Search Results (1,151)

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

Macrophages are key innate immune cells in the host defense against pathogens. Ionizing radiation can impair macrophage functions such as phagocytosis and activate them, potentially exacerbating tissue injury. Macrophage extracellular traps (METs) are formed upon stimulation of macrophages with PAMPs or DAMPs. We hypothesized that macrophages exposed to ionizing radiation can release extracellular traps. Peritoneal macrophages were collected from C57BL/6 mice and subjected to 5 Gy radiation. We performed assays to detect METs, including the immunofluorescence of citrullination of histone H3 and cell-free DNA measurement in cell culture medium as well as cell death. The exposure of ionizing radiation killed a significant number of mouse peritoneal macrophages through pyroptosis, which was mediated by Gasdermin D (GSDMD). The onset of pyroptosis eventually caused METs by suicidal METosis via pyroptosis and vital METosis occurring in the cells surviving after exposure to radiation. We found that exposure of peritoneal macrophages to 5 Gy radiation significantly increased METosis, as revealed by increased levels of citrullinated histone H3 and an increased surface area of extracellular DNA surrounding the cells. We discovered that peptidyl arginine deiminase (PAD) 2 and 4 are required for peritoneal macrophages to generate extracellular traps in response to radiation exposure. Our data demonstrate that the ionizing radiation induces METs via the activation of GSDMD, and we confirmed the requirement of PADs for METosis after exposure to the ionizing radiation. Targeting METs may direct a new therapeutic strategy for mitigating radiation-induced tissue injury. Full article

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)–extracellular signal-regulated kinase (ERK)–tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2–ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Full article

Domoic acid (DA) is a neurotoxic terpenoid compound produced by certain marine algae. It accumulates through the food web and poses a significant threat to humans and animals by selectively targeting hippocampal neurons, leading to neuronal degeneration, necrosis, and subsequent memory impairment. The primary mechanism involves its potent agonism at glutamate receptors, which induces excessive calcium influx, resulting in excitotoxic cell swelling and death. Recent studies have further elucidated the critical role of downstream oxidative stress and other pathogenic factors in DA-induced neurotoxicity. These insights into its multifaceted mechanism have paved the way for novel therapeutic strategies, highlighting promising directions for future treatment development. Full article

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Rhodoliths (from Greek etymology meaning red + stone) are spheroidal accretions composed of various types of crustose coralline red algae that dwell in relatively shallow waters where sunlight allows for photosynthesis. Unlike most other kinds of algae that are attached to the seabed by a holdfast, rhodoliths are free to roll about by circumrotary movements stimulated mainly by gentle wave action and bottom currents, as well as by disruptions by associated fauna. Frequent movement exposes every part of the algal surface to an equitable amount of sunlight, which generally results in an evenly concentric pattern of growth over time. Individual structures may attain a diameter of 10 to 20 cm, representing 100 years of growth or more. Initiation typically involves encrustation by founder cells on a rock pebble or shell fragment. In life, the functional outer surface is red or pink in complexion, whereas the structure’s inner core amounts to dead weight. Chemically, rhodoliths are composed of high magnesium calcite [(Ca,Mg)CO₃], with examples known around many oceanic islands and virtually all continental shelves in the present world. The oldest fossil rhodoliths appeared during the early Cretaceous, 113 million years ago. Geologically, rhodoliths may occur in massive limestone beds composed of densely packed accumulations. Living rhodoliths commonly occur in waters as shallow as −2 to −10 m, as well as seaward in mesophotic waters up to −100 m under exceptional conditions of water clarity. Especially in shallower waters, rhodoliths are vulnerable to transfer by storm waves to supratidal settings, which result in bleaching under direct sunlight and death. Increasingly, marine biologists recognize that rhodolith beds represent a habitat that offers shelter to a community of other algae and diverse marine invertebrates. Full article

The p53 tumor suppressor, a key transcription factor, acts as a cellular stress sensor that regulates hundreds of genes involved in responses to DNA damage, oxidative stress, and ischemia. Through these actions, p53 can arrest cell cycle, initiate DNA repair, or trigger cell death. In addition to its nuclear functions, p53 can translocate to mitochondria to promote apoptosis. Studies using isolated mitochondria have suggested that p53 drives the voltage-dependent anion channel (VDAC1) into high molecular mass complexes to mediate apoptosis. VDAC1 is a central regulator of cellular energy production and metabolism and also an essential player in apoptosis, induced by various apoptotic stimuli and stress conditions. We previously demonstrated that VDAC1 oligomerization, induced by various apoptosis stimuli and stress conditions, forms a large pore that enables cytochrome c release from mitochondria, thereby promoting apoptotic cell death. In this study, we show that p53 interacts with VDAC1, modulates its expression levels, and promotes VDAC1 oligomerization-dependent apoptosis. Using purified proteins, we found that p53 directly binds VDAC1, as revealed by microscale thermophoresis and by experiments using bilayer-reconstituted VDAC1, in which p53 reduced VDAC1 channel conductance. Furthermore, overexpression of p53 in p53-null cells or in cells expressing wild-type p53 increased VDAC1 expression and induced VDAC1 oligomerization even in the absence of apoptotic stimuli. Together, these findings identify VDAC1 as a direct p53 target whose expression, oligomerization, and pro-apoptotic activity are regulated by p53. They also reinforce the central role of VDAC1 oligomerization in apoptosis. Full article

Myocardial fibrosis (MF) is a common pathological feature of diverse cardiac disorders and is a key driving factor of cardiac dysfunction. It is marked by excessive deposition of extracellular matrix (ECM) proteins, particularly collagen type I and III, and a prolonged activation of cardiac fibroblasts. However, the molecular drivers of this process remain undetermined. Ferroptosis is an iron-catalyzed, lipid-peroxidation-dependent mode of regulated cell death. Research indicates that ferroptosis is significantly involved in the onset and advancement of MF; consequently, developing therapies that selectively modulate ferroptosis presents a promising direction of treatment options. Therefore, this paper systematically discusses the mechanisms associated with ferroptosis to explore the link between ferroptosis and MF from multiple dimensions, including iron metabolism disorders, lipid peroxidation, imbalance of glutathione metabolism, and the dysregulated activation of ferroptosis regulatory pathways, to provide innovative perspectives for the study of the specific molecular mechanisms and treatment of MF. Method: By retrieving the literature on the mechanism of ferroptosis in MF published in PubMed and Web of Science databases from 2020 to July 2025, the mechanism of action was systematically analyzed and reviewed. Full article

Background: Existing exercise metabolomics studies have predominantly focused on changes in the type and abundance of metabolites, while rarely addressing the toxicity risk of differential metabolites. Metabolic toxicity refers to the potential of endogenous or exogenous metabolites to induce oxidative stress, cell death, and other forms of biological damage when excessively accumulated and serves as a key driver of metabolic disorders. This study aims to characterize the toxicity risk of plasma differential metabolites before and after a single session of moderate-intensity running, so as to investigate the exercise-induced changes in metabolic toxicity. Methods: A single-group self-pretest–posttest control design was adopted in this study. Participants were recruited from Wuhan Sports University, China, with the inclusion criteria of healthy females aged 22–30 years and BMI 18.5–24.9. Individuals with a history of metabolic diseases or who met other exclusion criteria were excluded, and 5 females were finally enrolled. The exercise protocol consisted of a single 40 min session of moderate-intensity running on a treadmill. We collected plasma samples from five healthy females before and after exercise and performed untargeted LC-MS/MS metabolomic profiling. The gap-Δenergy algorithm was applied to calculate the toxicity scores of differential metabolites, and the proportion of metabolites with high toxic potential (score > 0.6) was compared. Results: Plasma metabolic profiles underwent notable remodeling after exercise. Thirty-two metabolites were upregulated and the phosphosphingolipid SM(d18:2(4E,14Z)/16:0) was the most significant. Meanwhile 32 metabolites were downregulated and the phosphosphingolipid PC(18:1(9Z)/14:0) was the most significant. The 64 differential metabolites were enriched in 9 KEGG pathways including amino acid metabolism and lipid metabolism. Moreover, we systematically evaluated the toxicity of these metabolites using the gap-Δenergy algorithm and found that the downregulated metabolites exhibited a significantly higher toxicity score compared to the upregulated ones. In addition, 37.5% of the downregulated metabolites had a high toxicity score, while the proportion of high toxicity in the upregulated group was only 15.6%. Conclusions: This study demonstrates that moderate-intensity running may confer metabolic health benefits to individuals by reducing metabolic toxicity, specifically through the downregulation of metabolites with high toxic potential. These findings offer novel evidence for exercise’s role in improving metabolic health. They also open a new direction for exercise-based interventions in metabolic disease–toxicity regulation. Full article

Cell surface immune checkpoint receptors are objects for therapeutic intervention to stimulate immune cell attack of cancers. Interference between the checking ectodomain (ECD) and the natural ligand lowers constitutive restraints exerted on immune cells. This approach assumes that immune cells can do more, that a checkpoint blocker will make immune cells more effective at killing cancer cells, and that checkpoint molecules might have limited physiological roles. These assumptions may be warranted, as in the case of checkpoint-blockers towards the programmed death-ligand 1 (PD-L1) ECD, where clinical outcomes are consistently good. However, this does not appear to be the case for the universally expressed CD47 ECD. Much effort has been directed at engineering molecules that bind to the CD47 ECD to increase T cell and macrophage killing of cancers. But a wealth of clinical data do not indicate strong signals, improved killing, or meaningful survival advantages. This suggests that the CD47 ECD is a subpar target for cancer therapy. Consideration of reasons accounting for the modest benefits realized by molecules that bind to the CD47 ECD in cancer, also known as Plan A, is provided. This is followed by thoughts on what might be done, known as plan B, to identify advantages within the CD47 ECD for modulating tolerance in autoimmune diseases. Full article

SARS-CoV-2, the causative agent of COVID-19, has led to over seven million deaths worldwide prior to May 2025. Despite widespread vaccination programs, COVID-19 remains a persistent global health challenge, underscoring the urgent need for new therapeutic approaches. Orientin is a flavonoid with reported antiviral activity, though its potential against SARS-CoV-2 remains poorly explored. This study aimed to investigate whether Orientin interacts with the viral Spike protein and impacts viral replication. Molecular docking simulations using DockThor were employed to predict the binding affinity between Orientin and the receptor-binding domain (RBD) of the Spike protein. Fluorescence spectroscopy assays were performed to assess direct interactions between Orientin and the trimeric form of the Spike protein. Additionally, cytotoxicity and viral replication assays were carried out in Vero cells to evaluate Orientin’s antiviral effects. Docking results indicated that Orientin likely binds to key RBD residues involved in ACE2 receptor recognition. Spectroscopic analyses showed a decrease in intrinsic tryptophan fluorescence, suggesting direct interaction. Orientin demonstrated no cytotoxicity in Vero cells and exhibited moderate inhibition of viral replication. These findings suggest that Orientin interacts with critical regions of the Spike protein and may act as a moderate in vitro inhibitor of SARS-CoV-2, warranting further investigation into its therapeutic potential. Full article

Background: Parvovirus B19 (B19V; Erythroparvovirus primate 1) is now the most commonly detected virus in human endomyocardial biopsies from patients with myocarditis or dilated cardiomyopathy; however, its true causal role remains uncertain. By contrast, Protoparvovirus carnivoran 1, also known as canine parvovirus type 2 (CPV-2), is an apparent cause of myocarditis in neonatal puppies, where it replicates in cardiomyocytes, induces extensive cell death, and often leaves fibrotic scars in survivors. Conclusions: This review compares B19V and CPV-2 from basic biology to clinical expression. Divergent tropism and replication kinetics produce distinct injury patterns: predominantly endothelial and microvascular dysfunction with immune-mediated damage in adult human B19V infection versus direct, age-restricted cardiomyocyte lysis in neonatal CPV-2 infection, often followed by fibrosis. Because parvoviral DNA can persist in cardiac tissue, detection alone does not prove causality. We advocate an “evidence bundle” integrating viral load by quantitative polymerase chain reaction (qPCR), detection of viral transcripts and/or proteins when feasible, spatial co-localization with histological injury, and concordant clinical markers (cardiac troponins and advanced imaging, including cardiac magnetic resonance imaging [CMR]) to support etiologic attribution and guide management in human and veterinary cardiology. Full article

Despite the known antitumor properties of echinacoside (ECH), its specific role and mechanism in hepatocellular carcinoma (HCC) require in-depth exploration. Our study aimed to decipher the mechanism of ECH against HCC through a multi-disciplinary strategy. We first identified tumor protein p53 (TP53) as a key mediator and ferroptosis as a critical process, through network pharmacology and enrichment analyses. The direct interaction between ECH and TP53 was validated by molecular docking and dynamics simulations. In vitro assessments demonstrated that ECH suppresses HCC proliferation by activating ferroptosis, marked by increased intracellular Fe²⁺, lipid peroxidation (LPO), and malondialdehyde (MDA), alongside reduced glutathione (GSH). The ferroptosis inhibitor ferrostatin-1 notably attenuated ECH’s effects, confirming ferroptosis as the primary mode of cell death. Further mechanistic investigation revealed that ECH acts through the TP53/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4) pathway. These results collectively identify ECH as a promising ferroptosis-inducing agent for HCC therapy via TP53 activation. Full article

The development of safer, more effective, and tumor-specific therapeutic strategies remains a major challenge in oncology. Conventional treatments such as chemotherapy and radiotherapy often cause severe side effects and are limited in their ability to target deep-seated or resistant tumors. In this context, sonodynamic therapy (SDT) has emerged as a promising, non-invasive option, harnessing low-intensity ultrasound to activate sonosensitizers deep within tissues and generate cytotoxic reactive oxygen species (ROS) that selectively induce cancer cell death. Interestingly, SDT can also be combined with other therapies to achieve synergistic effects. However, despite encouraging preclinical results, SDT clinical translation is hindered by the poor aqueous solubility, instability, and low tumor specificity of traditional sonosensitizers. To overcome these limitations, recent studies have focused on employing extracellular vesicles (EVs), especially exosomes, as natural, biomimetic nanocarriers for sonosensitizer delivery. EVs offer unique advantages, including high biocompatibility, low immunogenicity, and intrinsic tumor-targeting ability, which make them ideal platforms for improving the therapeutic precision of SDT. Although several delivery strategies have been proposed, a comprehensive and focused overview of approaches specifically designed to enhance SDT performance using EVs is currently lacking. This review summarizes recent advances in integrating EVs with SDT for cancer treatment. It discusses the mechanisms underlying SDT, the engineering strategies developed to enhance exosome functionality, and the synergistic effects achieved through this combination. Furthermore, this review emphasizes that EV-based SDT not only enhances tumor accumulation of the therapeutic nanoplatforms, but also actively remodels the tumor microenvironment by improving oxygen availability, reversing immunosuppressive conditions, and triggering durable antitumor responses. Finally, the review addresses the translational challenges and outlines the critical future directions required to advance this promising therapeutic approach toward clinical application. Full article

Glioblastoma multiforme (GBM) exhibits remarkable resistance to therapy, mainly due to its capacity to modulate regulated cell death pathways. Among these, apoptosis and autophagy are dynamically interconnected, determining cell fate under therapeutic stress. The interaction between beclin-1 and Bcl-2 proteins may represent a key molecular switch that controls whether glioma cells undergo survival or death. This review highlights the crucial role of the Bcl-2:beclin-1 complex in controlling apoptosis–autophagy axis in GBM, emphasising how survival signalling networks, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and PLCγ1/PKC pathways regulated by the TrkB receptor, modulate this balance. We summarise recent insights into how these pathways coordinate the shift between apoptosis and autophagy in glioma cells, contributing to drug resistance. Furthermore, we highlight how modulating this crosstalk can sensitise GBM to conventional and emerging therapies. Integrating new concepts of cell death reprogramming and systems-level signalling analysis, we propose that targeting the Bcl-2:beclin-1 complex and its upstream regulators could overcome the adaptive plasticity of glioblastoma multiforme and open new directions for combination treatment strategies. Full article