Search Results (12,048)

Background/Objectives: Oxidative stress, chronic inflammation, disrupted apoptosis, and altered autophagy are biological processes implicated in colorectal tumor development. Morin is a plant-derived flavonoid with antioxidant and anti-inflammatory properties, but its limited solubility and bioavailability may limit its biological activity. This study evaluated the effects of free morin and morin-loaded liposomes (MOR-Lips) on 1,2-dimethylhydrazine (DMH)-associated colonic biochemical, molecular, and histopathological alterations in rats. Methods: Rats were randomly assigned to six groups—vehicle control, MOR, MOR-Lips, DMH, DMH + MOR, and DMH + MOR-Lips—and treated for 10 weeks. Serum and colonic tissues were evaluated for cancer-associated biomarkers (CEA, CA19-9, CA125, HMG-CoA reductase), oxidative stress and antioxidant indices, nitrosative and oxidative DNA-damage markers (MDA, NO, 8-OHdG), inflammatory mediators (TLR4/NF-κB/COX-2, cytokines, MPO), proliferative indices (Ki-67, PCNA), apoptotic and autophagy-related regulators (Bax, caspase-3, p53, cytochrome c, BCL-2, p-AKT, LC3-II, Beclin-1, p62), and histopathological and immunohistochemical changes. Results: DMH exposure was associated with increased CEA, CA19-9, CA125, HMG-CoA reductase, MDA, NO, 8-OHdG, TLR4/NF-κB/COX-2, cytokines, MPO, Ki-67, and PCNA. DMH also reduced NRF2/HO-1 signaling and antioxidant defenses, shifted apoptosis-related markers toward a pro-survival profile, altered autophagy-related markers, and produced marked colonic histopathological abnormalities. Both free MOR and MOR-Lips attenuated several of these DMH-associated alterations, with MOR-Lips generally producing greater effects than free MOR. MOR-LIP treatment was associated with restoration of antioxidant marker profiles, reduced levels of inflammatory and proliferative markers, a shift toward a pro-apoptotic marker profile, partial normalization of autophagy-related markers, and improved colonic histopathological appearance. Conclusions: In DMH-exposed rats, MOR-Lips were associated with more favorable redox, inflammatory, proliferative, apoptosis-related, autophagy-related, and histopathological profiles than free MOR. These findings support further investigation of MOR-Lips as a formulation strategy for improving the biological activity of morin. Because quantitative preneoplastic and neoplastic endpoints were not measured, the results do not establish inhibition of colorectal carcinogenesis or chemopreventive efficacy. Full article

Background: Triple-negative breast cancer (TNBC) remains a major cause of cancer mortality due to its aggressive behavior, metabolic adaptability, and high therapeutic resistance. Extracellular vesicles (EVs) within the tumor microenvironment contribute to tumor progression and metastasis by transferring pro-tumorigenic cargo. While conventional Tumor Treating Fields use high-frequency alternating fields to disrupt mitosis, low-energy triple-frequency bioelectromagnetic approaches remain poorly characterized. Methods: We evaluated a device–drug strategy combining triple-frequency low-intensity electromagnetic stimulation (EMS2: 396 Hz, 285 Hz, 528 Hz) with the pleiotropic drug Fingolimod (FTY720). Treatments were tested in MDA-MB-231 and ARM-G breast cancer cells, with Paclitaxel as a positive control. Cell proliferation was assessed by MTS assay, and extracellular vesicles were isolated following individual and combination treatments. Quantitative LC-MS/MS proteomics was used to characterize treatment-induced changes in EVs cargo. Results: EMS2 reduced proliferation in both cell lines and produced morphological changes consistent with altered cell-cycle progression. EMS2 alone triggered adaptive metabolic responses, whereas combination with Fingolimod suppressed these compensatory signatures. EVs proteomics revealed combination-specific alterations associated with mitochondrial stress, ER stress, NF-κB suppression, and autophagy-associated pathways. The combination also reduced levels of metastasis- and stroma-associated proteins, including Mitogen-Activated Protein Kinase 12 (MAPK12) and collagen-associated ECM components (Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type VI Alpha 1 Chain (COL6A1), Collagen Type VI Alpha 3 Chain (COL6A3), and Matrilin 3 (MATN3)) in EVs. Bliss independence analysis identified a subset of metastasis-associated proteins suppressed in EVs beyond the level predicted by an additive model, an exploratory finding that will require further validation with dose–response and functional assays. Conclusions: Combined triple-frequency EMS2 and Fingolimod treatment altered the extracellular vesicle proteome, inducing signatures consistent with mitochondrial and endoplasmic reticulum stress, metabolic disruption, and reduced levels of metastasis-associated and stromal/ECM remodeling proteins, along with reduced proliferation. These findings suggest a coordinated anti-cancer effect of this tunable device–drug strategy, warranting further functional and in vivo validation to confirm therapeutic potential. Full article

Non-small cell lung cancer is one of the leading causes of cancer-related mortality. The effectiveness of treatment is limited by several factors, including significant tumoral heterogeneity, rapid development of drug resistance, high metastatic potential, and a complex tumor microenvironment. In recent years, natural products have emerged as valuable resources for the discovery of novel antitumor strategies against non-small cell lung cancer. These compounds possess diverse chemical properties, target multiple pathways, are abundant in nature, and exhibit relatively low toxicity. The utilization of existing medications with established pharmacokinetic profiles and safety records, combined with shorter development timelines, shows promise for advancing lung cancer treatment research. A growing body of evidence indicates that both naturally occurring compounds and commercially available drugs exert effects that extend beyond traditional cytotoxic mechanisms. These agents influence processes such as ferroptosis, oxidative stress, metabolic reprogramming, autophagy, apoptosis, epithelial–mesenchymal transition (EMT), tumor immune microenvironments, and epigenetic networks, suggesting that their activities can be leveraged for a robust multi-target antitumor strategy. Accordingly, this review summarizes research advances on natural products and repurposed marketed drugs for non-small cell lung cancer; outlines their potential for combination with chemotherapy, targeted therapy, radiotherapy and immunotherapy; and discusses future directions for clinical translation. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies worldwide because of delayed diagnosis, rapid metastatic progression, profound immune suppression, and limited therapeutic responsiveness. The pancreatic tumor microenvironment is characterized by severe hypoxia, stromal desmoplasia, metabolic stress, and oxidative imbalance, all of which contribute to tumor progression and resistance to therapy. Among immune cells involved in antitumor defense, natural killer (NK) cells play an important role through direct cytotoxicity and cytokine production. However, NK-cell activity is frequently impaired in PDAC due to oxidative stress, altered nutrient availability, mitochondrial dysfunction, and dysregulated signaling pathways such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). This review examines current evidence regarding the interactions among redox biology, nutrient sensing, NK-cell metabolism, and pancreatic cancer progression. Importantly, much of the available evidence derives from in vitro studies, animal models, or early-phase clinical investigations, and several findings remain controversial or inconsistent. Further well-designed clinical trials are needed to determine whether nutritional interventions, vitamin supplementation, and strategies targeting metabolic and redox pathways can safely and effectively enhance NK-cell function and improve clinical outcomes in patients with PDAC. Full article

Due to limitations in the use of antibiotics as feed additives to promote growth, the development of safe, effective, and environmentally friendly antibiotic alternatives is a critical and urgent research priority in animal nutrition and veterinary medicine. Plants contain abundant active substances, which are important sources for developing new feed additives or discovering new active substances. Ageratina adenophora (Spreng.) R.M.King & H.Rob. (A. adenophora) is an herb native to Central America and a globally invasive species that has spread across Asia, Australia, Africa, and other continents. Studies indicated that it possesses a complex chemical composition, with over 100 constituents identified, including terpenoids, flavonoids, and phenolic acids, which exhibit diverse biological activities, including antibacterial, antioxidant, insecticidal, acaricidal, anti-inflammatory, neuroprotective, antidiabetic, antitumor, and gut health regulation effects. However, it also possesses distinct toxicity, primarily targeting organs such as the intestines, liver, and spleen, causing tissue damage by activating specific signaling pathways. This may limit its utilization as a feed additive or in medical drug development. Therefore, this review systematically summarizes the botanical characteristics, geographic distribution, phytochemical composition, biological activities, and toxicological effects of A. adenophora. We also discussed its potential application and current challenges. We hope this review can promote its development and utilization as potential feed additives or medicinal resources. Full article

CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions. Full article

Objectives: Nasopharyngeal carcinoma (NPC) arises in an immune-suppressive milieu that frequently undermines treatment efficacy. TPPP3 has been implicated as a negative regulator of NPC aggressiveness, yet its relevance to immune modulation or chaperone networks remains poorly defined. We therefore sought to determine how TPPP3 shapes the NPC immune landscape and to identify its interacting protein partners. Methods: Public single-cell RNA-sequencing datasets from head and neck squamous cell carcinoma and nasopharyngeal carcinoma were analyzed using R. HK-1 and C666-1 cells stably overexpressing TPPP3 were established. These cells were used to construct humanized xenograft tumor models, with intratumoral immune cell infiltration evaluated by immunohistochemistry. In vitro, the same cells and their controls were indirectly co-cultured with peripheral blood mononuclear cells. Cellular lysates from TPPP3-overexpressing cells were subjected to immunoprecipitation–mass spectrometry and immunofluorescence staining, which identified HSPA8 as a TPPP3-interacting protein. Three groups—control, TPPP3-overexpressing, and TPPP3-overexpressing plus the HSPA8 inhibitor VER155008—were then compared in wound healing, colony formation, cell-cycle, and xenograft assays, with immunohistochemical staining for Ki67, TPPP3, and CD3 performed on tumor sections. Results: TPPP3 transcripts were barely detectable across most tumor cell subsets but showed preferential enrichment in NPC epithelial clusters. Enforced TPPP3 expression curtailed xenograft outgrowth while increasing intratumoral abundance of CD3⁺ T cells, CD8⁺ T cells, and CD11c⁺ dendritic cells. Pharmacological blockade of HSPA8 with VER155008 further enhanced TPPP3-driven suppression of migration, clonogenicity, and tumor expansion, and also altered cell-cycle progression while boosting CD3⁺ T-cell accumulation within grafts. Conclusions: These findings suggest a functional association between TPPP3 and HSPA8 that may contribute to tumor growth suppression and immune microenvironment remodeling in NPC. Pharmacological disruption of HSPA8-dependent proteostasis enhanced TPPP3-associated antitumor activity in both in vitro and in vivo models, indicating that this chaperone pathway represents a candidate mechanism worthy of further mechanistic investigation and therapeutic exploration. Full article

Hyperbaric oxygen therapy (HBOT) increases tissue oxygen availability through the administration of near-pure oxygen under elevated atmospheric pressure. Although HBOT is clinically established for several hypoxia-related conditions and selected radiation-induced tissue injuries, its role in oncology remains controversial. This review evaluates HBOT as a context-dependent modulator of tumor and normal-tissue biology by integrating evidence on hypoxia-inducible factor signaling, redox homeostasis, tumor metabolism, vascular remodeling, immune regulation, extracellular matrix organization, cancer stemness, and treatment sensitivity. Available preclinical and clinical evidence does not support the historical assumption that HBOT universally accelerates tumor growth, recurrence, or metastasis, but current evidence is also insufficient to support HBOT as a broadly applicable standalone anticancer therapy. The strongest clinical evidence concerns late radiation-induced normal-tissue injury, particularly radiation cystitis, whereas evidence for direct antitumor activity or treatment sensitization remains predominantly preclinical and context-dependent. Selected experimental models suggest that transient reoxygenation may attenuate hypoxia-dependent signaling, alter redox and metabolic adaptation, and enhance sensitivity to radiotherapy or systemic anticancer treatment, while other models demonstrate increased proliferation or vascular responses. Future studies should incorporate standardized HBOT protocols, direct or surrogate measurements of tumor oxygenation, mechanistic biomarkers, patient stratification based on measurable tumor characteristics such as baseline hypoxia, redox phenotype, and microenvironmental features, and precise treatment scheduling. HBOT may ultimately be most relevant as a biomarker- and timing-guided pharmacodynamic reoxygenation strategy in tumors in which a transient reoxygenation window can be therapeutically exploited. Full article

Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)—endogenous molecules that signal cellular stress and damage—contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group ^{Box 1} (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs—including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin—contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways. Full article

Clear cell renal cell carcinoma (ccRCC) is a highly immune-evasive malignancy that exhibits limited and often transient responses to immune checkpoint inhibitors (ICIs) and remains a major challenge for emerging cellular immunotherapies, including chimeric antigen receptor (CAR)-T cells. A defining feature of ccRCC, largely driven by von Hippel–Lindau (VHL) deficiency, is persistent activation of the transforming growth factor-β1 (TGF-β1) and hypoxia-inducible factor (HIF) signaling network. Acting as a central immunometabolic regulatory axis, TGF-β1/HIF promotes angiogenesis, metabolic reprogramming, epigenetic dysregulation, and immune escape through coordinated induction of immunosuppressive mediators, including PD-L1, VEGF, and CTLA-4, resulting in impaired T-cell infiltration, functional exhaustion, and resistance to immunotherapy. Preclinical studies have demonstrated that pharmacologic-dose Seleno-L-methionine (SLM) and its active metabolite, methylseleninic acid (MSA), suppress TGF-β1 and both HIF-1α and HIF-2α, leading to downregulation of multiple downstream immunosuppressive pathways at pharmacologically achievable, non-toxic concentrations. In addition to enhancing the antitumor activity of chemotherapy and VEGF-targeted agents, accumulating evidence suggests that SLM exerts broad immunologic, metabolic, and epigenetic effects that may overcome key mechanisms of therapeutic resistance. This review synthesizes current mechanistic and translational evidence supporting the repurposing of SLM as a first-in-class pleiotropic immunomodulatory agent. Using ccRCC as a model of TGF-β1/HIF-driven immune resistance, we discuss how simultaneous targeting of this central regulatory axis may restore immune surveillance, improve T-cell fitness and trafficking, enhance responses to ICIs and CAR-T cell therapy, and provide a mechanistically rational strategy for the treatment of advanced solid tumors. Full article

Cancer immunotherapy faces significant challenges in treating “cold” tumors, which respond poorly to current strategies. Breast cancer is a major cause of cancer-related mortality in women and is a representative immunosuppressive cold tumor. The luminal A subtype of breast cancer exhibits an immune-cold phenotype, with MCF-7 cells used as a representative cell model. Here, we identified (3β,5α,8α)-5,8-epidioxyergost-6-en-3β-ol (EEO), isolated from Gymnopilus orientispectabilis, as an inducer of immunogenic cell death (ICD) hallmarks in MCF-7 cells, including cell surface exposure of calreticulin (CRT) and the extracellular release of damage-associated molecular patterns (DAMPs), such as ATP and High Mobility Group Box 1 (HMGB1). These ICD-associated events subsequently promoted CRT-dependent dendritic cell (DC) activation in a co-culture system with bone marrow-derived DCs and MCF-7 cells. Furthermore, surface-exposed CRT enhanced the phagocytosis of EEO-treated MCF-7 cells by DCs, and this phagocytic activity promoted DC maturation, as indicated by increased cell surface levels of the maturation markers major histocompatibility complex class II (MHC II) and cluster of differentiation 86 (CD86). Moreover, CRT knockdown in MCF-7 cells reduced surface CRT exposure following EEO treatment, thereby suppressing DC-mediated phagocytosis and subsequent DC maturation. Taken together, these findings suggest that EEO is a promising candidate for enhancing the antitumor efficacy of existing breast cancer immunotherapies through ICD-mediated DC maturation and converting immunologically cold tumors into hot tumors. Full article

Background: Members of the tumor necrosis factor receptor superfamily (TNFRSF), including 4-1BB (CD137) and OX-40 (CD134), play central roles in regulating cytotoxic lymphocyte activation and anti-tumor immunity. In addition to their membrane-bound forms, soluble receptor isoforms may modulate signaling by influencing ligand availability and receptor engagement. However, the peripheral regulation of soluble and membrane 4-1BB and OX-40 in cervical cancer remains incompletely defined. Methods: Plasma concentrations of soluble 4-1BB (s4-1BB) and soluble OX-40 (sOX-40) were quantified by ELISA in 20 treatment-naïve cervical cancer (CC) patients and 20 healthy controls (HCs). Membrane expression (m4-1BB and mOX-40) on circulating T cells and NK cells was evaluated by flow cytometry. Correlation and stage-stratified analyses were performed. Results: Plasma levels of s4-1BB and sOX-40 were significantly elevated in CC patients compared with HCs. Membrane 4-1BB expression was increased on both T cells and NK cells, while OX-40 expression was selectively elevated in NK cells, with no difference observed in T cells. A moderate positive correlation was identified between s4-1BB and T-cell membrane 4-1BB expression. Notably, membrane 4-1BB expression decreased in advanced-stage disease, whereas soluble concentrations remained unchanged. Conclusions: These findings demonstrate differential regulation of soluble and membrane 4-1BB and OX-40 in the peripheral compartment in cervical cancer, highlighting distinct regulatory layers within the TNFRSF axis. Full article

Infantile hemangioma (IH) is the most common benign vascular tumor of infancy, characterized by a unique life cycle encompassing a rapid proliferative phase followed by spontaneous involution. Although the majority of cases exhibit a favorable prognosis, a small subset may be complicated by severe sequelae that adversely affect the physical and mental health of affected infants. Accumulating evidence indicates that the pathogenesis of IH involves a dynamic imbalance between angiogenesis and involution, which is tightly governed by the multilineage differentiation of hemangioma stem cells, core signaling pathway networks, and epigenetic regulation mediated by non-coding RNAs. A deeper understanding of the mechanisms underlying angiogenesis and involution will provide novel insights into both the fundamental biology and clinical management of IH. Furthermore, multiple bioactive constituents of the traditional Chinese medicine Salvia miltiorrhiza (Danshen) have demonstrated anti-angiogenic and pro-involution potential in tumor and ischemia models. This review systematically summarizes recent advances in the mechanistic understanding of IH angiogenesis and involution, and critically discusses the regulatory effects of Danshen active components on these processes, with the aim of offering a theoretical foundation for elucidating IH pathogenesis and facilitating the development of novel therapeutic agents. Full article

Background: Breast cancer remains the most common malignant tumor among women worldwide. Although conventional treatments including surgery, chemotherapy, and radiotherapy are effective, they are confronted with challenges such as tumor heterogeneity, systemic toxicity, and recurrence driven by drug resistance. To overcome these limitations, natural products have emerged as promising therapeutic alternatives owing to their multi-target efficacy and favorable biocompatibility. However, their clinical translation is still hindered by poor chemical stability, low aqueous solubility, and inadequate bioavailability. Nanodelivery systems offer a transformative solution by enhancing bioavailability and enabling precision targeting through the enhanced permeation and retention effect, thereby widening the therapeutic window and minimizing off-target toxicity. Purpose: This review evaluates diverse nanoparticle-based delivery systems and their targeting mechanisms in natural product-based breast cancer therapy. By examining inherent advantages and translational challenges, this analysis provides critical insights into the clinical development and application of these nanoformulations. Methods: A systematic literature search was performed in PubMed, ScienceDirect, Springer, Taylor & Francis, and Web of Science to identify relevant studies on natural product-based nanoformulations for breast cancer therapy. Results: Natural products exert anti-breast cancer effects through mechanisms such as inducing apoptosis, arresting the cell cycle, inhibiting invasion and metastasis, suppressing angiogenesis, and regulating autophagy. To overcome clinical hurdles, three complementary targeting strategies have been developed: passive, active, and stimuli-responsive targeting. These advances are shifting nanomedicines toward active precision therapy, markedly improving the therapeutic index. With multiple formulations already approved or in clinical pipelines, this field is rapidly progressing from laboratory research to clinical implementation. Conclusions: Natural products possess potent anti-breast cancer effects, and the application of nanodelivery technology effectively overcomes their inherent limitations of poor stability and low bioavailability. Although preliminary findings are promising, large-scale, randomized controlled clinical trials are urgently needed to systematically evaluate their safety, efficacy, and practical potential for clinical translation in breast cancer management. Full article

The gut microbiota can influence tumor immunity and treatment responses through microbial metabolism, intestinal barrier regulation, and immune–inflammatory signaling, but whether exercise engages these mechanisms through the muscle–gut axis remains uncertain. This review integrates evidence from exercise physiology, microbial metabolism, and tumor immunology to examine how exercise-associated host signals may reshape the intestinal ecological niche and microbial function. Three candidate muscle–gut axes are proposed: the myokine–enteroendocrine–substrate delivery–short-chain fatty acid (SCFA) axis, the exercise-associated lactate–microbial cross-feeding–propionate axis, and the muscle-derived endocrine signaling–intestinal epithelial repair–hypoxic niche axis. Separate studies support exercise-associated IL-6/GLP-1/PYY regulation and gastrointestinal transit, lactate entry into the intestinal lumen and lactate-associated microbial remodeling, Veillonella atypica-mediated propionate production, and irisin/apelin-related epithelial repair. Together, these pathways may influence microbial metabolism, barrier homeostasis, and immune–tumor interactions. However, tumor-related links remain incomplete, and none has been validated as a complete causal chain in a single tumor-bearing exercise model. Relatively complete preclinical evidence comes from mouse melanoma, where endurance exercise enhanced microbial folate-dependent one-carbon metabolism and formate output, with microbiota-derived formate promoting CD8⁺ T-cell antitumor activity and immune checkpoint inhibitor efficacy. Regular exercise with an appropriate load and adequate recovery may support microbial and intestinal barrier homeostasis, whereas excessive or prolonged exercise with inadequate recovery may impair barrier integrity. Human evidence remains limited and largely associative and does not establish microbiota-mediated improvements in tumor immunity or treatment responses. These candidate axes therefore require causal validation in tumor-bearing exercise models and prospective human studies. Full article