Search Results (605)

Histone deacetylase inhibitors (HDACis) induce the expression of multidrug resistance (MDR) pumps and can even display the MDR phenotype in cell lines. This is the first report to include the profiles of ATP-binding cassette (ABC) transporters in intrinsically expressed HeLa cells as well as those acquired due to a 5 mM valproic acid (VPA) treatment. Expression of ABC transporters related to the MDR phenotype was analyzed by RT-PCR in untreated HeLa cells and HeLa cells treated with 5 mM VPA. The ABCB5 protein was identified in HeLa cells by immunocytochemistry. HeLa cell treatment with 5 mM VPA increased ABCB1 expression and triggered the de novo expression of ABCB5 in mRNA and protein. Despite the expression of ABCB5 and the overexpression of ABCB1, VPA reduced the growth rate by 20%, delayed doubling time by 25%, and decreased the number of living cells per well to 50% after 72 h. Pretreatment with VPA for 24 h followed by cotreatment with doxorubicin (DOX) sensitized HeLa cells to DOX. However, for the de novo expression of ABCB5, HeLa cells did not acquire the MDR phenotype from the 5 mM VPA treatment. The ABCB5 isoform induced by VPA treatment probably lacks MDR activity. Full article

P-Glycoprotein (P-gp, also known as MDR1 or ABCB1) is an ATP-binding cassette (ABC) transporter that actively effluxes a wide range of structurally and functionally diverse molecules, playing a crucial role in drug absorption, distribution, and excretion. P-gp is highly expressed at key biological barriers, such as the blood–brain barrier (BBB), intestine, liver, and kidneys, and it serves as a gatekeeper against xenobiotics and therapeutics. Its dysregulation is involved in multidrug resistance (MDR), epilepsy, cancer, infectious diseases, and neurodegenerative disorders. Several small molecules were synthesized using SAfIR and SAR, and, among them, [¹⁸F]MC225 showed the most promising results for in vivo human studies, with appropriate pharmacodynamics and pharmacokinetics profiles for in vivo use. [¹⁸F]MC225 is currently being employed in PHASE II human trials at the UMC Groningen, the Netherlands, in patients diagnosed with AD, PD and MCI, as well as PHASE II human trials at the Policlinico Gemelli in Rome Italy to diagnose P-gp resistant depression. Preliminary studies show that [¹⁸F]MC225 radiotracer is behaving according to the initial predictions, that is, it accurately diagnoses the aforementioned pathologies, more so than previously developed small molecules for the same goal. Full article

Psychotropic medication is commonly used for the treatment of mental health conditions. However, the genetic factors that influence psychotropic medication responses in children have not been thoroughly investigated. To address this gap, a systematic review and thematic analysis were conducted to examine the genetic impact of psychotropic medication response in children. The Down and Blacks and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists assessed the quality of studies and health economics, respectively. Using PRISMA reporting guidelines, 50 articles were identified with a sample size ranging from 2 to 2.9 million individuals. Most of the studies reported on ethnicity, and approximately half of the studies (24/50) were performed in North America. Five themes emerged from the thematic analysis: (1) implications of non-CYP450 polymorphisms, (2) paediatric CYP450 pharmacogenetics, (3) genetic predictors of response, (4) insights for implementation and future research and (5) phenoconversion. The thematic analysis revealed that assessment of non-CYP450 polymorphisms and psychotropic medication response, especially in those with mental health conditions such as autism, would be helpful. Epilepsy onset, risk and treatment response were associated with non-CYP450 genetic variants. Phenoconversion of substrates associated with CYP2D6 and CYP2C19 metabolisers is common in individuals with mental health conditions, and ABCB1 variants can influence psychotropic medication responses. A multidisciplinary model could also help guide clinical decision-making in cases involving complex neurodevelopmental profiles. Using the Down and Blacks checklist, the average score from the 50 studies was 17.7 points (min. 14, max. 24). The health economic evaluation of studies using the CHEERS checklist gave an average score of 33.0% (range: 21.4% to 35.7%). The study provides an important resource of information for healthcare professionals, researchers and policymakers working at the intersection of child psychiatry, pharmacogenomics and precision medicine. Full article

Background/Objectives: In Ecuador, the prevalence of type 2 diabetes mellitus (T2DM) is the second leading cause of death after ischemic heart disease. Genetic variability in protein-coding genes, single nucleotide variants (SNVs), influences the response to antidiabetic drugs. The frequency of SNVs varies among different populations, so studying the ancestral proportions among SNVs is important for personalized medicine in the treatment of T2DM. This study aimed to evaluate the distribution of Native American, European, and African (NATAM, EUR, and AFR) ancestry in 23 allelic variants of the seven genes that encode the relevant enzymes that metabolize antidiabetic drugs in an Ecuadorian population. Methods: Twenty-three allelic variants of seven genes were analyzed in 297 patients with T2DM from Ecuador, and the molecular ancestry of the samples was analyzed considering three ancestral groups, NATAM, EUR, and AFR using 90 ancestry informative markers (AIMs). Allele and ancestry distributions were analyzed using Spearman’s correlation. Results: The Ecuadorian population presents NATAM (61.33%), EUR (34.48%), and AFR (2.60%) ancestry components. CYP2C8*1 and CYP2C9*1 were positively related to NATAM ancestry, while CYP2C8*4 and CYP2C9*2 were positively related to EUR ancestry. CYP2C19*17 was positively correlated to AFR ancestry. The correlation of SLC22A1 variants such as A in rs594709 was positively correlated with NATAM, while GAT in rs72552763 was positive for EUR. The G variant of rs628031 of the SLC22A1 gene was positively correlated with NATAM and negatively correlated with EUR. The C variant of rs2076828 of the SLC22A3 gene was positively correlated with NATAM ancestry. Conclusions: In the Ecuadorian population, a predominance of Native American ancestry has been observed. Among the allelic variants related to enzymes that metabolize antidiabetic drugs, a relationship has been observed between this ancestral component and variants of the CYP2C8*1, CYP2C9*1, SLC22A1 (rs594709 and rs628031), and SLC22A3 (rs2076828) genes. This information is fundamental for the development of strategies for the implementation of personalized medicine programs for Latin American patients. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a rising global incidence. Natural conjugated taurocholic acid (TCA) possesses anti-inflammatory properties and shows potential therapeutic effects against UC, although the underlying mechanisms remain unclear. Methods: This study employed an integrative approach—combining network pharmacology, bioinformatics, machine learning, immune infiltration analysis, and molecular docking—to investigate the therapeutic mechanisms of TCA in UC. UC-related gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database, and potential TCA targets were predicted using the Comparative Toxicogenomics Database (CTD) and TargetNet platforms. Differentially expressed genes (DEGs) were identified and analyzed via GO and KEGG enrichment analyses. Results: Four machine learning algorithms (XGBoost, RF, SVM, and NNet) were used to identify six hub genes (TGM2, MMP9, ABCB1, NOS2, ABCG2, CASP1), which were further validated using an artificial neural network. Immune infiltration analysis with CIBERSORT revealed significant alterations in immune cell populations in UC tissues. Further validation through an artificial neural network model confirmed their predictive ability. The enrichment analysis of the hub genes highlighted their roles in immune-related pathways, while the immune infiltration analysis indicated significant differences in immune cell populations between ulcerative colitis tissues and control tissues. The molecular docking results showed that the binding energies of these six proteins to TCA were lower than −5 kcal/mol, with TGM2 having the strongest binding affinity (−10 kcal/mol). The intervention of TCA on colitis mice could improve the inflammatory response by regulating the expression of the TGM2 gene. Conclusions: In conclusion, this study suggests that taurocholate alleviates ulcerative colitis by targeting key genes such as TGM2 and modulating immune-related pathways, providing a novel basis for future therapeutic exploration. Full article

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

Objectives: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. Methods: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. Results: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, p = 0.049) but less absolute IPSS improvement (p < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS_1–4) from the baseline to week 8 did not differ significantly (−5.78 ± 5.29 vs. −6.0 ± 4.54, p = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS_1–4 improvement (−6.25 ± 4.60 vs. 0.0 ± 9.53, p = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, p < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax_1–4 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, p = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (p = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). Conclusions: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings. Full article

Background: The etiology of liver disease remains unidentified in approximately 30% of patients, presenting a persistent diagnostic challenge. While whole-exome sequencing (WES) is well established for identifying rare genetic conditions in pediatric populations, its utility in adult hepatology is less defined. This study aimed to evaluate the diagnostic value of WES in adults with unexplained liver disorder. Methods: Fifty-three Turkish adult patients with idiopathic liver disease underwent a comprehensive clinical evaluation and WES at Gazi University Ankara in 2024–2025. The cohort included individuals with idiopathic cholestasis (6/53, 11%), hepatic steatosis (28/53, 53%), unexplained elevated liver enzymes (12/53, 23%), and cryptogenic cirrhosis (7/53, 13%). All patients had inconclusive results from prior standard investigations. Results: ES yielded a definitive molecular diagnosis in 11% (6/53) of cases. Definitive diagnoses were distributed across the following disease categories: idiopathic cholestasis (n = 1), hepatic steatosis (n = 1), elevated liver enzymes (n = 2), and cryptogenic cirrhosis (n = 2). Pathogenic variants were detected in the ABCB4, AGL, APOB, CP, and MTTP genes. One patient was identified with mosaic Turner syndrome. Conclusions: This study highlights the role of rare genetic variants in the etiology of unexplained liver disease in adults. Integrating whole-exome sequencing into hepatology practice can uncover novel disease mechanisms and improve diagnostic yield, informing more precise patient care. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder with a multifactorial pathogenesis and a well-established genetic component. While pathogenic variants in genes such as ABCB4 and ABCB11 are implicated in a subset of cases, many remain genetically unexplained. This study aimed to investigate the genetic background of ICP in a multi-generational family with recurrent hepatobiliary disease. Methods: Whole-exome sequencing was performed on the proband and five female relatives. Variant filtering prioritized rare, exonic or splice-site variants predicted to undergo damage by in silico tools and which were present in all affected family members. Identified variants were assessed using population databases and compared with a control group of 433 unrelated women with uncomplicated pregnancies. Variant confirmation was performed using Sanger sequencing and high-resolution melting analysis. Results: No pathogenic variants were identified in known ICP-associated genes. However, a rare heterozygous missense variant in ABCB5 (c.1610G>A; p.Arg537His; rs779950110) was found in all affected individuals and two younger female relatives. This variant is exceedingly rare in population databases, absent in controls, and predicted to be pathogenic by multiple algorithms. ABCB5, although not previously linked to ICP, is an ATP-binding cassette transporter expressed in various tissues, including liver compartments. Conclusions: This study reports a novel ABCB5 variant segregating with ICP and early-onset hepatobiliary disease in a family. These findings suggest ABCB5 as a potential new susceptibility gene in ICP, warranting further functional investigation. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a variety of enzymes that facilitate its metabolism or transportation. The structural characteristics of the genes that encode the enzymes may potentially impact the pharmacokinetics and pharmacodynamics of losartan, thereby modulating its effects on the treatment process. Methods: In this study, a computational model of losartan pharmacokinetics was developed, taking into account the influence of different alleles of the CYP2C9 gene, which plays a pivotal role in losartan metabolism, and the ABCB1 gene, which is responsible for losartan transport. Results: Alterations in the modeled activities of the enzymes encoded by CYP2C9 and ABCB1 result in changes in the losartan and its metabolite profiles that are consistent with known experimental data in real patients with different CYP2C9 and ABCB1 genotypes. Conclusions: The findings of the modeling can potentially be used to personalize drug therapy for arterial hypertension. Full article

Background/Objectives: Major depressive disorder (MDD), including late-onset forms, is a prevalent and disabling condition. Despite multiple pharmacological treatment options, over half of patients fail to achieve full remission. This systematic review aims to assess current evidence on the influence of pharmacogenetic factors on antidepressant response and safety, with a focus on patients with major and late-life depression. Methods: We conducted a systematic review following PRISMA guidelines (PROSPERO: CRD42020212345). Studies published in the past five years involving adult patients with MDD or late-onset depression and pharmacogenetic data were included. Results: From 793 abstracts screened, 29 studies with 39,975 participants were included. CYP2C19 and CYP2D6 were the most frequently analyzed genes (41% and 17% of studies, respectively). Poor metabolizers for CYP2C19 showed higher plasma levels of SSRIs, leading to increased adverse effects. In contrast, ultrarapid metabolizers had significantly lower response rates. Variants in SLC6A4 and other genes (e.g., HTR2A, ABCB1) were also associated with treatment outcomes. Combinatorial pharmacogenetic testing showed superior predictive value compared to single-gene approaches. Conclusions: Genetic variants in CYP2C19, CYP2D6, and SLC6A4 may affect the efficacy and tolerability of antidepressant therapy. Integrating this information into clinical practice may allow more personalized prescribing and improved outcomes. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log₁₀IC₅₀ values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives. Full article

Background/Objectives: Ibrutinib is a selective Bruton’s tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL). This drug exhibits significant variability in response and toxicity profile, possibly due to genetic polymorphisms in drug-metabolizing enzymes and transporters. The aim of this observational study is to address interindividual variability in the efficacy and safety of ibrutinib treatment in 49 CLL patients. Methods: Genotyping of nine polymorphisms was performed by quantitative polymerase chain reaction (qPCR) using a ViiA7^® PCR Instrument and TaqMan assays, and ibrutinib plasma concentrations were determined using high-performance liquid chromatography coupled to a tandem mass spectrometry detector (HPLC-MS/MS). Results: Our study confirmed a high response rate, with 62% of patients achieving complete remission (CR), 9% CR with incomplete hematologic recovery (CRi), and 24% partial remission (PR). The impact of genetic polymorphisms on the CR rate was evaluated, revealing no statistically significant associations for CYP3A4, CYP3A5, ABCB1, ABCG2, and SLCO1B1 variants. However, a tendency was observed for patients carrying ABCB1 rs1128503, rs1045642 T/T, or rs2032582 A/A genotypes to achieve a higher CR rate. Adverse drug reactions (ADRs) were frequent, with vascular disorders (39%) and infections (27%) being the most common. Genetic polymorphisms influenced ibrutinib toxicity, with CYP3A4 *1/*22 appearing to be protective against overall ADRs. Conclusions: The unexpected association between CYP3A4 *1/*22 genotype and lower ADR incidence, as well as the trend toward improved treatment response in patients carrying ABCB1 genotypes, suggests compensatory metabolic mechanisms. However, given the small sample size, larger studies are needed to confirm these findings and their clinical implications, while also aiming to uncover other non-genetic factors that may contribute to a better understanding of the variability in treatment response and toxicity. Full article