Front Immunol. 2025 Mar 31;16:1549277. doi: 10.3389/fimmu.2025.1549277. eCollection 2025.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by abnormal epithelial repair, persistent inflammation, and excessive extracellular matrix deposition, leading to irreversible scarring and respiratory failure. Central to its pathogenesis is the dysregulation of the PI3K/Akt signaling pathway, which drives fibroblast activation, epithelial-mesenchymal transition, apoptosis resistance, and cellular senescence. Senescent cells contribute to fibrosis through the secretion of pro-inflammatory and profibrotic factors in the senescence-associated secretory phenotype (SASP). Current antifibrotic therapies, Nintedanib and Pirfenidone, only slow disease progression and are limited by side effects, highlighting the need for novel treatments. This review focuses on the role of PI3K/Akt signaling in IPF pathogenesis, its intersection with inflammation and fibrosis, and emerging therapeutic approaches targeting molecules along this pathway.

PMID:40248697 | PMC:PMC12004373 | DOI:10.3389/fimmu.2025.1549277

ERJ Open Res. 2025 Apr 14;11(2):00978-2024. doi: 10.1183/23120541.00978-2024. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: A shared genetic component between coronavirus disease 2019 (COVID-19) and idiopathic pulmonary fibrosis (IPF) has been described based on analyses of individual risk variants. Here we used a whole-genome polygenic risk score (PRS) approach to further evaluate age- and sex-stratified genetic overlap between IPF and severe COVID-19 to give insight into shared biological mechanisms that might both inform therapeutic strategies for both diseases.

METHODS: We used results from the largest genome-wide association study of clinically defined IPF risk (4125 cases/20 464 controls) and individual-level data from the SCOURGE European study of COVID-19 (5968 cases/9056 controls). We calculated IPF PRSs and assessed their association with COVID-19 severity, stratified by age and sex. We performed replication in an independent dataset of Latin-American patients (1625 cases/1887 controls). Enrichment and pathway-specific PRS analyses were performed to study biological pathways associated with COVID-19 severity.

RESULTS: IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness in Europeans and replicated in a Latin-American cohort. The strongest association was found in <60 years patients, especially among younger males (p=6.39×10-5). Pathway-specific PRSs analyses supported a link to cadherin and integrin signalling pathways.

CONCLUSIONS: The study indicates age and sex-dependent genome-wide genetic overlap between IPF and severe COVID-19 and highlights specific shared biological mechanisms underlying both conditions. This could also imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.

PMID:40247961 | PMC:PMC12004260 | DOI:10.1183/23120541.00978-2024

Nucleic Acids Res. 2025 Apr 10;53(7):gkaf320. doi: 10.1093/nar/gkaf320.

ABSTRACT

With the explosive growth of whole-genome datasets, accurate detection of orthologous synteny has become crucial for reconstructing evolutionary history. However, current methods for identifying orthologous synteny face great limitations, particularly in scaling with varied polyploidy histories and accurately removing out-paralogous synteny. In this study, we developed a scalable and robust approach, based on the Orthology Index (OI), to effectively identify orthologous synteny. Our evaluation across a large-scale empirical dataset with diverse polyploidization events demonstrated the high reliability and robustness of the OI method. Simulation-based benchmarks further validated the accuracy of our method, showing its superior performance against existing methods across a wide range of scenarios. Additionally, we explored its broad applications in reconstructing the evolutionary histories of plant genomes, including the inference of polyploidy, identification of reticulation, and phylogenomics. In conclusion, OI offers a robust, interpretable, and scalable approach for identifying orthologous synteny, facilitating more accurate and efficient analyses in plant evolutionary genomics.

PMID:40248914 | DOI:10.1093/nar/gkaf320

Metab Eng Commun. 2025 Apr 2;20:e00261. doi: 10.1016/j.mec.2025.e00261. eCollection 2025 Jun.

ABSTRACT

Engineered type I polyketide synthases (T1PKSs) are a potentially transformative platform for the biosynthesis of small molecules. Due to their modular nature, T1PKSs can be rationally designed to produce a wide range of bulk or specialty chemicals. While heterologous PKS expression is best studied in microbes of the genus Streptomyces, recent studies have focused on the exploration of non-native PKS hosts. The biotechnological production of chemicals in fast growing and industrial relevant hosts has numerous economic and logistic advantages. With its native ability to utilize alternative feedstocks, Pseudomonas putida has emerged as a promising workhorse for the sustainable production of small molecules. Here, we outline the assessment of P. putida as a host for the expression of engineered T1PKSs and production of 3-hydroxyacids. After establishing the functional expression of an engineered T1PKS, we successfully expanded and increased the pool of available acyl-CoAs needed for the synthesis of polyketides using transposon sequencing and protein degradation tagging. This work demonstrates the potential of T1PKSs in P. putida as a production platform for the sustainable biosynthesis of unnatural polyketides.

PMID:40248344 | PMC:PMC12005932 | DOI:10.1016/j.mec.2025.e00261

Ecancermedicalscience. 2025 Feb 6;19:1839. doi: 10.3332/ecancer.2025.1839. eCollection 2025.

ABSTRACT

BACKGROUND: As one of the non-communicable diseases, cancer will overtake communicable, maternal, neonatal and nutritional diseases combined as the leading cause of mortality by 2040. Gastrointestinal (GI) cancers are predicted to increase by over 50% in the next 20 years, with a higher incidence in developing countries. In this study, we describe the national GI cancer trends in Zimbabwe using the annual reports from the Zimbabwe National Cancer Registry (ZNCR) from 2009 to 2018.

METHODS: Demographic data and incidence of GI cancer subtypes were collected and analysed from the ZNCR annual reports from 2009 to 2018. Age standardised rates (ASRs) for each GI cancer subtype were calculated and simple trend analysis was performed over the 10-year study period.

RESULTS: In total, 10,859 new GI cancer cases were reported during the study period, accounting for 17.2% of all cancers in Zimbabwe and 55% of these were males. The most prevalent GI cancers were oesophageal, liver, gastric, colon and rectal malignancies. In males, on average the incidence of ASR of oesophageal, liver and gastric cancer increased annually by 14.7%, 17% and 16%, respectively. In females, on average the ASR of oesophageal, liver and gastric cancer increased annually by 27.2%; 18% and 13%, respectively. Overall, one in ten new cases of oesophageal cancer were diagnosed in patients under 45 years of age and for liver cancer, one in four new male cases were diagnosed below the age of 45 years.

CONCLUSION: Zimbabwe faces an increasing trend in all GI cancer subtype incidence over the decade reviewed. The rate of increase in oesophageal and gastric cancers in females was particularly high and the male-to-female ratio observed requires further etiological studies. The increasing rate of young GI cancer patients requires both education regarding risk factors and national screening policies that are tailored to the Zimbabwean population's characteristics and context.

PMID:40248268 | PMC:PMC12003983 | DOI:10.3332/ecancer.2025.1839

Front Genet. 2025 Apr 3;16:1520325. doi: 10.3389/fgene.2025.1520325. eCollection 2025.

ABSTRACT

INTRODUCTION: The existing evidence indicates that atherosclerosis (AS) plays a pivotal role in the progression and exacerbation of cardiovascular diseases and their associated complications. Current diagnostic and therapeutic strategies for atherosclerosis are limited in their ability to facilitate early detection and personalized treatment. This study employs a systems biology approach to investigate the role of lactylation-related genes (LRGs) in the pathogenesis of atherosclerosis, while considering the well-established correlation between inflammatory responses and atherosclerosis development.

METHODS: In this study, we utilized datasets obtained from the Gene Expression Omnibus (GEO) as well as data from previous studies on lactylation-related genes (LRGs). Following this, we identified 17 lactylation related genes associate with atherosclerosis (AS-LRGs) from the GSE100927 dataset. Subsequently, we employed the validation dataset (GSE43292) to assess these 17 AS-LRGs, resulting in the identification of 12 more reliable candidate genes. These genes were further analyzed for functional enrichment through Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). To elucidate the potential utility of AS-LRGs in diagnosing high-risk plaques, we assessed their expression in both early and late stages of atherosclerosis, as well as in high- and low-risk plaques. We then constructed interaction networks to elucidate the potential regulatory relationships among LRGs, miRNAs, transcription factors, and drugs. Finally, we utilized the single sample Gene Set Enrichment Analysis (ssGSEA) method to investigate immune infiltration in AS and evaluate the levels of immune cell infiltration.

RESULTS: We identified 12 lactylation-related genes that are more reliably associated with atherosclerosis: five upregulated genes (LSP1, IKZF1, MNDA, RCC2, and WAS) and seven downregulated genes (CSRP2, PPP1CB, CSRP1, HEXIM1, CALD1, PDLIM1, and RANBP2).

DISCUSSION: This study elucidates the pivotal role of lactylation in atherosclerosis (AS) and establishes a robust foundation for future research into targeted therapies and clinical applications of the identified biomarkers.

PMID:40248193 | PMC:PMC12003320 | DOI:10.3389/fgene.2025.1520325

Front Plant Sci. 2025 Apr 1;16:1538669. doi: 10.3389/fpls.2025.1538669. eCollection 2025.

ABSTRACT

The HKT protein family plays a vital role in plant responses to salt stress by mediating sodium (Na+) and potassium (K+) transport and maintaining Na+-K+ balance. Ipomoea pes-caprae (IPC), a pantropical creeping plant distributed along coastal regions in tropical and subtropical zones, exhibits exceptional salt tolerance. Understanding its salt tolerance mechanisms provides valuable insights for developing salt-tolerant crops and identifying candidate genes for genetic engineering. In this study, we identified two HKT genes, IpcHKT1;1 and IpcHKT1;2, in IPC. Phylogenetic analysis with HKT genes from other Ipomoea species revealed that all analyzed species contain two HKT genes located adjacently on the same chromosome. Comparative analysis of conserved motifs and intron-exon structures indicated that, despite their close evolutionary relationship, the HKT genes in IPC may exhibit functional divergence. Promoter analysis showed that their regulatory regions are enriched with cis-elements associated with responses to biotic and abiotic stresses, hormonal signaling, and growth, highlighting functional diversity within the HKT family. Subcellular localization experiments demonstrated that IpcHKT1;1 and IpcHKT1;2 are ion transporters localized to the plasma membrane. Heterologous expression in yeast confirmed their role in Na+/K+ symporter. Furthermore, RT-qPCR analysis revealed distinct expression patterns under salt stress: IpcHKT1;2 was significantly upregulated in roots, while IpcHKT1;1 expression was transitionally downregulated at 400 mM NaCl treatment. Prolonged high expression of IpcHKT1;2 in roots suggests its critical role in sustained salt stress tolerance. These findings provide new insights into the molecular mechanisms of salt tolerance in IPC. The identification of IpcHKT1;1 and IpcHKT1;2 as key players in salt stress responses offers promising genetic resources for enhancing crop resilience to soil salinity, addressing challenges associated with global salinization.

PMID:40247947 | PMC:PMC12005088 | DOI:10.3389/fpls.2025.1538669

J Neurosci Res. 2025 Apr;103(4):e70039. doi: 10.1002/jnr.70039.

ABSTRACT

Sex and gender differences in the analgesic efficacy and side effects of opioids have been widely reported, but their underlying neurobiological mechanisms remain poorly understood. Preclinical animal models are essential tools for investigating these differences and providing insights into the neurobiology of opioid effects. Although studies in rats have revealed sex-specific effects of opioids, the sex-dependent behavioral profiles of opioids in mice, particularly across strains, remain largely unexplored. In this study, we characterized sex and strain differences in the antinociceptive and hyperlocomotor effects of morphine in the two most widely used mouse strains-CD1 and C57BL/6-and quantified regional expression of the μ-opioid receptor (MOR) in key brain and spinal cord regions. Both strains exhibited clear, dose-dependent antinociceptive and hyperlocomotor responses to morphine. While no significant sex or strain differences were observed in antinociceptive effects, C57BL/6 mice displayed significantly greater hyperlocomotor activity than CD1 mice. Western blot analyses revealed strain-specific MOR expression, with CD1 mice showing higher spinal cord and periaqueductal gray MOR levels, particularly in females, while C57BL/6 mice exhibited elevated MOR expression in the caudoputamen. Morphine treatment increased spinal MOR expression in CD1 mice but not C57BL/6, suggesting strain-dependent regulation of MOR. These findings highlight strain-specific behavioral and molecular responses to morphine, emphasizing the importance of strain and sex considerations in preclinical opioid research.

PMID:40247818 | DOI:10.1002/jnr.70039

Anal Chem. 2025 Apr 18. doi: 10.1021/acs.analchem.4c05407. Online ahead of print.

ABSTRACT

Liquid biopsy is an appealing approach for early diagnosis and assessment of treatment efficacy in cancer. Typically, liquid biopsy involves the detection of endogenous biomarkers, including circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), and proteins. The levels of these endogenous biomarkers are higher in cancer patients compared to those in healthy individuals. However, the clinical application of liquid biopsy using endogenous biomarker analysis faces challenges due to its low abundance and poor stability in circulation. Recently, a promising strategy involving the engineering of exogenous probes has been developed to overcome these limitations. These exogenous probes are activated within the tumor microenvironment, generating distinct exogenous markers that can be easily distinguished from background biological signals. Alternatively, these exogenous probes can be labeled with intrinsic endogenous biomarkers in vivo and detected in vitro after metabolic processes. In this review, we primarily focus on microfluidic-based liquid biopsy techniques that allow for the transition from analyzing existing endogenous biomarkers to emerging exogenous ones. First, we introduce common endogenous biomarkers, as well as synthetic exogenous ones. Next, we discuss recent advancements in microfluidic-based liquid biopsy techniques for analyzing both existing endogenous and emerging exogenous biomarkers. Lastly, we provide insights into future directions for liquid biopsy on microfluidic systems.

PMID:40247704 | DOI:10.1021/acs.analchem.4c05407

Phys Rev E. 2025 Mar;111(3-2):035401. doi: 10.1103/PhysRevE.111.035401.

ABSTRACT

Glassy soft matter is often continuously polydisperse, in which the sizes or various properties of the constituent particles are distributed continuously. However, most of the microscopic theories of the glass transition focus on the monodisperse particles. Here, we developed a replica theory for the dynamic glass transition of continuously polydisperse hard spheres. We focused on the limit of infinite spatial dimension, where replica theory becomes exact. In theory, the cage size A, which plays the role of an order parameter, appears to depend on the particle size σ, and thus, the effective free energy, the so-called Franz-Parisi potential, is a functional of A(σ). We applied this theory to two fundamental systems: a nearly monodisperse system and an exponential distribution system. We found that dynamic decoupling occurs in both cases; the critical particle size σ^{*} emerges, and larger particles with σ≥σ^{*} vitrify, while smaller particles σ<σ^{*} remain mobile. Moreover, the cage size A(σ) exhibits a critical behavior at σ≃σ^{*}, originating from spinodal instability of σ^{*}-sized particles. We discuss the implications of these results for finite dimensional systems.

PMID:40247574 | DOI:10.1103/PhysRevE.111.035401

Curr Med Chem. 2025 Apr 17. doi: 10.2174/0109298673327575250331145643. Online ahead of print.

ABSTRACT

Panax ginseng (PG), a staple in traditional medicine in Korea and China, holds a rich history of application for various diseases. Notably, its primary active components, ginsenosides, exhibit diverse therapeutic effects. Chemotherapy-induced side effects pose significant challenges to the treatment outcomes of cancer patients. Current strategies for managing the adverse effects of chemotherapy exhibit limited efficacy and have the potential to induce various detrimental side effects. In the realm of complications, cardiotoxicity poses a serious threat, ranking as the second major contributor to illness and death in individuals suffering cancer. It is linked to various cellular mechanisms such as oxidative stress, inflammation, apoptosis, autophagy, endoplasmic reticulum stress, and aberrant myocardial energy metabolism. Both in vivo and in vitro experiments confirm that ginsenosides undeniably present non-toxic and efficacious alternatives for addressing chemotherapy-induced side effects, including cardiotoxicity, neurotoxicity, nephrotoxicity, hepatotoxicity, immunotoxicity, and hematopoietic inhibition. Hence, there is a need to produce novel and potent drugs sourced from natural, non-toxic compounds to address the side effects induced by chemotherapy. The emphasis should be on the underlying mechanisms targeting mentioned cellular pathways. In this comprehensive review, we consolidate current knowledge and summarization with this aim and shed light on the future research of PG in cardio-oncology.

PMID:40248929 | DOI:10.2174/0109298673327575250331145643

Am J Hum Genet. 2025 May 1;112(5):1158-1172. doi: 10.1016/j.ajhg.2025.03.014. Epub 2025 Apr 16.

ABSTRACT

Rare diseases (RDs) are conditions affecting fewer than 1 in 2,000 people, with over 7,000 identified, primarily genetic in nature, and more than half impacting children. Although each RD affects a small population, collectively, between 3.5% and 5.9% of the global population, or 262.9-446.2 million people, live with an RD. Most RDs lack established treatment protocols, highlighting the need for proper care pathways addressing prognosis, diagnosis, and management. Advances in generative AI and large language models (LLMs) offer new opportunities to document the temporal progression of phenotypic features, addressing gaps in current knowledge bases. This study proposes an LLM-based framework to capture the natural history of diseases, specifically focusing on Noonan syndrome. The framework aims to document phenotypic trajectories, validate against RD knowledge bases, and integrate insights into care coordination using electronic health record (EHR) data from the Undiagnosed Diseases Program Singapore.

PMID:40245863 | DOI:10.1016/j.ajhg.2025.03.014

Orphanet J Rare Dis. 2025 Apr 17;20(1):186. doi: 10.1186/s13023-025-03655-x.

ABSTRACT

BACKGROUND: Use of artificial intelligence (AI) in rare diseases has grown rapidly in recent years. In this review we have outlined the most common machine-learning and deep-learning methods currently being used to classify and analyse large amounts of data, such as standardized images or specific text in electronic health records. To illustrate how these methods have been adapted or developed for use with rare diseases, we have focused on Fabry disease, an X-linked genetic disorder caused by lysosomal α-galactosidase. A deficiency that can result in multiple organ damage.

METHODS: We searched PubMed for articles focusing on AI, rare diseases, and Fabry disease published anytime up to 08 January 2025. Further searches, limited to articles published between 01 January 2021 and 31 December 2023, were also performed using double combinations of keywords related to AI and each organ affected in Fabry disease, and AI and rare diseases.

RESULTS: In total, 20 articles on AI and Fabry disease were included. In the rare disease field, AI methods may be applied prospectively to large populations to identify specific patients, or retrospectively to large data sets to diagnose a previously overlooked rare disease. Different AI methods may facilitate Fabry disease diagnosis, help monitor progression in affected organs, and potentially contribute to personalized therapy development. The implementation of AI methods in general healthcare and medical imaging centres may help raise awareness of rare diseases and prompt general practitioners to consider these conditions earlier in the diagnostic pathway, while chatbots and telemedicine may accelerate patient referral to rare disease experts. The use of AI technologies in healthcare may generate specific ethical risks, prompting new AI regulatory frameworks aimed at addressing these issues to be established in Europe and the United States.

CONCLUSION: AI-based methods will lead to substantial improvements in the diagnosis and management of rare diseases. The need for a human guarantee of AI is a key issue in pursuing innovation while ensuring that human involvement remains at the centre of patient care during this technological revolution.

PMID:40247315 | DOI:10.1186/s13023-025-03655-x

Biol Direct. 2025 Apr 17;20(1):55. doi: 10.1186/s13062-025-00644-9.

ABSTRACT

BACKGROUND: Celiac disease (CD) is an autoimmune disorder that primarily affects the gut of genetically predisposed individuals and is triggered by gliadin peptides (PT) produced by the digestion of gluten. Although inappropriate activation of the immune system is thought to be the main trigger of CD, the interaction between PT and intestinal epithelial cells (IECs) remains a key step. Recently, the possible involvement of ER stress in the pathogenesis of CD has been pointed out, although its role is still largely unclear. Therefore, discovering the molecular mechanism(s) activated in IECs exposed to PT represents a unique opportunity to better understand the disease and define new potential therapeutic targets.

METHODS: In this study we used three different experimental set-ups: intestinal biopsies from CD patients and non-CD control subjects, an in vitro model, based on human CaCo-2 cells, and an ex vivo model, based on our recently described mouse gut-ex-vivo system (GEVS), with the latter two systems were studied after stimulation with gliadin peptides (PT). To understand the signaling pathways involved we monitor the expression of a number of proteins by qPCR, Western blotting, IF, ELISA or a combination of tests. Specifically, we have analyzed the level of CD, ER stress, tissue permeability, and inflammation markers.

RESULTS: Indeed, our study demonstrated a prompt induction of the transcription factors ATF4, ATF6 and XBP1 in IECs upon PT exposure. Thus, the upregulation of TG2 and downregulation of CFTR were prevented by ER stress inhibition/buffering by a pharmacological chaperone, also leading to restored physiological expression of OCL, CLD-2 and CLD-15, while preventing the expression of IFNγ, IL-15 and IL-17 A.

CONCLUSION: Overall, our analysis has highlighted the key role of ER stress in the pathogenesis of CD and identified the chemical chaperones as a new potential valuable therapeutic treatment for CD patients.

PMID:40247380 | DOI:10.1186/s13062-025-00644-9

Antiviral Res. 2025 Apr 15:106167. doi: 10.1016/j.antiviral.2025.106167. Online ahead of print.

ABSTRACT

Cell-based drug repurposing screens have been a common approach to identifying compounds with antiviral properties. For Ebola virus (EBOV), such screens yield unexpectedly high hit rates. We investigated two mechanisms underlying the anti-EBOV activities of repurposed compounds. Phospholipidosis (PLD) is excessive accumulation of cellular lipids that confounds screens for SARS-CoV-2. We performed a meta-analysis of published screens and supplemented these with our own using infectious EBOV at biosafety level-4. A list of nearly 400 hit compounds from seven anti-EBOV screens was compiled. Most (61%) of these hits were predicted to induce PLD, and their anti-EBOV activities broadly correlated with PLD induction. PLD-inducing compounds did not inhibit infection by several other highly pathogenic viruses, suggesting that PLD was not a confounding factor for screens against Lassa, Crimean-Congo hemorrhagic fever, and Rift Valley fever viruses. Of four cells lines tested, HeLa cells were the least susceptible to PLD induction. In addition to PLD, many of the hit compounds identified disrupt cholesterol homeostasis. Previous research found inhibition of cholesterol synthesis by statins blocked EBOV infection. To understand if compounds inhibiting this mechanism could contribute to high hit rates, we further examined this pathway. We identified multiple additional inhibitors of cholesterol biosynthesis, that also blocked EBOV infection, albeit with varying potency and cytotoxicity across cell lines. EBOV inhibitors that acted through this mechanism were suppressed by the addition of exogenous cholesterol. Our findings help define the effects that contribute to anti-EBOV activities and hence facilitate the selection of lead molecules suitable for subsequent development.

PMID:40245950 | DOI:10.1016/j.antiviral.2025.106167

Sci Rep. 2025 Apr 17;15(1):13252. doi: 10.1038/s41598-025-97836-0.

ABSTRACT

Rare diseases present a significant economic burden on patients, families, and healthcare systems worldwide. As the prevalence of these diseases rises in China, data regarding their impact, specifically in Hainan Province, is scarce. Thus, this study aims to evaluate insurance coverage, economic costs, and the factors contributing to the burden of rare diseases in Hainan. We employed a bottom-up approach to analyse the prevalence and economic burden from 2019 to 2023, utilising data from the Hainan Provincial Health Commission Databases. We assessed insurance coverage as well as expenditures related to hospitalisation, diagnostics, medications, surgery, and out-of-pocket costs. Of 4,975 patients diagnosed with 99 distinct rare diseases, 83.01% were insured. From 2019 to 2023, the number of patients increased from 760 to 1,328, while economic costs surged from 34.26 million CNY (US$ 4.89 million) to 64.74 million CNY (US$ 8.86 million). Thalassemia major, one of the most prevalent conditions, generated the highest costs. Hospitalisation expenses accounted for 49.16% of the total costs, with out-of-pocket expenses averaging 17.52%. The findings reveal a significant economic burden associated with rare diseases in Hainan, highlighting the necessity for targeted policy interventions. Furthermore, additional research is needed to refine estimates of this economic burden.

PMID:40247032 | DOI:10.1038/s41598-025-97836-0

Per Med. 2025 Apr 17:1-10. doi: 10.1080/17410541.2025.2493606. Online ahead of print.

ABSTRACT

AIM: In this study, we aimed to reveal the sequence analysis of 69 pharmacogenes in 635 patients and the clinical explanation of variants.

MATERIALS AND METHODS: Genomic DNA was isolated from peripheral blood of patients. Next-Generation Sequence analysis and bioinformatic analysis were performed to identify 69 pharmacogene variants. Variants with clinical annotation were identified.

RESULTS: Analysis of 69 pharmacogenes in a total of 635 patients identified 9485 variants. The number of distinct variants identified in each gene was 1409. Of these 1409 variants, the number of variants registered in PharmGKB was 126. Among the 126 variants registered in PharmGKB, 26 variants were identified that had a direct association with clinical annotation and drug efficacy or toxicity. The most common variant genes were DPYD, CYP2C19, VKORC1,UGT1A1, RYR1 and MTHFR. These 26 variants with clinical annotation were identified in 327 (51%) different individuals.

CONCLUSIONS: Such a high frequency of critical variants (51%) points to the need for pharmacogenetic studies. The results are extremely important in terms of determining the drug dose according to the genomic status of individuals receiving drug therapy and preventing unnecessary health expenditures.

PMID:40247430 | DOI:10.1080/17410541.2025.2493606

Pharmacogenomics J. 2025 Apr 17;25(3):9. doi: 10.1038/s41397-025-00367-0.

ABSTRACT

Similarity between candidate drug targets and human proteins is commonly assessed to minimize the occurrence of side effects. Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.

PMID:40246834 | DOI:10.1038/s41397-025-00367-0

Lancet Child Adolesc Health. 2025 May;9(5):315-324. doi: 10.1016/S2352-4642(25)00058-6.

ABSTRACT

BACKGROUND: Many treatments for abdominal pain-related disorders of gut-brain interaction (AP-DGBI) in children have been studied. We aimed to assess the efficacy and safety of all known treatment options for paediatric AP-DGBI.

METHODS: For this systematic review and network meta-analysis, we searched Embase, MEDLINE, and CENTRAL databases from inception to Jan 16, 2025, for published randomised controlled trials. We included trials of any treatment for AP-DGBIs (irritable bowel syndrome, functional abdominal pain-not otherwise specified, and abdominal migraine, excluding functional dyspepsia) in children aged 4-18 years. We excluded randomised controlled trials that solely included children with functional dyspepsia, but we included studies in which children with functional dyspepsia were included alongside children with the other AP-DGBI diagnoses and outcome data could not be separated. Data extraction and quality appraisal were performed in duplicate. The primary outcome for this network meta-analysis was author-defined treatment success. Network meta-analysis methodology was used within a frequentist framework using multivariate meta-analysis and outcomes were assessed using the Grading of Recommendations, Assessment, Development and Evaluation methodology. Clinical relevance of effect sizes was interpreted according to consensus definitions.

FINDINGS: Of 19 337 records identified through the database search, 155 records representing 91 original randomised controlled trials were included in the network meta-analysis: these 91 trials comprised 7226 participants (4119 females and 2673 males). 12 studies assessed dietary treatments (n=730), 25 assessed pharmacological treatments (n=2140), 23 assessed probiotic treatments (n=1762), and 35 assessed psychosocial treatments (n=2952). Two treatments were probably more effective for treatment success than control treatments (moderate certainty): hypnotherapy (risk ratio [RR] 4·99 [95% CI 2·15 to 11·57]; large effect size) and cognitive behavioural therapy (CBT; RR 1·99 [95% CI 1·33 to 2·98]; moderate effect size). All other treatments evaluated for treatment success were either not effective or the data were of very low certainty and thus no conclusions could be made.

INTERPRETATION: Hypnotherapy and CBT show moderate certainty for treatment efficacy with clinically relevant effect sizes. No conclusions can be made about the other therapies and treatment success due to very low evidence certainty. Future randomised controlled trials should focus on improving the evidence certainty for those other therapies with regard to core AP-DGBI outcomes.

FUNDING: None.

PMID:40246358 | DOI:10.1016/S2352-4642(25)00058-6

Pharmacopsychiatry. 2025 Apr 17. doi: 10.1055/a-2560-4028. Online ahead of print.

ABSTRACT

Clozapine is a recommended treatment for psychotic symptoms in patients with Parkinson's disease (PD) and/or dementia. However, the therapeutic reference range for clozapine in these patients has not been established hitherto.The study was performed in three university hospitals in Germany and Switzerland, including clozapine-treated patients with PD and/or dementia. The primary outcome was tolerability based on reports of adverse drug reactions and/or changes in laboratory tests or electrocardiogram and/or clozapine discontinuation. We meta-analyzed demographic and pharmacokinetic parameters in patients tolerating clozapine well versus not. A meta-analytic summary receiver operating characteristic (SROC) to establish the clozapine upper level associated with poor tolerability was estimated.We analyzed a total of 99 patients suffering from PD (56.6%) and/or dementia (49.5%) with a mean age of 70.3±9.5 years and 41.4% females; poor tolerability was reported in 26 of 99 patients (26.3%). When comparing patients with and without poor tolerability, there were no differences in age, body mass index, sex, smoking, or clozapine dose, nor did we find statistically significant differences in clozapine levels (standardized mean difference 0.46, 95% confidence interval - 0.04 to 0.96, p=0.07), and heterogeneity was low (I2=0.0%). Clozapine blood levels above 193 ng/mL were associated with poor tolerability (SROC area-under-curve 0.6, sensitivity 39.7%, specificity 79.9%).One of four patients with PD and/or dementia treated with clozapine did not tolerate clozapine well, which was associated with a trend toward elevated clozapine concentrations. Monitoring drug levels may help to improve tolerability in these patients.

PMID:40245933 | DOI:10.1055/a-2560-4028