Crit Rev Oncol Hematol. 2025 Mar 8:104694. doi: 10.1016/j.critrevonc.2025.104694. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is the third most common and second most deadly cancer worldwide. Despite advances in screening and treatment, CRC is heterogeneous and the response to therapy varies significantly, limiting personalized treatment options. Certain molecular biomarkers, including microsatellite instability (MSI), are critical in planning personalized treatment, although only a subset of patients may benefit. Currently, the primary methods for assessing MSI status include immunohistochemistry (IHC) for DNA mismatch repair proteins (MMRs), polymerase chain reaction (PCR)-based molecular testing, or next-generation sequencing (NGS). However, these techniques have limitations, are expensive and time-consuming, and often result in inter-method inconsistencies. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) are critical predictive biomarkers of response to immune checkpoint inhibitor (ICI) therapy and MSI testing is recommended to identify patients who may benefit. There is a pressing need for a more robust, reliable, and cost-effective approach that accurately assesses MSI status. Recent advances in computational pathology, in particular the development of technologies that digitally scan whole slide images (WSI) at high resolution, as well as new approaches to artificial intelligence (AI) in medicine, are increasingly gaining ground. This review aims to provide an overview of the latest findings on WSI and advances in AI methods for predicting MSI status, summarize their applications in CRC, and discuss their strengths and limitations in daily clinical practice.

PMID:40064251 | DOI:10.1016/j.critrevonc.2025.104694

Front Cardiovasc Med. 2025 Feb 21;12:1529114. doi: 10.3389/fcvm.2025.1529114. eCollection 2025.

ABSTRACT

INTRODUCTION: Heart failure (HF) is a highly prevalent disease affecting roughly 7 million Americans. A transcriptome-wide analysis revealed RYR1 upregulation in HF patients with severe pulmonary hypertension. Therefore, we aimed to further characterize the role of RYR1 in HF progression and mortality.

METHODS: In a mouse model of HF, expression of Ryr1 was compared in cardiac pulmonary, and vascular tissue between HF and control mice. Candidate single nucleotide polymorphisms (SNPs) in the RYR1 gene region were identified, including variants affecting RYR1 expression in relevant tissue types. A Cox proportional hazard model was used to analyze genetic associations of candidate SNPs with all-cause mortality in HF patients. An exploratory analysis assessed significantly associated SNPs with risk of HF and arrhythmia development.

RESULTS: In the preclinical HF model, left ventricular expression of Ryr1 was increased compared to control (fold change = 2.08; P = 0.01). In 327 HF patients, decreased mortality risk was associated with two RYR1 SNPs: rs12974674 (HR: 0.59; 95% CI: 0.40-0.87; P = 0.007) and rs2915950 (HR: 0.62, 95% CI: 0.43-0.88; P = 0.008). Based on eQTL data, these SNPs were associated with decreased RYR1 expression in vascular tissue. Two missense variants, in linkage disequilibrium with rs2915950 (rs2915952 and rs2071089) were significantly associated with decreased mortality risk (P = 0.03) and decreased risk of atrial fibrillation/flutter (OR: 0.66, 95% CI: 0.44-0.96; P = 0.03 and OR: 0.67, 95% CI: 0.45-0.98; P = 0.04, respectively). Survival associations with these SNPs were replicated in HF patients self-identifying as Black in the UK Biobank, and the arrhythmia associations were replicated in the overall UK Biobank population.

CONCLUSION: Increased RYR1 expression may contribute to HF progression, potentially through the mechanisms associated with calcium handling and arrhythmia development. Our findings suggest that RYR1 should be further studied as a potential therapeutic target for reducing HF-related mortality.

PMID:40060969 | PMC:PMC11885062 | DOI:10.3389/fcvm.2025.1529114

ACS Omega. 2025 Feb 18;10(8):8619-8629. doi: 10.1021/acsomega.4c11184. eCollection 2025 Mar 4.

ABSTRACT

Hyperlipidemia, a condition characterized by elevated lipid levels, presents significant cardiovascular risks. Syringaldehyde (SA), a phenolic aldehyde derived from plants, exhibits antioxidant, antihyperglycemic, and anti-inflammatory properties. However, its potential toxicity and effects on hyperlipidemia have not been studied. In this study, we evaluated the safety profile and antihyperlipidemic effects of SA. To assess acute toxicity, Sprague-Dawley rats were divided into two groups (n = 5 in each group): the control group received a vehicle, while the treatment group was administered a single oral dose of SA 2000 mg/kg, and rats were observed up to 14 days. To investigate the antihyperlipidemic effects of SA, rats were allocated into six groups (n = 5 in each group). Group 1 (control) received a vehicle, group 2 (hyperlipidemic) was treated with tyloxapol (i.p 400 mg/kg), while groups 3-6 received atorvastatin 10 mg/kg and SA 10, 20, and 40 mg/kg, respectively, post tyloxapol injection. The acute toxicity results showed that SA exhibits LD50 above 2000 mg/kg. Hematological analyses showed no significant changes, except for a notable increase in the platelet count. Additionally, SA significantly decreases cholesterol, triglyceride, and creatinine levels, along with elevated alanine transaminase, alkaline phosphatase, and urea levels. Markers of oxidative stress confirmed SA's antioxidant properties, and histopathological examination revealed normal cellular structure of selected organs. In the hyperlipidemic model, SA effectively and dose dependently reduced hyperlipidemia by lowering total cholesterol, triglycerides, and LDL levels and improved hepatocellular structure affected by tyloxapol. Moreover, gene expression analysis demonstrated significant downregulation in SREBP-2 gene expression along with reduced HMG-CoA reductase activity. Overall, this study supports the safety and low toxicity of SA and its promising antihyperlipidemic effects.

PMID:40060812 | PMC:PMC11886728 | DOI:10.1021/acsomega.4c11184

bioRxiv [Preprint]. 2025 Mar 3:2025.02.27.640661. doi: 10.1101/2025.02.27.640661.

ABSTRACT

OBJECTIVE: The fast accumulation of vast pharmacogenomics data of cancer cell lines provide unprecedented opportunities for drug sensitivity prediction (DSP), a crucial prerequisite for the advancement of precision oncology. Recently, Generative Large Language Models (LLM) have demonstrated performance and generalization prowess across diverse tasks in the field of natural language processing (NLP). However, the structured format of the pharmacogenomics data poses challenge for the utility of LLM in DSP. Therefore, the objective of this study is multi-fold: to adapt prompt engineering for structured pharmacogenomics data toward optimizing LLM's DSP performance, to evaluate LLM's generalization in real-world DSP scenarios, and to compare LLM's DSP performance against that of state-of-the-science baselines.

METHODS: We systematically investigated the capability of the Generative Pre-trained Transformer (GPT) as a DSP model on four publicly available benchmark pharmacogenomics datasets, which are stratified by five cancer tissue types of cell lines and encompass both oncology and non-oncology drugs. Essentially, the predictive landscape of GPT is assessed for effectiveness on the DSP task via four learning paradigms: zero-shot learning, few-shot learning, fine-tuning and clustering pretrained embeddings. To facilitate GPT in seamlessly processing the structured pharmacogenomics data, domain-specific novel prompt engineering is employed by implementing three prompt templates (i.e., Instruction, Instruction-Prefix, Cloze) and integrating pharmacogenomics-related features into the prompt. We validated GPT's performance in diverse real-world DSP scenarios: cross-tissue generalization, blind tests, and analyses of drug-pathway associations and top sensitive/resistant cell lines. Furthermore, we conducted a comparative evaluation of GPT against multiple Transformer-based pretrained models and existing DSP baselines.

RESULTS: Extensive experiments on the pharmacogenomics datasets across the five tissue cohorts demonstrate that fine-tuning GPT yields the best DSP performance (28% F1 increase, p-value= 0.0003) followed by clustering pretrained GPT embeddings (26% F1 increase, p-value= 0.0005), outperforming GPT in-context learning (i.e., few-shot). However, GPT in the zero-shot setting had a big F1 gap, resulting in the worst performance. Within the scope of prompt engineering, performance enhancement was achieved by directly instructing GPT about the DSP task and resorting to a concise context format (i.e., instruction-prefix), leading to F1 performance gain of 22% (p-value=0.02); while incorporation of drug-cell line prompt context derived from genomics and/or molecular features further boosted F1 score by 2%. Compared to state-of-the-science DSP baselines, GPT significantly asserted superior mean F1 performance (16% gain, p-value<0.05) on the GDSC dataset. In the crosstissue analysis, GPT showcased comparable generalizability to the within-tissue performances on the GDSC and PRISM datasets, while statistically significant F1 performance improvements on the CCLE (8%, p-value=0.001) and DrugComb (19%, p-value=0.009) datasets. Evaluation on the challenging blind tests suggests GPT's competitiveness on the CCLE and DrugComb datasets compared to random splitting. Furthermore, analyses of the drug-pathway associations and log probabilities provided valuable insights that align with previous DSP findings.

CONCLUSION: The diverse experiment setups and in-depth analysis underscore the importance of generative LLM, such as GPT, as a viable in silico approach to guide precision oncology.

AVAILABILITY: https://github.com/bioIKEA/SensitiveCancerGPT.

PMID:40060567 | PMC:PMC11888479 | DOI:10.1101/2025.02.27.640661

Bioconjug Chem. 2025 Mar 10. doi: 10.1021/acs.bioconjchem.4c00561. Online ahead of print.

ABSTRACT

Cu(II) coordination complexes are emerging as promising anticancer agents due to their ability to induce oxidative stress through reactive oxygen species (ROS) generation. In this study, we synthesized and characterized two novel Cu(II) metallopeptide systems, 1/Cu(II) and 2/Cu(II), derived from the oligocationic bipyridyl cyclopeptides 1 and 2, and designed to enhance the transport of Cu(II) into cells and increase ROS levels. Spectroscopic and electrochemical analyses confirmed the formation of stable metallopeptide species in aqueous media. Inductively coupled plasma mass spectrometry (ICP-MS) studies demonstrated that both metallopeptides significantly increase intracellular Cu(II) accumulation in NCI/ADR-RES cancer cells, highlighting their role as efficient Cu(II) transporters. Additionally, ROS generation assays revealed that 1/Cu(II) induces a substantial increase in intracellular ROS levels, supporting the hypothesis of oxidative stress-induced cytotoxicity. Cell-viability assays further confirmed that both 1/Cu(II) and 2/Cu(II) exhibit strong anticancer activity in a number of cancer cell lines, with IC50 values significantly lower than those of their free cyclopeptide counterparts or Cu(II) alone, showing an order of activity higher than that of cisplatin. Finally, molecular modeling studies provided further insights into the structural stability and coordination environment of Cu(II) within the metallopeptide complexes. These findings suggest that these Cu(II) cyclometallopeptide systems hold potential as novel metal-based therapeutic agents, leveraging Cu(II) transport and ROS increase as key strategies for cancer treatment.

PMID:40059798 | DOI:10.1021/acs.bioconjchem.4c00561

J Child Adolesc Psychopharmacol. 2025 Mar 10. doi: 10.1089/cap.2024.0130. Online ahead of print.

ABSTRACT

Introduction: Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD. Methods: This study included 246 youth of European ancestry with BD (7-20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts. Results: Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake (β = -0.14, p = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: β = -0.21, p = 0.02; MDD-PRS: β = -0.22, p = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: β = 0.15, p = 0.04; MDD-PRS: β = 0.17, p = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable. Conclusions: This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.

PMID:40059772 | DOI:10.1089/cap.2024.0130

Small Methods. 2025 Mar 9:e2401860. doi: 10.1002/smtd.202401860. Online ahead of print.

ABSTRACT

Recent advances in the development of tumor-targeting nanoparticles (NPs) significantly enhance cancer therapies by effectively increasing the therapeutic window of drugs, improving the response of tumor cells, and augmenting anti-tumor immunity. However, the understanding of the tumor-targeting process remains elusive because of the complex in vivo behavior of nanoparticles. Various factors are reported to alter this process; however, systematic studies on tumor-targeting mechanisms remain limited. In this review, an overview of current strategies for improving tumor targeting and their applications in cancer chemotherapy and immunotherapy, with a focus on the advancement of the understanding of various in vivo barriers for effective tumor targeting and penetration is provided.

PMID:40059474 | DOI:10.1002/smtd.202401860

Herz. 2025 Mar 8. doi: 10.1007/s00059-025-05298-x. Online ahead of print.

ABSTRACT

Precision medicine in cardiac electrophysiology tailors diagnosis, treatment, and prevention by integrating genetic, environmental, and lifestyle factors. Unlike traditional, generalized strategies, precision medicine focuses on individual patient characteristics to enhance care. Significant progress has been made, especially in managing channelopathies, where genetic insights now already drive personalized therapies. Identifying specific mutations has clarified molecular mechanisms and enabled targeted interventions, improving outcomes in conditions such as long QT syndrome. The integration of big data from clinical records, omics datasets, and biosignals from devices such as cardiac implantable electronic devices (CIEDs) or wearables may be on the verge of revolutionizing the diagnosis of cardiac arrhythmias once again. Progress is also expected in the field of human-induced pluripotent stem cells (hiPSCs) and in silico modeling, which may overcome the limitations of traditional expression systems for the functional evaluation of patient-specific mutations. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) provide deeper insights into complex arrhythmogenic disorders, aiding in risk stratification and targeted treatment strategies. Finally, emerging technologies such as CRISPR/Cas9 promise gene editing for inherited and acquired arrhythmias. In summary, precision medicine offers the potential for individualized treatment of cardiac arrhythmias.

PMID:40056164 | DOI:10.1007/s00059-025-05298-x

NPJ Genom Med. 2025 Mar 7;10(1):20. doi: 10.1038/s41525-025-00479-3.

ABSTRACT

High on-treatment platelet reactivity (HTPR) with clopidogrel predicts ischemic events in adults with coronary artery disease, and while HTPR varies by ethnicity, no genome-wide association study (GWAS) of clopidogrel response has been conducted in Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of 511 Puerto Rican cardiovascular patients treated with clopidogrel, stratified by P2Y12 reaction units (PRU) into responders and non-responders (HTPR). Local ancestry inference (LAI) and traditional GWAS identified variants in the CYP2C19 region associated with HTPR, primarily in individuals with European ancestry. Three variants (OSBPL10 rs1376606, DERL3 rs5030613, RGS6 rs9323567) showed suggestive significance, and a variant in UNC5C was linked to increased HTPR risk. These findings highlight the unique genetic landscape of Caribbean Hispanics and challenge the significance of CYP2C19*2 in predicting clopidogrel response in patients with high non-European ancestry. Further studies are needed to replicate these results in other diverse cohorts.

PMID:40055373 | DOI:10.1038/s41525-025-00479-3

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Mar 5:111315. doi: 10.1016/j.pnpbp.2025.111315. Online ahead of print.

ABSTRACT

Few pharmacogenetic studies on the use of genetic variations to predict antidepressant response in obsessive-compulsive disorder (OCD) have been published. This study expanded on the limited literature on single nucleotide polymorphisms (SNPs) across previously identified putative susceptibility genes for OCD, by incorporating known functional regulatory elements for all genes of interest. We investigated 17 SNPs in 12 genes implicated in OCD risk in 206 European ancestry OCD patients with selective serotonin reuptake inhibitor (SSRI) antidepressant response data, examining functional polymorphisms in remote regulatory regions. No association was observed between any regulatory region markers tested and drug response. We observed nominally significant associations between SNPs within the serotonin 1B receptor (5HT1B; SNP rs1778258), SLIT and NTRK-like family member 5 (SLITRK5; SNP rs10450811), and fas apoptotic inhibitory molecule 2 (FAIM2; SNP rs706795), with response to any SSRI, which did not survive multiple comparisons. This study supports a potential role for a number of OCD-associated risk genes in response to antidepressant treatment, warranting further investigation.

PMID:40054571 | DOI:10.1016/j.pnpbp.2025.111315

Pharmacol Rev. 2025 Feb 5;77(3):100045. doi: 10.1016/j.pharmr.2025.100045. Online ahead of print.

ABSTRACT

Cytochrome P450 CYP1B1 is a heme-thiolate monooxygenase traditionally recognized for its xenobiotic functions and extrahepatic expressions. Recent studies have suggested that CYP1B1 is also expressed in hepatic stellate cells, immune cells, endothelial cells, and fibroblasts within the tumor microenvironment, as well as tumor cells themselves. CYP1B1 is responsible for the metabolism of a wide range of substrates, including xenobiotics such as drugs, environmental chemicals, and endobiotics such as steroids, retinol, and fatty acids. Consequently, CYP1B1 and its associated exogenous and endogenous metabolites have been critically implicated in the pathogenesis of many diseases. Understanding the mode of action of CYP1B1 in different pathophysiological conditions and developing pharmacological inhibitors that allow for systemic or cell type-specific modulation of CYP1B1 may pave the way for novel therapeutic opportunities. This review highlights the significant role of CYP1B1 in maintaining physiological homeostasis and provides a comprehensive discussion of recent advancements in our understanding of CYP1B1's involvement in the pathogenesis of diseases such as fibrosis, cancer, glaucoma, and metabolic disorders. Finally, the review emphasizes the therapeutic potential of targeting CYP1B1 for drug development, particularly in the treatment and prevention of cancers and liver fibrosis. SIGNIFICANCE STATEMENT: CYP1B1 plays a critical role in various physiological processes. Dysregulation or genetic mutations of the gene encoding this enzyme can lead to health complications and may increase the risk of diseases such as cancer and liver fibrosis. In this review, we summarize recent preclinical and clinical evidence that underscores the potential of CYP1B1 as a therapeutic target.

PMID:40054133 | DOI:10.1016/j.pharmr.2025.100045

J Proteome Res. 2025 Mar 7. doi: 10.1021/acs.jproteome.4c01068. Online ahead of print.

ABSTRACT

Computational toolkits for data exploration and visualization from widely used omics platforms often lack flexibility and customization. While many tools generate standardized output, advanced programming skills are necessary to create high-quality visualizations. Therefore, user-friendly tools that simplify this crucial, yet time-consuming, step are essential. We developed EasyPubPlot (Easy Publishable Plotting), a straightforward, easy-to-use, no-coding, user experience-oriented, open-source, and shiny web application along with its associated R package to streamline data exploration and visualization for functional omics-empowered research. EasyPubPlot generates publishable scores plots, volcano plots, heatmaps, box plots, dot plots, and bubble plots with minimal necessary steps. The tool was designed to guide new users to accurate and efficient navigation. Step-by-step tutorials for each type of plot are also provided. Herein, we demonstrated EasyPubPlot's competent functionality and versatility by showcasing metabolomics, proteomics, and transcriptomics data. Collectively, EasyPubPlot reduces the gap between data analysis and stunning visualization, thereby diminishing friction and focusing on science. The app can be downloaded and installed locally (https://github.com/Pharmaco-OmicsLab/EasyPubPlot) or used through a web application (https://pharmaco-omicslab.shinyapps.io/EasyPubPlot).

PMID:40053871 | DOI:10.1021/acs.jproteome.4c01068

Front Artif Intell. 2025 Feb 20;8:1557894. doi: 10.3389/frai.2025.1557894. eCollection 2025.

ABSTRACT

INTRODUCTION: Chronic pain affects approximately 30% of the global population, posing a significant public health challenge. Despite their widespread use, traditional pharmacological treatments, such as opioids and NSAIDs, often fail to deliver adequate, long-term relief while exposing patients to risks of addiction and adverse side effects. Given these limitations, medical cannabis has emerged as a promising therapeutic alternative with both analgesic and anti-inflammatory properties. However, its clinical efficacy is hindered by high interindividual variability in treatment response and elevated dropout rates.

METHODS: A comprehensive dataset integrating genetic, clinical, and pharmacological information was compiled from 542 Caucasian patients undergoing cannabis-based treatment for chronic pain. A machine learning (ML) model was developed and validated to predict therapy dropout. To identify the most influential factors driving dropout, SHapley Additive exPlanations (SHAP) analysis was performed.

RESULTS: The random forest classifier demonstrated robust performance, achieving a mean accuracy of 80% and a maximum of 86%, with an AUC of 0.86. SHAP analysis revealed that high final VAS scores and elevated THC dosages were the most significant predictors of dropout, both strongly correlated with an increased likelihood of discontinuation. In contrast, baseline therapeutic benefits, CBD dosages, and the CC genotype of the rs1049353 polymorphism in the CNR1 gene were associated with improved adherence.

DISCUSSION: Our findings highlight the potential of ML and pharmacogenetics to personalize cannabis-based therapies, improving adherence and enabling more precise management of chronic pain. This research paves the way for the development of tailored therapeutic strategies that maximize the benefits of medical cannabis while minimizing its side effects.

PMID:40051572 | PMC:PMC11882547 | DOI:10.3389/frai.2025.1557894

Biochem Genet. 2025 Mar 6. doi: 10.1007/s10528-025-11058-7. Online ahead of print.

ABSTRACT

Methotrexate (MTX) pharmacogenetics has been extensively investigated due to the high inter-individual variability in response to treatment. This wide variability can lead to treatment discontinuation or even death. Several genes involved in the pharmacodynamics and pharmacokinetics of MTX have been studied. However, there are still no guidelines for pharmacogenetics-guided MTX dosing. The FPGS rs1544105 and GGH rs3758149 gene polymorphisms were genotyped and their allele frequencies were determined. Their associations with MTX treatment response and toxicity in Uruguayan adults with haematological malignancies receiving high-dose MTX were analyzed. A worldwide systematic review of the association of these gene polymorphisms with response and toxicity to high-dose MTX treatment was also conducted. The allele frequencies of FPGS rs1544105 were 0.54 and 0.46 (C and T, respectively), and of GGH rs3758149 were 0.77 and 0.23 (C and T, respectively). Several associations were found between toxicity (gastrointestinal, hepatic and hematological) and the FPGS rs1544105 T allele (p = 0.01, p < 0.001 and p = 0.04, respectively) and between mucositis and the FPGS TT genotype (p < 0.001). The GGH rs375814 TT genotype was associated with gastrointestinal and hepatic toxicity (p = 0.01 and p < 0.001, respectively). Both the FPGS rs1544105 C allele and the GGH rs3758149 TT genotype were associated with remission (p < 0.001 and p = 0.04, respectively). The systematic review identified 247 publications and finally included 17 research articles. Few consistent data were found due to the lack of homogeneity between study groups.

PMID:40050537 | DOI:10.1007/s10528-025-11058-7

Eur J Pharmacol. 2025 Mar 4:177475. doi: 10.1016/j.ejphar.2025.177475. Online ahead of print.

ABSTRACT

Senescence, defined by the cessation of cell proliferation, plays a critical and multifaceted role in breast cancer progression and treatment. Senescent cells produce senescence-associated secretory phenotypes (SASP) comprising inflammatory cytokines, chemokines, and small molecules, which actively shape the tumor microenvironment, influencing cancer development, progression, and metastasis. This review provides a comprehensive analysis of the types and origins of senescent cells in breast cancer, alongside their markers and detection methods. Special focus is placed on pharmacological strategies targeting senescence, including drugs that induce or inhibit senescence, their molecular mechanisms, and their roles in therapeutic outcomes when combined with chemotherapy and radiotherapy. By exploring these pharmacological interventions and their impact on breast cancer treatment, this review underscores the potential of senescence-targeting therapies to revolutionize breast cancer management.

PMID:40049574 | DOI:10.1016/j.ejphar.2025.177475

Fungal Genet Biol. 2025 Mar 4:103975. doi: 10.1016/j.fgb.2025.103975. Online ahead of print.

ABSTRACT

Environmental conditions have a huge impact on the development of all living things but are especially important in the case of single-celled organisms such as Saccharomyces cerevisiae that must respond quickly and appropriately to any change. Many molecular mechanisms of response to stress have been identified in yeast, but only a few reports address physiological and morphological changes. To investigate S. cerevisiae recovery from ten mild stress conditions and to describe the viability and fitness, we performed a series of growth analysis experiments. Moreover, label-free live cell imaging of yeast subjected to ten environmental stresses has been achieved using holotomography - a leading-edge high resolution 3D quantitative phase imaging. We determined that recovery times of yeast cultures subjected to hyperosmotic and sugar starvation stresses were the shortest, as were the doubling times. Substantially lower proliferation capacity was recorded in yeast after applying sugar- and AA starvation, and high pH stresses, compared to control. Furthermore, the stationary growth was much shorter after subjecting yeast to hypoosmotic and heat stresses, and much longer after anaerobic and UV stresses. Further, we determined changes in shape, colony formation, cell wall damage, volume, sphericity, protein and lipid contents in yeast cells under stress conditions. The most prominent changes were observed for UV and hyperosmotic stresses. Condluding, stress conditions applied to yest cultures affected them differently, causing detrimental effects to their growth, metabolism, fitness and morphology. Moreover, we have proven that holotomography is excellent for precisely determining morphological changes of single cells.

PMID:40049444 | DOI:10.1016/j.fgb.2025.103975

Pharmacol Res. 2025 Mar 4:107684. doi: 10.1016/j.phrs.2025.107684. Online ahead of print.

NO ABSTRACT

PMID:40049427 | DOI:10.1016/j.phrs.2025.107684

Drug Resist Updat. 2025 Feb 28;80:101222. doi: 10.1016/j.drup.2025.101222. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.

METHODS: HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells in vitro. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of in vivo experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.

RESULTS: FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3+, CD4+ and CD8+ cells and reduced F4/80+ cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of Akkermansia and, importantly, Akkermansia administration enhanced the response to PDi in mice treated with antibiotics.

CONCLUSIONS: The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.

PMID:40048957 | DOI:10.1016/j.drup.2025.101222

PLoS One. 2025 Mar 6;20(3):e0319037. doi: 10.1371/journal.pone.0319037. eCollection 2025.

ABSTRACT

Clozapine has superior efficacy to other antipsychotics, especially in patients with treatment-resistant schizophrenia. However, its pharmacokinetics and pharmacodynamics vary largely among patients. We aimed to evaluate the clinical and genetic factors associated with the pharmacokinetics and pharmacodynamics of clozapine in patients with schizophrenia. Blood samples for clozapine pharmacokinetic assessment were collected from patients with schizophrenia at weeks 2 (visit 2), 8 (visit 3), and 18 (visit 4) from the initiation of clozapine treatment. The Positive and Negative Syndrome Scale (PANSS) score was assessed at baseline (visit 1) and visits 3 and 4. Linear mixed models were used to identify the clinical and genetic variables associated with the clozapine concentration and total PANSS score. A total of 45 patients were included in the pharmacogenomic analysis. Owing to the small sample size, we categorized concomitant medications into four groups. However, individual drugs may have different effects on clozapine concentration. Clozapine concentration was significantly associated with smoking status and cumulative clozapine dose. Clozapine concentration was significantly associated with five single nucleotide polymorphisms (SNPs) in three genes (rs28371726 and rs202102799 in CYP2D6, rs4148323 and rs34946978 in UGT1A1, and rs2011404 in UGT1A4). Furthermore, follow-up time, body mass index, and total bilirubin levels were significantly associated with the total PANSS scores. The PANSS score was significantly associated with four SNPs in two genes (rs7787082 and rs10248420 in ABCB1 and rs2133251840 and rs762502 in DRD4). This study suggests potential clinical and genetic predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia treated with clozapine. With further investigations in diverse populations, our findings may provide important information on variables to be considered in individualized clozapine treatment.

PMID:40048458 | DOI:10.1371/journal.pone.0319037

Metab Brain Dis. 2025 Mar 6;40(3):136. doi: 10.1007/s11011-025-01560-7.

ABSTRACT

Astaxanthin derived from natural sources has excellent antioxidant and anti-inflammatory effects, and it is currently being widely researched as a neuroprotectant. However, astaxanthin possesses low oral bioavailability, and thus, astaxanthin extract from Haematococcus pluvialis was formulated into a nanoemulsion to improve its bioavailability and administered to Alzheimer's disease (AD)-like rats to study its possible neuroprotective benefits. Astaxanthin nanoemulsion was administered orally once a day for 28 days to streptozotocin (STZ)-induced AD rats at concentrations of 160, 320, and 640 mg/kg of body weight (bw) and subsequently assessed for cognitive function using behavioral assessments. Brain samples were collected for the assessment of AD biomarkers. Astaxanthin nanoemulsion at a dosage of 640 mg/kg bw significantly improved spatial learning, spatial memory, and recognition memory against STZ-AD rats. At 320 and 640 mg/kg bw, astaxanthin nanoemulsion significantly reduced levels of hippocampus synaptosomal amyloid beta and paired-helical fibrillary tau protein while increasing neuron survival. Additionally, astaxanthin nanoemulsion at 640 mg/kg bw significantly increased acetylcholine levels in the hippocampus and cerebellum. Astaxanthin nanoemulsion at all treatment dosages significantly reduced malondialdehyde, a lipid peroxidation product, and neuroinflammatory mediators (GFAP and TNF-α). Astaxanthin nanoemulsion supplementation has the potential to improve cognitive function and synaptic function by lowering amyloid beta and tau levels, as well as preserve neuron integrity by reducing neuroinflammation and lipid peroxidation, indicating that it may be able to treat some of the underlying causes of AD.

PMID:40047916 | DOI:10.1007/s11011-025-01560-7