Search Results (17,658)

Kahweol is an active diterpene with anti-inflammatory, antioxidant, and anticancer properties; however, its use may be limited by unfavorable pharmacokinetic characteristics. This study aimed to develop kahweol-loaded poly(lactic-co-glycolic acid) (PLGA) and red blood cell membrane-coated PLGA (RBC-PLGA) nanoparticles and evaluate their in vitro release behavior and in vivo pharmacokinetic profiles. Kahweol-loaded PLGA nanoparticles were prepared using the emulsification-solvent evaporation method and subsequently coated with rabbit erythrocyte membranes, a type of blood cell membrane, to obtain RBC-PLGA nanoparticles. Particle size, zeta potential, morphology, and encapsulation efficiency were characterized. In vitro release studies were performed using the dialysis bag method. Pharmacokinetic profiles of free kahweol, kahweol-loaded PLGA, and kahweol-loaded RBC-PLGA nanoparticles were evaluated in rabbits following intravenous administration (0.5 mg/kg), and plasma kahweol concentrations were analyzed by LC-MS/MS. PLGA and RBC-PLGA nanoparticles showed high encapsulation efficiency (>90%) and sustained biphasic release compared with the rapid burst release of free kahweol. Pharmacokinetic analysis demonstrated that PLGA and RBC-PLGA nanoparticles reduced peak plasma concentrations and prolonged systemic exposure. Among the nanoparticles, RBC-PLGA exhibited the most prolonged pharmacokinetic profile, with delayed time to maximum plasma concentration (T_max), extended half-life, and increased overall exposure. The nanoparticles improved the pharmacokinetic profile of kahweol by enabling sustained release and prolonged systemic exposure, supporting their potential as delivery platforms for future applications. Full article

Panaxadiol (PD) is a bioactive dammarane triterpenoid with limited antiproliferative potency, and systematic optimization of its C3 and C12 positions remains underexplored. Here, a stepwise, site-differentiated strategy was established by combining selective C3 esterification with late-stage C12 diversification through a chloroacetyl–piperazine linker, affording 23 PD derivatives and enabling complementary C3/C12 structure–activity analysis. Antiproliferative screening in AGS gastric cancer cells identified compounds 6, 11, and 17 as the most active analogues, with IC₅₀ values of 8.41, 5.08, and 6.78 μM, respectively, all outperforming 5-fluorouracil under identical conditions. Compound 6 provided a relatively favorable balance between low-micromolar activity and preservation of non-malignant GES-1 cells within a defined concentration range and was therefore selected for mechanistic investigation. Transcriptomic profiling identified 298 differentially expressed genes associated with cellular stress, cytokine signaling, epithelial growth regulation, and extracellular remodeling, whereas metabolomic analysis revealed marked perturbation of glycerophospholipid, choline, polyunsaturated fatty acid, and glutathione metabolism. Integrated analysis highlighted membrane-lipid remodeling, redox dysregulation, and ferroptosis-related processes as central features of the response. These findings establish a modular platform for PD optimization and identify compound 6 as a promising lead for further anti-gastric cancer development. Full article

Despite advances in oncology, cancer remains a leading cause of mortality worldwide, and both μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling have been implicated in the regulation of tumor proliferation, survival, and progression, positioning them as attractive targets for multifunctional anticancer strategies. In the present study, a series of novel casomorphin–ranatensin hybrid peptides were designed, synthesized, and evaluated as putative dual-target anticancer agents combining MOR and D2R pharmacophores. Among the evaluated analogues, KAZO_5.2 and KAZO_7.2 reduced viability of HCT116 colorectal cancer cells in a dose- and time-dependent manner, with a modest selectivity ratio compared to non-tumorigenic MCF 10A cells. Both compounds showed favorable docking scores toward MOR and D2R, while single 100 ns molecular dynamics trajectories showed that the peptides remained associated with their respective receptor models over the simulated timescale. Partial reversal of the viability-reducing effect by naloxone suggested involvement of opioid-sensitive pathways, while only low baseline MOR expression was detected in HCT116 cells under our experimental conditions, consistent with a possible contribution of additional receptor-mediated mechanisms to the observed activity. Neither compound induced pronounced apoptosis or cell cycle arrest, suggesting cytostatic rather than cytotoxic effects. Both peptides exhibited negligible hemolytic activity and high proteolytic stability in human plasma, with intact peptides remaining predominant after 24 h of incubation at 37 °C. These findings identify casomorphin–ranatensin hybrids as a promising scaffold for dual-target anticancer peptide development, warranting further structural optimization and mechanistic investigation. Full article

CD24 is an emerging innate immune checkpoint that regulates inflammatory and antiviral immune responses through interactions with Siglec family receptors. Although CD24 has been extensively studied in immune regulation and has recently gained attention as a therapeutic target in infectious and inflammatory diseases, its role in cancer remains incompletely understood. CD24 is overexpressed in multiple human malignancies, where accumulating evidence suggests that it promotes tumor progression and immune evasion through activation of diverse intracellular and extracellular signaling pathways. However, the importance of its subcellular localization and associated signaling remains poorly defined. Here, we investigated CD24 expression, localization, signaling associations, immune-cell infiltration, and clinical outcomes using publicly available cancer datasets, focusing on breast cancer (BRCA), cervical squamous cell carcinoma (CESC), and glioblastoma multiforme (GBM). Our analyses revealed prominent membrane-associated CD24 localization in BRCA and CESC, whereas CD24 was predominantly cytoplasmic in GBM. BRCA and CESC exhibited increased integrin β1 expression and distinct associations between CD24 and components of integrin β1/SRC and TGFβ-associated signaling networks, including MEK1 and SMAD7. In addition, we identified a structurally consistent and energetically favorable predicted interface between CD24 and Siglec-10, suggesting a mechanism by which CD24 may suppress anti-tumor immunity. Elevated CD24 expression was associated with immune-infiltration patterns consistent with an immunosuppressive tumor microenvironment in BRCA and CESC, including negative associations with M1 macrophage, CD8⁺ T-cell, and NK-cell infiltration. Importantly, high CD24 expression was associated with unfavorable overall survival in BRCA and CESC, whereas the opposite relationship was observed in GBM. Collectively, these findings suggest that the subcellular distribution of CD24 may be associated with distinct tumor signaling, the immune microenvironment, and prognostic profiles, highlighting the potential importance of CD24 localization in determining its tumor-type-specific biological functions. Full article

Background: Moroccans employ Eucalyptus globulus Labill., a medicinal herb, to cure a variety of ailments. This research aimed to evaluate the chemical constituents of Eucalyptus globulus essential oil (EGEO) to determine their composition and potential use as hemolytic, antioxidant, and antimicrobial agents. Methods: GC analysis was utilized to determine the composition of EGEO harvested in the province of Meknes. Using the disk diffusion technique, MIC, MBC, and MFC tests, antibacterial and antifungal activity were assessed against pathogenic microorganisms. DPPH, TAC, and FRAP experiments were used to evaluate the antioxidant potential of EGEO and Eucalyptol. The main chemical binding affinities were predicted by Molecular Docking analysis. GraphPad Prism (v8) was used to evaluate these findings using a Tukey and ANOVA analysis. Results: GC-MS revealed 27 components, including Eucalyptol (1,8-Cineole) (55.07%). Hemolysis recorded the greatest value, 8.16 ± 0.13. Staphylococcus aureus had the highest MIC values (1.25 mg/mL). Bacillus subtilis had a 65 mm inhibitory zone. The fungicidal effectiveness of EGEO and its major component varies according to the studied fungus strain. In terms of antioxidant characteristics, DPPH radical inhibition revealed that 1,8-Cineole has a higher IC₅₀ (4.7 ± 0.5 µg/mL). The Total Antioxidant Capacity was 22 ± 0.02 mg AAE/g. FRAP analysis showed that Eucalyptol is more potent than EGEO. Conclusion: Antimicrobial and antioxidant studies support the use of EGEO and eucalyptol in traditional and therapeutic medicine, and show their numerous possible uses as natural preservatives for perfumes and foods, as well as anticancer agents due to their hemolytic capacity. Full article

As of 2020, liver cancer has emerged as the fifth most common cancer and the third leading cause of cancer death worldwide, following lung and colorectal cancers. The most prevalent type is hepatocellular carcinoma (HCC), originating from hepatocytes. Despite advancements, liver cancer treatment outcomes remain poor due to metastasis and recurrence. Existing anticancer drugs often exhibit narrow therapeutic windows and limited selectivity for cancer cells. Manilkara zapota (L.) P. Royen has attracted significant scientific attention because of its diverse bioactive constituents and potential therapeutic properties. Of particular interest in this review, we explored the molecular connectivity of oxidative stress-induced liver cancer. We discussed the underlying mechanisms of Manilkara zapota (L.) P. Royen involved in cancer and inflammation. The phytochemical constituents were also highlighted in this study. The phytochemicals reported from Manilkara zapota (L.) P. Royen included flavonoids, tannins, saponins, and phenolic compounds. These compounds demonstrated potential anticancer activities through mechanisms such as induction of apoptosis, inhibition of cell proliferation, modulation of oxidative stress, and regulation of PI3K/Akt and NF-κB signaling pathways. Further investigations are required to clarify the benefit–risk profile of Manilkara zapota (L.) P. Royen through large-scale clinical trials. Collectively, the current evidence suggests that this plant may offer a promising strategy for cancer management, provided that such interventions are optimized to minimize adverse effects. Full article

Despite increasing awareness about cancer, it still remains one of the biggest threats to human life. Breast cancer is among the most commonly diagnosed types of cancer. Pentacyclic triterpenoids are a group of plant compounds commonly known in traditional medicine due to their anti-inflammatory, antibacterial, antidiabetic, cardioprotective and anticancer effects. This review examined the potential of pentacyclic triterpenoid acids in the treatment of breast cancer, focusing on research from the past 15 years. Although the subject literature demonstrates that pentacyclic acids show anticancer activity, it also reveals their limitations such as low bioavailability, aqueous solubility, or high IC₅₀ values. Therefore, to overcome these limitations, structural modifications, mostly at the C3 and C28 positions, were made, and several novel derivatives with oleanane, lupane and ursane skeletal types were synthesized. This review not only identified pentacyclic acids derivatives but also evaluated how structural modifications enhanced their biological activity and potential in breast cancer treatment. The findings revealed that even though the obtained derivatives enhanced anticancer potential against breast cancer, the main issues of bioavailability and solubility remain unsolved, suggesting that future research in synthesis should focus not only on improving cytotoxicity but also on the bioavailability of novel compounds. Full article

Doxorubicin (Dox)-induced cardiotoxicity (DIC) is a major clinical challenge in cancer therapy. Camel milk exosomes (CMEs) have been applied in anti-tumor treatments as they have a variety of effects, including on inflammation, oxidative stress, metastasis, and apoptosis. However, their role in DIC treatment remains incompletely understood. This research was designed to evaluate the protection provided by CMEs against DIC. The DIC mice were treated with Dox intraperitoneally and divided into a model group and groups treated with different doses of CMEs. Dox-induced H9c2 cell injury was also established and divided into a model group and groups treated with different concentrations of CMEs. The evaluation parameters in vitro included H9c2 cell viability, reactive oxygen species (ROS), mitochondria, and apoptotic cells. The apoptosis and autophagy markers, as well as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were assessed via Western blotting both in vivo and in vitro. In addition, transcriptome sequencing of cardiac tissue was also applied to investigate the related mechanisms. Our results indicate that CMEs significantly attenuated the cell viability reduction, apoptosis, and ROS production in H9c2 cells caused by Dox. CMEs also regulated autophagy, inhibited apoptosis, and inhibited the NF-κB and MAPK pathways. In conclusion, our findings demonstrate that CMEs exert a cardiac protective effect against DIC by inhibiting apoptosis and regulating autophagy via NF-κB and MAPK signaling pathways. Full article

The lymphocytic choriomeningitis virus (LCMV) represents a strong T cell activating virus with anti-tumoral properties. In recent work, we developed an attenuated cancer cell-adapted reassortant LCMV strain carrying tumor-tropic mutations. The immunological mechanisms underlying these mutations remained unknown. Here, we passaged wild-type LCMV-WE in human lung cancer H1975 cells for 52 passages. After 29 passages, the virus acquired the GP1 mutations I181M and R185W, involved in viral receptor interactions, which remained stable throughout the subsequent 33 passages. Compared with wild-type LCMV-WE, LCMV-P52 showed increased infectivity, partly concomitant with enhanced propagation in human tumor cells. In vivo, LCMV-P52 induced reduced type I interferon (IFN-I) responses and showed accelerated expansion in CD169⁺ macrophages. Propagation within the splenic marginal zone correlated with accelerated priming of virus-specific CD8⁺ T cells and limited liver tissue damage. Mechanistic in vitro experiments showed that the I181M and R185W mutations were associated with substantially reduced infection of plasmacytoid dendritic cells (pDCs). Collectively, the I181M and R185W mutations limit systemic IFN-I induction and accelerate LCMV propagation in CD169⁺ macrophages, correlating with improved CD8⁺ T cell function and reduced liver damage. These findings provide mechanistic insight into how defined GP mutations can modulate viral tropism and antiviral immune responses. Full article

Background: Ovarian cancer is frequently diagnosed at an advanced stage and remains one of the most lethal gynecologic malignancies. The development of multidrug resistance (MDR) during repeated chemotherapy is a major cause of treatment failure and is often associated with increased drug efflux mediated by transporters such as P-glycoprotein (P-gp). In this study, D-α-tocopheryl polyethylene glycol succinate (TPGS) and Soluplus^® (SOL) mixed micelles, abbreviated as TS, were developed to co-deliver apatinib (APA), a VEGFR-2 inhibitor, and etoposide (ETP), a topoisomerase II inhibitor, for MDR ovarian cancer models. The formulation was designed to improve the aqueous dispersion, cellular accumulation, and antitumor activity of APA and ETP. Methods: APA/ETP-loaded TS micelles (APA/ETP-mTS) were prepared and characterized in terms of particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), storage stability, and in vitro drug release. Anticancer efficacy was assessed using MTT assays, cellular uptake assays, and 3D tumor spheroid studies employing HeyA8-MDR cells, followed by in vivo toxicity and antitumor efficacy studies. Micellar formulations were denoted using the cargo–carrier format, where APA/ETP indicates co-loaded APA and ETP, C6 indicates coumarin-6 (C6) used as a fluorescent probe, mTS indicates TPGS/SOL mixed micelles, and mSOL indicates SOL-only micelles. Results: The selected APA/ETP-mTS formulation showed a particle size of 20.0 ± 5.1 nm, a PDI of 0.16 ± 0.05, near-neutral zeta potential, and encapsulation efficiencies exceeding 60% for both drugs. The micelles maintained colloidal stability at 4 °C for 4 weeks, although partial decreases in encapsulation efficiency were observed. Compared with APA/ETP solution, APA/ETP-mTS delayed the release of both drugs. C6-mTS showed higher intracellular fluorescence intensity than C6-mSOL, suggesting enhanced cellular accumulation associated with TPGS incorporation. APA/ETP-mTS showed greater cytotoxicity than free drugs in HeyA8-MDR monolayer cells and produced the strongest spheroid growth inhibition among the tested micellar formulations. In the HeyA8-MDR xenograft model, APA/ETP-mTS suppressed tumor growth and resulted in the lowest final tumor weight without apparent overt toxicity based on body weight and survival observations. Conclusions: These results suggest that APA/ETP-mTS is a promising micellar co-delivery platform for hydrophobic anticancer drugs in MDR ovarian cancer. Full article

Background/Objectives: Prostate cancer remains a major cause of cancer-related mortality in men. Arctigenin (ATG) and curcumin (CUR) exhibit anticancer activity; however, their combined effects on redox and metabolic stress remain incompletely understood. This study investigated the anticancer effects of combined ATG and CUR treatment in prostate cancer cells. Methods: PC-3 prostate cancer cells and normal human prostate epithelial (HPrEC) cells were treated with ATG and CUR alone or in combination. Cell viability, combination index, reactive oxygen species (ROS), GSH/GSSG ratio, ATP levels, AMPK phosphorylation, and apoptosis-related responses were evaluated. The contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC), and treatment effects were further assessed in three-dimensional (3D) spheroids. Results: Combined ATG and CUR treatment produced greater growth-inhibitory and apoptotic responses in PC-3 cells than in HPrEC cells and was synergistic under the tested condition in PC-3 cells. The combination increased ROS, reduced the GSH/GSSG ratio and ATP levels, increased AMPK phosphorylation, and enhanced apoptosis-related responses. NAC attenuated ROS accumulation, partially restored cell viability and ATP levels, and reduced caspase-3/7 activity in PC-3 cells. In 3D PC-3 spheroids, NAC also partially restored viability and ATP levels and attenuated increases in cleaved caspase-3 and cleaved PARP. Conclusions: Combined ATG and CUR treatment induces redox and metabolic stress and enhanced apoptotic responses in PC-3 cells, with weaker effects in HPrEC cells. NAC rescue supports a functional contribution of oxidative stress. These findings support an association between ROS-related metabolic stress, AMPK phosphorylation, and apoptotic signaling, while precise causal relationships require further investigation. Full article

Background/Objectives: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have recently gained attention for their potential anticancer properties. However, their effects in bladder cancer remain poorly understood. In this preliminary study, we assessed the effects of canagliflozin, dapagliflozin, and empagliflozin on metabolic activity, cell cycle distributions, migratory behavior, and SGLT2 expression in the human bladder cancer cell line T24. Methods: Cellular metabolic activity, cell cycle distribution, apoptosis and necrosis, migration, and SGLT2 protein expression were assessed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, wound-healing and single-cell migration assays, Western blotting, and fluorescence microscopy. Bioinformatic analyses of SLC5A2 were additionally performed. Results: All three compounds reduced MTT-derived metabolic activity in a concentration-dependent manner and induced G0/G1 cell-cycle accumulation without increasing apoptosis or necrosis after 24 h. Flozins also impaired collective wound closure and altered single-cell migration parameters, although replicate-level analysis showed no significant differences between individual treatment conditions and control after multiple-comparison correction. SGLT2 protein was detected in T24 cells and decreased following treatment, with compound-dependent differences in magnitude. Conclusions: Flozins affect metabolic activity, cell-cycle progression, wound closure, and migratory behavior in T24 cells. However, these findings do not establish SGLT2-specific mechanisms and were obtained at concentrations exceeding typical clinical plasma exposure. Further target-validation and mechanistic studies are required. Full article

Inocutis levis (I. levis) is a rare edible and medicinal macrofungus with a traditional history of consumption as a dietary supplement and functional food raw material. However, the material basis and molecular mechanisms underlying its anti-breast cancer activity remain unclear. The present work aimed to systematically investigate the anti-proliferative activity of WYS, an active mycelial fraction isolated from I. levis, against MCF-7 breast cancer cells and to explore its underlying mechanisms. Firstly, 152 metabolites were putatively annotated in the WYS fraction via ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with database matching. Through an integrated strategy combining network pharmacology and multi-algorithm machine learning screening, four core metabolites (dihydroartemisinin, cortisol, cinnamic acid, and guanosine) and five hub targets (CDK1, EGFR, TOP2A, FGF2, and KIT) were prioritized. Furthermore, 100 ns molecular dynamics simulations and molecular docking predicted favorable binding affinities between the core metabolites and their cognate target proteins and predicted that the anti-breast cancer effect of WYS may be associated with the regulation of cell cycle progression, mitochondrial apoptosis, and the MAPK signaling pathway. Subsequent in vitro functional assays validated that WYS inhibited the proliferation of MCF-7 cells in both dose- and time-dependent fashions, triggered G2/M phase arrest and intrinsic mitochondrial apoptosis, and inhibited the EGFR/MEK/ERK signaling axis, exhibiting limited cytotoxicity toward normal HUVEC cells. In vivo, WYS dose-dependently attenuated xenograft tumor growth, and its modulatory effects on cell cycle, apoptosis, and related signaling pathways were consistent with the in vitro observations. This study provides the first evidence that I. levis mycelial fraction WYS modulates EGFR/MEK/ERK-related signaling and induces G2/M cell cycle arrest, thereby exerting anti-proliferative and pro-apoptotic effects on MCF-7 breast cancer cells, providing a scientific basis for further investigation of I. levis as a functional food. Full article

Background: Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related mortality. Current therapies are limited by drug resistance and adverse effects, highlighting the need for new strategies. Panduratin A (PA), a chalcone from Boesenbergia rotunda, has reported anticancer activity. This study investigated the effects of PA in NSCLC cells and whether PA enhances tumor necrosis factor alpha (TNF-α)-associated cell death. Methods: Human NSCLC cell lines A549 and H1299 were treated with PA alone or in combination with TNF-α. Cytotoxicity and apoptosis were assessed using cell-viability assays, cell-number analysis, and flow cytometry. Western blotting was used to evaluate caspase-3 activation and PARP-1 cleavage. Cell-cycle distribution was analyzed to determine the impact of PA on cell-cycle progression. Results: PA reduced cell number and induced cell death in both A549 and H1299 cells, and co-treatment with TNF-α increased apoptosis compared with single-agent treatment. PA increased the G1-phase fraction and, in a concentration-dependent manner, reduced expression of thymidine kinase and cyclin A2, consistent with a G1-associated arrest phenotype. Combination treatment also increased the sub-G1 population. Conclusions: PA promotes apoptosis in NSCLC cells and enhances TNF-α-associated apoptotic cell death in vitro, accompanied by a G1-associated cell-cycle phenotype. These findings provide an in vitro framework for studying natural compounds as modulators of TNF-α-driven apoptosis and support further mechanistic validation in more disease-relevant models. Full article

Nickel(II) offers an appealing base for metallodrug design as it is abundant, inexpensive and forms well-defined complexes with N,O-donor ligands. Therefore, five Ni(II) complexes containing two tridentate 2-imine-8-hydroxyquinoline Schiff base ligands, derived from morpholine, piperidine, imidazole or 2-methyl-1H-limidazole, were synthesized and characterized in solution and solid state via analytical and spectroscopic techniques. Single crystals were solved using X-ray diffraction for the complex derived from 4-(2-aminopropyl)morpholine (1). This Ni(II) complex exhibits a distorted octahedrally coordinated Ni(II) center bound to two monodeprotonated NNO-tridentate ligands, adopting a meridional coordination mode, with the two oxygen atoms arranged cis to each other. The stability of the complexes in aqueous media buffered at pH 7.4 was evaluated with UV–Vis spectroscopy and their binding to bovine serum albumin (BSA) was assessed with fluorescence titrations. All complexes show strong reversible binding to BSA (K_SV ~10⁵), which stabilizes the lipophilic complexes in aqueous media. The antiproliferative activity of the complexes was screened against colon cancer cell lines (Colo205 and Colo320). They exhibit moderate anticancer activity (IC₅₀ = 15.1–92.5 μM), with structure–activity relationships favoring imidazole derivatives and maintaining activity against the doxorubicin-resistant cell line (Colo320) with resistance indices (1.3–3.1) comparable to or lower than doxorubicin. Overall, the complexes represent a platform to develop new anticancer Ni-based drugs. Full article