Search Results (5,888)

Cancer remains a significant global health challenge, with China being particularly affected because of its large population. Regulated cell death (RCD) mechanisms, including autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, play complex roles in cancer development and progression. This review explores the dual roles of autophagy and apoptosis in cancer, highlighting their tumor-suppressive and tumor-promoting functions. Autophagy can maintain genomic stability, induce apoptosis, and suppress protumor inflammation, but it may also support tumor cell survival and drug resistance. Apoptosis, while primarily tumor-suppressive, can paradoxically promote cancer progression in certain contexts. Other RCD mechanisms, such as necroptosis, pyroptosis, and ferroptosis, also exhibit dual roles in cancer, influencing tumor growth, metastasis, and immune responses. Understanding these mechanisms is crucial for developing targeted cancer therapies. This review provides insights into the intricate interplay between RCD mechanisms and cancer, emphasizing the need for context-dependent therapeutic strategies. Full article

Background: DEAD/H box 5 (DDX5) serves as a transcriptional coactivator for several transcription factors including E2F1, the primary target of the tumor suppressor pRB. E2F1 physiologically activated by growth stimulation activates growth-related genes and promotes cell proliferation. In contrast, upon loss of pRB function due to oncogenic changes, E2F1 is activated out of restraint by pRB (deregulated E2F1) and stimulates tumor suppressor genes such as ARF, which activates the tumor suppressor p53, to suppress tumorigenesis. We have recently reported that DDX5 augments deregulated E2F1 activity to induce tumor suppressor gene expression and apoptosis. During the analyses, we noted that over-expression of E2F1 increased DDX5 expression, suggesting a feed forward loop in E2F1 activation through DDX5. Objective: We thus examined whether the DDX5 gene is a target of deregulated E2F1. Method: For this purpose, we performed promoter analysis and ChIP assay. Result: The DDX5 promoter did not possess typical E2F binding consensus but contained several GC repeats observed in deregulated E2F1 targets. Insertion of point mutations in these GC repeats decreased responsiveness to deregulated E2F1 induced by over-expression of E2F1, but scarcely affected responsiveness to growth stimulation. ChIP assays showed that deregulated E2F1 induced by over-expression of E2F1 or expression of E1a, which binds pRB and releases E2F1, bound to the DDX5 gene, while physiological E2F1 induced by growth stimulation did not. Conclusions: These results suggest that the DDX5 gene is a target of deregulated E2F1, generating a feed forward loop mediating tumor suppressive E2F1 activity. Full article

Gastrointestinal (GI) malignancies are diverse and particularly challenging in terms of current immunotherapy but hold great opportunity for impact given that they constitute the highest cancer incidence and mortality rates worldwide. Traditional treatment options for solid GI malignancies include surgical intervention, chemotherapy, radiation, or a combination of these treatments. Emerging modalities within immunotherapy are anticipated to extend the results with conventional therapy by stimulating the patient’s own intrinsic potential for tumor-specific immunologic rejection. Combination regimens of chemotherapy and tumor-infiltrating lymphocyte (TIL) therapy in advanced colorectal cancer and pancreatic cancer, autologous monocyte therapy in advanced gastric cancer, and CAR-T therapy trained against GI-selective tumor antigens such as carcinoembryonic antigen are currently being studied. Clinical trials are underway to study the combination of various chemotherapeutic agents along with immunotherapy in the management of cholangiocarcinoma, hepatocellular carcinoma, and esophageal cancer. Alternative therapies are needed based on the tumor immune microenvironment, which can lead to a personalized approach to treatment. In this review, we discuss the current status of various modalities of immunotherapy in common GI malignancies, along with their mechanisms of immune activation and cancer suppression. We will also discuss the use of immunotherapy in less common solid GI malignancies and touch on recent advancements and clinical trials. Full article

Background: Obese women have a significantly higher risk of bearing breast tumors that are resistant to therapies and are associated with poorer prognoses/treatment outcomes. Breast cancer-promoting action of obesity is often attributed to elevated levels of insulin, glucose, inflammatory mediators, and misbalanced estrogen production in adipose tissue under obese conditions. Metabolic endotoxemia, characterized by chronic presence of extremely low levels of bacterial endotoxin (lipopolysaccharide [LPS]) in the circulation, is a less explored obesity-associated factor. Results: Here, utilizing in vitro and in vivo models of breast carcinoma (BC), we report that subclinical levels of LPS typical for metabolic endotoxemia enhance the malignant phenotype of breast cancer cells and accelerate breast tumor progression. Conclusions: Our study, while focusing primarily on the direct effects of metabolic endotoxemia on breast tumor progression, also suggests that metabolic endotoxemia can contribute to obesity–breast cancer link. Thus, our findings add novel mechanistic insights into how obesity-associated metabolic changes, particularly metabolic endotoxemia, modulate the biological and clinical behavior of breast carcinoma. In turn, understanding of the mechanistic aspects underlying the association between obesity and breast cancer could help inform better strategies to reduce BC risk in an increasingly obese population and to suppress the breast cancer-promoting consequences of excess adiposity. Full article

Elevated extracellular potassium (K⁺) in the tumor microenvironment (TME) of breast and other cancers is increasingly recognized as a critical factor influencing tumor progression and immune suppression. Current methods for noninvasive mapping of the potassium distribution in tumors are limited. Here, we employed photoacoustic chemical imaging (PACI) with a solvatochromic dye-based, potassium-sensitive nanoprobe (SDKNP) to quantitatively visualize extracellular potassium levels in an orthotopic metaplastic breast cancer mouse model, Ccn6-KO. Tumors of three distinct sizes (5 mm, 10 mm, and 20 mm) were imaged using multi-wavelength photoacoustic imaging at five laser wavelengths (560, 576, 584, 605, and 625 nm). Potassium concentration maps derived from spectral unmixing of the photoacoustic images at the five laser wavelengths revealed significantly increased potassium levels in larger tumors, confirmed independently by inductively coupled plasma mass spectrometry (ICP-MS). The PACI results matched ICP-MS measurements, validating PACI as a robust, noninvasive imaging modality for potassium mapping in tumors in vivo. This work establishes PACI as a promising tool for studying the chemical properties of the TME and provides a foundation for future studies evaluating the immunotherapy response through ionic biomarker imaging. Full article

Periodontitis, a chronic inflammatory disease, causes alveolar bone loss. Current treatments show limitations in achieving dual antimicrobial and anti-inflammatory effects. We evaluated an emodin-loaded thermoresponsive hydrogel as a local drug delivery system for periodontitis treatment. Emodin itself demonstrated antibacterial activity against Porphyromonas gingivalis, with minimal inhibitory and minimal bactericidal concentrations of 50 μM. It also suppressed mRNA expression of proinflammatory cytokines [tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6] in lipopolysaccharide-stimulated RAW 264.7 cells. The hydrogel, formulated with poloxamers and carboxymethylcellulose, remained in a liquid state at room temperature and formed a gel at 34 °C, providing sustained drug release for 96 h and demonstrating biocompatibility with human periodontal ligament stem cells while exhibiting antibacterial activity against P. gingivalis. In a rat model of periodontitis, the hydrogel significantly reduced alveolar bone loss and inflammatory responses, as confirmed by micro-computed tomography and reverse transcription quantitative polymerase chain reaction of gingival tissue. The dual antimicrobial and anti-inflammatory properties of emodin, combined with its thermoresponsive delivery system, provide advantages over conventional treatments by maintaining therapeutic concentrations in the periodontal pocket while minimizing systemic exposure. This shows the potential of emodin-loaded thermoresponsive hydrogels as effective local delivery systems for periodontitis treatment. Full article

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article

The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer’s disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders. Full article

Chamaecyparis obtusa (Siebold & Zucc.) Endl. (C. obtusa) is an evergreen conifer native to temperate regions such as South Korea and Japan, traditionally used for its anti-inflammatory properties. However, the molecular mechanisms underlying the anti-inflammatory effects of C. obtusa bark extracts remain poorly understood. In this study, I compared the biological activities of C. obtusa bark extracts prepared using boiling water (COWB) and 70% ethanol (COEB), and investigated their anti-inflammatory mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. COEB significantly suppressed both mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with decreased production of their respective inflammatory mediators, nitric oxide (NO) and prostaglandin E₂ (PGE₂). Additionally, COEB selectively downregulated interleukin (IL)-1β expression, without affecting tumor necrosis factor-α (TNF-α), and unexpectedly upregulated IL-6. Notably, COEB did not inhibit the LPS-induced activation of major inflammatory signaling pathways, including mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT). These findings suggest that COEB exerts anti-inflammatory effects by modulating key inflammatory mediators independently of canonical signaling pathways and may offer a novel therapeutic strategy for controlling inflammation. Full article

Colorectal cancer (CRC) remains a predominant cause of global cancer-related mortality, highlighting the pressing demand for innovative therapeutic strategies. Natural polysaccharides have emerged as promising candidates in cancer research due to their multifaceted anticancer mechanisms and tumor-suppressive potential across diverse malignancies. In this study, we enzymatically extracted a polysaccharide, named ERPP, from Ruditapes philippinarum and comprehensively evaluated its anti-colorectal cancer activity. We conducted in vitro assays, including CCK-8 proliferation, clonogenic survival, scratch wound healing, and Annexin V-FITC/PI apoptosis staining, and the results demonstrated that ERPP significantly inhibited HT-29 cell proliferation, suppressed colony formation, impaired migratory capacity, and induced apoptosis. JC-1 fluorescence assays provided further evidence of mitochondrial membrane potential (MMP) depolarization, as manifested by a substantial reduction in the red/green fluorescence ratio (from 10.87 to 0.35). These antitumor effects were further validated in vivo using a zebrafish HT-29 xenograft model. Furthermore, ERPP treatment significantly attenuated tumor angiogenesis and downregulated the expression of the vascular endothelial growth factor A (Vegfaa) gene in the zebrafish xenograft model. Mechanistic investigations revealed that ERPP primarily activated the mitochondrial apoptosis pathway. RT-qPCR analysis showed an upregulation of the pro-apoptotic gene Bax and a downregulation of the anti-apoptotic gene Bcl-2, leading to cytochrome c (CYCS) release and caspase-3 (CASP-3) activation. Additionally, ERPP exhibited potent antioxidant capacity, achieving an 80.2% hydroxyl radical scavenging rate at 4 mg/mL. ERPP also decreased reactive oxygen species (ROS) levels within the tumor cells, thereby augmenting anticancer efficacy through its antioxidant activity. Collectively, these findings provide mechanistic insights into the properties of ERPP, underscoring its potential as a functional food component or adjuvant therapy for colorectal cancer management. Full article

Background/Objectives: Alterations in DNA damage repair mechanisms can impair the therapeutic effectiveness of cisplatin. MicroRNAs (miRNAs), key regulators of DNA damage repair processes, have been proposed as promising biomarkers for predicting the response to platinum-based chemotherapy (CT) in non-small cell lung cancer (NSCLC). In this study, by using a bioinformatics approach, we identified six miRNAs, which were differentially expressed (DE) between NSCLC patients characterized as responders and non-responders to platinum-based CT. We further validated the differential expression of the selected miRNAs on tumor and matched normal tissues from patients with resected NSCLC. Methods: Two miRNA microarray expression datasets were retrieved from the Gene Expression Omnibus (GEO) repository, comprising a total of 69 NSCLC patients (N = 69) treated with CT and annotated data from their response to treatment. Differential expression analysis was performed using the Linear Models for Microarray Analysis (Limma) package in R to identify DE miRNAs between responders (N = 33) and non-responders (N = 36). Quantitative real-time PCR (qRT-PCR) was used to assess miRNA expression levels in clinical tissue samples (N = 20). Results: Analysis with the Limma package revealed 112 DE miRNAs between responders and non-responders. A random-effects meta-analysis further identified 24 miRNAs that were consistently up- or downregulated in at least two studies. Survival analysis using the Kaplan–Meier plotter (KM plotter) indicated that 22 of these miRNAs showed significant associations with prognosis in NSCLC. Functional and pathway enrichment analysis revealed that several of the identified miRNAs were linked to key pathways implicated in DNA damage repair, including the p53, Hippo, PI3K and TGF-β signaling pathways. We finally distinguished a six-miRNA signature consisting of miR-26a, miR-29c, miR-34a, miR-30e-5p, miR-30e-3p and miR-497, which were downregulated in non-responders and are involved in at least three DNA damage repair pathways. Comparative expression analysis on tumor and matched normal tissues from surgically treated NSCLC patients confirmed their differential expression in clinical samples. Conclusions: In summary, we identified a signature of six miRNAs that are suppressed in NSCLC and may serve as a predictor of cisplatin response in NSCLC. Full article

Background: Androgen deprivation therapy (ADT) is a primary treatment for prostate cancer (PCa) that effectively reduces androgen levels to suppress tumor progression. However, growing evidence suggests potential cognitive side effects, raising concerns about the long-term neurological consequences of this treatment. Objective: This scoping review aims to synthesize the existing evidence linking ADT to cognitive changes in men with PCa, identifying the key cognitive domains affected and outlining gaps in the existing literature. Methods: A systematic literature search was conducted according to the PRISMA-ScR guidelines in CINAHL, PubMed, Scopus, and Web of Science. Studies investigating cognitive function in ADT-treated PCa patients were included, covering randomized controlled trials (RCTs) and cohort, case–control, and cross-sectional studies. The extracted data included the study design, evaluated cognitive characteristics, measurement tools, and overall findings. Results: A total of 22 studies met the inclusion and exclusion criteria. Cognitive assessments varied across studies. While some studies reported cognitive impairments in ADT-treated patients—particularly in working, verbal, and visual memory and executive function—others found no significant effects. The variability in prostate cancer staging, epidemiological study designs, and treatment regimens; the exclusion of comorbid conditions; and the differences in assessment tools, sample sizes, and study durations hinder definitive conclusions about the cognitive effects of ADT. Conclusions: This scoping review highlights the heterogeneous and often contradictory evidence regarding ADT-associated cognitive dysfunction. While certain cognitive domains may be affected, methodological inconsistencies limit robust conclusions. Standardized cognitive assessments and longer longitudinal studies are required to clarify ADT’s role in cognitive decline. As the PCa survival rate increases with extended ADT use, integrating routine cognitive monitoring into clinical practice should be considered for PCa patients. Full article

Eukaryotic elongation factor 1A (eEF1A), the second most abundant intracellular protein, not only plays a key role in peptide elongation, but is also capable of numerous moonlighting functions. Within malignant cells, eEF1A is by no means a neutral bystander but instead actively participates in oncogenic transformations via a myriad of molecular pathways. Thus far, a broad range of small-molecule inhibitors have been identified, which, despite their structural diversity, suppress tumor growth by targeting eEF1A. Interestingly, just as eEF1A enables its oncogenic potential far beyond boosting protein translation, these targeted agents disrupt this oncoprotein via multiple axes distinct from mere protein synthesis inhibition. Whereas the oncogenic mechanisms of eEF1A has been well documented, there lacks a systemic survey of the eEF1A-targeting agents in terms of their mechanisms. Accordingly, the present work aims to examine their multifaceted modes of action more than just blocking protein synthesis. By unveiling these insights, our deepened knowledge of these eEF1A-binding inhibitors will inform the development of future eEF1A-targeted drugs for cancer treatment. Full article

In this study, using 70% anhydrous ethanol as the extraction solvent, Moringa oleifera Lam. seed powder was extracted with the microwave-assisted extraction method, followed by purification using macroporous adsorbent resin NKA-9. The purified glucosinolate was subsequently hydrolyzed with myrosinase. The glucosinolate and its enzymatic product were identified as 4-(α-L-rhamnopyranosyloxy) benzyl glucosinolate (4-RBMG) and benzyl isothiocyanate (BITC) by UV–Vis, FT-IR, NMR, and MS. The bioactivities, including anti-oxidation, anti-inflammation, and anti-tumor activities of 4-RBMG and BITC, were systematically evaluated and compared. The results show that at 5–20 mg/mL, the anti-oxidation effects of 4-RBMG on DPPH and ABTS free radicals are superior to those of BITC. However, at the same concentrations, BITC has stronger anti-inflammatory and anti-tumor activities compared to 4-RBMG. Notably, at a concentration of 6.25 μmol/L, BITC significantly inhibited NO production with an inhibitory rate of 96.67% without cytotoxicity. Additionally, at a concentration of 40 μmol/L, BITC exhibited excellent inhibitory effects on five tumor cell lines, with the cell inhibitory rates of leukemia HL-60, lung cancer A549, and hepatocellular carcinoma HepG2 exceeding 90%. This study provides some evidence that the enzymatic product, BITC, shows promise as a therapeutic agent for tumor suppression and inflammation reduction. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. Methods: KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Results: Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Conclusions: Our findings establish the KYNU–HDAC6–complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches—such as HDAC6 and BET inhibition—represents a promising strategy to overcome complement-driven resistance in GBM therapy. Full article