BMC Cancer. 2025 Jan 24;25(1):139. doi: 10.1186/s12885-025-13566-6.

ABSTRACT

BACKGROUND: Patients who developed immune-related adverse events (irAEs) could benefit more from treatment with immune checkpoint inhibitors (ICIs) than those who did not develop irAEs. This study was designed to assess whether the occurrence of irAEs or their characteristics are correlated with survival in advanced patients treated with ICIs.

METHODS: This retrospective cohort study enrolled a panel of cancer patients who received ICIs at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics.

RESULTS: A total of 238 patients were enrolled, 83 (34.9%) of whom developed at least one irAE. Overall, irAE development was associated with prolonged OS (not reached vs. 17.8 months, P < 0.001), PFS (8.7 vs. 4.8 months, P = 0.003), and an improved objective response rate (24.1% vs. 10.3%, P = 0.005). Furthermore, only skin or endocrine toxicities were associated with improved OS and PFS. On the basis of the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (P < 0.001) and PFS (P < 0.001). A protective irAE burden score based on organ-specific irAEs was further developed to show the significant protective effect of total irAEs on patient outcomes.

CONCLUSIONS: Not all irAEs are associated with prolonged survival. The identification of organ-specific irAEs is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.

PMID:39856626 | DOI:10.1186/s12885-025-13566-6

J Neurol Sci. 2025 Mar 15;470:123395. doi: 10.1016/j.jns.2025.123395. Epub 2025 Jan 14.

ABSTRACT

OBJECTIVE: Rare neurologic diseases (RNDs) are difficult to diagnose and treat due to their low prevalence and complex nature. This survey evaluated awareness and current care status of RNDs among esteemed neurologists affiliated with the World Federation of Neurology (WFN).

METHODS: A 34-question survey was distributed to renowned neurologists, including delegates from national neurology societies in the WFN Assembly, various WFN committees, and members of the Rare Neurologic Diseases Specialist group. Responses were stratified by geographical regions, including Africa, the Americas, Asia/Oceania, and Europe, and into four income groups based on the World Bank Indicator. Descriptive statistics summarized responses, stratified by geographical regions or income groups, and significant differences were assessed by Fisher's exact test.

RESULTS: Of 190 invited neurologists, 64 responded (34 % response rate). Among respondents, 89 % agreed that RND patients should receive timely and effective care on par with more common neurological conditions. Additionally, 77 % of respondents overall thought most RNDs could be accurately diagnosed in their country. However, there were significant differences in the perceived ability of respondents' country of practice to diagnose RNDs by region, specifically in Africa (25 %), and by income of country of practice, specifically in the lower-income group (17 %).

CONCLUSIONS: This global survey highlights varying RND diagnosis and care by country socioeconomic status, suggesting potential disparities in resources and preparedness. To improve outcomes and quality-of-life for RND patients, efforts should focus on improving diagnostic capabilities, fostering collaboration among neurology centers, and promoting education on the unique challenges and treatment options of RNDs.

PMID:39855013 | DOI:10.1016/j.jns.2025.123395

Vaccines (Basel). 2024 Dec 29;13(1):19. doi: 10.3390/vaccines13010019.

ABSTRACT

Safeguarding patients from emerging infectious diseases demands strategies that prioritise patient well-being and protection. Immunobridging is an established trial methodology which has been increasingly employed to ensure patient protection and provide clinicians with swift access to vaccines. It uses immunological markers to infer the effectiveness of a new drug through a surrogate measure of efficacy. Recently, this method has also been employed to authorise novel drugs, such as COVID-19 vaccines, and this article explores the concepts behind immunobridging trials, their advantages, issues, and significance in the context of COVID-19 and other infectious diseases. Our goal is to improve awareness among clinicians, patient groups, regulators, and health leaders of the opportunities and issues of immunobridging, so that fewer patients are left without protection from infectious diseases, particularly from major pathogens that may emerge.

PMID:39852798 | PMC:PMC11768488 | DOI:10.3390/vaccines13010019

Eur J Pharm Biopharm. 2025 Jan 22:114636. doi: 10.1016/j.ejpb.2025.114636. Online ahead of print.

ABSTRACT

Recent developments in pharmacogenetics have emphasised the importance of customised medication, driving interest in technologies like FDM 3D-printing for tailored drug delivery. FDM 3D-printing is a promising technique for the on-demand manufacturing of customised oral dosage forms, providing flexibility in terms of shape and size, dose and drug release profiles. This study investigates the fabrication and characterisation of 3D-printed oral dosage forms using PEO as the primary polymer and PEG 6 K as a plasticiser. Firstly, the printability of the PEO filaments with different propranolol hydrochloride concentrations was explored using the hot-melt extrusion technology. The influence of the propranolol hydrochloride concentrations on the mechanical properties of the filaments was examined was then examined after which surface characteristics, including roughness and wettability, were evaluated. Dissolution imaging was used to visualise the effects of drug content on the swelling and dissolution characteristics of the PEO-based 3D-printed tablets. Results showed a reduction in the flexural stress of the filaments with increasing drug load. It was also observed that increasing the drug load led to higher surface roughness and lower contact angles of the 3D-printed PEO tablets, implying increased surface hydrophilicity. The swelling behaviour of the tablets increased with higher drug concentrations, resulting in a larger gel layer formation. When comparing the drug release percentages, the release rate was higher in the 10 mg propranolol tablets, suggesting that a lower drug content led to a faster release. The greater gel layer of the 40 mg PPN tablets hindered the drug release by acting as a diffusion barrier, while the 10 mg PPN tablets, with less swelling and gel formation, experienced a faster drug release. These findings show the importance of drug content in modifying the surface properties, swelling behaviour, and drug release profiles of 3D-printed PEO tablets. The study also demonstrates the novel use of dissolution imaging for 3D-printed dosage forms, providing valuable quantitative and qualitative insights into swelling dynamics and channel formation to optimise 3D-printed tablets for drug delivery systems.

PMID:39855578 | DOI:10.1016/j.ejpb.2025.114636

Epilepsy Behav. 2025 Jan 23;164:110272. doi: 10.1016/j.yebeh.2025.110272. Online ahead of print.

ABSTRACT

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy marked by drug-resistant seizures and profound cognitive and behavioral impairments, with nearly 95% of individuals affected by moderate to severe intellectual disability. This review comprehensively explores the cognitive and behavioral impacts of current treatment options for LGS, including antiseizure medications (ASMs), neuromodulation strategies, the ketogenic diet, and surgical interventions. Given the limited availability of LGS-specific data for several ASMs, the evidence base is supplemented with findings from general epilepsy populations and individuals with epilepsy and intellectual disabilities. The evidence reveals that ASMs exert varied cognitive and behavioral effects in LGS. Medications such as valproate, lamotrigine, cannabidiol, fenfluramine, levetiracetam, brivaracetam, felbamate, and rufinamide generally support cognitive stability, while topiramate and zonisamide are associated with cognitive challenges. Behavioral outcomes also vary: stability is observed with valproate, lamotrigine, rufinamide, cannabidiol, and fenfluramine, whereas medications like levetiracetam, perampanel, brivaracetam, clobazam, and zonisamide can increase aggression or irritability. Nonpharmacological therapies, particularly when they reduce seizure frequency, typically provide greater cognitive and behavioral stability, with some offering improvement. Early intervention-especially through surgical options-appears most beneficial for preserving cognitive function. Additionally, therapies such as the ketogenic diet and neuromodulation may provide independent cognitive benefits beyond seizure control. This review emphasizes the importance of personalized treatment strategies, integrating cognitive and behavioral evaluations in therapy selection. Key components include baseline cognitive and behavioral assessments, followed by regular follow-up evaluations, particularly after therapy changes. Consideration of minimizing ASM polytherapy, careful evaluation of drug-drug interactions, pharmacogenomic implications, and the need for therapeutic drug monitoring in cases of cognitive adverse effects is essential. Future research should focus on developing assessment tools tailored to the unique needs of individuals with LGS, utilizing connectivity measures to assess intervention impacts, and advancing precision therapeutics to improve cognitive and behavioral outcomes.

PMID:39854829 | DOI:10.1016/j.yebeh.2025.110272

BMJ Open. 2025 Jan 23;15(1):e092209. doi: 10.1136/bmjopen-2024-092209.

ABSTRACT

OBJECTIVES: To determine the diagnostic yield of cystic fibrosis (CF) using a two-tiered genetic testing approach. Although newborn screening includes CF, this typically only covers a selection of common genetic variants, and with over 2000 reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, we hypothesised that patients will be missed and present clinically later in life.

DESIGN: A retrospective study over a 5-year period (January 2018-December 2022).

SETTING: A single pathology service in South Australia.

PARTICIPANTS: A total of 1909 CF test referrals from patients with clinical suspicion indicated by respiratory and gastrointestinal manifestations, foetal echogenic bowel and male infertility and asymptomatic CF requests for reproductive carrier screening.

PRIMARY AND SECONDARY OUTCOME MEASURES: The number and type of CFTR gene variants detected in symptomatic and asymptomatic testing referrals.

RESULTS: A total of 25 patients were diagnosed with CF or CF-related disorders (2.5%) with gastrointestinal symptoms yielding the highest diagnostic rate of 4.4%. Additionally, a total of 79 carriers (4.1%) were identified uncovering a carrier frequency of 1 in 24, which is consistent with the 1 in 25 reported in the Caucasian population. CF was found to be causative of foetal echogenic bowel in 0.83% of cases.

CONCLUSIONS: This study highlights the importance of considering CF in symptomatic patients, even in a nation with >99% of newborns screened for CF. Additionally, the identification of CF in this population supports the recommendation for CF genetic testing in reproductive healthcare.

PMID:39855646 | DOI:10.1136/bmjopen-2024-092209

Gene. 2025 Jan 22:149271. doi: 10.1016/j.gene.2025.149271. Online ahead of print.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal interstitial lung disease, characterized by excessive extracellular matrix (ECM) secretion that disrupts normal alveolar structure. This study aims to explore the potential molecular mechanisms underlying the promotion of IPF development.

METHODS: Firstly, we compared the transcriptome and single-cell sequencing data from lung tissue samples of patients with IPF and healthy individuals. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on the differentially expressed genes (DEGs). Furthermore, we employed sodium alginate hydrogels with varying degrees of crosslinking to provide differential mechanical stress, mimicking the mechanical microenvironment in vivo during lung fibrosis. On this basis, we examined cytoskeletal remodeling in fibroblasts MRC-5, mRNA expression of multiple related genes, immunofluorescence localization, and cellular proliferation capacity.

RESULTS: Bioinformatics analysis revealed a series of DEGs associated with IPF. Further functional and pathway enrichment analyses indicated that these DEGs were primarily enriched in ECM-related biological processes. Single-cell sequencing data revealed that fibroblasts and myofibroblasts are the main contributors to excessive ECM secretion and suggested activation of mechanotransduction and the Hippo/YAP signaling pathway in myofibroblasts. Cellular experiments demonstrated that sodium alginate hydrogels with different stiffness can simulate different mechanical stress environments, thereby affecting cytoskeletal rearrangement and Hippo/YAP pathway activity in MRC-5 lung fibroblasts. Notably, high levels of mechanical stress promoted YAP nuclear translocation, increased expression of type I collagen and α-SMA, and enhanced proliferative capacity. Additionally, we also found that fibroblasts primarily participate in mechanotransduction through the Rho/ROCK and Integrin/FAK pathways under high mechanical stress conditions, ultimately upregulating the gene expression of CCNE1/2, CTGF, and FGF1.

CONCLUSION: Our study uncovers the crucial role of cytoskeletal mechanotransduction in myofibroblast transformation and IPF development through activation of the Hippo/YAP pathway, providing new insights into understanding the pathogenesis of IPF.

PMID:39855369 | DOI:10.1016/j.gene.2025.149271

Am J Pathol. 2025 Jan 22:S0002-9440(25)00028-8. doi: 10.1016/j.ajpath.2024.12.015. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung disease have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin induced pulmonary fibrosis was assessed. Primary HLFs from non-fibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is upregulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNAseq data showed that Piezo2 is expressed in the pro-fibrotic Cthrc1+ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared to that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression alpha smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents and its presence is key in the differentiation of fibroblasts to the pro-fibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and thus be a novel therapeutic approach to treat pulmonary fibrosis.

PMID:39855300 | DOI:10.1016/j.ajpath.2024.12.015

Nat Cancer. 2025 Jan 24. doi: 10.1038/s43018-024-00900-3. Online ahead of print.

ABSTRACT

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.

PMID:39856421 | DOI:10.1038/s43018-024-00900-3

Int J Obes (Lond). 2025 Jan 24. doi: 10.1038/s41366-025-01724-6. Online ahead of print.

ABSTRACT

BACKGROUND: Metabolic dysregulation, a defining feature of obesity, disrupts essential signalling pathways involved in nutrient sensing and mitochondria homeostasis. The nuclear factor erythroid 2-related factor 2 (NRF-2) serves as a pivotal regulator of the cellular stress response, and recent studies have implicated it in the pathogenesis of obesity, diabetes, and metabolic syndrome. Curcumin, a polyphenolic compound derived from turmeric, has been identified as a potent activator of NRF-2. Evidence suggests curcumin impacts obesity and metabolic disorders by modulating gut microbiota composition, increasing energy expenditure, and regulating lipid metabolism. Orlistat, an anti-obesity drug, inhibits fat absorption in the gastrointestinal tract, but its side effects limits its broader use.

OBJECTIVES: The present study aims to investigate the potential synergetic effect of a hybrid combination between orlistat and curcumin. Additionally, we provide a detailed understanding of the molecular mechanisms through which this combination mitigates glucose-induced lipid accumulation in Caenorhabditis elegans, with a focus on the role of the skinhead 1 (SKN-1) transcription factor, an orthologue of NRF2.

METHODS: We assessed the lipid accumulation and the changes in skn-1 transcriptional activity in C. elegans using confocal GFP-based detection, alongside mRNA expression analysis of genes from lipid metabolism and oxidative stress response in wild-type, QV225 and LD1 strains. Furthermore, we evaluated locomotion, chemotaxis and mitochondrial dynamics to enhance our understanding of the proposed molecular-based model.

RESULTS: Our findings reveal that the orlistat/curcumin combination exerts an anti-obesogenic effect through SKN-1/NRF2-dependent regulation of conserved genes involved in carbohydrate and lipid metabolism in C. elegans. Moreover, the combination stimulates mitochondrial potential, further contributing to the observed synergistic effects.

CONCLUSION: The hybrid combination of orlistat and curcumin demonstrates significant anti-obesity activity by regulating nutrient-sensing pathways through SKN-1/NRF-2 modulation. This approach may allow for the reduction of orlistat dosage, thereby minimizing its adverse effects while maintaining its therapeutic efficacy.

PMID:39856245 | DOI:10.1038/s41366-025-01724-6

Nat Commun. 2025 Jan 24;16(1):989. doi: 10.1038/s41467-025-55923-w.

ABSTRACT

NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell-cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46- counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46-NF-κB-IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity.

PMID:39856052 | DOI:10.1038/s41467-025-55923-w

New Phytol. 2025 Jan 24. doi: 10.1111/nph.20420. Online ahead of print.

ABSTRACT

Temperature is a critical environmental factor affecting nearly all plant processes, including growth, development, and yield. Yet, despite decades of research, we lack the ability to predict plant performance at different temperatures, limiting the development of climate-resilient crops. Further, there is a pressing need to bridge the gap between the prediction of physiological and molecular traits to improve our understanding and manipulation of plant temperature responses. Here, we developed the first enzyme-constrained model of Arabidopsis thaliana's metabolism, facilitating predictions of growth-related phenotypes at different temperatures. We showed that the model can be employed for in silico identification of genes that affect plant growth at suboptimal growth temperature. Using mutant lines, we validated the genes predicted to affect plant growth, demonstrating the potential of metabolic modeling in accurately predicting plant thermal responses. The temperature-dependent enzyme-constrained metabolic model provides a template that can be used for developing sophisticated strategies to engineer climate-resilient crops.

PMID:39856022 | DOI:10.1111/nph.20420

Sheng Wu Gong Cheng Xue Bao. 2025 Jan 25;41(1):199-215. doi: 10.13345/j.cjb.240350.

ABSTRACT

Petroleum hydrocarbon pollution has become one of the global environmental problems, posing a serious threat to the environment and human health. Microbial remediation plays an important role in the remediation of petroleum hydrocarbon-contaminated environment. Nevertheless, the stress factors present in the environment polluted by petroleum hydrocarbons limit the effectiveness of microbial remediation. This paper reviews the common stress factors in petroleum hydrocarbon-polluted environment and the response mechanisms of microorganisms to these factors. Furthermore, we introduce the methods to improve microbial tolerance, such as irrational modification, rational modification based on systems biology tools or tolerance mechanisms, and the construction of microbial consortia. The application of these methods is expected to improve the viability and remediation efficiency of microorganisms in petroleum hydrocarbon-contaminated environment and provide new perspectives and technical support for environmental remediation.

PMID:39855688 | DOI:10.13345/j.cjb.240350

Biotechnol Adv. 2025 Jan 22:108520. doi: 10.1016/j.biotechadv.2025.108520. Online ahead of print.

ABSTRACT

Sustainable agriculture practices are indispensable for achieving a hunger-free world, especially as the global population continues to expand. Biotic stresses, such as pathogens, insects, and pests, severely threaten global food security and crop productivity. Traditional chemical pesticides, while effective, can lead to environmental degradation and increase pest resistance over time. Plant-derived natural products such as secondary metabolites like alkaloids, terpenoids, phenolics, and phytoalexins offer promising alternatives due to their ability to enhance plant immunity and inhibit pest activity. Recent advances in molecular biology and biotechnology have improved our understanding of how these natural compounds function at the cellular level, activating specific plant defense through complex biochemical pathways regulated by various transcription factors (TFs) such as MYB, WRKY, bHLH, bZIP, NAC, and AP2/ERF. Advancements in multi-omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, have significantly improved the understanding of the regulatory networks that govern PSM synthesis. These integrative approaches have led to the discovery of novel insights into plant responses to biotic stresses, identifying key regulatory genes and pathways involved in plant defense. Advanced technologies like CRISPR/Cas9-mediated gene editing allow precise manipulation of PSM pathways, further enhancing plant resistance. Understanding the complex interaction between PSMs, TFs, and biotic stress responses not only advances plant biology but also provides feasible strategies for developing crops with improved resistance to pests and diseases, contributing to sustainable agriculture and food security. This review emphasizes the crucial role of PSMs, their biosynthetic pathways, the regulatory influence of TFs, and their potential applications in enhancing plant defense and sustainability. It also highlights the astounding potential of multi-omics approaches to discover gene functions and the metabolic engineering of genes associated with secondary metabolite biosynthesis. Taken together, this review provides new insights into research opportunities for enhancing biotic stress tolerance in crops through utilizing plant secondary metabolites.

PMID:39855404 | DOI:10.1016/j.biotechadv.2025.108520

Cell. 2025 Jan 20:S0092-8674(24)01436-3. doi: 10.1016/j.cell.2024.12.023. Online ahead of print.

ABSTRACT

Despite recent advances in imaging- and antibody-based methods, achieving in-depth, high-resolution protein mapping across entire tissues remains a significant challenge in spatial proteomics. Here, we present parallel-flow projection and transfer learning across omics data (PLATO), an integrated framework combining microfluidics with deep learning to enable high-resolution mapping of thousands of proteins in whole tissue sections. We validated the PLATO framework by profiling the spatial proteome of the mouse cerebellum, identifying 2,564 protein groups in a single run. We then applied PLATO to rat villus and human breast cancer samples, achieving a spatial resolution of 25 μm and uncovering proteomic dynamics associated with disease states. This approach revealed spatially distinct tumor subtypes, identified key dysregulated proteins, and provided novel insights into the complexity of the tumor microenvironment. We believe that PLATO represents a transformative platform for exploring spatial proteomic regulation and its interplay with genetic and environmental factors.

PMID:39855194 | DOI:10.1016/j.cell.2024.12.023

Mol Biol Rep. 2025 Jan 24;52(1):154. doi: 10.1007/s11033-025-10264-1.

ABSTRACT

BACKGROUND: Current treatment strategies for hormone-dependent breast cancers, including adjuvant endocrine therapy, often fail due to persistence of breast cancer stem cells (brCSCs), which are significant contributors to tumor recurrence and treatment resistance. Therefore, gaining deeper insights into the molecular regulators driving breast cancer aggressiveness is important. Moreover, given the complexities and expenses involved in developing new pharmacological agents, the strategic repurposing of existing FDA-approved drugs to target these key molecular pathways presents a compelling approach for identifying novel therapeutic interventions aimed at mitigating tumor refractoriness.

METHODS: The study employs survival analysis from TCGA database, protein expression analyses alongside aldefluor assays, sphere formation efficiency tests to evaluate cellular stemness, and DCFDA analysis combined with antioxidant enzyme assays to investigate redox imbalance in brCSCs. These analyses were conducted following the genetic deletion of YAP/TAZ and pharmacological treatment with verteporfin.

RESULTS: The study demonstrated that transcriptional co-activators YAP/TAZ are significantly upregulated in chemotreated ER+ patient breast tumors and MCF-7 mammospheres, where it was found to interact with the transcription factor SOX2 within the nuclear compartment. Genetic ablation and pharmacological inhibition of YAP/TAZ markedly impaired stemness properties and disrupted redox homeostasis in the mammospheres. Additionally, treatment with verteporfin led to a substantial reduction in the frequency and viability of brCSCs, suggesting their effective eradication.

CONCLUSION: This study highlights the potential of repurposing verteporfin, an FDA-approved drug originally formulated for age-related macular degeneration, as a therapeutic agent for targeting YAP/TAZ-mediated stemness and redox balance in brCSCs, thereby reducing their viability in ER-positive breast cancers.

PMID:39853518 | DOI:10.1007/s11033-025-10264-1

Curr Issues Mol Biol. 2025 Jan 20;47(1):67. doi: 10.3390/cimb47010067.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is a complex and increasingly prevalent malignancy with significant challenges in its treatment and prognosis. This study aims to explore the role of the SLC4A4 transporter as a biomarker in CRC progression and its potential as a therapeutic target, particularly in relation to tumor acidity and immune response.

METHODS: The study utilized computational approaches, including receptor-based virtual screening and high-throughput docking, to identify potential SLC4A4 inhibitors. A model of the human SLC4A4 structure was generated based on CryoEM data (PDB ID 6CAA), and drug candidates from the DrugBank database were evaluated using two computational tools (DrugRep and CB-DOCK2).

RESULTS: The study identified the compound (5R)-N-[(1r)-3-(4-hydroxyphenyl)butanoyl]-2-decanamide (DB07991) as the best ligand, demonstrating favorable binding affinity and stability. Molecular dynamics simulations revealed strong protein-ligand interactions with consistent RMSD (~0.25 nm), RMSF (~0.5 nm), compact Rg (4.0-3.9 nm), and stable SASA profiles, indicating that the SLC4A4 structure remains stable upon ligand binding.

CONCLUSIONS: The findings suggest that DB07991 is a promising drug candidate for further investigation as a therapeutic agent against CRC, particularly for targeting SLC4A4. This study highlights the potential of computational drug repositioning in identifying effective treatments for colorectal cancer.

PMID:39852182 | DOI:10.3390/cimb47010067

Curr Med Chem. 2025 Jan 23. doi: 10.2174/0109298673341391241231054936. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.

PMID:39851113 | DOI:10.2174/0109298673341391241231054936

Metabolites. 2025 Jan 10;15(1):39. doi: 10.3390/metabo15010039.

ABSTRACT

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) "phenoconversion" factors, like drug-drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine.

PMID:39852382 | DOI:10.3390/metabo15010039

Curr Issues Mol Biol. 2024 Dec 24;47(1):2. doi: 10.3390/cimb47010002.

ABSTRACT

Tacrolimus and mycophenolate are important immunosuppressive agents used to prevent organ rejection in post-transplant patients. While highly effective, their use is associated with significant toxicity, requiring careful management. Tacrolimus, a calcineurin inhibitor, is linked to nephrotoxicity, neurotoxicity, metabolic disturbances such as diabetes mellitus and dyslipidemia, and cardiovascular complications such as hypertension and arrhythmias. Mycophenolate, a reversible inhibitor of inosine monophosphate dehydrogenase, frequently causes gastrointestinal disturbances, including diarrhea and colitis, as well as hematologic side effects like anemia and leukopenia, which increase infection risk. Therapeutic drug monitoring (TDM) and pharmacogenomics have emerged as essential strategies for mitigating these toxicities. TDM ensures tacrolimus trough levels are maintained within a therapeutic range, minimizing the risks of nephrotoxicity and rejection. Pharmacogenomic insights, such as CYP3A5 polymorphisms, allow for personalized tacrolimus dosing based on individual metabolic profiles. For mycophenolate, monitoring inosine monophosphate dehydrogenase activity provides a pharmacodynamic approach to dose optimization, reducing gastrointestinal and hematologic toxicities. Emerging tools, including dried blood spot sampling and pharmacokinetic modeling, offer innovative methods to simplify monitoring and enhance precision in outpatient settings. Despite their utility, the toxicity profiles of these drugs, including those of early immunosuppressants such as cyclosporine and azathioprine, necessitate further consideration of alternative immunosuppressants like sirolimus, everolimus, and belatacept. Although promising, these newer agents require careful patient selection and further research. Future directions in immunosuppressive therapy include integrating individual pharmacogenetic data to refine dosing, minimize side effects, and improve long-term graft outcomes. This narrative review underscores the importance of personalized medicine and advanced monitoring in optimizing post-transplant care.

PMID:39852117 | DOI:10.3390/cimb47010002