Acta Pharm Sin B. 2025 Feb;15(2):963-972. doi: 10.1016/j.apsb.2024.11.002. Epub 2024 Nov 7.

ABSTRACT

One of the leading therapies for acute lymphoblastic leukemia (ALL) is the chemotherapeutic agent PEGylated E. coli-derived-l-asparaginase (PEG-ASNase). Due to the high risk of dose-limiting liver injury, characterized by clinically elevated levels of hepatic transaminases, PEG-ASNase therapy is generally avoided in adult patients. Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids (FFAs) from white adipose tissue (WAT), suggesting potential lipotoxic effects. However, it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity. Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation. Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase (ATGL), activates the lipase, and stimulates adipose tissue lipolysis, suggesting that the FFAs from WAT may contribute to the observed liver injury. Moreover, treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity. Mechanistically, our RNA-sequencing (RNA-seq) analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1. We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1. Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.

PMID:40177540 | PMC:PMC11959929 | DOI:10.1016/j.apsb.2024.11.002

Front Pharmacol. 2025 Mar 19;16:1538432. doi: 10.3389/fphar.2025.1538432. eCollection 2025.

ABSTRACT

BACKGROUND: Tacrolimus, an approved first-line calcineurin inhibitor, is widely prescribed in organ transplantation to prevent allograft rejection. Its narrow therapeutic index requires precise management to achieve optimal dosing and to minimize adverse drug events (ADEs) while ensuring its therapeutic efficacy. Among several factors, genetic differences contribute significantly to the inter-individual and inter-ethnic variability in pharmacokinetics (PK) of tacrolimus in kidney transplant recipients. As a result, investigating the role of genetic variation in Greek transplant recipients becomes crucial to optimizing therapeutic strategies and enhancing the efficacy of immunosuppressive treatment.

HYPOTHESIS: Genetic variants which are known to influence the activity of enzymes or drug-transporters critical to tacrolimus pharmacokinetics, may significantly affect the required kidney post-transplant tacrolimus daily dose.

AIM: To assess the correlation of ABCB1 genetic variants (rs1128503, rs2229109) and CYP3A4 (rs2242480, rs4986910) with tacrolimus dose-adjusted trough concentration (C0/D), in Greek kidney transplant recipients.

METHODS: Ninety-four unrelated Greek kidney transplant recipients were included in this study from the Department of Nephrology and Kidney Transplantation of the University General Hospital of Patras. Patients' dose-adjusted trough levels were measured at five distinct time points after transplantation and analyzed in relation to the possible influence of CYP3A4 and correlated with the abovementioned ABCB1 genetic variants using standard genotyping analysis and Sanger sequencing.

RESULTS: The genetic variants rs1128503, rs2229109, rs2242480, rs4986910 did not show any significant association with the daily dosing requirements of tacrolimus for at least 1 year, in Greek patients who have undergone kidney transplant.

CONCLUSION: It remains uncertain whether these genetic variants influence the assessment of the appropriate tacrolimus dosing 1 year after transplantation in Greek kidney transplant recipients.

PMID:40176889 | PMC:PMC11962430 | DOI:10.3389/fphar.2025.1538432

Curr Rev Clin Exp Pharmacol. 2025 Mar 28. doi: 10.2174/0127724328356429250315163111. Online ahead of print.

ABSTRACT

INTRODUCTION: Statin-induced myopathy (SIM) is a prevalent adverse event impacting treatment adherence. Despite extensive exploration of genotypes, conflicting evidence obscures their role in SIM incidence, prompting this network meta-analysis.

METHODS: Observational studies meeting eligibility criteria (patients on any statin with reported SNPs and SIM details) were systematically reviewed. Severe SIM was defined as creatine kinase elevations exceeding 10 times the upper limit of normal. Mixed treatment comparison pooled estimates were generated from direct and indirect pooled estimates, represented by odds ratios (OR) with 95% confidence intervals (CI), and validated via bootstrap analysis.

RESULTS: Thirty-four studies (26,152 participants) examining genotypes spanning drug transporters, metabolizing enzymes, reactive oxygen species production, and myopathy-related genes were analyzed. Significant associations were observed with drug transporters (OR: 1.4; 95% CI: 1.04, 1.5). Notably, solute carrier organic anion transporter 1B1 (SLCO1B1) (rs4149056) exhibited a moderate association with SIM (OR: 2.1; 95% CI: 1.7, 2.6), validated by bootstrap analysis (OR: 2.1; 95% CI: 1.7, 2.8). Similar associations were found for severe SIM with SLCO1B1 (rs4149056) (OR: 3.8; 95% CI: 1.4, 10.4) and ATP Binding Cassette Subfamily B Member 1 (ABCB1) (rs2373588) (OR: 2.8; 95% CI: 1.4, 5.4). Intraclass differences in genetic predictor risks were noted among statins.

CONCLUSION: Our meta-analysis underscores the significant association of SLCO1B1 with SIM, supporting its clinical utility. Further research is warranted to clarify additional genetic predictors. These findings endorse current guidelines advocating for SLCO1B1 genotyping in statin therapy decisions.

PMID:40176697 | DOI:10.2174/0127724328356429250315163111

Mol Divers. 2025 Apr 2. doi: 10.1007/s11030-025-11135-4. Online ahead of print.

ABSTRACT

The process of various virus entry into host cells, including SARS-CoV-2, is mediated by clathrin-mediated endocytosis (CME). AP-2 plays a crucial role in this process by recognizing membrane receptors and binding with clathrin, facilitating the formation of clathrin-coated vesicles and promoting CME. AAK1 catalyzes the phosphorylation of AP2M1 subunit at Thr156. Therefore, suppressing AAK1 activity can hinder virus invasion by blocking CME. indicating that AAK1 could be a potential target for developing novel antiviral drugs against SARS-CoV-2. In this study, we present a series of novel AAK1 inhibitors based on previously reported AAK1 inhibitors. Drug design was carried out by fusing the 1H-indazole scaffold of SGC-AAK1-1 with pharmacophore groups of compound 6, and further optimized with the assistance of molecular docking. Among the 42 compounds novelly synthesized, compounds 9i, 9s, 11f and 11l exhibited comparable antiviral activity against SARS-CoV-2 infection compared to reference compound 6 at the concentration of 3 μM. Particularly, 11f showed almost no cytotoxicity at all tested concentrations. Additionally, 11f exhibited favorable predictive pharmacokinetic properties. These findings support the potential of 11f as a lead compound for developing antiviral drugs targeting SARS-CoV-2 infection, as well as potentially other viruses which are dependent on the CME process to enter host cells. In summary, we have expanded the structural types of AAK1 inhibitors and successfully obtained effective AAK1 inhibitors with antiviral capabilities.

PMID:40175846 | DOI:10.1007/s11030-025-11135-4

Am J Hum Genet. 2025 Mar 24:S0002-9297(25)00102-8. doi: 10.1016/j.ajhg.2025.03.003. Online ahead of print.

ABSTRACT

Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. In the Netherlands, pharmacogenetic information is most often obtained using dedicated single-gene assays, making it expensive and time consuming to generate complete multi-gene PGx profiles. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost, clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks, we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a CYP2D6 copy-number-variant-calling tool, forgoing the need to use separate PCR-based copy-number detection. Ultimately, we returned 1,227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost, clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.

PMID:40174590 | DOI:10.1016/j.ajhg.2025.03.003

Allergy. 2025 Apr 2. doi: 10.1111/all.16544. Online ahead of print.

NO ABSTRACT

PMID:40171941 | DOI:10.1111/all.16544

Ann Hum Genet. 2025 Apr 2:e12596. doi: 10.1111/ahg.12596. Online ahead of print.

ABSTRACT

Pharmacological responses can vary significantly among patients from different ethnogeographic backgrounds. This variability can, at least in part, be attributed to population-specific genetic patterns in genes involved in drug absorption, distribution, metabolism, and excretion, as well as in genes associated with drug-induced toxicity. Identification of such ethnogeographic variability is thus crucial for the optimization of precise population-specific drug treatments. In this review, we summarize the current knowledge about the clinically actionable pharmacogenetic diversity of genes involved in drug metabolism (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, TPMT, NUDT15, UGT1A1, and NAT2), drug-induced hypersensitivity reactions (HLA-A and HLA-B), and drug-induced acute hemolytic anemia (G6PD). We highlight risk populations with distinct allele frequencies and discuss implications for the customization of treatment. Subsequently, we discuss key challenges and opportunities in population pharmacogenomics, including the importance of considering distinct allele frequency patterns in indigenous or founder populations, interpreting pharmacogenomic response in admixed populations, addressing the investigation bias of the pharmacogenomic literature, and difficulties in including rare and population-specific variants into drug response predictions. The information provided here underscores the critical role of population pharmacogenomics in refining pharmacological treatment strategies and aspires to provide further guidance to maximize the benefits of precision medicine across populations.

PMID:40171627 | DOI:10.1111/ahg.12596

Front Pharmacol. 2025 Mar 18;16:1577547. doi: 10.3389/fphar.2025.1577547. eCollection 2025.

NO ABSTRACT

PMID:40170722 | PMC:PMC11959060 | DOI:10.3389/fphar.2025.1577547

Ann Lab Med. 2025 Apr 2. doi: 10.3343/alm.2024.0652. Online ahead of print.

ABSTRACT

Pharmacogenomics is a rapidly evolving field with a strong foundation in basic science dating back to 1960. Pharmacogenomic findings have been translated into clinical care through collaborative efforts of clinical practitioners, pharmacists, clinical laboratories, and research groups. The methods used have transitioned from targeted genotyping of relatively few variants in individual genes to multiplexed multi-gene panels, and sequencing-based methods are likely on the horizon; however, no system exists for classifying and reporting rare variants identified via sequencing-based approaches. Laboratory testing in pharmacogenomics is complex for several genes, including cytochrome P450 2D6 (CYP2D6), HLA-A, and HLA-B, owing to a high degree of polymorphisms, homology with other genes, and copy-number variation. These loci require specialized methods and familiarity with each gene, which may persist during the transition to next-generation sequencing. Increasing implementation across laboratories and clinical facilities has required cooperative efforts to develop standard testing targets, nomenclature, and reporting practices and guidelines for applying the results clinically. Beyond standardization, harmonization between pharmacogenomics and the broader field of genomic medicine may be essential for facilitating further adoption and realizing the full potential of personalized medicine. In this review, we describe the evolution of clinical laboratory testing for pharmacogenomics, including standardization efforts and the anticipated transition from targeted genotyping to sequencing-based pharmacogenomics. We speculate on potential upcoming developments, including pharmacoepigenetics, improved understanding of the impact of non-coding variants, use of large-scale functional genomics to characterize rare variants, and a renewed interest in polygenic risk or combinatorial approaches, which will drive the progression of the field.

PMID:40170583 | DOI:10.3343/alm.2024.0652

Front Pharmacol. 2025 Mar 17;16:1553536. doi: 10.3389/fphar.2025.1553536. eCollection 2025.

ABSTRACT

BACKGROUND: Pharmacogenomics offers a possibility of anticipating drug response based on individuals' genetic profiles and represents a step toward implementation of personalized treatment through routine genetic testing. Development of highthroughput sequencing technologies aided identification and interpretation of variants in many pharmacogenes simultaneously. Nonetheless, the integration of pharmacogenomics into clinical practice is arduous, partly due to insufficient knowledge of ethnic pharmacogenetic data. The aim of our study was to assemble the most comprehensive pharmacogenomics landscape of the Serbian population so far.

METHODS: We used genomic data of 881 individuals from Serbia obtained by clinical and whole exome sequencing. Raw sequencing files were processed using an in-house pipeline for alignment and variant calling. For annotation of pharmacogenetics star alleles and determination of phenotypes, we used the PharmCAT and Stargazer tools. Star allele and phenotype frequencies were calculated and compared to worldwide and European populations. Population differentiation was presented through calculation of Wright's fixation index.

RESULTS: Our results showed that population differentiation was the highest between the Serbian and the worldwide population. In the Serbian population, the most relevant pharmacogenes in terms of star allele frequencies and actionable phenotypes were CYP2B6, NAT2, SLCO1B1, UGT1A1 and VKORC1, that had significantly different distribution compared to other European populations.

CONCLUSION: In conclusion, significant differences in frequencies of pharmacogenetic phenotypes that influence response to several drug categories including statins and antidepressants indicate that inclusion of data relevant for drug response to genetic reports would be beneficial in the Serbian population. Implementation of pharmacogenetic testing could be achieved through analysis of clinical and whole exome sequencing data.

PMID:40166472 | PMC:PMC11955590 | DOI:10.3389/fphar.2025.1553536

Front Med (Lausanne). 2025 Mar 17;12:1535099. doi: 10.3389/fmed.2025.1535099. eCollection 2025.

ABSTRACT

INTRODUCTION: Gaucher disease (GD), a lysosomal storage disorder, results from the accumulation of glycosphingolipids due to deficient lysosomal glucocerebrosidase activity. This pathological accumulation triggers immune activation, which paradoxically induces UDPglucose ceramide glucosyltransferase (UGCG), further exacerbating the metabolic defect. Eliglustat, a highly specific inhibitor of UGCG, functions as a substrate reduction therapy (SRT) and has demonstrated efficacy in reversing GD manifestations in clinical trials and real-world settings. Despite its established safety profile, preclinical studies have shown that supratherapeutic concentrations of eliglustat can inhibit ion channels involved in cardiac electrophysiology. However, pharmacogenomic-guided dosing ensures therapeutic efficacy while maintaining a wide safety margin, minimizing such risks. Nevertheless, lingering concerns regarding cardiac safety have persisted, particularly in patients with preexisting cardiac comorbidities.

METHODS: We report a single-center experience of eliglustat use in 13 patients with type 1 Gaucher disease (GD1) and concurrent cardiac comorbidities. Patients underwent standard cardiac evaluations, including electrocardiogram (EKG) with QTc interval assessment and echocardiogram. Eliglustat dosing was guided by CYP2D6 metabolizer status, and potential drug-drug interactions (DDIs) were carefully monitored.

RESULTS: Cardiac comorbidities included prior myocardial infarction (n = 2), aortic stenosis (n = 2), atrial fibrillation (n = 2), Wolff-Parkinson-White syndrome (n = 1), pericarditis (n = 1), premature ventricular complexes (n = 2), severe pulmonary arterial hypertension with right heart strain (n = 1), mitral annular calcification with diastolic dysfunction (n = 1), and mildly prolonged QTc interval (n = 1). No patients experienced arrhythmia, QTc prolongation, or arrhythmia-related symptoms. Treatment discontinuation was not required. All patients achieved expected therapeutic outcomes, as evidenced by serial reductions in glucosylsphingosine (GlcSph) levels and other disease indicators.

CONCLUSION: This study represents the first real-world clinical evidence evaluating Eliglustat's cardiac safety in a high-risk GD1 population. Unlike prior theoretical concerns derived from in vitro ion channel studies, our findings demonstrate that Eliglustat does not induce clinically significant cardiac events when administered according to pharmacogenomic guidelines. The misinformation regarding Eliglustat's cardiotoxicity, largely driven by speculative interpretations rather than clinical data, is effectively countered by our findings, which show no significant QT prolongation or arrhythmias over a median treatment duration of 8 years.

PMID:40166071 | PMC:PMC11956841 | DOI:10.3389/fmed.2025.1535099

Am J Chin Med. 2025 Mar 29:1-30. doi: 10.1142/S0192415X25500223. Online ahead of print.

ABSTRACT

Bile acid metabolism mediated by gut microbiota is significantly related to immunity regulation that plays an important role in the development and treatment of inflammatory bowel disease (IBD). Our previous study has demonstrated that Panax notoginseng saponins (PNS) alleviate colitis due to the regulation of T helper 17/Regulatory T cells (Th17/Treg) balance via gut microbiota. However, the effects and mechanism of PNS on colitis pertinent to bile acid metabolism mediated by gut microbiota remain elusive. This study aims to investigate the anti-colitis mechanism of PNS by regulating the Th17/Treg balance pertinent to gut microbiota-bile acid metabolism. Results showed that PNS significantly decreased the relative abundance of Allobaculum, Dubosiella, Muribaculum, and Alistipes, and up-regulated the relative contents of conjugated bile acids, such as TCA and TCDCA. Fecal microbiota transplantation (FMT) showed that the gut microbiota remodeled by PNS had a regulatory effect on bile acid metabolism, and up-regulated the relative contents of TCA and TCDCA, which alleviated IBD and promoted Treg cell expression in vivo and in vitro. Taken together, PNS could reshape the profiling of gut microbiota to generate more TCA and TCDCA, which improve the balance of Th17/Treg to exert anti-IBD effects.

PMID:40165428 | DOI:10.1142/S0192415X25500223

Commun Biol. 2025 Mar 31;8(1):530. doi: 10.1038/s42003-025-07959-3.

ABSTRACT

The presence of pre-existing or acquired drug-resistant cells within the tumor often leads to tumor relapse and metastasis. Single-cell RNA sequencing (scRNA-seq) enables elucidation of the subtle differences in drug responsiveness among distinct cell subpopulations within tumors. A few methods have employed scRNA-seq data to predict the drug response of individual cells to date, but their performance is far from satisfactory. In this study, we propose SSDA4Drug, a semi-supervised few-shot transfer learning method for inferring drug-resistant cancer cells. SSDA4Drug extracts pharmacogenomic features from both bulk and single-cell transcriptomic data using semi-supervised adversarial domain adaptation. This allows us to transfer knowledge of drug sensitivity from bulk-level cell lines to single cells. We conduct extensive performance evaluation experiments across multiple independent scRNA-seq datasets, demonstrating SSDA4Drug's superior performance over current state-of-the-art methods. Remarkably, with only one or two labeled target-domain samples, SSDA4Drug significantly boosts the predictive performance of single-cell drug responses. Moreover, SSDA4Drug accurately recapitulates the temporally dynamic changes of drug responses during continuous drug exposure of tumor cells, and successfully identifies reversible drug-responsive states in lung cancer cells, which initially acquire resistance through drug exposure but later restore sensitivity during drug holidays. Also, our predicted drug responses consistently align with the developmental patterns of drug sensitivity observed along the evolutionary trajectory of oral squamous cell carcinoma cells. In addition, our derived SHAP values and integrated gradients effectively pinpoint the key genes involved in drug resistance in prostate cancer cells. These findings highlight the exceptional performance of our method in determining single-cell drug responses. This powerful tool holds the potential for identifying drug-resistant tumor cell subpopulations, paving the way for advancements in precision medicine and novel drug development.

PMID:40164749 | DOI:10.1038/s42003-025-07959-3

Trop Biomed. 2025 Mar 1;42(1):10-14. doi: 10.47665/tb.42.1.002.

ABSTRACT

Typhoid is an acute febrile illness primarily caused by Salmonella enterica serotype typhi (S. Typhi) which could be challenging to diagnose in children, owing to its non-specific clinical signs and symptoms which may resemble other febrile illnesses. Here, we present a case of typhoid which was atypically presented as fever of unknown origin (FUO) in a two-year-old boy with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency. This child was initially diagnosed and managed as acute tonsillopharyngitis, however remained febrile despite medications. A series of investigations were performed and S. Typhi was isolated from the bone marrow culture after almost a month of admission. The antibiotic was started based on antibiotic susceptibility testing and he recovered well. Our case underscores the challenges of diagnosis establishment and clinical management of typhoid in paediatric patients who has underlying disease and emphasizes the importance of having high index of clinical suspicion to ascertain timely and proper diagnosis.

PMID:40163397 | DOI:10.47665/tb.42.1.002

Drug Metab Rev. 2025 Mar 31:1-18. doi: 10.1080/03602532.2025.2485055. Online ahead of print.

ABSTRACT

Paclitaxel is a widely used chemotherapeutic agent recognized for its efficacy against various malignancies. However, its clinical utility is often limited by paclitaxel-induced peripheral neuropathy (PIPN), a dose-dependent and debilitating side effect that significantly impacts patient quality of life. Genetic predisposition plays a critical role in individual susceptibility to PIPN, influencing both drug metabolism and neuropathic responses. This review examines the genetic basis of PIPN, focusing on polymorphisms in key genes associated with paclitaxel metabolism, transport, neuroinflammation, and neuronal signaling. Variants in CYP2C8, CYP3A4, and CYP2C9 affect drug metabolism, while polymorphisms in ABCB1 and SLCO1B1 influence drug transport. Genes involved in neuroinflammatory pathways (TNF-α, IL-6, IL-1β), peripheral nerve integrity (MAPT, TUBB2), and neuronal signaling (SCN9A) have also been implicated in PIPN susceptibility. Understanding genetic contributions to PIPN is essential for unraveling its pathophysiology and developing targeted interventions. Integrating genetic markers into clinical practice can facilitate personalized treatment strategies, minimizing PIPN risk and enhancing therapeutic outcomes. Further studies are needed to validate these findings across diverse populations and uncover novel genetic determinants.

PMID:40162869 | DOI:10.1080/03602532.2025.2485055

Pharmacogenomics. 2025 Mar 31:1-7. doi: 10.1080/14622416.2025.2478810. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to identify the impact of CYP2C19 polymorphism testing on clinical outcomes in patients who have undergone carotid artery stenting (CAS).

METHODS: This was a single-center retrospective cohort study. CYP2C19 polymorphisms were identified based on the presence of two normal functional alleles in normal metabolizers (NMs), a normal functional allele and a nonfunctional allele in intermediate metabolizers and two nonfunctional alleles in poor metabolizers. Patients were recommended for the CYP2C19 polymorphism testing followed by the change in dual antithrombotic drugs (DAPT) at the discretion of the supervising physician. The primary clinical endpoint was stent thrombosis (ST). Logistic regression was used to evaluate the relative risk of clinical outcomes.

RESULTS: A total of 273 patients were included. The relative risk of ST was not reduced in patients who underwent CYP2C19 polymorphism testing than in patients without this test (3.1% vs. 3.9%, OR = 0.914, 95% CI = 0.218-3.841). The ST in NMs and non-NMs was 3.4% and 2.9%, respectively, and showing no reduction in NMs (OR = 1.145, 95% CI = 0.162-8.105). Changing DAPT did not reduce the relative risk of ST compared with non-changing (2.3% vs. 3.2%, OR = 1.604, 95% CI = 0.024-107.033).

CONCLUSIONS: CYP2C19 polymorphism was not related to stent thrombosis in patients with CAS.

PMID:40162622 | DOI:10.1080/14622416.2025.2478810

J Cell Mol Med. 2025 Apr;29(7):e70511. doi: 10.1111/jcmm.70511.

ABSTRACT

Valve interstitial cells (VICs) play a critical role in aortic valve calcification and angiogenic processes associated with calcific aortic valve stenosis (CAVS). Within the same valve, VICs from differently calcified regions can exhibit diverse phenotypic and functional properties. We hypothesised that VICs isolated from noncalcified (NC-VICs) and calcified (C-VICs) areas of human aortic valves possess distinct angiogenic characteristics. In this study, we isolated C-VICs and NC-VICs from 23 valves obtained after aortic valve replacement due to CAVS. Both VIC types exhibited similar phenotypes in culture, characterised by morphology, expression of mesenchymal/fibroblastic markers, proliferation and osteogenic differentiation. No significant differences were observed in the secretion of angiogenic factors, including VEGF-A, Ang-1, Ang-2, PlGF, bFGF between NC-VICs and C-VICs. However, when co-injected with endothelial colony-forming cells (ECFCs) into Matrigel implants in vivo in mice, implants containing NC-VICs showed significantly higher microvessel density compared to those with C-VICs (p < 0.001). Additionally, NC-VICs co-cultured with ECFCs expressed significantly higher levels of the perivascular markers αSMA and calponin compared to C-VICs (p < 0.001 and p < 0.05, respectively). In conclusion, our study reveals the heterogeneity in VIC plasticity within the aortic valve during CAVS. The diminished capacity of VICs from calcified areas to differentiate into perivascular cells suggests a loss of function as valve disease progresses. Furthermore, the ability of VICs to undergo perivascular differentiation may provide insights into valve homeostasis, angiogenesis and the exacerbation of calcification.

PMID:40159645 | DOI:10.1111/jcmm.70511

Parkinsonism Relat Disord. 2025 Mar 20:107804. doi: 10.1016/j.parkreldis.2025.107804. Online ahead of print.

NO ABSTRACT

PMID:40157818 | DOI:10.1016/j.parkreldis.2025.107804

Mol Cell Neurosci. 2025 Mar 27:104006. doi: 10.1016/j.mcn.2025.104006. Online ahead of print.

ABSTRACT

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O2·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O2.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.

PMID:40157469 | DOI:10.1016/j.mcn.2025.104006

J Pharm Sci. 2025 Mar 26:103772. doi: 10.1016/j.xphs.2025.103772. Online ahead of print.

ABSTRACT

OATP2B1, encoded by SLCO2B1, is a drug transporter expressed widely throughout the body in tissues such as the intestine and liver. Genetic variation of this transporter may lead to altered disposition of OATP2B1 substrate drugs, but especially the effects of rare variants are poorly understood. The aim of this study was to characterize the effects of naturally occurring missense single nucleotide variants of SLCO2B1 (c.601G>A, c.935G>A, c.953C>T, c.1175C>, c.1457C>T, c.1559G>C, c.1596C>A, and the c.601G>A + c.935G>A haplotype) on the in vitro functionality of OATP2B1. To characterize transport activity, cellular uptake of dibromofluorescein, 5-carboxyfluorescein, estrone sulfate, and rosuvastatin was compared in OATP2B1 reference- and variant-expressing HEK293 cells. The abundance of OATP2B1 variants in HEK293 crude membrane preparations was quantified with LC-MS/MS-based quantitative targeted absolute proteomics analysis. Variant c.1559G>C impaired OATP2B1-mediated uptake of all tested substrates almost completely, but protein abundance was not reduced to the same extent. Other studied variants had comparable or only modestly reduced protein abundance and transport function compared to reference OATP2B1. These results can be utilized to understand findings from clinical pharmacogenetic studies. More importantly, the results can aid in predicting the consequences of rare variants, such as the loss-of-function variant c.1559G>C, which can be difficult to detect in clinical studies.

PMID:40154787 | DOI:10.1016/j.xphs.2025.103772