Search Results (5,902)

Background: Glioblastoma (GBM) is among the malignant tumors with the lowest five-year survival rate. Current treatments offer limited efficacy and first-line options are scarce, highlighting the urgent need for novel drugs. Cariprazine can cross the blood–brain barrier and has been reported to inhibit certain tumors; however, its effect on GBM remains unknown. This study aims to elucidate its anti-GBM effects and mechanisms. Methods: Cell proliferation and apoptosis were assessed by wound healing, Transwell, colony formation assays, flow cytometry and JC−10 staining. Co-immunoprecipitation (Co-IP) examined the effect of cariprazine on D2/D3–ARRB2 interaction. Direct binding of cariprazine to ARRB2 was determined by molecular docking and CETSA. Western blotting and immunofluorescence detected changes in proliferation and apoptosis-related proteins. In vivo anti-GBM activity was evaluated in subcutaneous mouse models. Results: Cariprazine inhibited GBM cell proliferation and migration, promoted apoptosis, and showed low astrocyte toxicity. In mice, it suppressed GBM allograft growth without overt systemic toxicity. These effects were mediated through D2/D3 receptors, as cariprazine disrupted the D2/D3–ARRB2 interaction and thereby inhibited ERK signaling. It also upregulated ARRB2, further inhibiting the growth of GBM. Molecular docking and CETSA confirmed the direct binding of cariprazine to ARRB2 at LEU-245 and PHE-246. Conclusions: This study is the first to repurpose cariprazine for GBM, elucidating a unique ARRB2-centered dual mechanism, thus offering a new therapeutic strategy. Full article

Background/Objectives: Vernodalin (VD) and crude extracts from Gymnanthemum extensum leaves have previously demonstrated anticancer activity; however, their underlying molecular effects remain incompletely understood. This study investigated the anticancer activities of VD and G. extensum extracts and characterized their associated molecular responses in breast (MDA-MB-231) and ovarian (A2780) cancer cells. Methods:G. extensum leaves were extracted with dichloromethane and ethyl acetate to obtain DEGE and EAGE, respectively. VD was isolated from EAGE and characterized by ¹H-NMR and HPLC. Phytochemical profiles of the extracts were analyzed by GC-MS and HPLC. Cytotoxicity, clonogenic survival, cell cycle progression, migration, and protein expression were evaluated using MTT assay, colony formation assay, flow cytometry, wound healing assay, and Western blotting. Results: GC–MS analysis revealed distinct phytochemical compositions between DEGE and EAGE, although both extracts contained high levels of neophytadiene and phytol. VD, DEGE, and EAGE inhibited cell proliferation and migration in both cancer cell lines. VD suppressed proteins associated with cancer progression, including SMYD3, BRAF, MELK, FOXM1, Cyclin B1, MDR1/ABCB1, and MMP-9, with molecular responses differing between MDA-MB-231 and A2780 cells. DEGE and EAGE exhibited molecular regulatory patterns distinct from those of purified VD, suggesting contributions from multiple phytochemical constituents. Conclusions: VD and G. extensum crude extracts exhibit significant in vitro anticancer activity against breast and ovarian cancer cells and induce distinct molecular responses. The differential effects of DEGE and EAGE may be attributable to differences in their phytochemical constituents. Full article

Background/Objectives: Burn injuries represent a global public health concern, accounting for approximately 265,000 deaths annually and often leading to severe infections. With the increasing prevalence of multidrug-resistant (MDR) bacteria, innovative therapeutic strategies such as nanoparticle-based topical formulations have gained attention. This study proposed the development of a hydrogel for burn treatment containing biogenic silver nanoparticles (BioAgNPs), hyaluronic acid (HA), and allantoin (AL). Methods: BioAgNPs were previously characterized by transmission electron microscopy (TEM) and incorporated into a hydrogel containing HA and AL, which was physicochemically characterized by pH, spreadability, and energy-dispersive X-ray spectroscopy (EDX). Antibacterial activity was evaluated by broth microdilution, agar diffusion, and time–kill assays against standard and MDR bacterial strains. Cytotoxicity was assessed using the MTT assay in L929 cells, and wound-healing potential was investigated through an in vitro scratch assay to evaluate cell migration and proliferation. Results: BioAgNPs exhibited antibacterial activity against reference strains and MDR isolates, determining the minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC). HA and AL were non-toxic, while BioAgNPs demonstrated low cytotoxic activity. Although HA and AL did not exhibit antibacterial properties, they promoted cell migration and proliferation. The formulation exhibited physicochemical and pharmaceutical stability, showing suitable properties for topical use, and presented significant antimicrobial action, with bacterial elimination occurring within 2 h of contact, except for S. aureus. Conclusions: Thus, the hydrogel presents a promising alternative for the topical treatment of infected burns, with potential application in combating multidrug-resistant bacteria, being able to eliminate MDR Acinetobacter baumannii. Full article

Background/Objectives: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, driven by invasive behavior and frequent resistance to systemic therapies. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit patients with EGFR-mutant NSCLC, but their efficacy is often limited by tumor-intrinsic and environmental resistance mechanisms. Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon from tobacco smoke, combustion, and dietary sources, is a known carcinogen; however, its role in modulating therapeutic responses is poorly understood. Studies, including ours, implicate the platelet-activating factor-receptor (PAFR) pathway in mediating environmental pollutant and therapy-induced effects on tumor growth and microvesicle particle (MVP) release. We hypothesized that PAFR activation mediates BaP-induced NSCLC progression and influences EGFR-TKI responses. Methods: We assessed the effects of BaP, PAFR agonist CPAF, EGFR-TKIs, and their combinations on cell viability, proliferation, migration, anchorage-independent growth, and MVP secretion. Results: BaP did not alter cell survival but significantly increased migration, growth, colony formation, and MVP release, similar to CPAF, and these effects were blocked by a PAFR antagonist or acid sphingomyelinase inhibitor. Notably, BaP did not significantly reduce EGFR-TKI efficacy at tested concentrations. Conclusions: These results show that environmental carcinogens modulate NSCLC behavior through PAFR signaling without compromising EGFR-TKI responsiveness, highlighting PAFR as a potential therapeutic target. Full article

Melanoma is a highly aggressive and invasive form of skin cancer that arises from the uncontrolled growth of melanocytes. It is characterized by early spread through the lymphatic system and metastasis. The success of metastasis is linked to the ability of melanoma and other cancer cells to resist anoikis, a type of cell death that occurs when cells lose their adhesion to the extracellular matrix. Redox signaling plays an essential role in anoikis resistance. The balance between intracellular levels of nitric oxide (NO) and the reactive oxygen species (ROS) O₂⁻ and H₂O₂ stimulate signaling pathways related to proliferation and survival or cell death. A375 and SK-MEL-28 human melanomas cell lines, representing primary melanoma and lymph node metastatic melanoma cells, respectively, under suspension and adherent culture conditions were used to investigate the redox regulation of anoikis resistance. Both cell lines express the three isoforms of nitric oxide synthases (NOS) and NADPH oxidase 4 (NOX4) as endogenous sources of NO and ROS, respectively. When A375 cells in suspension were treated with the pan-NOS inhibitor L-NAME, their viability decreased. The treatment resulted in a decrease in FAK phosphorylation at Tyr397 and in ERK 1/2 phosphorylation. The expression of FAK, ERK 1/2, β-actin, and α-tubulin were significantly reduced. Treatment with L-NAME led to an increase in the expression of the metalloprotease MMP-9. SK-MEL-28 cells in suspension and treated with the NOX4 inhibitor, GKT36901, exhibited reduced viability. This was accompanied by the inhibition of FAK phosphorylation at Tyr397, ERK 1/2 phosphorylation, and a reduction in the expression of FAK, ERK 1/2, β-actin, and α-tubulin, with a slight elevation in the expression of MMP-9. Migration and invasion were strongly inhibited in A375 cells upon treatment with L-NAME, while treatment with GKT36901 had a marginal effect on the migration and invasion capacities of SK-MEL-28 cells. In summary, melanoma cells employ nitrosative and oxidative stress to shield themselves from anoikis. Nitric oxide was essential for melanoma cells at the primary site for resisting anoikis, while H₂O₂ contributed to anoikis resistance in metastatic melanoma cells. Full article

Objectives: Alzheimer’s disease (AD) is associated with impaired adult hippocampal neurogenesis (AHN). This study aimed to establish an in vitro model of Aβ_1–42 oligomer-damaged neural stem cells (NSCs) and to employ the 5×FAD mouse model of AD in vivo, and to evaluate the therapeutic effects of brain-derived neurotrophic factor-loaded hyaluronic acid hydrogel (BDNF-HA gel) on AHN. Methods: In vitro, BDNF-HA gel was co-cultured with Aβ_1–42 oligomer-impaired NSC spheres and evaluate NSC proliferation, migration, and differentiation. In vivo, BDNF-HA gel was infused intracerebroventricularly into 5×FAD mice. Using BrdU labeling, immunofluorescence, anterograde transsynaptic viral tracing, and behavioral tests, we assessed the effects of BDNF-HA gel on adult neurogenesis, newborn neuron integration into memory circuits, and cognitive function. Results: In vitro, BDNF-HA gel attenuated Aβ_1–42-induced NSC apoptosis, restored proliferation and migration, promoted differentiation into neuroblasts, newborn neurons, and oligodendrocytes, and alleviated mitochondrial depolarization and loss of mitochondrial mass. In vivo, despite the absence of significant Aβ plaques reduction in 5×FAD mice, BDNF-HA gel markedly enhanced NSC proliferation and neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Behavioral tests further revealed significant improvements in object recognition, spatial working memory, and spatial reference memory. Conclusions: BDNF-HA gel can effectively counteract the toxic microenvironment induced by Aβ oligomers, promoting NSC proliferation, migration, and differentiation into neurons. Without altering the Aβ burden, it significantly enhances adult neurogenesis and rescues cognitive deficits in AD mice. Full article

Background: Polygonum cuspidatum (Hu Zhang) is a polyphenol-rich botanical in which resveratrol occurs at low levels mainly as polydatin. In this study, we generated a microbially converted P. cuspidatum extract (CPE) with markedly enriched resveratrol content from the unconverted P. cuspidatum extract (PE), and evaluated its anticancer efficacy and safety in comparison with those of the unconverted extract. Methods: High-performance liquid chromatography (HPLC), A549 cell-based assays, an A549 xenograft model, and a 28-day repeated-dose rat study were performed. Results: HPLC showed near-complete depletion of polydatin, marked enrichment of resveratrol, and a modest reduction in emodin. CPE more effectively inhibited A549 cell proliferation and migration than PE, suppressed NLRP3 inflammasome and nuclear factor kappa B (NFκB) signaling, and promoted reactive oxygen species (ROS) accumulation and mitochondrial apoptosis. Oral CPE also significantly reduced tumor growth in an A549 xenograft model. In a 28-day repeated-dose rat study, no treatment-related abnormalities were observed in blood biochemistry or histopathology. Conclusions: These findings support CPE as a promising functional food ingredient. Full article

Clear cell renal cell carcinoma (ccRCC) is notorious for its clinical unpredictability. While Aquaporin-1 (AQP1) is a major water channel in healthy kidneys, its specific role and regulatory mechanisms in ccRCC remain unclear. Using bioinformatics analysis of 610 TCGA-KIRC patients (RNA sequencing and DNA methylation), single-cell transcriptomics of 27,402 cells, and experimental validation (CCK-8, scratch, Transwell, and xenograft assays, with Western blotting, HE staining, and immunohistochemistry), we systematically characterized AQP1 expression, regulation, and function. AQP1 was significantly downregulated in ccRCC via promoter hypermethylation, with single-cell analysis confirming tumor cell-specific loss. Low AQP1 correlated with worse prognosis; multivariate Cox regression identified AQP1 as an independent protective factor (HR = 0.510, p < 0.001), and a prognostic nomogram showed good predictive accuracy for 1-, 3-, and 5-year survival. AQP1 overexpression suppressed proliferation, migration, invasion, and xenograft growth, accompanied by upregulation of TNF-α, TNFRSF1A, Bax, and Cleaved Caspase-3 and reduced Vimentin, suggesting activation of TNF-related pro-apoptotic signaling. AQP1 is epigenetically silenced in ccRCC and suppresses tumor growth via TNF-mediated apoptosis, establishing it as an independent prognostic biomarker and candidate therapeutic target. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the lipid metabolism-associated gene PTGDS has been implicated in tumorigenesis, its functional significance and regulatory mechanisms in LUAD are poorly understood. Methods: We integrated multi-omics data from TCGA and GEO cohorts to evaluate PTGDS expression and its clinicopathological relevance. Functional characterization was performed using gain-of-function models in LUAD cell lines and a xenograft mouse model, assessing proliferation, migration, invasion, and immune microenvironment alterations. Results: PTGDS expression is markedly reduced in LUAD tissues and correlates strongly with advanced disease stage and unfavorable prognosis. Clinically, low PTGDS expression is associated with specific driver mutations and reduced tumor mutation burden. Notably, PTGDS levels correlate with enhanced cytotoxic T-cell infiltration and suppressed M2 macrophage polarization, suggesting immunomodulatory functions. Ectopic expression of PTGDS significantly suppressed malignant behaviors in vitro and tumor growth in vivo. Mechanistically, PTGDS overexpression was associated with reduced expression of CDK1 and PLK1 and increased expression of p21 and p27. Conclusions: Our findings establish PTGDS as a novel tumor suppressor in LUAD that restrains tumor progression through cell cycle modulation and immune microenvironment remodeling, highlighting its potential as both a prognostic biomarker and a therapeutic target. Full article

Background: The formation of wounds or scars often compromises skin anatomy and function, necessitating effective management to restore tissue integrity. Current interventions, including wound debridement, hyperbaric oxygen therapy, antibiotics, wound dressings, and surgical procedures, can be effective but are sometimes limited by high costs and the increasing prevalence of drug resistance. These challenges highlight the need for innovative, cost-effective, and therapeutic alternatives. Method. Our earlier studies assessed the wound closure of wounded human-equivalent epidermal full-thickness skin model (HEFT-SM) with a limited number of Phytoceutical^® retinol micellar formulations for a six-day treatment and found that the retinol micellar formulation accelerated wound closure significantly. In this work, three different types of Phytoceutical^® retinoid formulations, namely 0.3% retinol, 0.3% retinaldehyde, and 0.03% retinoic acid on the early-stage wound healing efficacy and its collagen structure were studied. Haematoxylin and eosin (H&E) staining analysis was used to assess the wound repair of the 3 mm punch wound after two days and the wound healing efficacy defined as the wound diameter contraction in percentage was assessed. The collagen matrix was examined through the use of Masson’s trichrome staining and confocal laser scanning microscopy (CLSM) for both qualitative and spatial assessment. Results. All formulations promoted wound contraction, with efficacy ranging from 15 ± 1% to 35 ± 2% after two days. The 0.3% retinol micelles showed the highest activity (35 ± 2%), followed by retinaldehyde (32 ± 3%) and retinoic acid (15 ± 1%). In addition, all treatments appeared to stimulate collagen architectural changes suggestive of remodelling activity. Conclusions. The enhanced wound healing observed may be attributed to increased cellular proliferation and migration within the wound microenvironment, supporting epidermal differentiation and tissue stratification. Furthermore, this work showed that combination of Masson’s trichrome staining and confocal laser scanning microscopy (CLSM) is a novel approach for qualitative and spatial assessment of collagen structure. Full article

Background: Esophageal squamous cell carcinoma (ESCA) represents one of the most common aggressive malignancies worldwide. Insulin-like growth factor binding protein 1 (IGFBP1), a typical member of the IGF superfamily, is closely linked to adverse prognosis in numerous cancers. Up to now, little is known about its functional relevance to cell migration and tumor progression in ESCA. This work focuses on clarifying the relationship between IGFBP1 expression and the progression and migratory characteristics of ESCA. Methods: mRNA expression profiles from ESCA patients were obtained from the TCGA and GEO databases. Differential expression analysis was performed using R software(version 4.2.2), followed by an intersection of DEGs between datasets. The STRING database was applied to establish PPI networks. Cytoscape software(Version 3.7.2) was then used for visual presentation and hub gene identification. IGFBP1 expression was validated in ESCA tissues versus adjacent normal tissues. Prognostic correlation was assessed using GEPIA, while diagnostic and predictive values were evaluated through ROC analysis and Cox regression. Genetic alterations of IGFBP1 were analyzed via cBioPortal. Immune cell infiltration patterns were investigated using TIMER. Functional enrichment analyses (GO, KEGG) were performed on IGFBP1-associated DEGs. In the in vitro experiments, esophageal cancer cell lines (such as Eca109 and TE-1) and normal human esophageal epithelial cell lines (such as HEEC) were selected. The transcriptional level of IGFBP1 was examined using RT-qPCR, while Western blot analysis was conducted to validate its protein expression changes. Changes in the proliferative capacity of cancer cells after IGFBP1 silencing were detected by the CCK-8 assay, and cell migration capacity was determined via wound scratch assays to clarify the related biological effects. Results: Overall, 2870 DEGs were screened from the GEO database, 153 DEGs were screened from the TCGA database, and 34 genes were found to be common to both databases; 10 core genes were screened from the PPI network. IGFBP1 was abnormally expressed in esophageal cancer. Cox regression confirmed that IGFBP1 is an independent risk factor, and prognostic analysis indicated that IGFBP1 is closely associated with poor prognosis. Gene mutation analysis showed that amplification mutations are the most common type of IGFBP1 gene mutation, and genetic alterations in IGFBP1 in ESCA patients are significantly associated with overall survival (OS) (p = 0.0002568). GO analysis indicated that IGFBP1-related differentially expressed genes were enriched in organic anion transport, epidermal development, apical cell components, and metal ion transmembrane transporter activity. Pathway enrichment based on the KEGG database illustrated the main enrichment of target genes in neuroactive ligand–receptor interactions, calcium signaling and cAMP signaling pathways. Additionally, remarkable differences in immune cell infiltration were observed between IGFBP1 high-expression and low-expression subgroups through tumor immune profiling. IGFBP1 expression differed significantly between esophageal cancer cells and normal esophageal epithelial cells, as detected by RT-qPCR (p < 0.05). Moreover, knockdown of IGFBP1 markedly inhibited the proliferation (p < 0.05) and migration abilities (p < 0.05) of TE-1 and Eca109 cells. Conversely, IGFBP1 overexpression facilitated these cellular processes. Conclusions: As a key oncogenic driver for ESCA, IGFBP1 may participate in the oncogenesis of ESCA, possibly influencing clinical outcomes via IGF signaling and the tumor microenvironment. Its dual functions in tumor and immune systems suggest it might be a candidate for ESCA immunotherapy research. Full article

Drug repurposing presents as a promising strategy in oncology, particularly for urological prostate and bladder cancers, where resistance to current therapy remains a challenge. This study evaluated the anticancer potential of three antiretroviral drugs, namely ritonavir (RIT), saquinavir (SAQ), and rilpivirine (RPV), in PC-3 and UM-UC-5 cancer cell lines, using MTT, clonogenic, wound healing, toxicity assessment with fibroblast cells, and DCFDA assays; this last method included efavirenz (EFV) and etravirine (ETV) for intracellular reactive oxygen species (ROS) production. RIT and SAQ showed stronger antiproliferative effects than RPV, with lower concentration- and cell-line-dependent activity, while clonogenic assays confirmed a reduction in long-term proliferation, particularly for RIT in both cell lines and SAQ for UM-UC-5. In contrast, effects on cell migration were limited for all drugs. ROS production was cell-dependent, with EFV increasing ROS in PC-3 and SAQ and RIT in UM-UC-5 cells. Generally, all drugs showed minimal toxicity in non-malignant cells, with SAQ exhibiting some toxicity but only for concentrations higher than those required for anticancer activity. Overall, these findings suggest that antiretroviral, especially protease inhibitors, may cause anticancer effects, although these are concentration- and context-dependent, and further investigation is needed to understand the mechanisms involved. Full article

Recent studies indicate that ferroptosis shows unique advantages in oncotherapy, particularly in reversing multidrug resistance (MDR). Despite current therapeutic advancements, the treatment of high-incidence malignancies with dismal prognoses continues to face challenges, including limited clinical efficacy, significant side effects, and drug resistance. In recent years, Chinese herbal medicine (CHM) has gained increasing attention in anti-tumor therapy. CHM bioactive components are highly effective in inducing tumor cell ferroptosis, inhibiting tumor proliferation and migration, and reversing drug resistance. Additionally, some components can protect normal cells and improve the tumor microenvironment. This review systematically summarizes the regulatory roles of various CHM bioactive components in ferroptosis across common human cancers. We further analyze the underlying molecular mechanisms, focusing on the modulation of key regulatory targets (e.g., GPX4, SLC7A11, and Nrf2) and critical signaling cascades (e.g., PI3K/AKT/mTOR and p53). Furthermore, the differential effects of bioactive compounds from CHM on common tumors were evaluated, alongside their potential in combination therapy. This review provides a theoretical foundation for the development of novel anticancer drugs targeting ferroptosis regulation and offers new perspectives for the clinical application of CHM in oncology. Full article

Chronic wounds are characterized by persistent inflammation and impaired fibroblast function, leading to defective tissue repair. Pannexin-1 (Panx1) channels regulate extracellular ATP release and purinergic signaling, processes implicated in inflammation and regeneration. Probenecid (PBN), a clinically approved Panx1 inhibitor, has emerged as a potential therapeutic modulator in chronic wounds; however, its compatibility with growth factor-mediated regenerative responses remains unclear. Here, we evaluated whether pharmacological inhibition of Panx1 alters βFGF-induced responses in human neonatal dermal fibroblasts (HDFn). Cells were treated with βFGF (10 ng/mL) in the presence or absence of PBN (200 μM), and migration, proliferation, extracellular matrix-related gene expression, extracellular ATP release, intracellular Ca²⁺ signaling, and Panx1 expression/localization were assessed. PBN did not significantly alter βFGF-induced migration, proliferation, or most extracellular matrix-related transcriptional responses, except for a further reduction in COL1A1 expression. In addition, βFGF did not modify PANX1 transcript levels, Panx1 protein abundance, or membrane localization. Although βFGF reduced extracellular ATP release and transiently modulated ATP-induced Ca²⁺ signaling, these effects occurred without detectable changes in Panx1 expression or localization. These findings support the compatibility of PBN with βFGF-driven regenerative responses in HDFn cells. Full article

Mechanisms of primary and acquired resistance are responsible for treatment failure with the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in the majority of patients with advanced Non-Small-Cell Lung Cancer (NSCLC) carrying EGFR-activating mutations. MicroRNAs (miRNAs) are important modulators of EGFR signaling in lung cancer. Recent studies suggested the role of miR-23c as a tumor suppressor or oncogenic miRNA in different tumor types. However, the role of miR-23c in NSCLC carrying EGFR mutations and its involvement in resistance to EGFR-TKIs has not been explored yet. We found that miR-23c was strongly downregulated in H1975 and HCC827-Gefitinib-Resistant (GR) NSCLC cell lines with intrinsic and acquired resistance to gefitinib, respectively, as compared to gefitinib-sensitive cell lines. Moreover, we demonstrated that miR-23c mimic inhibited proliferation, migration, invasion, and epithelial–mesenchymal transition of resistant cells and that Interleukin-6 Receptor (IL-6R) is a direct target of miR-23c in H1975 and HCC827-GR cell lines. Importantly, miR-23c mimic re-sensitized NSCLC-resistant cells to gefitinib, whereas the combination of miR-23c mimic with a neutralizing IL-6R antibody potentiated the sensitivity to the drug. Collectively, our data demonstrated that miR-23c acts as a tumor suppressor in NSCLC cell lines carrying EGFR mutations and that the axis miR-23c/IL-6R might represent a potential target for the development of therapeutic approaches to overcome resistance to gefitinib. Full article