCD1-TOprJ1 mediating high-level tigecycline resistance, and TNfxB3-TMexCD3-TOprJ1. Mechanistic studies demonstrated that in nfxB-mexCD-oprJ, MexCD expression was under a weaker promoter, PmexC and inhibited by a strong repressor NfxB. For tmexCD1-toprJ1, TMexCD1 was highly expressed owing to the presence of a strong promoter, PtmexC1, and an inactive suppressor, TNfxB1, with a T39R mutation that rendered it unable to bind to promoter DNA. In tnfxB3-tmexCD3-toprJ1b, TMexCD3 expression was intermediate because of the local regulator TNfxB3, which binds to two inverted repeat sequences of PtmexC. Additionally, TNfxB3 exhibited lower protein expression and weaker DNA binding affinity than its ancestor NfxB, together with their promoter activities difference explaining the different expression levels of tmexCD-toprJ homologs. Distinct fitness burdens on these homologs-carrying bacteria were observed due to the corresponding expression level, which might be associated with their global prevalence. In summary, our data depict the mechanisms underlying the evolution and dissemination of an important mobile antibiotic resistance gene from an intrinsic chromosomal gene.IMPORTANCEAs antibiotic resistance seriously challenges global health, tigecycline is one of the few effective drugs in the pipeline against infections caused by multidrug-resistant pathogens. Our previous work identified a novel tigecycline resistance efflux pump gene cluster tmexCD1-toprJ1 in animals and humans, together with its various variants, a rising clinical concern. Herein, this study focused on how the local regulation modes of tmexCD1-toprJ1 evolved to a highly expressed efflux pump. Through comparative analysis between three tnfxB-tmexCD-toprJ homologs and their progenitor nfxB-mexCD-oprJ, modes, we demonstrated the evolutionary dynamics from a chromosomal silent gene to an active state. We found the de-repression of the local regulator and an increase of the promoter activity work together to promote a high production of drug efflux machines and enhance multidrug resistance. Our findings revealed that TMexCD1-TOprJ1 adopts a distinct evolutionary path to achieve higher multidrug resistance, urgently needing tight surveillance.

The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.

AIMS: Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons. METHODS: The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (Gm) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using 14C-malate. RESULTS: OGC increases proton Gm only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism. CONCLUSION: OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.

On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.

INTRODUCTION: Genome-wide association studies have identified numerous disease susceptibility loci (DSLs) for Alzheimer's disease (AD). However, only a limited number of studies have investigated the dependence of the genetic effect size of established DSLs on genetic ancestry. METHODS: We utilized the whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) including 35,569 participants. A total of 25,459 subjects in four distinct populations (African ancestry, non-Hispanic White, admixed Hispanic, and Asian) were analyzed. RESULTS: We found that nine DSLs showed significant heterogeneity across populations. Single nucleotide polymorphism (SNP) rs2075650 in translocase of outer mitochondrial membrane 40 (TOMM40) showed the largest heterogeneity (Cochran's Q = 0.00, I2 = 90.08), followed by other SNPs in apolipoprotein C1 (APOC1) and apolipoprotein E (APOE). Two additional loci, signal-induced proliferation-associated 1 like 2 (SIPA1L2) and solute carrier 24 member 4 (SLC24A4), showed significant heterogeneity across populations. DISCUSSION: We observed substantial heterogeneity for the APOE-harboring 19q13.32 region with TOMM40/APOE/APOC1 genes. The largest risk effect was seen among African Americans, while Asians showed a surprisingly small risk effect.

Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps.

Efflux is a natural process found in all prokaryotic and eukaryotic cells that removes a diverse range of substrates from inside to outside. Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism utilized by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics has been considered a promising approach for antimicrobial chemotherapy over two decades, and various strategies have been employed. In this review, we provide an overview of bacterial multidrug resistance (MDR) efflux pumps, of which the resistance nodulation division (RND) efflux pumps are considered the most clinically relevant in Gram-negative bacteria, and describe over 50 efflux inhibitors that target such systems. Although numerous efflux inhibitors have been identified to date, none have progressed into clinical use because of formulation, toxicity, and pharmacokinetic issues or a narrow spectrum of inhibition. For these reasons, the development of efflux inhibitors has been considered a difficult and complex area of research, and few active preclinical studies on efflux inhibitors are in progress. However, recently developed tools, including but not limited to computational tools including molecular docking models, offer hope that further research on efflux inhibitors can be a platform for research and development of new bacterial efflux inhibitors.

An Automated Imaging-Based Screen for Genetic Modulators of ER Organisation in Cultured Human Cells.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of mono-genetic inherited neurological disorders, whose primary manifestation is the disruption of the pyramidal system, observed as a progressive impaired gait and leg spasticity in patients. Despite the large list of genes linked to this group, which exceeds 80 loci, the number of cellular functions which the gene products engage is relatively limited, among which endoplasmic reticulum (ER) morphogenesis appears central. Mutations in genes encoding ER-shaping proteins are the most common cause of HSP, highlighting the importance of correct ER organisation for long motor neuron survival. However, a major bottleneck in the study of ER morphology is the current lack of quantitative methods, with most studies to date reporting, instead, on qualitative changes. Here, we describe and apply a quantitative image-based screen to identify genetic modifiers of ER organisation using a mammalian cell culture system. An analysis reveals significant quantitative changes in tubular ER and dense sheet ER organisation caused by the siRNA-mediated knockdown of HSP-causing genes ATL1 and RTN2. This screen constitutes the first attempt to examine ER distribution in cells in an automated and high-content manner and to detect genes which impact ER organisation.

The potassium transporter TaNHX2 interacts with TaGAD1 to promote drought tolerance via modulating stomatal aperture in wheat.

Drought is a major global challenge in agriculture that decreases crop production. γ-Aminobutyric acid (GABA) interfaces with drought stress in plants; however, a mechanistic understanding of the interaction between GABA accumulation and drought response remains to be established. Here we showed the potassium/proton exchanger TaNHX2 functions as a positive regulator in drought resistance in wheat by mediating cross-talk between the stomatal aperture and GABA accumulation. TaNHX2 interacted with glutamate decarboxylase TaGAD1, a key enzyme that synthesizes GABA from glutamate. Furthermore, TaNHX2 targeted the C-terminal auto-inhibitory domain of TaGAD1, enhanced its activity, and promoted GABA accumulation under drought stress. Consistent with this, the tanhx2 and tagad1 mutants showed reduced drought tolerance, and transgenic wheat with enhanced TaNHX2 expression had a yield advantage under water deficit without growth penalty. These results shed light on the plant stomatal movement mechanism under drought stress and the TaNHX2-TaGAD1 module may be harnessed for amelioration of negative environmental effects in wheat as well as other crops.

Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Identification of transporters involved in aromatic compounds tolerance through screening of transporter deletion libraries.

Aromatic compounds are used in pharmaceutical, food, textile and other industries. Increased demand has sparked interest in exploring biotechnological approaches for their sustainable production as an alternative to chemical synthesis from petrochemicals or plant extraction. These aromatic products may be toxic to microorganisms, which complicates their production in cell factories. In this study, we analysed the toxicity of multiple aromatic compounds in common production hosts. Next, we screened a subset of toxic aromatics, namely 2-phenylethanol, 4-tyrosol, benzyl alcohol, berberine and vanillin, against transporter deletion libraries in Escherichia coli and Saccharomyces cerevisiae. We identified multiple transporter deletions that modulate the tolerance of the cells towards these compounds. Lastly, we engineered transporters responsible for 2-phenylethanol tolerance in yeast and showed improved 2-phenylethanol bioconversion from L-phenylalanine, with deletions of YIA6, PTR2 or MCH4 genes improving titre by 8-12% and specific yield by 38-57%. Our findings provide insights into transporters as targets for improving the production of aromatic compounds in microbial cell factories.

Type 1 secretion necessitates a tight interplay between all domains of the ABC transporter.

Type I secretion systems (T1SS) facilitate the secretion of substrates in one step across both membranes of Gram-negative bacteria. A prime example is the hemolysin T1SS which secretes the toxin HlyA. Secretion is energized by the ABC transporter HlyB, which forms a complex together with the membrane fusion protein HlyD and the outer membrane protein TolC. HlyB features three domains: an N-terminal C39 peptidase-like domain (CLD), a transmembrane domain (TMD) and a C-terminal nucleotide binding domain (NBD). Here, we created chimeric transporters by swapping one or more domains of HlyB with the respective domain(s) of RtxB, a HlyB homolog from Kingella kingae. We tested all chimeric transporters for their ability to secrete pro-HlyA when co-expressed with HlyD. The CLD proved to be most critical, as a substitution abolished secretion. Swapping only the TMD or NBD reduced the secretion efficiency, while a simultaneous exchange abolished secretion. These results indicate that the CLD is the most critical secretion determinant, while TMD and NBD might possess additional recognition or interaction sites. This mode of recognition represents a hierarchical and extreme unusual case of substrate recognition for ABC transporters and optimal secretion requires a tight interplay between all domains.

Emerging roles for ABC transporters as virulence factors in uropathogenic Escherichia coli.

Urinary tract infections (UTI) account for a substantial financial burden globally. Over 75% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which have demonstrated an extraordinarily rapid growth rate in vivo. This rapid growth rate appears paradoxical given that urine and the human urinary tract are relatively nutrient-restricted. Thus, we lack a fundamental understanding of how uropathogens propel growth in the host to fuel pathogenesis. Here, we used large in silico, in vivo, and in vitro screens to better understand the role of UPEC transport mechanisms and their contributions to uropathogenesis. In silico analysis of annotated transport systems indicated that the ATP-binding cassette (ABC) family of transporters was most conserved among uropathogenic bacterial species, suggesting their importance. Consistent with in silico predictions, we determined that the ABC family contributed significantly to fitness and virulence in the urinary tract: these were overrepresented as fitness factors in vivo (37.2%), liquid media (52.3%), and organ agar (66.2%). We characterized 12 transport systems that were most frequently defective in screening experiments by generating in-frame deletions. These mutant constructs were tested in urovirulence phenotypic assays and produced differences in motility and growth rate. However, deletion of multiple transport systems was required to achieve substantial fitness defects in the cochallenge murine model. This is likely due to genetic compensation among transport systems, highlighting the centrality of ABC transporters in these organisms. Therefore, these nutrient uptake systems play a concerted, critical role in pathogenesis and are broadly applicable candidate targets for therapeutic intervention.

[Genetic basis of postoperative cognitive dysfunction]. / Geneticheskie osnovy postoperatsionnoi kognitivnoi disfunktsii.

This review highlights literature data on potential genetic markers that potentially influence the development of postoperative cognitive dysfunction, such as TOMM40, APOE, TREM2, METTL3, PGC1a, HMGB1 and ERMN. The main pathogenetic mechanisms triggered by these genes and leading to the development of cognitive impairment after anesthesia are described. The paper systematizes previously published works that provide evidence of the impact of specific genetic variants on the development of postoperative cognitive dysfunction.