Search Results (161)

Sitosterol (Sito) is a phytosterol with bioactive properties, including reducing atherosclerosis risk and anti-inflammatory and antitumoral effects. However, it can be oxidized by reactive oxygen species such as ozone (O₃), producing oxyphytosterols with harmful effects such as cytotoxicity, oxidative stress, and proatherogenicity. Ozone, a strong oxidant and common pollutant, can alter plant steroid compounds, raising concerns about dietary oxyphytosterol intake. Studies identify β-Secosterol (βSec) as the primary ozone-derived oxyphytosterol from Sito, exhibiting cytotoxic effects on HepG2 human liver tumor cells. This study investigated βSec’s biological effects on two rat liver cell lines: BRL-3A (immortalized) and HTC (tumoral), examining cell death, cell cycle progression, morphology, and cytoskeleton organization. While Sito influenced cell metabolic activity without affecting cell survival or morphology, βSec demonstrated significant cytotoxicity in both cell lines. It induced G0/G1 cell cycle arrest and disrupted cytoskeleton organization, with different implications: BRL-3A cells showed persistent cytoskeletal changes potentially linked to tumor induction, while HTC cells displayed chemoresistance, restoring cytoskeletal integrity and enhancing metastatic potential. These findings reveal βSec’s complex, context-dependent effects, suggesting it may promote tumor-like behavior in non-tumoral cells and resistance mechanisms in cancer cells, contributing to understanding oxyphytosterols’ implications for physiological and pathological conditions. Full article

Parietaria judaica L. (alfavaca-de-cobra) was investigated as a potential source of anticancer compounds. Leaf extracts obtained using solvents of different polarities were evaluated for their phytochemical profiles and cytotoxic activities against a panel of human cancer cell lines (glioblastoma LN-229, lung NCI-H1563, breast MDA-MB-231, liver HepG2, renal 769-P, cervical HeLa, and melanoma A-375) and a noncancerous HEK-293 cell line. LC-ESI-MS/MS analysis confirmed that the extracts are rich in polyphenols, including phenolic acids and flavonoids. Cytotoxicity was assessed via MTT and SRB assays, demonstrating dose-dependent antiproliferative effects. Among the extracts, the ethanolic fraction (PJ-E) exhibited the strongest cytotoxicity, with an IC₅₀ of 11.82 µg/mL against HeLa cells, while displaying a significantly higher IC₅₀ (139.42 µg/mL) against HEK-293, indicating tumor selectivity. The water extract (PJ-W) showed selective activity against lung cancer cells (IC₅₀ = 87.69 µg/mL), with minimal toxicity toward normal cells. The methanol/acetone extract (PJ-M) displayed intermediate activity, whereas the hexane extract (PJ-H) was the least effective. These findings highlight P. judaica, particularly its ethanolic extract, as a promising source of natural anticancer agents. Further research focusing on the isolation of active constituents, formulation development, and in vivo validation is warranted to support its therapeutic potential. Full article

The Fabaceae family is known for the presence of isoflavones—phytoestrogens with potential chemopreventive effects against hormone-dependent cancers. This study aimed to optimize isoflavones extraction using a fractional factorial design and to quantitatively and qualitatively analyze 32 Fabaceae species native to Polish flora by HPLC-UV-VIS to indicate new, rich plant sources of isoflavones. The optimal extraction method was a 60 min reflux with 50% methanol and a plant material-to-solvent ratio of 1:125. The highest isoflavone levels were found in Trifolium medium (26.70 mg/g d.m.), Genista tinctoria (19.65 mg/g d.m.), and Trifolium pratense (12.56 mg/g d.m.). The obtained extracts were further evaluated for cytotoxic and antiproliferative activity against MCF7 and MDA-MB-231 human breast cancer cells. Genista tinctoria showed the highest cytotoxicity against MCF7, while Cytisus scoparius and Ononis arvensis were most effective against MDA-MB-231 at a dose of 500 µg/mL. The extracts were also characterized by varied, potent antioxidant properties, important in chemoprevention. A strong correlation was observed between isoflavone content and cytotoxic and antiproliferative activity exclusively in the estrogen receptor-positive MCF7 cell line. Importantly, the tested extracts demonstrated no toxic effects on normal human liver (HepG2), thyroid (Nthy-ori 3-1), or breast (MCF10A) cells, indicating a favorable safety profile. Full article

Wheat bran, rich in phenolic compounds like ferulic acid, possesses notable antioxidant properties that may contribute to cancer treatment strategies. This study examined the effects of hydrolyzed arabinoxylan oligomers (HAOs) linked with ferulic acid from hard wheat bran on three human cancer cell lines: colon cancer (SW480), liver cancer (HepG2), and cervical cancer (HeLa). Cells were cultured in a three-dimensional (3D) 0.5% PGS matrix and exposed to varying concentrations (100, 500, and 1000 μg/mL) of wheat bran antioxidants (WBA) extracts. Results show that WBA inhibited growth of SW480 cells, significantly reducing spheroid expansion and promoting dehydration. In contrast, HepG2 cells exhibited increased growth under WBA treatment, suggesting a non-toxic, growth-enhancing effect. No significant changes were observed in HeLa cell growth, with cell viability remaining high across all treatments. These findings highlight the selective influence of WBA on cancer cell behavior, underscoring its potential for targeted, personalized cancer therapies. This study provides valuable insights into the application of antioxidant-rich compounds for modulating specific cancer cell dynamics, paving the way for novel therapeutic approaches. Full article

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients’ quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum—CVE, Melissae extractum—ME, Taraxaci extractum—TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings. Full article

Near-infrared light (NIR)-responsive metal-based nanoparticles (NPs) could be used for tumour therapy. We examined how platinum (Pt), gold (Au), and core-shell Pt-Au NPs affect the viability of human hepatocellular carcinoma (HCC) cell lines (Hep3B, HepG2, and Huh7D-12) alone and in combination with NIR exposure. In addition, the expression of immune checkpoint molecules (ICMs) on the tumour cells was analysed. We revealed that the cytotoxicity and programmed cell death induction of Au and Pt-Au NPs toward HCC cells could be enhanced by NIR with 960 nm in a different way. Pt-Au NPs were the only particles that resulted in an additional temperature increase of up to 2 °C after NIR. Regarding the tumour cell immune phenotype, not all of the cells experienced changes in immune phenotype. NIR itself was the trigger of the alterations, while the NPs did not significantly affect the expression of most of the examined ICMs, such as PD-L1, PD-L1, HVEM, CD70, ICOS-L, Ox40-L, and TNFRSF9. The combination of Pt-Au NPs with NIR resulted in the most prominent increase of ICMs in HepG2 cells. We conclude that the thermotherapeutic effect of Pt-Au NP application and NIR could be beneficial in multimodal therapy settings in liver cancer for selected patients. Full article

Cardiotonic steroids modulate various aspects of the inflammatory response. The synthetic cardiotonic steroid γ-benzylidene digoxin 15 (BD-15), a digoxin derivative, has emerged as a promising candidate with potential immunomodulatory effects. However, its biological activity remains largely unexplored. This study investigated the anti-mycobacterial and anti-inflammatory effects of BD-15 in an in vitro macrophage infection model with Mycobacterium spp. Unlike digoxin, which showed significant toxicity at higher concentrations, BD-15 exhibited no cytotoxicity in RAW 264.7 cells (a murine macrophage cell line). Both compounds were evaluated in Mycobacterium smegmatis-infected RAW 264.7 cells, reducing bacterial burden without direct bactericidal activity. Additionally, both modulated pro-inflammatory cytokine levels, notably by decreasing tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels. BD-15 specifically reduced NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome expression and increased interleukin-10 (IL-10) production. Notably, BD-15 reduced colony-forming unit (CFU) counts in Mycobacterium tuberculosis-infected RAW 264.7 cells. Toxicity assays in HepG2 cells (a human liver cancer cell line) showed that BD-15 had minimal hepatotoxicity compared to digoxin, and both demonstrated negligible acute toxicity in an Artemia salina bioassay. These findings revealed the immunomodulatory effects of cardiotonic steroids in a bacterial infection model and highlighted BD-15 as a safer alternative to digoxin for therapeutic applications. Full article

Liver cancer is one of the most prevalent cancers worldwide. The first-line therapeutic drug sorafenib offers only a moderate improvement in patients’ conditions. Therefore, an approach to enhancing its therapeutic efficacy is urgently needed. It has been revealed that hepatocellular carcinoma (HCC) cells with heightened intracellular quiescin sulfhydryl oxidase 1 (QSOX1) exhibit increased sensitivity to sorafenib. QSOX1 is a secreted disulfide catalyst, and it is widely recognized that extracellular QSOX1 promotes the growth, invasion, and metastasis of cancer cells through its participation in the establishment of extracellular matrix. Inhibiting QSOX1 secretion can increase intracellular QSOX1 and decrease extracellular QSOX1. Such an approach would sensitize HCC cells to sorafenib but remains to be established. Since (−)-epigallocatechin-3-gallate (EGCG) has been demonstrated to be an effective inhibitor of α-fetal protein secretion from HCC cells, we screened QSOX1 secretion inhibition using polyphenolic compounds. We examined eight dietary polyphenols (EGCG, quercetin, fisetin, myricetin, caffeic acid, chlorogenic acid, resveratrol, and theaflavin) and found that EGCG and quercetin effectively inhibited QSOX1 secretion from human HCC cells (HepG2 or Huh7), resulting in high intracellular QSOX1 and low extracellular QSOX1. The combination of EGCG or quercetin, both of which change the cellular distribution of QSOX1, with sorafenib, which has no influence on the cellular distribution of QSOX1, exhibited multiple synergistic effects against the HCC cells, including the induction of apoptosis and inhibition of invasion and metastasis. In conclusion, our current results suggest that dietary EGCG and quercetin have the potential to be developed as adjuvants to sorafenib in the treatment of HCC by modulating the cellular distribution of QSOX1. Full article

Rhus typhina, an invasive plant species, contains valuable compounds that can be utilized in various fields. The main aim of this paper was to find the optimal conditions for extracting high amounts of bioactive compounds from R. typhina fruits using ultrasound-assisted and bead-beating techniques under different parameters (solvent concentration, solvent/solid ratio, extraction time, bead size, and material). A Box–Behnken design was applied for ultrasound-assisted extraction. The following process parameters were found to be optimal: 20/1 solvent/solid ratio (v/w), 61.51% aqueous ethanol, 10 min extraction time, with a composite desirability of 0.7719. The HPLC profile indicates that p-coumaric acid was the most abundant phenolic compound found in the BBE extract. The BBE extract was subjected to in vitro biological tests. The results indicate a high antimicrobial activity on Streptococcus pyogenes (20 mm inhibition zone) and Salmonella enterica (12 mm inhibition zone). A hemolysis rate of 19.85% was found at an extract concentration of 1000 µg/mL on sheep erythrocytes. We report for the first time the protective role of the extract on cell viability of human gingival fibroblasts, but also a weak antiproliferative effect on the HepG2 human liver cancer cell line. Overall, we conclude that R. typhina fruits are rich in bioactive compounds that can be recovered using proper extraction conditions. Further research is required to understand and valorize their biological potential. Full article

Hepatocellular carcinoma (HCC) is the most common form of liver cancer in humans, with an increasing incidence worldwide. The current study aimed to explore the molecular mechanisms that inhibit the proliferation of HepG2 cells, a hepatoblastoma-derived cell line. MSC-derived exosomes (UC-MSCs) were prepared with a median particle size (N50) of 135.8 nm. Concentrations of UC-MSCs ranging from 10 μg/mL to 1000 μg/mL were applied to HepG2 cell cultures and compared to untreated and anticancer drug-treated HepG2 cells. A combined approach was employed, integrating a proteomic analysis of UC-MSCs, metabolomic analysis of HepG2 cells, and transcriptomic profiling of HepG2 cells to decipher the inhibitory mechanisms of UC-MSC exosomes on HepG2 cell growth. Treatment with a high concentration of UC-MSCs led to a notable reduction in HepG2 cell viability, with survival decreasing by 65%. A proteomic analysis of UC-MSCs revealed enriched degranulation processes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in addition to the known exosomal pathways. Transcriptomic profiling showed distinct changes in the expression of genes related to hepatocellular diseases in UC-MSC-treated HepG2 cells, contrasting with changes observed in HepG2 cells treated with the chemotherapeutic agent doxorubicin (DOX). Combined with a metabolomic analysis, the detailed GO and KEGG pathway analyses indicated that pathways associated with neutrophil extracellular trap formation played a critical role in mediating protein degradation and suppressing central carbon metabolism in cancer cells. Our results revealed that the UC-MSC treatment mimicked molecular mechanisms similar to those involved in neutrophil extracellular trap formation, exhibiting effects on HepG2 cell growth suppression that differed from those of chemical cancer drugs. Notably, the UC-MSC treatment demonstrated that protein degradation in HepG2 cells was regulated through canonical signaling pathways activated by bacterial peptides in neutrophils. This research has provided valuable insights into the potential of MSC-derived exosomes as a therapeutic approach for cancer treatment in the future. Full article

Hydroxycamptothecin (HCPT) is commonly used in the treatment of liver cancer; however, its low water solubility and poor stability significantly limit its clinical application. In recent years, research on exosomes has deepened considerably. Exosomes possess a unique phospholipid bilayer structure, enabling them to traverse tissue barriers, which provides natural advantages as drug carriers. Nevertheless, delivering exosomes safely and efficiently to target cells remains a major challenge. In this study, we utilized the affinity of the SP94 peptide for human liver cancer cell receptors. HCPT was coated with exosomes in our experimental design, and the exosome membrane was modified with SP94 peptide to facilitate drug delivery to liver cancer cells. Exosomes were purified from bone marrow mesenchymal stem cells, and targeted peptides were attached to their surfaces via post-insertion techniques. Subsequently, HCPT was incorporated into the exosomes through electroporation. Using the HepG2 hepatoma cell line, we evaluated a series of in vitro pharmacodynamics and studied pharmacokinetics and tissue distribution in animal models. The results indicated that ligand-targeted, modified drug-carrying exosomes significantly enhance drug bioavailability, prolong retention time in vivo, and facilitate liver targeting. Moreover, this approach reduces drug nephrotoxicity, enhances anti-tumor efficacy, and lays the groundwork for the development of novel liver cancer-targeting agents. Full article

Interleukin-32γ (IL-32γ) has diverse functions in various malignancies. In this study, we investigated the role of IL-32γ in autophagy induction in liver cancer cells and delineated the underlying mechanisms. We found that the increased IL-32γ expression inhibited the growth, cell cycle progression, and migration of HepG2 and Hep3B cell lines; it also decreased the expression of related proteins. Furthermore, the IL-32γ overexpression induced autophagy, as indicated by the number of puncta, the expression of LC3, and the expression of autophagy-related markers. The expression levels of LAMP1, a protein essential for autophagosome formation, and colocalization with LC3 also increased. Big data analysis revealed that the expression of MET, a well-known target of autophagy, and the expression of mTOR and mTOR-related proteins were decreased by the IL-32γ overexpression. The combination treatment of MET inhibitor, cabozantinib (2 µM), and IL-32γ overexpression further increased the number of puncta, the colocalization of LC3 and LAMP1, and the expression of autophagy-related proteins. In vivo, liver tumor growth was suppressed in the IL-32γ-overexpressing mouse model, and autophagy induction was confirmed by the increased expression of LC3 and LAMP1 and the decreased expression of autophagy pathway markers (MET and mTOR). Autophagy was also decreased in the liver tumor sample of human patients. ROC curve and spearman analysis revealed that the expression levels of LC3 and IL-32γ were significantly correlated in human tumor serum and tissues. Therefore, IL-32γ overexpression induced autophagy in liver tumors through the suppression of MET and mTOR pathways critical for tumor growth inhibition. Full article

Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and STAT3 signaling pathways involved in inflammatory processes and cell proliferation in human liver cancer cells. Cell survival was assessed for cancer (HepG2) and normal (THLE-2) cell lines. Activation of NF-κB and STAT3 signaling pathways and the expression of proteins controlled by these pathways were estimated by Western blot, and qRT-PCR assessed the expression of NF-κB and STAT3 target genes. We also evaluated the impact on the selected kinases responsible for the phosphorylation of the studied transcription factors by MagneticBead-Based Multiplex Immunoassay. Among the thio-derivatives tested, especially derivatives 1 and 5, there was an impact on cell viability, cell cycle, apoptosis, and activation of NF-κB and STAT3 pathways in hepatocellular carcinoma (HCC), which confirms the possibilities of using them in combinatorial molecular targeted therapy of HCC. The tested synthetic thio-chalcones exhibit anticancer activity by initiating proapoptotic processes in HCC while showing low toxicity to non-cancerous cells. These findings confirm the possibility of using chalcone thio-derivatives in molecularly targeted combination therapy for HCC. Full article

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a–i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC₅₀ = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC₅₀ = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity. Full article

In this study, we hypothesized that biotinylated and/or glycidol-flanked fourth-generation polyamidoamine (PAMAM G4) dendrimers could be a tool for efficient drug transport into glioma and liver cancer cells. For this purpose, native PAMAM (G4) dendrimers, biotinylated (G4B), glycidylated (G4gl), and biotinylated and glycidylated (G4Bgl), were synthesized, and their cytotoxicity, uptake, and accumulation in vitro and in vivo were studied in relation to the transport mediated by the sodium-dependent multivitamin transporter (SMVT). The studies showed that the human temozolomide-resistant glioma cell line (U-118 MG) and hepatocellular carcinoma cell line (HepG2) indicated a higher amount of SMVT than human HaCaT keratinocytes (HaCaTs) used as a model of normal cells. The G4gl and G4Bgl dendrimers were highly biocompatible in vitro (they did not affect proliferation and mitochondrial activity) against HaCaT and U-118 MG glioma cells and in vivo (against Caenorhabditis elegans and Wistar rats). The studied compounds penetrated efficiently into all studied cell lines, but inconsistently with the uptake pattern observed for biotin and disproportionately for the level of SMVT. G4Bgl was taken up and accumulated after 48 h to the highest degree in glioma U-118 MG cells, where it was distributed in the whole cell area, including the nuclei. It did not induce resistance symptoms in glioma cells, unlike HepG2 cells. Based on studies on Wistar rats, there are indications that it can also penetrate the blood–brain barrier and act in the central nervous system area. Therefore, it might be a promising candidate for a carrier of therapeutic agents in glioma therapy. In turn, visualization with a confocal microscope showed that biotinylated G4B penetrated efficiently into the body of C. elegans, and it may be a useful vehicle for drugs used in anthelmintic therapy. Full article