Search Results (2,894)

Prevalent cancers primarily include breast, lung and bronchus, prostate, and colorectal cancers. In contrast, cancer of the epididymis is very rare, and we propose that this tissue could carry inherent anticancer components, in particular, small extracellular vesicles (EVs) with antineoplastic properties. All cell types release extracellular vesicles (EVs) into their intercellular space, which act in the crosstalk required to achieve homeostasis. Among these, small EVs, which are membrane-bound vesicles with an average diameter of 30–200 nm, can transfer cell-specific cargo, such as lipids, proteins, DNA and RNA, which can be selectively received by neighboring or distant cells, and trigger specific cell processes, such as growth, division, or apoptosis. Here, we isolated small EVs from epididymis tissue, and examined their effect on morphology, viability, apoptosis, cell cycle phases, and certain gene and protein expression levels, particularly of the pro-apoptotic p53 protein, in HCC38 and MCF-7 breast cancer cell lines, as well as in a normal fibroblast cell line. The various analyses demonstrated effects on breast cancer cells but not on normal cells. Specifically, epididymis-derived EVs (Ep-EVs) selectively induced apoptosis and cell cycle arrest in cancer cells, while normal cells were unaffected. Moreover, the relative uptake of Ep-EVs in HCC38 and MCF-7 breast cancer cells was significant, indicating a direct association between vesicle internalization and the biological response. Taken together, these findings demonstrate a solid experimental foundation supporting the therapeutic potential of Ep-EVs in breast cancer, with promising implications for their development as a broader anticancer platform. Full article

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a leading cause of cancer-related mortality worldwide. MicroRNAs (miRNAs) are critical regulators of tumor progression; however, the biological role and molecular mechanisms of miR-589-3p in LUAD remain unclear. In this study, the expression levels of miR-589-3p and WWC2 were analyzed using The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) datasets via the UALCAN platform. Flow cytometric apoptosis analysis and functional assays including CCK-8, colony formation, AO/EB staining, and Transwell invasion assays were performed in LUAD cell lines. The interaction between miR-589-3p and WWC2 was validated using dual-luciferase reporter assays, Western blotting, and rescue experiments. miR-589-3p expression was significantly elevated in LUAD tissues compared with normal lung tissues (p < 0.05) and was positively associated with an advanced tumor stage and lymph node metastasis (p < 0.05). Inhibition of miR-589-3p significantly suppressed proliferation and colony formation (p < 0.05), reduced invasive capacity (p < 0.05), and markedly increased apoptosis (p < 0.01) in LUAD cells. Dual-luciferase reporter assays confirmed WWC2 as a direct target of miR-589-3p, with miR-589-3p mimics significantly reducing WWC2 wild-type reporter activity (p < 0.05). WWC2 expression was significantly downregulated in LUAD tissues (p < 0.05), and WWC2 knockdown reversed the anti-proliferative, pro-apoptotic, and anti-invasive effects induced by miR-589-3p inhibition (p < 0.01). These findings demonstrate that miR-589-3p promotes lung adenocarcinoma progression by directly suppressing WWC2. The miR-589-3p/WWC2 axis represents a novel molecular mechanism contributing to LUAD malignancy and may provide a foundation for future mechanistic and translational studies. Full article

Acute myocardial infarction (AMI) causes high mortality, with cardiomyocyte apoptosis playing a critical role. Although circular RNAs modulate cardiac disorders, related mechanisms remain unclear. Here, we identify circRERE as a previously unrecognized pro-apoptotic regulator under ischemic stress. circRERE is markedly upregulated in ischemic myocardium and promotes apoptosis by sponging miR-27a-3p to elevate Caspase9. Using epigallocatechin gallate-primed exosomes (EGCG-primed exosomes, Exo^EGCG) as a tool to modulate circRERE, we found that Exo^EGCG significantly reduced circRERE levels, restored miR-27a-3p activity, and suppressed Caspase9. Gain- and loss-of-function tests confirmed that circRERE mediates Exo^EGCG-derived protection. Collectively, circRERE represents a novel and actionable target for AMI, with Exo^EGCG serving as an effective delivery platform. Full article

Hexavalent chromium, a widespread heavy metal, induces apoptosis via the mitochondrial pathway through Bax (pro-apoptotic) and Bcl2 (anti-apoptotic) proteins. Hypericum perforatum, rich in antioxidants, can neutralise free radicals. This study investigated the effects of CrVI on the pancreas and the protective role of Hypericum perforatum. Five groups of animals were used: control, Cr (CrVI for 3 months), CrH (CrVI + 2.5% Hypericum perforatum extract made from flowers, for 3 months), Cr2 (CrVI for 3 months + distilled water for 1 month), and CrH2 (CrVI for 3 months + Hypericum perforatum extract for 1 month). Samples were collected for histological analysis, gene expression (qRT-PCR), and blood glucose level analysis. CrVI exposure (Cr, Cr2) caused pancreatic damage: oedema, reduced islet size, endocrine cell vacuolisation, and endothelial swelling. Lesions were milder in CrH, while CrH2 resembled the control group. The Bax/Bcl2 ratio increased under CrVI (highest in Cr2), indicating apoptosis, but decreased toward control values in CrH and CrH2. Blood glucose levels confirmed these findings. CrVI proved toxic to the endocrine pancreas, inducing structural and molecular alterations that impaired carbohydrate metabolism. Administration of Hypericum perforatum extract reduced these effects, confirming its antioxidant action and potential as a protective agent against CrVI-induced oxidative stress. Full article

Colorectal cancer (CRC), characterized by epidermal growth factor receptor (EGFR) overexpression, is often associated with poor prognosis and limited therapeutic response to conventional chemotherapy. In this study, we developed EGFR-targeted extracellular vesicles (EGFR-tEVs) by transiently engineering donor cells to display the GE11 peptide, aiming to enhance the precision of doxorubicin (Dox) delivery. The physicochemical properties of EGFR-tEVs were characterized using TEM, NTA, and Western blot. In vitro, EGFR-tEV-Dox exhibited increased cellular uptake in EGFR-overexpressing HCT-116 cells, leading to the activation of the p53-Bax-cleaved PARP1 apoptotic pathway. Notably, while Dox treatment induced p53 in normal colon fibroblasts (CCD18-Co), it did not trigger significant Bax activation or PARP1 cleavage, suggesting a preference for survival-related signaling in non-malignant cells. In a xenograft mouse model, EGFR-tEVs + Dox administration resulted in a 33.1% reduction in tumor volume and an 82.8% decrease in Ki-67 expression compared to the control group. These results indicate that transient receptor-mediated targeting enhances functional drug delivery to malignant tissues while minimizing pro-apoptotic induction in normal cells. Our findings suggest that EGFR-tEVs + Dox represents a balanced therapeutic strategy that improves antitumor efficacy with a favorable safety profile for EGFR-positive colorectal cancer. Full article

Corneal alkali burn induces severe inflammation and tissue damage, leading to loss of corneal transparency and vision impairment. In this study, we evaluated the therapeutic potential of rapamycin (RAPA) compared with cyclosporine A (CsA) in a mouse model of corneal alkali burn, focusing on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–mediated inflammatory signaling and its impact on corneal wound healing and repair. Notably, RAPA robustly suppressed NF-κB activation, reduced infiltration of F4/80 macrophages and MPO neutrophils, and downregulated pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. RAPA also markedly inhibited corneal neovascularization, as evidenced by decreased VEGF expression, reduced CD31 vessel formation, and suppression of Ang-2. RAPA substantially inhibited pathological fibrotic remodeling by reducing TGF-β1 expression, attenuating myofibroblast activation (α-SMA), decreasing collagen III deposition, and modulating matrix remodeling through suppression of MMP-9. Crucially, RAPA preserved epithelial barrier integrity by maintaining occludin expression, supported proper epithelial differentiation through sustained expression of CK12, and enhanced mucin layer stability by increasing MUC1 expression. It also restored tear production, reduced apoptotic cell death (TUNEL), and decreased dysregulated epithelial proliferation (Ki67). In conclusion, RAPA showed superior efficacy compared with CsA, primarily by enhancing corneal wound healing and facilitating structural and functional outcomes in the burned cornea. These findings underscore RAPA as a promising therapeutic candidate for ocular surface repair and vision restoration in extensive corneal injury. Full article

Dezhou donkey is a premium indigenous Chinese livestock breed with high economic value for meat, hide and medicinal uses, and growth rate is a core trait determining farming profitability. However, the molecular and metabolic mechanisms underlying divergent growth rates in this breed have not been fully characterized, with no integrated transcriptomic and metabolomic studies reported. Here, 12 age-matched healthy male Dezhou donkeys were assigned to faster-growing (n = 6) and slower-growing (n = 6) groups by average daily gain, followed by plasma transcriptome sequencing and untargeted LC-MS/MS metabolomics. We identified 480 differentially expressed genes, with the slower-growing group enriching in immune/inflammatory/apoptotic pathways, and the faster-growing group in energy metabolism and transmembrane transport. Lipids and lipid-like molecules represented the largest proportion (44.9%) of the differential metabolites; the slower-growing group was enriched in lipid peroxidation and pro-inflammatory mediators, while the faster-growing group was enriched in unsaturated fatty acids and antioxidants. Integrated analysis revealed core pathways (cAMP signaling, arachidonic acid/unsaturated fatty acid biosynthesis) and key candidate genes/metabolites. Our findings clarify that excessive lipid peroxidation and inflammatory imbalance restrict growth, while efficient energy metabolism promotes faster growth, providing theoretical support for genetic improvement and precision nutrition of Dezhou donkeys. Full article

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy. Full article

Oxidative stress occurs when there is an excess of reactive oxygen species (ROS) in the cell, primarily produced by mitochondria. Excess ROS trigger membrane lipid peroxidation (LPO), cause mitochondrial swelling, and release proapoptotic proteins into the cytoplasm, which can lead to apoptosis. It is assumed that antioxidants that reduce excessive ROS formation by mitochondria can increase the body’s resistance to stress factors. We investigated the effects of hypoxia and the antioxidant Ambiol (2-methyl-4-dimethylaminomethylbenzimidazole-5-ol dihydrochloride) on the functional characteristics of mitochondria, which were assessed by measuring lipid peroxidation intensity using spectrofluorimetry, mitochondrial membranes fatty acid composition using chromatography, mitochondrial morphology using atomic force microscopy, and respiration rate using polarography. Injecting mice with Ambiol at a dose of 10⁻⁶ mol/kg for 5 days prevented the stress-induced activation of lipid peroxidation, a decrease in the unsaturation index of C₁₈ and C₂₀ fatty acids in mitochondrial membranes, and swelling of these organelles. The drug also increased the efficiency of oxidative phosphorylation during the oxidation of NAD-dependent substrates. Furthermore, Ambiol increased the lifespan of mice by 3.0–4.0 times under various types of hypoxia. Ambiol’s ability to maintain initial (control) levels of C₁₈ and C₂₀ unsaturated fatty acids appears to protect against stress-induced mitochondrial dysfunction. Full article

Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma and to explore the underlying mechanisms under both two-dimensional (2D) and three-dimensional (3D) conditions. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) based on the Chou–Talalay method. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using fluorometric methods, and N-acetyl-L-cysteine (NAC) was used for functional modulation of oxidative stress. Three-dimensional tumor spheroid models were used to assess treatment effects under conditions that partially recapitulate tumor architecture. Gene expression levels of apoptosis-related markers and PI3K/Akt/mTOR pathway components were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The combination of quercetin and topotecan was associated with synergistic cytotoxic effects in Y79 cells (CI < 1), accompanied by increased ROS levels, mitochondrial membrane depolarization, and elevated apoptotic cell death. NAC co-treatment partially attenuated ROS levels and restored cell viability. In 3D spheroid models, combination treatment induced structural disruption, reduced viability, and increased cell death, effects that were partially reversed by NAC. Gene expression analysis revealed upregulation of pro-apoptotic genes and downregulation of survival-related genes, along with increased PTEN expression. Quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma cells under both 2D and 3D conditions. These effects were associated with ROS-associated cellular stress, mitochondrial dysfunction, and modulation of apoptotic and survival-related pathways. The partial rescue by NAC supports a contributory, but not exclusive, role of oxidative stress. These findings should be interpreted within a preclinical context and suggest that quercetin may represent a potential adjunct strategy warranting further validation in translational and in vivo models. Full article

Naringenin (NRG), a poorly water-soluble flavonoid with anticancer potential, suffers from limited bioavailability due to low aqueous solubility and poor membrane permeation. In this study, NRG nanocrystals (NRG-NCs) were developed using an optimized antisolvent precipitation–probe sonication method and incorporated into a 20% (w/w) Pluronic^® F127 hydrogel for enhanced delivery. The optimized NRG-NCs exhibited a mean particle size of ~195 ± 5 nm, polydispersity index of ~0.20 ± 0.02, and zeta potential of −24 ± 3 mV. Percentage yield and drug loading capacity were 88.6 ± 2.3% and 78.4 ± 1.8%, respectively. Nanocrystal formation resulted in ~9-fold enhancement in saturation solubility compared to raw NRG. The NRG-NCs gel demonstrated rapid dissolution (~90% release within 120 min) and ~2.5-fold higher ex vivo permeation across the Strat-M^® membrane relative to pure NRG. The hydrogel exhibited suitable physicochemical properties (viscosity ~12,850 cP; pH 6.2 ± 0.1; spreadability 5.8 ± 0.3 cm) and maintained >92% drug content after 30 days of refrigerated storage. Mechanistic studies revealed dose-dependent cytotoxicity, characterized by increased intracellular ROS, mitochondrial membrane depolarization, and elevated caspase-3 activity, confirming ROS-mediated apoptosis. In conclusion, the nanocrystal–hydrogel platform significantly enhances the solubility, permeation, and pro-apoptotic efficacy of NRG, demonstrating its potential for skin cancer treatment. Full article

Background: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and remains a major health concern due to its high recurrence and mortality rates. Recent studies suggest that anesthetic agents, including ketamine, may have direct effects on cancer cell viability and apoptosis. Objective: This study aimed to investigate the in vitro effects of ketamine on the HT-29 human colorectal adenocarcinoma cell line, focusing on its cytotoxic and pro-apoptotic potential. Material and Methods: HT-29 cells were treated with ketamine for 24 h. Cell viability was evaluated using the MTT assay. Apoptosis rates were determined by flow cytometry with Annexin V-FITC/7-AAD staining. Furthermore, quantitative PCR (qPCR) was performed to assess the expression levels of key genes associated with proliferation and apoptosis. GeneQuery™ Human Basal Cell Carcinoma qPCR Array Kit (GQH-BCC-GK015-C) was used for qPCR analysıs. Molecular docking simulations were performed to investigate the potential molecular interactions between ketamine and three target proteins: the N-methyl-D-aspartate (NMDA) receptor, epidermal growth factor receptor (EGFR), and casein kinase 1 delta (CSNK1D). To ensure robustness of predictions, two independent docking methods were employed. Results: Ketamine significantly reduced cell viability in a dose-dependent manner, with an IC₅₀ value of approximately 1.05 µM. Flow cytometry analysis demonstrated a marked increase in early apoptosis (23.9%) in treated cells. These findings suggest that ketamine exhibits potential anti-proliferative and pro-apoptotic effects on HT-29 colorectal cancer cells. Conclusions: These findings suggest that ketamine exhibits potential anti-proliferative and pro-apoptotic effects on HT-29 colorectal cancer cells in vitro. Further studies are warranted to elucidate the underlying molecular mechanisms and potential clinical implications. Full article

Oleanolic acid (OA) is a hydrophobic pentacyclic triterpene widely distributed in the plant kingdom and characterized by broad biological activity, including antioxidant, anti-inflammatory, neuroprotective, renoprotective, and anticancer effects. Increasing evidence suggests, however, that many of these actions are better explained not by single molecular targets, but by OA-dependent modulation of an integrated organelle stress network involving mitochondria, the endoplasmic reticulum (ER), autophagy, mitophagy, and apoptosis. This review critically analyzes the available evidence on the effects of OA on the mitochondria–ER–autophagy–apoptosis axis, with particular emphasis on mechanisms governing the transition between cellular adaptation and cell death. The available literature indicates that, in non-cancer models, OA most commonly lowers reactive oxygen species (ROS), stabilizes mitochondrial function, attenuates the ER stress signature, and promotes adaptive autophagy and mitophagy. In contrast, in many cancer models, OA may enhance mitochondrial dysfunction, lower the threshold for mitochondrial apoptosis, and induce autophagy that can be either protective or cytotoxic depending on the biological context. Overall, the current evidence supports a model in which OA acts as a context-dependent modulator of the organelle stress threshold, shifting the balance of an integrated mitochondria–ER–autophagy–apoptosis network rather than functioning as a uniformly cytoprotective or uniformly proapoptotic compound. At the same time, the literature remains heterogeneous with respect to models, doses, exposure times, and markers used, while poor aqueous solubility and limited bioavailability continue to constrain translation. Future studies should therefore integrate analyses of mitochondria, ER, mitochondria–ER contact sites (MERCS), autophagy, apoptosis, pharmacokinetics, formulation, and safety in order to define the true potential of OA as a modulator of biological stress. Full article

Background: Lung cancer recurrence and metastasis are major causes of cancer-related mortality, but the molecular determinants underlying these processes remain incompletely understood. This study aimed to identify key regulators of lung cancer progression through integrative analyses of bulk and single-cell transcriptomic datasets. Methods: Bulk transcriptomic and single-cell RNA sequencing data from multiple cohorts were integrated to identify genes associated with survival, recurrence, and metastasis. Tumor microenvironment features were further analyzed to prioritize core progression-related genes. ANLN was subsequently evaluated in independent single-cell datasets, followed by functional validation using CRISPR–Cas9-mediated gene knockout in lung cancer cells. Network-based drug prediction and molecular docking were performed to identify candidate compounds targeting ANLN-related programs. Results: ANLN was identified as a core progression-related gene associated with poor prognosis. ANLN was upregulated in recurrent and metastatic lung tumors and correlated with worse overall survival. Single-cell analyses showed that ANLN was predominantly expressed in epithelial and proliferating tumor cells and was associated with microenvironment remodeling, enhanced proliferative and migratory programs, and progression toward an invasive phenotype. These findings were validated in an independent single-cell dataset capturing the transition from in situ to invasive lung cancer. Functional experiments showed that ANLN deletion reduced proliferation and promoted apoptosis in lung cancer cells. Drug prediction and molecular docking identified several candidate compounds, among which Trifluridine and Monobenzone showed favorable binding potential and pro-apoptotic effects in lung cancer cells. Conclusions: ANLN is a potential regulator of lung cancer recurrence and metastasis and marks a conserved invasion-prone epithelial state. ANLN-associated pathways may represent potential therapeutic targets in lung cancer. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article