Search Results (610)

Background: Insomnia and stress-related sleep disorders are increasingly recognized as systemic conditions linked to the microbiota–gut–brain axis (MGBA). With growing clinical interest in natural products that modulate the gut environment, this systematic review evaluates the efficacy and mechanisms of non-pharmacological interventions, specifically probiotics, prebiotics, dietary indices, and botanicals, in alleviating insomnia, restoring circadian rhythms, and modulating neurochemical markers. Methods: In strict accordance with PRISMA 2020 guidelines, we searched PubMed, ScienceDirect, Scopus, and The Cochrane Library for English language studies published from inception to March 31, 2026. Eligibility was restricted to studies with rigorously controlled designs, specifically randomized controlled trials (RCTs) and controlled in vivo animal studies. Interventions had to target the gut microbiota, with primary outcomes measuring sleep quality (subjective or objective) or sleep-related neurochemical markers. We excluded uncontrolled, single-arm, or observational designs; in vitro studies; non-original research; and studies involving subjects with severe medical or psychiatric comorbidities (e.g., cancer, ADHD, severe psychiatric disorders) to prevent confounding variables, though mild-to-moderate anxiety and depression were permitted. Risk of bias was assessed using the Cochrane RoB 2.0 and SYRCLE tools. Due to significant methodological heterogeneity, a narrative synthesis stratified by intervention and population was conducted. This review was not registered in PROSPERO. Results: A total of 56 studies (33 humans, 23 animals) met the inclusion criteria. Taxonomic nomenclature was updated to reflect 2020 reclassifications (e.g., Lactiplantibacillus plantarum). In human trials, interventions significantly improved subjective sleep metrics (PSQI, ISI). Recent additions demonstrated the efficacy of the Dietary Index for Gut Microbiota (DI-GM) and the improvement in N3 sleep latency by yeast mannan. Furthermore, whole-food patterns (e.g., the MIND diet) and Traditional Chinese Medicine (TCM) decoctions successfully enriched beneficial taxa, such as Bacteroides coprophilus, and increased short-chain fatty acid (SCFA) production. Animal models demonstrated that “psychobiotic” strains (Bifidobacterium breve, Lacticaseibacillus paracasei), prebiotics (GOS/PDX), and TCM formulas effectively restored GABA/5-HT profiles, lowered morning cortisol, and facilitated REM rebound in PCPA-induced models, while also consolidating non-rapid eye movement (NREM) sleep and downregulating clock genes (Per1/Per2). Conclusions: Psychobiotics, prebiotics, and botanicals represent a highly viable non-pharmacological strategy for treating insomnia. However, current evidence is constrained by a heavy reliance on subjective human questionnaires, short follow-up durations limiting insight into long-term stability, and a substantial translational gap between mechanistic rodent models and human clinical outcomes. Full article

Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM. Full article

Hepatoblastoma (HB), the most common pediatric liver cancer, exhibits marked variability in therapeutic response despite minimal genetic heterogeneity, implicating epigenetic regulation as a key driver of tumor behavior. Among these, polycomb repressor complexes (PRC) remain poorly explored as therapeutic targets. Integrative analysis of samples from patients with HB and public datasets identified BMI1, a core component of PRC1, as significantly upregulated, with high expression strongly associated with aggressive disease and poor survival. Functional screening of epigenetic inhibitors across 15 HB cell lines revealed BMI1 inhibition as the most effective therapeutic strategy, with strong concordance between in vitro predictions and in vivo responses in patient-derived xenograft (PDX) models. The BMI1 inhibitor PTC596 demonstrated the highest potency, consistently suppressing tumor growth across models. Mechanistically, PTC596 induced BMI1 degradation, reduced histone H2A ubiquitination, impaired microtubule dynamics, and restored intrinsic apoptosis by shifting the BCL2–BAX balance, leading to caspase-3/7 activation. Transcriptomic profiling confirmed apoptosis as the most significantly enriched pathway. In vivo, PTC596 markedly reduced tumor burden and proliferation while inducing pro-apoptotic signaling, without detectable toxicity. Together, these findings establish BMI1 as a critical oncogenic dependency in HB, demonstrate the value of robust preclinical tumor modeling for therapeutic validation, and identify PTC596 as a promising, mechanism-based treatment strategy. Full article

Aims: Murine studies show a promising effect of high-fiber β-glucan on glycemic control and serum lipids. In addition, β-glucan has recently been found to have strong antioxidant and immunomodulatory effects. Oat flakes are a natural source of β-glucan. However, the effects of oat flakes on glycemic variability, dyslipidemia, and pancreatic duodenum homeobox-1 (PDX-1) levels in type 1 diabetes (T1D) remain unclear. Hence, this study assessed the effect of oat flakes on glycemic variability, dyslipidemia, and PDX-1 among adolescents with T1D. Materials and Methods: Sixty adolescents with T1D were divided into 2 equally matched groups. Group A received oat flakes β-glucan 6 g per day for 3 months in addition to an ordinary diet and insulin regimen. Group B received an ordinary diet and insulin regimen. This was followed by crossing over both arms for another 3 months after a two-week washout period. All participants underwent auxological assessment, continuous glucose monitoring (CGM), hemoglobin A1c (HbA1c), fasting lipids, and PDX-1 measurements at baseline, 3 months, and 6 months. Results: Oat flakes consumption resulted in a significant decrease in the coefficient of variation, HbA1c, serum cholesterol, triglycerides, and LDL-C levels (p < 0.001), with a significant increase in TIR, HDL-C, and PDX-1 levels (p < 0.001). However, all these effects waned after the stoppage of the oat flakes, except for HDL-C. Conclusions: Oat flakes have a favorable outcome on glycemic metrics, lipid profile, and PDX-1 in adolescents with T1D. Full article

Background: Platinum-based chemotherapy, including cisplatin and carboplatin, is widely used to treat various cancers, including ovarian cancer. However, its clinical application is limited by dose-limiting toxicities and resistance, with a poor 5-year overall survival rate for ovarian cancer (35–40%). In this study, we used ionisable lipids and developed pH-responsive lipid nanoparticles (LNPs) to address platinum-resistance in ovarian carcinoma. Methods: Cisplatin was loaded into three LNP systems containing monoolein (MO) and synthetic cationic ionisable lipids (OE-Mo, OA-Py, and OA-Pi) dispersed in Pluronic F-127 with 0.9% NaCl. Cisplatin-loaded LNPs (Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP) were characterised for size, zeta potential, and internal mesophase structure. Encapsulation efficiencies were determined via HPLC after removing free drug by ultrafiltration. In vivo efficacy was tested using cisplatin-resistant human patient-derived xenograft (PDX) models. Results: The LNPs were well dispersed with particle size of 219–250 nm and a drug loading of ~1.2 mg/mL. Encapsulation efficiencies were 62%, 59%, and 64%, for Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP, respectively. Small angle X-ray scattering (SAXS) results showed that the LNPs are pH responsive with structural transitions from a cubic to a hexagonal phase at an acidic pH. Among the tested formulations, Cis-OA-Py-NP resulted in the most significant reduction in tumour volume by ~60% compared to treatment with cisplatin alone. However, they also showed significant toxicity, including >10% weight loss and gross lung and kidney damage, as confirmed by histology. Conclusions: These findings highlight the potential of Cis-OA-Py-NP in reducing tumour volume but underscore the need for further optimisation to improve safety and therapeutic applicability. Full article

Hepatoblastoma (HB) is the most common malignant liver tumor in children, yet therapeutic options remain largely confined to conventional chemotherapy. To identify novel therapeutic targets, we performed gene set enrichment analysis on three publicly available HB datasets and found consistent activation of the proteasome pathway, with marked overexpression of the β5 proteolytic subunit encoded by PSMB5. High PSMB5 expression was associated with poor survival in adult hepatocellular carcinoma, highlighting the proteasome as a candidate for therapeutic vulnerability. Targeting the β5 proteolytic subunit with its selective inhibitor carfilzomib in HB patient-derived xenograft (PDX) models resulted in dose-dependent reductions in cell viability, proliferation, and clonogenic growth, accompanied by induction of apoptosis. Importantly, carfilzomib retained efficacy in three-dimensional PDX cultures, underscoring its activity in physiologically relevant tumor models. Bioinformatic analyses revealed that carfilzomib activates apoptosis and reactive oxygen species (ROS) signaling. Validation experiments in HB cells demonstrated increased ROS levels, with ROS induction correlating with drug sensitivity. Notably, pharmacological scavenging of ROS completely abrogated carfilzomib-induced cytotoxicity, establishing oxidative stress as a key mediator of therapeutic response. Together, these findings identify PSMB5 as a therapeutically actionable target in HB and support proteasome inhibition as a promising precision medicine strategy in HB. Full article

Background: Acute erythroid leukemia (AEL) or AML-M6 predominantly affects older adults and is rare in childhood. Compared with other AML subtypes, AEL remains relatively understudied because of its rarity. We established LS-CHM, a novel AEL cell line derived from the ascitic fluid of a patient with congenital leukemia. Interestingly, leukemic cells persisted in the ascitic fluid even after successful eradication from the bone marrow and extramedullary sites. Method: Leukemia cells from the ascites fluid exhibited robust proliferation in culture independent of cytokine requirement and were further characterized by flow cytometric immunophenotyping, cytogenetics, cell cycle and doubling time analysis, colony formation, genome and RNA sequencing, myeloid gene next generation sequencing, and cytotoxicity analysis. Results: LS-CHM displayed CD36, partial CD235a, CD31, CD43, and CD71 expression and demonstrated in vitro robust growth and high sensitivity to chemotherapeutic agents. A PDX mouse model showed development of leukemia. Genomic analysis revealed a frameshift BCOR mutation in the absence of additional mutations and downregulated TP53 expression with an exonic non-deleterious mutation. RNA sequencing of LS-CHM cells revealed upregulation of two cohesin complex genes, RAD21 and SMC3, whose high levels are associated with hematopoietic stem cell differentiation into erythroid lineage. Conclusions: LS-CHM represents the first congenital AEL-derived cell line, in contrast to the predominantly adult-origin and often secondary erythroid leukemia cell lines available currently. Thus, LS-CHM provides a unique pediatric and extramedullary AEL model, expanding the existing spectrum of AEL cell lines and offering valuable opportunities for biologic and therapeutic investigations. Full article

Triple-negative breast cancer (TNBC) remains a significant challenge in oncology, contributing to a significant portion of cancer-related deaths among women. Current therapeutic options, including chemotherapy, surgery, radiation, and hormonal targeting therapies, exhibit limited efficacy, necessitating the exploration of innovative treatment modalities. The emergence of drug resistance and the persistence of cancer stem cells (CSCs) further emphasize the urgent need for novel therapeutic strategies. In this context, natural killer cell-derived extracellular vesicles (NK-EVs) have emerged as a promising cell-free therapeutic approach that exhibits high tumor infiltration and cytotoxicity against cancer cells and CSCs. This study aims to investigate the efficacy of NK-EVs as a therapeutic strategy for TNBC using various clinically relevant models, including patient-derived xenografts. Pathway analysis suggests strong activation of apoptosis via canonical caspase activation, as well as necrosis, thereby confirming the important cytotoxic effect of NK-EVs. Interestingly, NK-EVs were also found to suppress TNBC CSCs by disrupting their functionality and viability, and NK-EV treatment increased the expression of apoptosis markers in both CSCs and non-CSCs. By elucidating the therapeutic efficacy and translational potential of NK-EV-based interventions in TNBC, these findings offer critical insights for the development of future immunotherapeutic strategies against this aggressive subtype of breast cancer. Full article

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer. Full article

Fusobacterium nucleatum (F. nucleatum), a key oral pathogen, promotes colorectal cancer (CRC) progression via gut translocation. Although gut probiotics provide colonization resistance against pathogens, antibiotic-induced dysbiosis may facilitate F. nucleatum integration and increase the risk of CRC. The mechanisms underlying probiotic—F. nucleatum antagonism and antibiotic modulation remain unclear. A 33-strain probiotic consortium and F. nucleatum subsp. Polymorphum (F. polymorphum) ATCC 10953 were co-cultured. The inhibitory effects of probiotics on F. nucleatum and the impacts of antibiotics (ABXs) on the microbial community structure in the co-culture system and on the probiotic-mediated inhibition of F. nucleatum were evaluated using spent medium assays, plate confrontation tests, growth curves, qRT-PCR, metagenomic sequencing, and transcriptomics. Hydrogen peroxide/pH/lysine assays and coaggregation models were performed to probe the associated mechanisms. Probiotics strongly inhibited the growth of F. nucleatum in a dose-dependent manner, primarily via organic acids, while F. nucleatum enriched amino acid/vitamin biosynthesis pathways without major growth suppression. Antibiotics weakened probiotic antagonism, shifted species abundance (↓ L. plantarum, ↑ L. paracasei), induced adaptive stress responses in F. nucleatum (↑ nucleotide metabolism, propanediol degradation, pdxS), and reduced lysine biosynthesis. Lysine supplementation restored probiotic abundance and disrupted F. nucleatum coaggregation. Multi-strain probiotics exert potent colonization resistance effects against F. nucleatum, mainly through organic acids and metabolic interference. Antibiotic-induced dysbiosis impairs this protective effect and may promote the persistence of F. nucleatum, which has been implicated in CRC risk. Targeted probiotic strategies may offer novel preventive approaches. Full article

Capsicum annuum is a Solanaceae crop that is sensitive to cold, which affects its growth and development upon prolonged exposure and ultimately reduces yield. In response, a complex regulatory network of cold-responsive genes is activated. Earlier studies have shown that SnRKs play a positive role in enhancing cold tolerance in different crops, including peppers; however, the underlying molecular mechanisms and downstream targets have yet to be fully elucidated. In this study, yeast hybrid screening using CaSnRK2.4 identified a potential interacting partner CaPDX1. The interaction between CaPDX1 and CaSnRK2.4 was further confirmed through Y2H, luciferase complementation, and bimolecular fluorescence complementation assays. Subcellular localization showed that CaPDX1 and CaSnRK2.4 are localized in the nucleus as well as in the cell membrane. Silencing of CaPDX1 through VIGS showed increased susceptibility of peppers to cold stress, negatively influenced antioxidant enzymatic activities, and increased relative electrolyte leakage and malondialdehyde levels. Conversely, transient overexpression of CaPDX1 in peppers enhanced cold tolerance by reducing the accumulation of REL and MDA. Ectopic expression of CaPDX1 in Arabidopsis thaliana significantly improved its cold tolerance, accompanied by enhanced activity of antioxidant enzymes and increased chlorophyll content. In summary, these results indicate that CaPDX1 is a positive regulator of cold tolerance in pepper, and its mechanism of action involves interaction with CaSnRK2.4 and the regulation of physiological and molecular responses in pepper under cold stress. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) commonly arises from oral potentially malignant disorders (OPMDs), yet reliable molecular biomarkers that predict malignant transformation remain scarce. Because epithelial carcinogenesis follows similar multistep trajectories across multiple organs, pan-cancer transcriptional analyses may reveal conserved pathways relevant to early oral tumorigenesis. This study aimed to identify shared transcriptional signatures across carcinomas and evaluate their applicability to precancerous-to-carcinoma progression. Methods: Bulk RNA-seq data from five carcinomas (lung, colon, breast, prostate, and head and neck squamous cell carcinoma, HNSCC) were obtained from TCGA to identify shared differentially expressed genes (DEGs) (|log₂FC| ≥ 2; FDR < 0.05). Functional enrichment, clustering, and gene–pathway network analyses characterized conserved biological processes. Independent GEO datasets containing premalignant and malignant samples, including OPMD and OSCC cohorts, were examined to assess early-stage relevance. Results: A conserved 45-gene signature was identified, enriched for transcriptional regulation, chromatin organization, and RNA polymerase II-mediated processes. Regulatory hubs, including ZIC5, MYBL2, ONECUT2, POU4F1, and PDX1, and strong upregulation of cancer-testis antigens (MAGEA3, MAGEA6, MAGEC2) were notable. Integration with premalignant datasets revealed 13 genes consistently dysregulated across early lesions, involving pathways such as cell differentiation, apoptosis, and lipid transport. Several genes remained altered from normal tissue through OPMD to OSCC, supporting their potential as stable biomarkers. Conclusions: This study identifies conserved transcriptional programs shared across epithelial cancers and detectable in OPMDs. These findings highlight promising biomarker and regulatory candidates for improving early detection and risk stratification of oral precancer, addressing a critical unmet need in OSCC prevention and clinical management. Full article

Sepsis is a life-threatening syndrome driven by dysregulated immune activation and multi-organ dysfunction, with limited effective therapies. Oxylipins are endogenous lipid mediators that promote the resolution of inflammation and tissue repair, yet their therapeutic potential in systemic inflammatory diseases remains incompletely understood. In this study, we evaluated the effects of two oxylipins, 10-epi-Protectin DX (10-epi-PDX) and Resolvin D5_{n-3 DPA} (RvD5_{n-3 DPA}), in a lipopolysaccharide (LPS)-induced murine endotoxemia model. Given that this model recapitulates key features of systemic inflammation and multi-organ injury relevant to sepsis-associated conditions, oxylipin effects were assessed across major organs implicated in systemic inflammatory pathology. Administration of either oxylipin significantly reduced systemic tissue injury and inflammatory damage in the lungs, kidneys, and liver. These protective effects were accompanied by suppression of inflammatory responses and marked improvements in histopathological outcomes. These findings indicate that 10-epi-PDX and RvD5_{n-3 DPA} possess organ-protective, anti-inflammatory properties in endotoxemia and support further investigation of their potential as therapeutic candidates for limiting systemic inflammatory injury. Full article

A major limitation in studying gastroesophageal adenocarcinoma (GEA) has been the lack of reliable models that represent the disease’s complexity. We present lessons learned from a comprehensive large-scale biobanking effort combining traditional sample collection with several in vitro models, including 3-dimensional patient-derived organoids (PDOs), 2-dimensional cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs), and/or in vivo xenografts. This initiative started in 2018, integrating multiple advanced ex vivo models such as PDOs, patient-derived xenografts (PDXs), and organoids (PDXOs). This unique resource now includes tumor avatars from over 380 consented patients, making it the world’s largest living GEA biobank. We achieved a >90% success rate in creating per-patient models, including 227 tumor-derived and 203 neighboring normal PDOs. These organoids accurately mirror key features of the original tumors, such as their histology (e.g., microsatellite instability), mutations, and drug response across treatment points. Notably, PDOs can predict individual patient responses to chemotherapy within five weeks, underscoring their clinical relevance. Furthermore, high-throughput drug screening on PDO subsets with known genetic landscapes generates personalized chemosensitivity profiles for 22 drugs. Through a process of continued refinement of culture techniques and tumor sampling approach, our large-scale comprehensive collection of GEA avatars represents a unique and valuable preclinical experimental resource for precision oncology. Full article

Background/Objectives: Understanding the mechanisms of drug response plays an essential role in predicting effects prior to drug administration and advancing personalized medicine by optimizing treatment strategies. This study aimed to identify gene combinations that can predict the antitumor activity of lenvatinib, which is a multi-targeted tyrosine kinase inhibitor. Methods: Cancer- and drug-response-related gene sets were identified by mapping gene expression profiles of previously reported syngeneic mouse tumor models onto a protein–protein interaction network and extracting subnetworks comprising nodes where high expression levels were clustered. The scores for these network modules were calculated using the expression data of mouse tumor models prior to drug administration. These scores were used to train a machine learning (ML) model of drug response to lenvatinib by narrowing down the parameter space using hepatocellular carcinoma patient-derived xenograft (HCC PDX) models acquired in this study. Results: Using this integrative framework, we identified several network modules including those involved in the nerve growth factor signaling pathway, Wnt signaling pathway, and interleukin signaling pathways, that were consistently prioritized as informative features across PDX models and human patient data from The Cancer Genome Atlas. Conclusions: These network modules exhibit biological functions that are linked to the known targets of lenvatinib in the cancer cells or the tumor microenvironment, highlighting their potential relevance as determinants of drug response. Full article