Search Results (3,406)

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

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune–stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons. Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration. Full article

Background/Objectives: Dihydroartemisinin (DHA), a bioactive metabolite of Artemisia annua, displays potent antitumor activity in multiple cancers. However, its dose-dependent transcriptional regulatory networks in colorectal cancer (CRC) remain insufficiently understood. This study aimed to clarify the molecular mechanisms of low- and high-dose DHA in human CRC cells and reveal the dose-dependent crosstalk among related biological processes. Methods: We integrated RNA-seq transcriptomic profiling and functional validation in HCT116 cells treated with 20 μM (low-dose) or 50 μM (high-dose) DHA. Differentially expressed genes (DEGs) were screened at FDR ≤ 0.05 and |log₂(fold change)| ≥ 1, followed by GO and KEGG enrichment analyses. Results: DHA inhibited cell viability dose-dependently, with an IC₅₀ of 50 μM. We identified 280 and 678 DEGs in low-and high-dose groups, respectively. Low-dose DHA induced apoptosis via GADD45α/β and ATF4/DDIT3-mediated endoplasmic reticulum stress and triggered senescence through G2/M phase arrest. High-dose DHA mainly modulated gene expression signatures associated with ferroptosis by regulating iron homeostasis and lipid peroxidation at the transcriptional level. Both doses suppressed glycolysis, lipid, and folate metabolism; high-dose DHA also inhibited MGAT5B-mediated glycosylation. DHA regulated five core signaling pathways dose-dependently, with high-dose DHA further repressing Wnt3a/16 and BMP4/6. Conclusions: This study first identifies ferroptosis-related gene networks as key transcriptional targets. It reveals dose-dependent crosstalk among cell death, senescence, metabolic reprogramming, and signaling, providing a transcriptomic framework and gene targets for optimizing DHA-based colorectal cancer therapy. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Quercetin (QE) is a widely distributed dietary flavonol with antioxidant and anti-inflammatory properties that has attracted interest as a modulator of bone remodeling and osteoporosis-related bone loss. In vitro data on osteoblasts, osteoclasts, and mesenchymal stem cells indicate that QE attenuates oxidative stress, suppresses pro-inflammatory signaling, and promotes osteogenic differentiation through modulation of pathways such as Nrf2/ARE, NF-κB, Wnt/β-catenin, and ER stress-related cascades. In vivo findings from animal models of estrogen deficiency, diabetes, and glucocorticoid-induced osteoporosis demonstrate that QE improves bone mineral density, trabecular microarchitecture, and biomechanical strength while reducing osteoclast number and activity, thereby attenuating osteoporotic bone deterioration. Collectively, preclinical evidence positions QE as a pleiotropic agent promoting osteoblastogenesis, inhibiting osteoclastogenesis, and balancing redox/inflammatory homeostasis in bone, despite bioavailability challenges. Future research should prioritize clinical trials with optimized formulations (e.g., nanoparticles) to validate efficacy, safety, and fracture outcomes in humans. The present review critically evaluates the chemical characteristics, pharmacokinetics, safety profile, and bone-targeted biological activity of QE, emphasizing effects on bone cells and skeletal metabolism. Full article

Oral squamous cell carcinoma (OSCC) remains a major global health burden due to aggressive invasion, early metastasis, therapeutic resistance, and poor long-term survival. Beyond tumor-intrinsic genetic and epigenetic alterations, accumulating evidence highlights the critical role of the tumor microenvironment in shaping OSCC progression and clinical outcomes. Cancer-associated fibroblasts (CAFs) and immune cells orchestrate tumor initiation, immune evasion, and recurrence through extracellular matrix remodeling, cytokine signaling, angiogenesis, and metabolic and redox regulation. Key oncogenic pathways, including EGFR/PI3K/AKT/mTOR, TGF-β, Wnt, and Notch, integrate with non-coding RNA networks to reinforce stemness, epithelial–mesenchymal transition, and therapy resistance. Moreover, PD-1/PD-L1-mediated immune escape, CAF-driven biomechanical remodeling, and metabolic reprogramming such as aerobic glycolysis and lipid metabolism contribute to OSCC heterogeneity. This review synthesizes current insights into OSCC across genomic, epigenetic, metabolic, and microenvironmental dimensions, emphasizing CAF biology, immune landscape reprogramming, and non-coding RNA regulation. We further discuss emerging biomarkers, liquid biopsy approaches, and targeted therapeutic strategies, providing a system-level framework for biomarker-guided stratification and precision combination therapies in OSCC. Full article

Millions of new cancer cases and deaths worldwide annually demonstrate the pressing need for predictive preclinical models that go beyond standard two-dimensional (2D) cultures and animal systems. Recent developments in three-dimensional (3D) organoid technology have yielded a powerful platform for generating patient-specific mini-organ models that faithfully recapitulate primary tumors at the genetic, phenotypic, and architectural levels. Organoids retain functional fidelity by preserving key stem cell signaling pathways, including Wnt, Notch, and Hippo, making them robust platforms for disease modeling and high-throughput drug screening. This review describes representative organoid systems, ranging from patient-derived organoids (PDOs) to induced pluripotent stem cell (iPSC)-derived organoids, that serve as disease-specific “avatars” for personalized therapeutics. Predictive accuracy rates greater than 90% have been shown in clinical studies, providing evidence for the relevance of organoids in functional precision medicine. In addition to drug discovery, the extended use of organoids in regenerative oncology can provide a unique regulatory mechanism by selectively targeting CSCs and enhancing tissue repair after cytotoxic treatments. Recent advances in organoid-on-a-chip platforms, 3D bioprinting, and artificial intelligence (AI) address critical challenges involving vascularization, immune system integration, and scalability. With the advent of standardized, GMP-compliant platforms and recent regulatory initiatives, such as the FDA Modernization Act 2.0, organoids are well-positioned to support next-generation cancer research and therapy. This review aims to bridge the gap between stem cell-derived organoids (SCDOs), providing a fully humanized platform for preclinical cancer modeling and their clinical application, and to discuss their potential to advance ethically guided, personalized cancer therapeutics with improved predictive and translational power. Full article

Cadmium (Cd) is an environmental toxicant originating from both natural processes and human activities. Cd has been strongly associated with multiple diseases, including breast cancer (BC). Background/Objective: Environmental Cd exposure represents a significant contributor to BC onset and progression. Cd-induced breast carcinogenesis is driven by a constellation of molecular events, including DNA damage, oxidative stress (OS), and the dysregulation of key signaling pathways. These include the ERK/JNK/p38 MAPK cascade, the PI3K/AKT/mTOR axis, NF κB activation, and Wnt signaling, all of which collectively promote tumor initiation, survival, and metastasis. This review underscores the complex interplay between Cd exposure and its effects on cancer-triggering factors. Methods: The complexity of the mechanisms Cd-induced BC, underlying Cd-induced BC makes it challenging to treat, highlighting the need for novel therapeutic strategies that complement or enhance conventional chemotherapy. Therefore, this review was developed by reviewing the literature and presenting the different aspects of the challenge associated with Cd exposure and BC therapy. Results: Phytochemicals, especially phenolics, alkaloids, carotenoids, terpenoids, and related plant-derived compounds, have emerged as promising candidates for mitigating Cd-induced BC. Their antioxidants, anti-estrogenic, and anti-inflammatory properties position them as potential chemopreventive and therapeutic agents capable of counteracting Cd’s molecular toxicity. Conclusions: The review presents current evidence linking Cd exposure to BC development and highlights the protective potential of selected phytochemicals in preventing or attenuating Cd-induced BC. Understanding these interactions reinforces the importance of phytochemical-based interventions as a strategy to reduce Cd-related cancer risk and support breast health. Full article

This systematic review aimed to synthesize experimental evidence on the anticancer effects of Lacticaseibacillus rhamnosus (L. rhamnosus) and its derivatives against colorectal cancer (CRC) cell models. Eligible studies investigated probiotics, postbiotics, or bioactive compounds derived from L. rhamnosus with an in vitro component; studies relying solely on in vivo animal models, clinical trials, or observational designs were excluded. PubMed and Scopus were searched to identify relevant studies. Risk of bias was assessed using a modified QUIN tool, and extracted data were tabulated. Owing to incomplete numerical data, meta-analysis was not feasible, and the results were synthesized accordingly. Seventeen studies were included. L. rhamnosus and its derivatives reduced CRC cell proliferation, induced apoptosis, and caused cell cycle arrest. Reported mechanisms included upregulation of Bax, caspase-3/9, and p53; downregulation of Bcl-2/Bcl-xl; inhibition of Wnt/β-catenin signaling; reduced invasion and migration; increased reactive oxygen species; and immunomodulatory effects. Key limitations were heterogeneity in interventions, dosages, exposure periods, and cell lines, along with incomplete reporting, which precluded quantitative synthesis. Overall, preclinical evidence indicates multimodal anticancer effects of L. rhamnosus in CRC models; however, standardized reporting and translational research are required. Full article

The interplay between TP53 alterations and Wnt/β-catenin signaling in colorectal cancer (CRC) remains unclear regarding mismatch repair (MMR) status, tumor budding (TB), poorly differentiated cluster (PDC), and prognosis. We analyzed 146 resected CRC cases, quantifying p53, Wnt3, and β-CTN indices and assessing MMR by PMS2 and MSH6 immunohistochemistry. p53 overexpression was associated with younger patients, left-sided tumors, nodal metastasis, and advanced stage, whereas wild-type tumors showed more mucinous differentiation. Deficient MMR was enriched among wild-type p53 cases. Principal component analysis identified distinct axes defined by p53, Wnt3, and β-CTN. Despite comparable Wnt3 levels, nuclear β-CTN accumulation was enhanced in tumors with aberrant (overexpression or null) p53 tumors, with increased TB and PDC indices. Low nuclear β-CTN independently predicted recurrence in stage I–III disease and worse overall survival in proficient MMR tumors (HR 3.07 and 2.52; p = 0.03 for both). A composite score integrating p53 binary status (aberrant vs. wild) with Wnt3 and whole β-CTN indices predicted survival beyond stage; each 1-point increase conferred a 2.56- and 1.77-fold higher risk of cancer-specific and overall mortality (p = 0.004 and 0.04). These findings suggest that p53 dysfunction is associated with alterations in Wnt/β-CTN signaling and that integrating signaling markers with staging may improve prognostic assessment in colorectal cancer. Full article

Skin aging is characterized by fibroblast senescence, extracellular matrix (ECM) degradation, and impaired wound healing, driven by oxidative stress and telomere dysfunction. Here, we investigated the anti-aging effects of a standardized microwave-assisted propolis extract (MAPE) in both H₂O₂-induced and replicative senescence models of human dermal fibroblasts (HDFs). MAPE significantly reduced reactive oxygen species (ROS) accumulation and enhanced antioxidant gene expression (NQO1, GCLM), indicating activation of NRF2-dependent defense pathways. It suppressed senescence markers (CDKN2A, CDKN1A, IL6), decreased SA-β-gal activity, and attenuated inflammaging. Moreover, MAPE inhibited MMP1 expression, restored COL1A1, and improved fibroblast wound closure, thereby maintaining ECM homeostasis. Importantly, MAPE modulated Wnt/β-catenin signaling by upregulating WNT3A and LEF1 while suppressing DKK1, and increased TERT expression, suggesting involvement of telomerase-related regulatory pathways. These effects resembled those of CHIR99021, a canonical Wnt activator, while providing additional antioxidant protection. Together, our findings suggest that MAPE is a propolis-derived bioactive ingredient that counteracts fibroblast senescence through coordinated modulation of NRF2 and Wnt/β-catenin–TERT signaling pathways, supporting its potential as a cosmeceutical ingredient for mitigating skin aging. Full article

Impaired blood–brain barrier (BBB) integrity is a common hallmark of neurological disorders associated with neuroinflammation, neurodegeneration and aging. The function of the BBB relies heavily on the interaction between astrocytes and endothelial cells, the most closely connected elements of the neurovascular unit. Under inflammatory conditions, astrocytes can undergo a range of metabolic changes, becoming pro-inflammatory and harmful to endothelial cells. Upon activation, astrocytes secrete a plethora of inflammatory mediators that severely disrupt the barrier function of the BBB. ω-3 polyunsaturated fatty acids (PUFAs), mainly docosahexaenoic and eicosapentaenoic acids, exhibit protective anti-inflammatory and antioxidant effects demonstrated in various neurological disorders. This review focused on the role of ω-3 PUFAs and their oxidative derivatives, specialized pro-resolving mediators, in preserving the BBB’s integrity via suppression of astrocytes’ activation or even promotion of their transition from an A1 to an A2 phenotype. We considered mainstream mechanisms of the anti-inflammatory and antioxidant effects of ω-3 PUFAs on reactive astrocytes, such as stimulation of the Nrf2/ARE and Wnt/β-catenin signaling pathways, inhibition of NF-κB/matrix metalloproteinase activity and the JAK/STAT3 signaling axis, as well as the contribution of ω-3 PUFA-activated GPCRs and PPAR transcriptional factors, particularly regarding the role of these mechanisms in preserving the BBB’s integrity. Full article

Canine mammary cancers (CMCs) are one of the most prevalent types of neoplasm in dogs, are frequently malignant, and display high tumour heterogeneity, making evaluating prognosis and predicting successful treatment outcomes difficult. In a previous pilot study, overexpression of the Wnt pathway-associated protein SFRP1 was found to correlate with negative metastasis status in CMCs at both mRNA and protein levels. To establish SFRP1 as a potential biomarker for CMC progression, additional verification of these results in an independent dataset is required, as well as an investigation as to whether SFRP1 expression in CMCs is associated with altered Wnt- or RANKL signalling pathways. In an independent verification cohort of 122 cases of archival CMC FFPE material, expression of SFRP1 was assessed by RT-qPCR and immunohistochemistry. The same tumours were further assessed for RANKL, phosphoROCK2, and NFkB-p65 protein expression. Our data verified that SFRP1 mRNA (p = 0.025) was negatively associated with metastasis status; however, differences in protein expression did not reach statistical significance (p = 0.139). Neither did SFRP1 significantly correlate with expression of any of the other proteins tested. Instead, a strong association was found for RANKL positivity with increased metastasis status (p < 0.001). Co-expression of SFRP1 significantly lowered the higher risk of metastatic spread when compared to RANKL_pos/SFRP1_neg CMCs (p = 0.033). Noticeably, all vascular-invasive cell clusters observed in tissue section vessels stained positive for RANKL. Our study identified RANKL expression as a strong marker for cancer progression with a strong link to vascular-invasive cells. However, SFRP1 expression may potentially suppress the pro-metastatic nature of RANKL_pos CMCs. Full article

(1) Background: The “Bider marking” on the shoulder of the Dun Mongolian horse represents a unique pigmentation pattern, the molecular formation mechanism of which remains incompletely understood. This study investigates the differential expression and protein localization of pigment-related genes—specifically the core transcription factor MITF, as well as EDN3, SLC7A11, and WNT3A—in the skin. The analysis focuses on three distinct regions: the dark-colored area of the ‘Bider marking’ shoulder (BIDC), the light-colored area of the ‘Bider marking’ shoulder (BILC), and the non-Bider-marked shoulder area (NBIS). The aim is to clarify their correlation with the formation of this distinctive pigmentation pattern. (2) Methods: Skin tissue samples from both the “Bider marking” and non-Bider-marked shoulder regions were collected (n ≥ 3). The mRNA expression levels were quantified using RT-qPCR, protein levels were analyzed through Western blotting, and protein localization was assessed via immunohistochemistry and immunofluorescence. (3) Results: Compared to the NBIS group, both the BIDC and BILC groups exhibited significantly elevated protein expression of MITF and WNT3A. Further immunofluorescence showed that the distribution of MITF protein exhibits regional specificity in the epidermis and hair follicles. In the BIDC region, the protein is localized specifically to the stratum corneum of the epidermis, the dermal papilla, and the outer root sheath of hair follicles. In contrast, the mRNA and protein expression levels of SLC7A11 and EDN3 did not display consistent patterns among the three groups, and no specific differences were observed in tissue localization. (4) Conclusions: The findings show that the specific pigmentation in dark “Bider marking” regions is closely linked to the upregulated protein levels and unique spatial patterns of MITF and WNT3A; SLC7A11 and EDN3 may not be primary regulators of this trait. Full article

Calcific aortic valve disease (CAVD) is an active pathological process driven by complex cellular and molecular mechanisms rather than passive aging. The disease is characterized by endothelial dysfunction, lipid infiltration, inflammation, extracellular matrix remodeling, and osteogenic differentiation of valvular interstitial cells, ultimately leading to hydroxyapatite deposition and progressive valve calcification. Key signaling pathways, including Notch, Wnt/β-catenin, BMP2, and TGF-β, play critical roles in osteogenic reprogramming, while inflammatory cytokines such as IL-6, IL-1β, and TNF-α contribute to a pro-calcific microenvironment. To summarize current knowledge on CAVD pathophysiology and emerging therapeutic strategies, relevant preclinical studies were identified through searches of PubMed, and clinical trials were identified through ClinicalTrials.gov. Evidence indicates that extracellular matrix remodeling, fibrosis, and dysregulated phosphate metabolism, particularly involving TNAP and DPP-4, further accelerate disease progression. Despite advances in understanding disease mechanisms, effective pharmacological therapies remain limited, with the current treatment largely restricted to valve replacement. Emerging therapeutic approaches targeting molecular pathways, including enzyme inhibition, RNA-based therapeutics, and advanced drug delivery systems, may offer promising strategies for disease modification. A deeper understanding of CAVD pathophysiology may facilitate the development of targeted therapies to delay or prevent disease progression. Full article