Literature Watch
Predictive models and WTAP targeting for idiopathic pulmonary fibrosis (IPF)
Sci Rep. 2025 Apr 26;15(1):14622. doi: 10.1038/s41598-025-98490-2.
ABSTRACT
Emerging evidence suggests that N6-methyladenosine (m6A) modification significantly influences lung injury, lung cancer, and immune responses. The current study explores the potential involvement of m6A modification in the development of IPF. This research analyzed the GSE93606 dataset of 20 non-IPF and 154 IPF patients, identifying 26 m6A regulators and developing predictive models with RF and SVM, assessed via ROC curves. A nomogram was created with selected m6A factors, including molecular subtyping, PCA for m6A features, immune cell analysis, DEG identification, and functional enrichment. In vitro experiments on MRC-5 cells used RT-qPCR and Western blotting, and virtual drug screening targeted the WTAP protein through molecular docking. Analysis revealed 26 differential m6A regulators in IPF patients, with 16 significant; IGFBP2 and YTHDF2 were overexpressed, while others decreased. RF and SVM models identified predictive m6A regulators, and a nomogram was developed using five factors to predict IPF incidence. Distinct m6A patterns showed changes in RNA levels of specific genes in the BLM-induced group, and five compounds targeting WTAP were identified. This research explored m6A factors' impact on IPF diagnosis and prognosis, identifying WTAP as a potential biomarker.
PMID:40287490 | DOI:10.1038/s41598-025-98490-2
Pan-genome analysis of the Enterobacter hormaechei complex highlights its genomic flexibility and pertinence as a multidrug resistant pathogen
BMC Genomics. 2025 Apr 26;26(1):408. doi: 10.1186/s12864-025-11590-1.
ABSTRACT
BACKGROUND: Enterobacter hormaechei is of increasing concern as both an opportunistic and nosocomial pathogen, exacerbated by its evolving multidrug resistance. However, its taxonomy remains contentious, and little is known about its pathogenesis and the broader context of its resistome. In this study, a comprehensive comparative genomic analysis was undertaken to address these issues.
RESULTS: Phylogenomic analysis revealed that E. hormaechei represents a complex, comprising three predicted species, E. hormaechei, E. hoffmannii and E. xiangfangensis, with the latter putatively comprising three distinct subspecies, namely oharae, steigerwaltii and xiangfangensis. The species and subspecies all display open and distinct pan-genomes, with diversification driven by an array of mobile genetic elements including numerous plasmid replicons and prophages, integrative conjugative elements (ICE) and transposable elements. These elements have given rise to a broad, relatively conserved set of pathogenicity determinants, but also a variable set of secretion systems. The E. hormaechei complex displays a highly mutable resistome, with most taxa being multidrug resistant.
CONCLUSIONS: This study addressed key issues pertaining to the taxonomy of the E. hormaechei complex, which may contribute towards more accurate identification of strains belonging to this species complex in the clinical setting. The pathogenicity determinants identified in this study could serve as a basis for a deeper understanding of E. hormaechei complex pathogenesis and virulence. The extensive nature of multidrug resistance among E. hormaechei complex strains highlights the need for responsible antibiotic stewardship to ensure effective treatment of these emerging pathogens.
PMID:40287657 | DOI:10.1186/s12864-025-11590-1
HSPA2 influences the differentiation and production of immunomodulatory mediators in human immortalized epidermal keratinocyte lines
Cell Death Dis. 2025 Apr 26;16(1):344. doi: 10.1038/s41419-025-07565-5.
ABSTRACT
Chaperone proteins constitute a molecular machinery that controls proteostasis. HSPA2 is a heat shock-non-inducible member of the human HSPA/HSP70 family, which includes several highly homologous chaperone proteins. HSPA2 exhibits a cell type-specific expression pattern in the testis, brain, and multilayered epithelia. It is a crucial male fertility-related factor, but its role in somatic cells is poorly understood. Previously, we found that HSPA2 deficiency can impair epidermal keratinocyte differentiation. In this study, we confirmed the crucial role of HSPA2 in keratinocyte differentiation by investigating immortalized keratinocytes cultured in a reconstructed human epidermis model. Moreover, we uncovered the influence of HSPA2 on immunomodulation. Transcriptomic analysis revealed that the total loss of HSPA2 affected the expression of genes related to keratinocyte differentiation and interleukin- and interferon-mediated signaling. The functional analysis confirmed bidirectional changes associated with the loss of HSPA2. The HSPA2 knockout in HaCaT and Ker-CT keratinocytes, but not HSPA2 overproduction, impaired granular layer development as evidenced by reduced levels of late keratinocyte differentiation markers, filaggrin and involucrin, along with structural abnormalities in the upper epidermal layer. Differentiation defects were accompanied by increased mRNA expression and extracellular secretion of keratinocyte-derived pro-inflammatory IL-6 cytokine and CCL2, CCL8, CXCL1, CXCL6, and CXCL10 chemokines. The loss of HSPA2 also led to increased expression of extracellular HSPA1 and interferon-stimulated genes and secretion of immune cell modulator SLAMF7. Knocking down HSPA1 expression in keratinocytes decreased the secretion of IL-6 and CCL5 release, suggesting extracellular HSPA1's role in the HSPA2-regulated molecular network. To summarize, we uncovered the complex homeostatic role of HSPA2 in epidermal keratinocytes. Our results suggest that dysfunction in HSPA2 activity could be an important pathogenicity factor and potential therapeutic target for inflammatory cutaneous diseases.
PMID:40287440 | DOI:10.1038/s41419-025-07565-5
Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy
Life Sci. 2025 Apr 24:123658. doi: 10.1016/j.lfs.2025.123658. Online ahead of print.
ABSTRACT
AIMS: Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.
MATERIALS AND METHODS: H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.
KEY FINDINGS: PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release in vitro. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. In vivo, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both in vitro and in vivo.
SIGNIFICANCE: P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.
PMID:40287058 | DOI:10.1016/j.lfs.2025.123658
Short-term aircraft noise stress induces a fundamental metabolic shift in heart proteome and metabolome that bears the hallmarks of cardiovascular disease
Sci Total Environ. 2025 Apr 25;979:179484. doi: 10.1016/j.scitotenv.2025.179484. Online ahead of print.
ABSTRACT
Environmental stressors in the modern world can fundamentally affect human physiology and health. Exposure to stressors like air pollution, heat, and traffic noise has been linked to a pronounced increase in non-communicable diseases. Specifically, aircraft noise has been identified as a risk factor for cardiovascular and metabolic diseases, such as arteriosclerosis, heart failure, stroke, and diabetes. Noise stress leads to neuronal activation with subsequent stress hormone release that ultimately activates the renin-angiotensin-aldosterone system, increases inflammation and oxidative stress thus substantially affecting the cardiovascular system. However, despite the epidemiological evidence of a link between noise stress and metabolic dysfunction, the consequences of exposure at the molecular, metabolic level of the cardiovascular system are largely unknown. Here, we use a murine model system of short-term aircraft noise exposure to show that noise stress profoundly alters heart metabolism. Within 4 days of noise exposure, the heart proteome and metabolome bear the hallmarks of reduced potential for generating ATP from fatty-acid beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain. This is accompanied by the increased expression of glycolytic metabolites, including the end-product, lactate, suggesting a compensatory shift of energy production towards anaerobic glycolysis. Intriguingly, the metabolic shift is reminiscent of what is observed in failing and ischaemic hearts. Mechanistically, we further show that the metabolic rewiring is likely driven by reactive oxygen species (ROS), as we can rescue the phenotype by knocking out NOX-2/gp91phox, a ROS inducer, in mice. Our results suggest that within a short exposure time, the cardiovascular system undergoes a fundamental metabolic shift that bears the hallmarks of cardiovascular disease. These findings underscore the urgent need to comprehend the molecular consequences of environmental stressors, paving the way for targeted interventions to mitigate health risks associated with chronic noise exposure in modern, environments heavily disturbed by noise pollution.
PMID:40286622 | DOI:10.1016/j.scitotenv.2025.179484
Cardiac Output Estimation in the Intensive Care Unit
JACC Adv. 2025 Mar 26;4(5):101663. doi: 10.1016/j.jacadv.2025.101663. Online ahead of print.
ABSTRACT
BACKGROUND: Cardiac output (CO) is a quintessential property of the cardiovascular system, one whose estimation is vital to patient care in critical illness. The most common techniques for assessing CO, thermodilution (TD) and the estimated Fick (eFick) approximation, force tradeoffs that motivate a need for new methods.
OBJECTIVES: The purpose of this study was to novel CO estimators to fill key gaps in critical care medicine.
METHODS: Machine learning was used to estimate CO from physiology measurements made during routine clinical care in the intensive care unit (ICU) or cardiac catheterization lab. Models were trained and validated using a curated set of 13,172 ground-truth measurements of TD-CO from 4,825 patients. Model performance was evaluated using regression metrics, trajectory analysis, classification accuracy, and ΔCO tracking.
RESULTS: Three established eFick models all performed poorly in the ICU because their static estimates of oxygen consumption could not track the dynamics of critical illness. In the postcardiac surgery intensive care unit, the best eFick model erred in its CO predictions by 30% (mean absolute percentage error [MAPE]) with a coefficient of determination (R2) of -1.5. The best model derived here, labeled CORE (Catheter Optimized caRdiac output Estimation), predicted CO with an MAPE of 14% (P < 0.001 vs eFick) and an R2 of 0.58. These estimates could be calculated from measurements obtained with either a pulmonary artery catheter or a central venous catheter. The CORE model was also robust to the presence of moderate or severe tricuspid regurgitation, achieving an MAPE of 16% and R2 of 0.65 relative to a ground-truth determined by the direct Fick technique with measured oxygen consumption.
CONCLUSIONS: CO models that account for dynamic physiology in ICU patients were more accurate than widely used eFick models and more versatile than TD. The performance of these models combined with their adaptation to vascular access, broad applicability, ease of use, and ease of deployment should enable them to benefit patients across diverse ICU settings.
PMID:40286350 | DOI:10.1016/j.jacadv.2025.101663
In Silico and In Vitro Studies of the Approved Antibiotic Ceftaroline Fosamil and Its Metabolites as Inhibitors of SARS-CoV-2 Replication
Viruses. 2025 Mar 28;17(4):491. doi: 10.3390/v17040491.
ABSTRACT
The SARS-CoV-2 proteases Mpro and PLpro are critical targets for antiviral drug development for the treatment of COVID-19. The 1,2,4-thiadiazole functional group is an inhibitor of cysteine proteases, such as papain and cathepsins. This chemical moiety is also present in ceftaroline fosamil (CF), an FDA-approved fifth-generation cephalosporin antibiotic. This study investigates the interactions between CF, its primary metabolites (M1 is dephosphorylated CF and M2 is an opened β-lactam ring) and derivatives (protonated M1H and M2H), and its open 1,2,4-thiadiazole rings derivatives (open-M1H and open-M2H) with SARS-CoV-2 proteases and evaluates CF's effects on in vitro viral replication. In silico analyses (molecular docking and molecular dynamics (MD) simulations) demonstrated that CF and its metabolites are potential inhibitors of PLpro and Mpro. Docking analysis indicated that the majority of the ligands were more stable with Mpro than PLpro; however, in vitro biochemical analysis indicated PLpro as the preferred target for CF. CF inhibited viral replication in the human Calu-3 cell model at submicromolar concentrations when added to cell culture medium at 12 h. Our results suggest that CF should be evaluated as a potential repurposing agent for COVID-19, considering not only viral proteases but also other viral targets and relevant cellular pathways. Additionally, the reactivity of sulfur in the 1,2,4-thiadiazole moiety warrants further exploration for the development of viral protease inhibitors.
PMID:40284934 | DOI:10.3390/v17040491
Correction: Suriya et al. Integration of In Silico Strategies for Drug Repositioning towards P38alpha Mitogen-Activated Protein Kinase (MAPK) at the Allosteric Site. Pharmaceutics 2022, 14, 1461
Pharmaceutics. 2025 Mar 26;17(4):419. doi: 10.3390/pharmaceutics17040419.
ABSTRACT
In the original publication [...].
PMID:40284534 | DOI:10.3390/pharmaceutics17040419
Thymoquinone Enhances Doxorubicin Efficacy via RAS/RAF Pathway Modulation in Ovarian Adenocarcinoma
Pharmaceutics. 2025 Apr 19;17(4):536. doi: 10.3390/pharmaceutics17040536.
ABSTRACT
Background/Objectives: Ovarian cancer remains one of the most commonly diagnosed malignancies among women worldwide. The heterogeneity among tumor subtypes and the emergence of treatment resistance have raised significant concerns regarding the long-term efficacy of chemotherapy, radiotherapy, and immunotherapy. In response to these challenges, drug repurposing strategies-utilizing existing drugs in novel therapeutic contexts-have gained increasing attention. This study aimed to investigate the cytotoxic and apoptotic effects of the combined application of doxorubicin (DX) and thymoquinone (TQ) on ovarian adenocarcinoma cells (OVCAR3). Methods: OVCAR3 cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. Cell viability and proliferation were assessed using the MTT assay following treatment with various concentrations of DX and TQ. NucBlue immunofluorescence staining was employed to examine nuclear morphology and to identify apoptosis-associated changes. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was per-formed to evaluate the expression levels of apoptosis-related and oncogenic pathway genes, including RAF, RAS, Bcl-2, and Bax. Results: The results demonstrated that the combination of DX and TQ significantly reduced OVCAR3 cell viability and induced apoptosis in a dose-dependent manner. qRT-PCR analysis revealed a downregulation of RAS, RAF, and Bcl-2 expression, along with an upregulation of Bax, indicating activation of the intrinsic apoptotic pathway. These findings suggest that thymoquinone exerts an-ti-proliferative and pro-apoptotic effects by modulating the RAS/RAF signaling cascade. Furthermore, the co-administration of thymoquinone with doxorubicin potentiated these effects, suggesting a synergistic interaction between the two agents. Conclusions: Histopathological and molecular evaluations further confirmed the activation of apoptosis and the suppression of key oncogenic pathways. Collectively, these results underscore the therapeutic potential of thymoquinone as both a monotherapy and an adjuvant to conventional chemotherapy, warranting further validation in preclinical and clinical studies.
PMID:40284530 | DOI:10.3390/pharmaceutics17040536
Wrangling Real-World Data: Optimizing Clinical Research Through Factor Selection with LASSO Regression
Int J Environ Res Public Health. 2025 Mar 21;22(4):464. doi: 10.3390/ijerph22040464.
ABSTRACT
Data-driven approaches to clinical research are necessary for understanding and effectively treating infectious diseases. However, challenges such as issues with data validity, lack of collaboration, and difficult-to-treat infectious diseases (e.g., those that are rare or newly emerging) hinder research. Prioritizing innovative methods to facilitate the continued use of data generated during routine clinical care for research, but in an organized, accelerated, and shared manner, is crucial. This study investigates the potential of CURE ID, an open-source platform to accelerate drug-repurposing research for difficult-to-treat diseases, with COVID-19 as a use case. Data from eight US health systems were analyzed using least absolute shrinkage and selection operator (LASSO) regression to identify key predictors of 28-day all-cause mortality in COVID-19 patients, including demographics, comorbidities, treatments, and laboratory measurements captured during the first two days of hospitalization. Key findings indicate that age, laboratory measures, severity of illness indicators, oxygen support administration, and comorbidities significantly influenced all-cause 28-day mortality, aligning with previous studies. This work underscores the value of collaborative repositories like CURE ID in providing robust datasets for prognostic research and the importance of factor selection in identifying key variables, helping to streamline future research and drug-repurposing efforts.
PMID:40283693 | DOI:10.3390/ijerph22040464
Repurposing Antiepileptic Drugs for Cancer: A Promising Therapeutic Strategy
J Clin Med. 2025 Apr 14;14(8):2673. doi: 10.3390/jcm14082673.
ABSTRACT
Epilepsy is a neurological disorder characterized by repeated convulsions. Antiepileptic drugs (AEDs) are the main course of therapy for epilepsy. These medications are given according to each patient's personal medical history and the types of seizures they suffer. They have been employed for decades to manage epilepsy, thus delivering relief from seizures through numerous mechanisms of action. Aside from their anticonvulsant attributes, current evidence suggests that certain AEDs may display potential inhibitory effects against cancer invasion and metastasis. This review explored the complicated interactions between the modes of action of AEDs and the pathways causing cancer, and the potential impact of AEDs on the invasion and metastasis of various forms of cancer, while addressing their associated side effects. For example, valproic acid inhibits histone deacetylase, causing hyperacetylation of genes, especially those regulating cell cycle, culminating in cell cycle arrest. Topiramate inhibits carbonic anhydrase, thus disrupting the acidic microenvironment needed for cancer cells to thrive. Lacosamide increases the slow inactivation of the voltage gated Na+ channel, thus inhibiting the growth, proliferation, and metastasis of many cancers. Although drug development is a complex task due to regulatory, intellectual property, and economic challenges, researchers are exploring drug repurposing tactics to overcome these challenges and to find new therapeutic alternatives for diseases like cancer. Thus, drug repurposing is considered among the most effective ways to develop drug candidates using novel properties and therapeutic characteristics, and this review also discusses these issues.
PMID:40283503 | DOI:10.3390/jcm14082673
The Impact of Beta Blockers on Survival in Cancer Patients: A Systematic Review and Meta-Analysis
Cancers (Basel). 2025 Apr 18;17(8):1357. doi: 10.3390/cancers17081357.
ABSTRACT
BACKGROUND/OBJECTIVES: Beta adrenergic signaling has been implicated in cancer progression, leading to interest in repurposing beta blockers (BBs) as adjunctive anti-cancer agents. However, clinical findings are inconsistent. This systematic review and meta-analysis evaluates the association between BB use and survival outcomes in cancer patients.
METHODS: A systematic search of OVID Medline, EMBASE, and CENTRAL was conducted through 13 September 2023, for studies comparing survival outcomes in solid tumor patients using BBs versus non-users. Eligible studies reported hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), or cancer-specific survival (CSS). Perioperative studies and those without BB-specific HRs were excluded. Data extraction and quality assessment were performed in duplicate using ROBINS-I. A random-effects model was used, with heterogeneity assessed by the I2 statistic.
RESULTS: Seventy-nine studies (492,381 patients) met the inclusion criteria; 2.5% were prospective. The most frequently studied cancers were breast (n = 33), ovarian (n = 30), and colorectal (n = 28). BB use was associated with improved PFS (HR 0.78, 95% CI: 0.66-0.92, I2 = 79.8%), with significance maintained after excluding high-bias studies (HR 0.74, 95% CI: 0.61-0.91, I2 = 36.6%). No significant associations were observed for OS (HR 0.99, 95% CI: 0.94-1.04, I2 = 84.9%) or CSS (HR 0.95, 95% CI: 0.91-1.00, I2 = 77.4%).
CONCLUSIONS: BB use may be associated with longer PFS in cancer patients, but findings are limited by study design and heterogeneity; high-quality prospective studies are needed.
PMID:40282534 | DOI:10.3390/cancers17081357
Expanded Spectrum and Increased Incidence of Adverse Events Linked to COVID-19 Genetic Vaccines: New Concepts on Prophylactic Immuno-Gene Therapy, Iatrogenic Orphan Disease, and Platform-Inherent Challenges
Pharmaceutics. 2025 Mar 31;17(4):450. doi: 10.3390/pharmaceutics17040450.
ABSTRACT
The mRNA- and DNA-based "genetic" COVID-19 vaccines can induce a broad range of adverse events (AEs), with statistics showing significant variation depending on the timing and data analysis methods used. Focusing only on lipid nanoparticle-enclosed mRNA (mRNA-LNP) vaccines, this review traces the evolution of statistical conclusions on the prevalence of AEs and incidents associated with these vaccines, from initial underestimation of atypical, severe toxicities to recent claims suggesting the possible contribution of COVID-19 vaccinations to the excess deaths observed in many countries over the past few years. Among hundreds of different AEs listed in Pfizer's pharmacovigilance survey, the present analysis categorizes the main symptoms according to organ systems, with nearly all of them being affected. Using data from the US Vaccine Adverse Event Reporting System and a global vaccination dataset, a comparison of the prevalence and incidence rates of AEs induced by genetic versus flu vaccines revealed an average 26-fold increase in AEs with the use of genetic vaccines. The difference is especially pronounced in the case of severe 'Brighton-listed' AEs, which are also observed in COVID-19 and post-COVID conditions. Among these, the increases in incidence rates relative to flu vaccines, given as x-fold rises, were 1152x, 455x, 226x, 218x, 162x, 152x, and 131x for myocarditis, thrombosis, death, myocardial infarction, tachycardia, dyspnea, and hypertension, respectively. The review delineates the concept that genetic vaccines can be regarded as prophylactic immuno-gene therapies and that the observed chronic disabling AEs might be categorized as iatrogenic orphan diseases. It also examines the unique vaccine characteristics that could be causally related to abnormal immune responses which potentially lead to adverse events and complications. These new insights may contribute to improving the safety of this platform technology and assessing the risk/benefit balance of various products.
PMID:40284445 | DOI:10.3390/pharmaceutics17040450
Registries for bronchiectasis in the world: an opportunity for international collaboration
Int J Tuberc Lung Dis. 2025 May 25;29(5):199-201. doi: 10.5588/ijtld.25.0157.
ABSTRACT
Until relatively recently, bronchiectasis (not due to cystic fibrosis) was considered an orphan disease, lacking clinical and commercial interest, and was rarely diagnosed. Since the 2000s, several working groups have emerged in Europe and the US - with the first register for bronchiectasis launching in Spain - and these have demonstrated the impact bronchiectasis has on health. Today, bronchiectasis is considered the third most common chronic inflammatory disease of the airways, after COPD and asthma, and represents a significant economic burden. We make the case for further characterization of these registries to better understand the heterogeneous epidemiology of bronchiectasis.
PMID:40281677 | DOI:10.5588/ijtld.25.0157
Challenges and Solution Directions for the Integration of Smart Information Systems in the Agri-Food Sector
Sensors (Basel). 2025 Apr 8;25(8):2362. doi: 10.3390/s25082362.
ABSTRACT
Traditional farming has evolved from standalone computing systems to smart farming, driven by advancements in digitalization. This has led to the proliferation of diverse information systems (IS), such as IoT and sensor systems, decision support systems, and farm management information systems (FMISs). These systems often operate in isolation, limiting their overall impact. The integration of IS into connected smart systems is widely addressed as a key driver to tackle these issues. However, it is a complex, multi-faceted issue that is not easily achievable. Previous studies have offered valuable insights, but they often focus on specific cases, such as individual IS and certain integration aspects, lacking a comprehensive overview of various integration dimensions. This systematic review of 74 scientific papers on IS integration addresses this gap by providing an overview of the digital technologies involved, integration levels and types, barriers hindering integration, and available approaches to overcoming these challenges. The findings indicate that integration primarily relies on a point-to-point approach, followed by cloud-based integration. Enterprise service bus, hub-and-spoke, and semantic web approaches are mentioned less frequently but are gaining interest. The study identifies and discusses 27 integration challenges into three main areas: organizational, technological, and data governance-related challenges. Technologies such as blockchain, data spaces, AI, edge computing and microservices, and service-oriented architecture methods are addressed as solutions for data governance and interoperability issues. The insights from the study can help enhance interoperability, leading to data-driven smart farming that increases food production, mitigates climate change, and optimizes resource usage.
PMID:40285052 | DOI:10.3390/s25082362
Pharmacometabolomics Detects Various Unreported Metoprolol Metabolites in Urine of (Potential) Living Kidney Donors and Kidney Transplant Recipients
Clin Pharmacokinet. 2025 Apr 26. doi: 10.1007/s40262-025-01502-7. Online ahead of print.
ABSTRACT
BACKGROUND AND OBJECTIVE: Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-driven therapy personalization. However, the field relies heavily on knowledge of a drug's metabolism, often originating from early-phase clinical trials with single-dose administration in small samples of healthy volunteers. Pharmacogenetics could thus benefit from real-world drug metabolism studies.
METHODS: We conducted a real-world drug metabolism study for metoprolol in 18 (potential) living kidney donors and 374 kidney transplant recipients from the Transplant Lines Food and Nutrition Biobank and Cohort Study (NCT02811835) using existing liquid chromatography-high resolution mass spectrometry pharmacometabolomic data.
RESULTS: In both groups, we confirmed the presence of seven expected metabolites, including the high-abundance substances metoprolol acid and hydroxymetoprolol. We were unable to detect deisopropylmetoprolol and a metabolite known as "H 119/68". However, we did find putative further oxidized forms, namely the expected variant of deisopropylmetoprolol in which the primary amine is removed and the leftover methyl group is oxidized into a carboxylic acid ("H 104/83") and an unknown/unreported metoprolol metabolite that we refer to as "metoprolol benzoic acid". Moreover, we found nine other previously unknown/unreported metabolites, putatively reflecting N-glucuronidated metoprolol, four glucuronidated versions of hydroxymetoprolol, and a formylated, a glucuronidated, and two hydroxylated versions of metoprolol acid. Interestingly, the same metabolites were detected in potential living kidney donors and kidney transplant recipients, and metabolite profiles did not differ between both groups in principal component analysis.
CONCLUSION: We found more metoprolol metabolites than previously reported, calling for replication studies and evaluation of pharmacogenetic testing approaches to realize safer, more effective metoprolol therapy.
PMID:40285825 | DOI:10.1007/s40262-025-01502-7
Optimizing Treatment: The Role of Pharmacology, Genomics, and AI in Improving Patient Outcomes
Drug Dev Res. 2025 May;86(3):e70093. doi: 10.1002/ddr.70093.
ABSTRACT
Recent advances in pharmacology are revolutionizing drug discovery and treatment strategies through personalized medicine, pharmacogenomics, and artificial intelligence (AI). The objective of the present study is to review the role of personalized medicine, pharmacogenomics, and AI-based strategies in optimizing patient outcomes with improved drug efficacy and reduced side effects. A comprehensive review was performed to debate the utility of pharmacogenomics in the prediction of drug response, the role of AI in drug discovery, and the utility of personalized medicine in the clinic. This review highlights how drug discovery and treatment techniques are evolving with the aid of personalized medicine, pharmacogenomics, and AI. Personalized medicine makes the treatment fit the DNA pattern for higher efficacy and minimal side effects. Pharmacogenomics forecasts the action of a drug in terms of genetic difference. AI speeds up drug discovery to enhance the effectiveness and accuracy of finding and evaluating drug leads. Studies show that customized medicine charts therapy to an individual patient's individual genetic profile, resulting in better therapy. Pharmacogenomics facilitates precise drug selection by considering genetic variations, reducing adverse reactions. AI speeds up drug discovery by applying predictive modeling and data-driven evaluation to propel optimized drug development pathways. Together, these advances are enabling more efficient and safer treatment practices across medical disciplines. The combination of pharmacology, genomics, and AI is revolutionizing contemporary healthcare through the personalization of treatments, improved drug safety, and therapeutic outcomes. The future of research should be on optimizing these techniques and overcoming ethical and regulatory issues to facilitate broader clinical implementation.
PMID:40285487 | DOI:10.1002/ddr.70093
The Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants
Clin Transl Sci. 2025 May;18(5):e70239. doi: 10.1111/cts.70239.
ABSTRACT
Previous pharmacogenetic findings for beta-blocker pharmacodynamic candidate genes (ADRB1, ADRB2, ADRA2C, GRK4, and GRK5) have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta-blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self-reported African American and 49% self-reported White race, 36% female, and 240 died (27%) over a median follow-up of 2.8 years. The primary outcome was all-cause mortality. Using Cox proportional hazards models with time-varying beta-blocker exposure and adjusted for clinical risk factors and ancestry, interactions of ADRB1 Arg389Gly, ADRB1 Ser49-Arg389Gly haplotype, ADRA2C Del322-325, and GRK4 Ala486Val with beta-blocker exposure were significant before correction for multiple comparisons (p < 0.1), but only GRK4 Ala486Val remained significant in African Americans after correction for multiple comparisons using the adaptive Hochberg method (p = 0.022). Beta-blocker exposure only associated with a significant reduction in the risk of mortality in the African American HFrEF patients with the GRK4 Ala486/Ala486 genotype (HR = 0.44; 95% CI = 0.20-0.96; p = 0.04). In conclusion, the interaction of GRK4 Ala486Val with beta-blocker exposure significantly associated with survival in African American HFrEF patients. Larger sample sizes or meta-analyses are needed to have more statistical power to better assess beta-blocker pharmacogenetic interactions for ADRB1 Arg389Gly, ADRB1 Ser49-Arg389Gly haplotype, and ADRA2C Del322-325 in the future.
PMID:40285373 | DOI:10.1111/cts.70239
sTPLS: identifying common and specific correlated patterns under multiple biological conditions
Brief Bioinform. 2025 Mar 4;26(2):bbaf195. doi: 10.1093/bib/bbaf195.
ABSTRACT
The rapidly emerging large-scale data in diverse biological research fields present valuable opportunities to explore the underlying mechanisms of tissue development and disease progression. However, few existing methods can simultaneously capture common and condition-specific association between different types of features across different biological conditions, such as cancer types or cell populations. Therefore, we developed the sparse tensor-based partial least squares (sTPLS) method, which integrates multiple pairs of datasets containing two types of features but derived from different biological conditions. We demonstrated the effectiveness and versatility of sTPLS through simulation study and three biological applications. By integrating the pairwise pharmacogenomic data, sTPLS identified 11 gene-drug comodules with high biological functional relevance specific for seven cancer types and two comodules that shared across multi-type cancers, such as breast, ovarian, and colorectal cancers. When applied to single-cell data, it uncovered nine gene-peak comodules representing transcriptional regulatory relationships specific for five cell types and three comodules shared across similar cell types, such as intermediate and naïve B cells. Furthermore, sTPLS can be directly applied to tensor-structured data, successfully revealing shared and distinct cell communication patterns mediated by the MK signaling pathway in coronavirus disease 2019 patients and healthy controls. These results highlight the effectiveness of sTPLS in identifying biologically meaningful relationships across diverse conditions, making it useful for multi-omics integrative analysis.
PMID:40285361 | DOI:10.1093/bib/bbaf195
Pharmacogenetics as a Future Tool to Risk-Stratify Breast Cancer Patients According to Chemotoxicity Potential from the Doxorubicin Hydrochloride and Cyclophosphamide (AC) Regimen
Pharmaceuticals (Basel). 2025 Apr 7;18(4):539. doi: 10.3390/ph18040539.
ABSTRACT
Background: Studying single-nucleotide polymorphisms (SNPs) in xenobiotic-transporting and metabolizing enzyme genes before administering the doxorubicin hydrochloride and cyclophosphamide (AC) regimen may help optimize breast cancer (BC) treatment for individual patients. Objective: Genotyping specific SNPs on genes encoding for the transport and metabolism of the AC regimen and study their association with its chemotherapeutic toxicity. Method: This prospective cohort study was conducted in two hospitals in Egypt. Before receiving AC therapy, venous blood was collected from female patients with BC for DNA extraction and the genotyping of four SNPs: rs2228100 in ALDH3A1 gene, rs12248560 in CYP2C19 gene, rs1045642 in ABCB1 gene, and rs6907567 in SLC22A16 gene. Patients were then prospectively monitored for hematological, gastrointestinal, and miscellaneous toxicities throughout the treatment cycles. Results: The ALDH3A1 gene polymorphism demonstrated a significant increase in nausea, stomachache, and peripheral neuropathy among patients carrying the GC+CC genotype, compared to those with the GG genotype (p = 0.023, 0.036, and 0.008, respectively). Conversely, patients with the GG genotype exhibited significantly higher fever grades after cycles 1, 2, and 3 of the AC regimen compared to those with the GC+CC genotype (p = 0.009, 0.017, and 0.018, respectively). Additionally, fatigue severity was significantly increased among patients with the GG genotype compared to those with the GC+CC genotype following AC administration (p = 0.008). Conclusions: The SNP variation of ALDH3A1 (rs2228100) gene significantly influenced AC regimen toxicity in female BC patients. Meanwhile, SNPs in CYP2C19 (rs12248560), ABCB1 (rs1045642), and SLC22A16 (rs6907567) genes showed a significant influence on the recurrence rate of certain toxicities.
PMID:40283974 | DOI:10.3390/ph18040539
Pages
