Search Results (2,974)

Background: Pyroptosis, a pro-inflammatory programmed cell death process, is a key player in tumor biology, including in triple-negative breast cancer (TNBC). Inhibiting G9a has been proven to exert anticancer effects; however, the molecular mechanism of the effects remains unclear. The study aimed to illustrate whether inhibiting G9a can suppress the process of TNBC cells by promoting pyroptosis and investigate the underlying mechanisms. Methods: MCF-10A, MDA-MB-231 and SUM159PT cell lines were used for in vitro study. CCK8 and EdU staining assay were used to examine the cell proliferation, and flow cytometry assay was performed to evaluate cell death. Inflammatory factors were measured by ELISA kits. The mRNA and protein expression levels were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Transmission electron microscopy was used to observe the morphological changes in cells. Results: We found that knockdown of G9a suppressed the growth and the abilities of invasion and migration, induced pyroptosis, and increased the expression of RIG-I, p-STAT1, and GSDME of TNBC. Furthermore, a RIG-I inhibition Cyclo (Phe-Pro) partially rescued the activation of pyroptosis enhanced by knockdown of G9a. Conclusions: These findings indicate that inhibiting the function of G9a induces pyroptosis in TNBC cells by the RIG-1/STAT1/GSDME pathway, which provides a new therapeutic target for TNBC treatment. Full article

Resistance to apoptosis represents a major limitation of platinum-based chemotherapy in colorectal carcinoma, frequently arising from impaired p53 signaling and inefficient execution of programmed cell death. In this study, we investigated the anticancer activity of Erica spiculifolia extract (ESE) and its ability to synergistically enhance cisplatin cytotoxicity in HT-29 colorectal carcinoma cells. Cell viability was assessed using the MTT assay, followed by formal combination analysis based on the Chou–Talalay methodology. Combination experiments employed a non-constant ratio regimen in which a fixed ESE concentration (45 µg/mL) was combined with serial cisplatin dilutions (45.0–2.8 µg/mL) to define interaction behavior across multiple effect levels. Quantitative analysis revealed a strong superadditive effect, with Combination Index values well below 1 and markedly elevated Dose Reduction Indices for cisplatin, indicating substantial dose-sparing across effect levels. To elucidate the molecular basis of this synergism, apoptosis-related protein expression was profiled using a membrane-based immunoassay. Combined ESE and cisplatin treatment induced full-scale p53 reactivation, including restoration of phosphorylated p53 isoforms associated with DNA damage-dependent apoptotic signaling. Acridine orange/propidium iodide staining confirmed a pronounced increase in early and late apoptotic/necrotic cells following combination treatment. UHPLC-HRMS analysis identified kaempferol 3-O-glucoside (8830.19 ± 11.01 ng/mg dw) and myricitrin (3074 ± 3.12 ng/mg) as predominant flavonols, followed by naringenin 7-O-glucoside (5958.96 ± 9.98 ng/mg), while chlorogenic, cinnamic, quinic, and gallic acids were the main phenolic acids detected. These constituents may contribute to HT-29 cell sensitization to cisplatin. Full article

The early identification of patients with highly active multiple sclerosis (HAMS) is crucial for guiding therapeutic decisions and initiating high-efficacy treatment strategies. This study aimed to characterize peripheral immune profiles that can distinguish between patients who are candidates for intensive therapy at disease onset and in later stages. Using spectral flow cytometry, we identified distinct immune signatures to differentiate early-stage patients from those with refractory, long-standing disease. In newly diagnosed individuals, decreased herpesvirus entry mediator (HVEM) expression on effector T helper (Th) cells distinguished HAMS from non HAMS cases. In contrast, patients with therapeutic resistance exhibited reduced CD28 expression on naïve regulatory and CD8⁺ T cells. Disability progression was associated with elevated HVEM on classical monocytes, decreased CD70 on CD56^bright natural killer cells (NK), and lower programmed cell death protein 1 (PD-1) expression on memory Th cells. Notably, CD28 expression on terminal effector CD8⁺ T cells and HVEM levels on plasmablasts emerged as strong predictors of progression independent of relapse activity, while higher PD-1 memory Th cell frequencies predicted clinical stability. This study identifies two panels of immune biomarkers: one distinguishing candidates for early high-efficacy intervention, and another defining patients with refractory disease. The immunological landscape of HAMS evolves across disease stages. In addition, we defined progression-associated markers detectable at the outset of follow-up, enabling the timely recognition of patients at heightened risk of disability accumulation, discriminating between neurodegeneration-driven and inflammation-driven mechanisms of progression. Full article

Influenza A virus remains a major global health threat, causing annual epidemics and occasional pandemics. Programmed cell death, including apoptosis, pyroptosis, and necroptosis, with emerging evidence for ferroptosis, plays a dual role in influenza pathogenesis, both limiting viral replication and contributing to immunopathology. Most mechanistic insights have been derived from murine genetic models, which have been invaluable for establishing causal roles of these pathways. However, murine models and cancer-derived cell lines differ significantly from human physiology. This review systematically compares influenza-induced programmed cell death across human-relevant platforms, including primary cells, immortalized non-cancerous lines, co-cultures, organoids, and precision-cut lung slices. The increasing complexity of these models reveals distinct aspects of pathway activation, bystander effects, cell-type vulnerability, and spatial dynamics. We highlight critical divergences between model systems, identify gaps in comparative analyses across viral strains and experimental platforms, and outline future directions leveraging advanced model systems, multi-omics, and functional genomics to enhance translational relevance and guide the development of host-directed therapies. Full article

Background: Nano- and microplastics (N/MPs) are widespread pollutants in aquatic ecosystems and may interfere with the physiology of diatoms. However, the underlying molecular mechanisms remain poorly understood. Methods: Cultures of the diatom species Skeletonema marinoi, a key contributor to marine primary production and biogeochemical cycles, were exposed for 10 days to polyethylene (PE) N/MPs (25 and 75 µg/mL). Growth, morphology, and cell viability were monitored, while gene expression of stress, inflammation, programmed cell death (PCD), and extracellular polymeric substance (EPS) biosynthesis markers was assessed by RT-qPCR. Results: Growth was not significantly affected. Gene expression showed biphasic regulation of antioxidant enzymes, induction of HSP70/90, transient modulation of prostaglandin-related genes, and dose- and time-dependent activation of PCD markers. Selected CAZymes possibly involved in EPS synthesis were downregulated at early stages, suggesting impaired aggregation potential. Conclusions: Exposure to PE N/MPs elicited subtle yet multifaceted effects in S. marinoi, including oxidative stress, inflammatory-like responses, modulation of EPS pathways, and PCD activation. Despite apparent growth resilience, the molecular alterations observed may impact bloom dynamics and carbon export. Full article

Cancer continues to be a significant cause of death worldwide, particularly cancers with high incidence and mortality such as colorectal, breast, and lung, motivating the continued search for novel anticancer agents. Among potential new molecules with anticancer effects, members of the benzazolo[3,2-a]quinolinium salts (BQs) family, including ABQ-48, have shown promising cytotoxic activity in various cancer models. This study aimed to evaluate the cytotoxic potential and mechanism of action of ABQ-48 (3-amino-7-benzylbenzimidazo[3,2-a]quinolinium chloride) across non-small cell lung carcinoma (NCI-H460), colorectal adenocarcinoma (COLO-205), and breast ductal carcinoma (T-47D) cell lines. Cancer cells were treated for 48 h with ABQ-48, cisplatin, or vehicle, and cytotoxicity was assessed by determining IC₅₀ by fluorescence analysis. Mechanistic evaluation included Annexin V apoptosis detection, caspase-3/7/8 activation assays, mitochondrial membrane permeability analysis, and DNA fragmentation assessment. ABQ-48 exhibited dose-dependent cytotoxicity in all three cancer cell lines, with IC₅₀ values of 6.02 µM (NCI-H460), 14.33 µM (COLO-205), and 33.59 µM (T-47D), surpassing cisplatin’s overall efficacy. Annexin V assays confirmed apoptotic induction, while caspase activation demonstrated engagement of both intrinsic and extrinsic pathways. ABQ-48 demonstrates potent anticancer activity through activation of multiple programmed cell death mechanisms, supporting further investigation as promising therapeutic candidate. Full article

Programmed death-ligand 1 (PD-L1) has become a central biomarker and therapeutic target across multiple solid tumors, yet its clinical meaning in prostate cancer (PCa) remains unsettled. PCa is commonly described as an immunologically ‘cold’ malignancy, characterized by limited baseline cytotoxic T-cell infiltration and a tumor microenvironment (TME) shaped by myeloid-driven suppression and low neoantigen load in many cases. Against this background, PD-L1 expression in PCa is typically low in untreated primary tumors but can increase in aggressive variants, advanced stages, and metastatic castration-resistant disease, where therapy pressure and microenvironmental cues may select for immune-evasive phenotypes. The literature is further complicated by major analytic variability, including differences in antibody clones and platforms, scoring algorithms (tumor proportion score, combined positive score, immune-cell scoring), cut-offs, tissue sites and timing, and pre-analytical variables such as fixation and decalcification. Collectively, available studies suggest that higher PD-L1 expression tends to be associated with adverse clinicopathological features and may enrich for responses to immune checkpoint inhibitors in selected settings, but PD-L1 immunohistochemistry alone is insufficient as a stand-alone predictive tool in unselected patients. This review synthesizes the biological drivers of PD-L1 regulation in PCa, dissects key methodological sources of heterogeneity in PD-L1 assessment, summarizes clinicopathological and therapeutic correlations, and outlines emerging biomarkers and approaches (including mismatch repair deficiency/microsatellite instability, tumor mutational burden, gene-expression signatures, liquid biopsies, and neuro-immune interactions) that may enable more actionable patient stratification. Full article

Penicillium expansum inflicts significant economic damage in the fruit and vegetable industry due to its wide distribution and ability to infect a diverse range of hosts. Therefore, developing safe and environmentally sustainable strategies to suppress the growth of this pathogen is of critical importance. Bacillus subtilis, recognized for its broad antimicrobial activity and widespread occurrence, has been widely utilized in the biological management of plant diseases. This research seeks to assess the inhibitory potential of B. subtilis against P. expansum. The cell-free supernatant (CFS) derived from B. subtilis significantly suppresses the germination of spores, germ tube extension, and hyphal development of P. expansum. It also reduces disease incidence in grapes and citrus and suppresses the expansion of lesions. Further investigation had shown that it induced mycelium reactive oxygen species (ROS) accumulation, destroyed the cell membrane integrity, led to leakage of cytoplasmic contents and induced membrane lipid peroxidation. Moreover, exposure to high concentrations of CFS results in mycelial contraction and morphological abnormalities, triggering the disintegration of intracellular organelles and markedly upregulating the expression of apoptosis-like programmed cell death genes. The self-protective response elicited by 5% CFS is insufficient to counteract the extent of cellular damage, ultimately driving cells toward a dynamic, multistage, and disintegrative form of cell death. The findings of this study offer a theoretical foundation for managing P. expansum after harvest. Full article

Spi-C is a member of the ETS (E26 transformation-specific) family of transcription factors, a group of proteins that regulate gene expression in animals by binding to specific DNA sequences. Spi-C has emerged as a central regulator of macrophage adaptation to iron exposure, inflammatory stress, and tissue injury. Studies show that Spi-C programs iron-recycling macrophages by promoting expression of key iron-handling genes, thereby supporting iron efflux, safe intracellular iron storage, and the development of red pulp macrophages critical for systemic iron recycling. Its expression is strongly induced by heme and iron, enabling macrophages to respond adaptively to increased heme turnover, whereas Spi-C deficiency leads to impaired iron recycling and pathological iron accumulation. Beyond iron homeostasis, Spi-C is increasingly recognized as a regulator of inflammatory disease, functioning as an anti-inflammatory and tissue-protective factor across multiple models, including lipopolysaccharide (LPS)–induced systemic inflammation and colitis, where Spi-C deficiency leads to enhanced cytokine production, increased tissue injury, and impaired repair. By integrating NF-κB-driven inflammatory cues with metabolic adaptation, Spi-C maintains macrophage homeostasis across tissues. This short review summarizes these known functions and provides a forward-looking perspective that Spi-C may also regulate macrophage susceptibility to ferroptosis, an iron-dependent form of cell death implicated in diverse inflammatory and degenerative conditions. Full article

Duck Tembusu virus (DTMUV), an emerging Flavivirus, is a major avian pathogen that imposes enormous economic losses on the global duck industry, necessitating urgent development of effective countermeasures. Although Interferon-gamma (IFNγ) is a crucial broad-spectrum antiviral cytokine, its role against DTMUV infection remains mechanistically undefined. In this study, we first demonstrated that DTMUV induced duck IFNγ (duIFNγ) production in immune and non-immune cells. Importantly, duIFNγ exhibited a dual anti-DTMUV function in vitro: it not only prevented viral replication but also displayed the capacity to clear existing virus from infected cells. Mechanistically, cycloheximide (CHX) experiments confirmed that duIFNγ exerts its antiviral effect by disrupting the viral RNA synthesis/translation phase. Furthermore, transcriptomic profiling (RNA-seq) precisely revealed that duIFNγ restricts DTMUV replication by activating multiple host defense pathways, notably Programmed Cell Death (e.g., Caspase signaling) and the RIG-I-like Receptor (RLR) signaling pathways. Collectively, these findings provide critical insights into the function and mechanism of duIFNγ in combating DTMUV in vitro, laying a robust theoretical foundation for exploring duIFNγ or its induced effectors as novel therapeutics for DTMUV infection. Full article

Background: Periodontitis is a disease characterized by the destruction of periodontal tissue and tooth loss. The molecular mechanisms behind this disease, however, are not clearly understood. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that seems to play a role in periodontal pathogenesis by increasing oxidative stress and reducing tissue regeneration. Objective: The current narrative review aims to summarize current knowledge of the involvement of ferroptosis in periodontal tissue destruction and potentially to identify new targets of therapy. Methods: A comprehensive search of PubMed, Embase, and Web of Science databases was conducted. Original human, animal, and in vitro studies published in English were selected. Data on experimental models, molecular markers, and key outcomes were extracted and synthesized in the review. Results: After screening, four studies were identified and selected. Ferroptosis activation in periodontal ligament fibroblasts, stem cells, and gingival tissues was associated with increased ACSL4 and decreased GPX4 expression, iron accumulation, and oxidative stress. The administration of Ferrostatin-1 or antioxidants like curcumin seemed to reduce inflammation and alveolar bone loss in vivo. Transcriptomic analyses further revealed immune-related ferroptosis gene signatures in human periodontitis tissues. Conclusions: Ferroptosis represents a crucial mechanism in periodontal tissue destruction through not yet completely understood. Understanding these molecular pathways could be the key to developing new therapeutic strategies for periodontal treatment. Full article

Background/Objectives: In recent years, growing evidence that the tumor microenvironment (TME) plays crucial roles in the progression and treatment responses of various cancers has emerged. Unfortunately, we still do not fully understand the mechanisms through which the TME influences cancer development. Therefore, the aim of this study is to assess the impact of the TME on the clinical course of the disease, comparing primary and metastatic tumors. Materials and Methods: This retrospective study included 30 colorectal cancer patients for which tissue samples from primary and metastatic tumors were available for immunohistochemistry. A multiple Cox proportional hazards regression analysis was performed to characterize differences between the microenvironments of primary and metastatic tumors, as well as between lesions diagnosed at different times after resection. Results: Immune cell infiltration was higher in metastatic than primary tumors. Statistically significant differences were observed only in the central part of the tumor, while cell infiltration at the periphery had no prognostic significance. In the multivariate analysis, a positive correlation was revealed between the expression of Programmed Death-Ligand 1 (PD-L1) on primary tumor cells (TCs) and survival (HR: 5.43; 95% CI: 1.89–15.61; p = 0.0017). Conclusions: Primary and metastatic tumors differ regarding their tumor microenvironment. As such, the tumor immune status should be considered as a key factor when selecting a therapeutic strategy, as well as for post-treatment surveillance. Full article

Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L generation and degradation, the role of NIX/BNIP3L in mediating apoptosis and mitophagy and to advance the understanding of the roles of NIX/BNIP3L in glioblastoma, lung cancer, hepatocellular carcinoma, breast cancer, pancreatic cancer, colorectal cancer and hematologic neoplasms, aiming to enhance treatment precision and improve patient outcomes. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet 70% of patients experience disease progression, underscoring the critical need for predictive biomarkers. Programmed death-ligand 1 (PD-L1) expression remains the most adopted biomarker for ICIs. With the emergence of machine learning, the development of radiomics algorithms based on CT scan images has demonstrated potential as a novel addition to the biomarker landscape in oncology. In this study, we aimed to develop a non-invasive surrogate of PD-L1 expression (rad-PDL1) derived from computed tomography (CT) scan imaging and compare its predictive value to pathological assessments. Furthermore, we evaluated its generalizability across advanced and limited-stage NSCLC. Methods: Radiomics features extracted from pretreatment CT were analyzed using a self-training pipeline that incorporated the feature tokenizer Transformer model to classify tumors as high vs. low PD-L1 expression. We included 482 advanced NSCLC patients treated with ICIs across three medical centers who were divided into training and hold-out validation sets. The algorithm was then further validated in an independent cohort of 51 patients with limited NSCLC treated with neoadjuvant ICI and chemotherapy. Results: Our pipeline demonstrated strong predictive performance in primary and independent validation (AUC = 0.75 and 0.68, accuracy = 0.73 and 0.69, respectively), highlighting its generalizability and adaptability to various disease stages. Kaplan–Meier curves revealed a longer progression-free survival for patients in the high rad-PDL1. Conclusions: These results demonstrate the feasibility of a CT-based radiomic surrogate of PD-L1 expression, showing partial generalization to an independent neoadjuvant cohort, while highlighting the need for larger prospective multi-site validation before clinical implementation. Full article

Background/Objectives: Although curcumin (CUR) and resveratrol (RSV) are natural polyphenolic compounds with reported anticancer and anti-inflammatory properties, their combined anticancer effects in melanoma cells remain incompletely characterized. This study aimed to evaluate the anticancer efficacy of CUR and RSV, individually, and in combination, in melanoma cells compared to normal melanocytes. Methods: Cell viability and intracellular ATP levels were quantified, and dose–response analyses performed. Cellular morphology and nuclear alterations were examined by phase-contrast microscopy and DAPI staining. Cell cycle distribution and apoptosis were analyzed by Muse™ Cell Analyzer with dedicated assay kits. Survival- and death-related signaling proteins were evaluated by Western blotting. Results: Combined treatment with CUR (60 μM) and RSV (40 μM) for 48 h synergistically reduced melanoma cell viability and markedly depleted intracellular ATP levels, while exerting minimal cytotoxic effects on normal melanocytes. CUR/RSV co-treatment induced pronounced morphological and nuclear alterations, significantly increased apoptotic cell populations, and modulated key signaling pathways regulating cell survival and programmed cell death in melanoma cells. Conclusions: These findings demonstrate that combined CUR and RSV treatment exerts enhanced, melanoma-selective anticancer activity while sparing normal melanocytes. The results provide a strong experimental rationale for further in vivo validation of CUR/RSV-based combination strategies as a potential therapeutic approach for melanoma. Full article