Search Results (5,190)

Porcine recombinant NK-lysin (prNK-lysin) has been shown to inhibit the proliferation and metastasis of hepatocellular carcinoma (HCC) cells in vitro. However, its effects on the proliferation and metastasis of HCC cells in vivo remain unclear. In this study, an allograft murine model using the murine HCC cell line Hepa1-6 was employed to investigate the anticancer effects of prNK-lysin. Initially, the in vitro anticancer efficacy of prNK-lysin was evaluated in Hepa1-6 cells, demonstrating that prNK-lysin effectively inhibited both proliferation and metastasis. These effects were mediated through the induction of oncosis and suppression of Fascin-1, MMP-2, and MMP-9 protein expressions. Subsequently, the in vivo anticancer efficacy of prNK-lysin was assessed using a mouse liver orthotopic implantation model and a lung metastasis model of Hepa1-6 cells in BALB/cA-nu mice. The administration of 13 mg/kg of prNK-lysin could inhibit tumor growth in the liver and metastasis to the lungs. Our results demonstrate that prNK-lysin possesses strong anti-HCC effects both in vitro and in vivo, with the induction of oncosis and the inhibition of Fascin-1, MMP-2, and MMP-9 protein expressions as potential molecular mechanisms for its anticancer activity. Full article

Hepatitis B virus (HBV) infection remains a global health challenge, affecting over 254 million individuals chronically and contributing significantly to cirrhosis, liver failure, and hepatocellular carcinoma. Despite advancements in antiviral therapy, HBV reactivation remains a critical concern, particularly in immunosuppressed individuals, including non-transplant patients undergoing immunosuppressive therapy and solid organ transplant recipients. This review provides screening and management strategies for HBV reactivation in these populations. Full article

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocellular carcinoma (HCC), acting as a tumor suppressor in early stages by inducing cell cycle arrest and apoptosis, and as a promoter in advanced stages by fostering tumor progression, epithelial–mesenchymal transition (EMT), and metastasis. Understanding TGF-β’s role in HCC progression, particularly its impact on tumor–stroma interactions, is crucial for developing personalized therapies. This study aims to clarify TGF-β function in HCC using patient-derived cell lines and advanced 2D and 3D culture models. Three new cell lines (HLC21, HLC19 tumoral, and HLC19 metastatic) were isolated from HCC patient biopsies, characterizing their phenotypic markers and responses to TGF-β and its inhibitor, galunisertib. HLC21 cells displayed a mixed epithelial–mesenchymal phenotype, responding to TGF-β suppressing growth and undergoing EMT, which were inhibited by galunisertib. Conversely, HLC19 tumoral and metastatic cells exhibited mesenchymal phenotypes and were resistant to both TGF-β suppression and galunisertib effects. In 3D co-cultures with hepatic fibroblasts, TGF-β inhibitory effects were diminished for responsive cell lines, while resistant lines maintained their non-responsiveness. These findings highlight TGF-β’s dual role in HCC and its influence on tumor–stroma crosstalk, offering valuable models for exploring personalized anti-TGF-β therapies based on tumor characteristics. Full article

Background: Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied. Methods: The cell viability, proliferation, and cuproptosis-related protein levels were detected to investigate whether EGCG enhances the sensitivity of HCC cells to cuproptosis. The intracellular copper level, related copper metabolism proteins, and gene expression were detected to explore the mechanisms. In addition, a nude mouse xenograft model was established to determine the effects of EGCG on cuproptosis in tumor tissues. Results: The combination of EGCG and copper ionophores significantly enhanced the mortality of HCC cells and heightened the sensitivity of HCC cells to cuproptosis. There was a notable reduction in the expression of copper export protein copper-transporting P-type ATPase (ATP7B). EGCG effectively suppressed metal regulatory transcription factor (MTF1) expression and subsequently hindered the transcriptional regulation of ATP7B. EGCG also facilitated the intratumoral accumulation of copper and augmented susceptibility to cuproptosis in vivo. Conclusions: EGCG can increase the sensitivity of hepatocellular carcinoma cells to cuproptosis by promoting intracellular copper accumulation through the MTF1/ATP7B axis. Full article

Background/Objective: Hepatocellular carcinoma (HCC) is an aggressive disease that is known to be resistant to conventional chemotherapy and radiotherapy. While surgical resection and transarterial therapy can improve overall survival, the biological aspects of HCC contribute to the complexity of its management and limit the effectiveness of current treatment options. The purpose of this scoping review is to identify the limitations of the currently available therapies for HCC and explore the emerging role that histotripsy could play in addressing these limitations, with the intent of informing the direction of future research and clinical management. Methods: The PRISMA checklist for scoping reviews was followed to structure this review, and a systematic search was conducted in the following online databases: PubMed/MEDLINE (National Library of Medicine), Embase (Elsevier), and Scopus (Elsevier). Results: The current evidence supports that histotripsy offers several key advantages that address the limitations of the current treatment strategies for HCC. Clinical trials have highlighted the ability of this technology to destroy solid tumors and induce remission with minimal side effects. In addition, current preclinical studies point to the potent immunostimulatory effects of histotripsy, including the induction of abscopal effects. This poses significant promise in treating tumor metastasis as well as improving clinical regimens by combining histotripsy with immunotherapy. Future research should aim to overcome the current limitations of histotripsy and enhance clinical outcomes for patients. This review examines existing treatments for HCC, emphasizing the promising potential of combining histotripsy with immunotherapy to target the metastatic and advanced stages of the disease. Full article

Background/Objectives: The molecular heterogeneity and metabolic flexibility of Hepatocellular Carcinoma (HCC) pose significant challenges to the efficacy of systemic therapy for advanced cases. Early screening difficulties often delay diagnosis, leading to more advanced stages at presentation. Combined with the inconsistent responses to current systemic therapies, HCC continues to have one of the highest mortality rates among cancers. Thus, this paper seeks to contribute to the development of systemic therapy options through the consideration of HCC’s metabolic vulnerabilities and lay the groundwork for future in vitro studies. Methods: Transcriptomic data were used to calculate single and double knockout options for HCC using genetic Minimal Cut Sets. Furthermore, using QSAR modeling, drug repositioning opportunities were assessed to inhibit the selected genes. Results: Two single knockout options that were also annotated as essential pairs were found within the pyrimidine metabolism pathway of HCC, wherein the knockout of either DHODH or TYMS is potentially disruptive to proliferation. The result of the flux balance analysis and gene knockout simulation indicated a significant decrease in biomass production. Three machine learning algorithms were assessed for their performance in predicting the pIC50 of a given compound for the selected genes. SVM-rbf performed the best on unseen data achieving an R² of 0.82 for DHODH and 0.81 for TYMS. For DHODH, the drugs Oteseconazole, Tipranavir, and Lusutrombopag were identified as potential inhibitors. For TYMS, the drugs Tadalafil, Dabigatran, Baloxavir Marboxil, and Candesartan Cilexetil showed promise as inhibitors. Conclusions: Overall, this study suggests in vitro testing of the identified drugs to assess their capabilities in inducing pyrimidine starvation on HCC. Full article

Background and Objectives: Primary liver cancer is a major cause of mortality, ranking third among the most fatal cancers. In Egypt, liver cancer constitutes 11.75% of gastrointestinal malignancies, with HCC representing 70.5% of cases. The landscape of HCC management was revolutionized by locoregional modalities, which offer a comparable alternative to conventional techniques, with low complications and minimal invasiveness. RFA is a technique that is suitable for early-stage lesions in the liver, with a high overall survival and low complication rates. However, the associated complications cause potential mortality and morbidity. The proper selection of patients may avoid such complications. This study presents a five-year experience of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) in Egypt, analyzing the predictors of complications and the computed tomography (CT) features associated with complications post-ablation. Materials and Methods: The study included 1000 cases (84% males with a mean age of 60), with 90% having HCC. Exclusion criteria included prior chemoembolization and non-HCC primary hepatic tumors. Patients underwent RFA at Cairo University Hospital and two private centers from January 2014 to January 2019. The workup involved clinical assessments, lab tests, and CT scans. Complications were classified as major or minor. Statistical analysis was conducted via SPSS software Version 22.0, with associations evaluated using a chi-square test. A decision tree was employed to determine the predictive values for different variables associated with the complications. Results: Overall, the rate of complications was 4%, and mortality stood low at 0.1%. Subcapsular lesions were associated with complications, as well as the lesion size, site, Child–Pugh classification, and the number of RFA sessions. Decision tree analysis determined the size of a lesion to be the most predictive factor of major complications, whereas the site of the lesion predicted the occurrence of minor complications. Conclusions: RFA offers low complication rates; however, precise patient selection is critical. The approach and imaging modality choice influence the outcomes. Clinician experience enhances early complication detection, thereby allowing for effective treatments. Full article

Background/Objectives: Tartrazine (TRZ), a synthetic red azo dye derived from coal tar, is widely used as a food colorant in various food products, pharmaceuticals, and cosmetics. This study aims to investigate the impact of TRZ on the expression levels of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) and histone deacetylases (HDAC5 and HDAC6). Additionally, we evaluate genomic DNA stability using the alkaline comet assay in three human cell lines: immortalized human keratinocyte (HaCaT), human hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). The research question focuses on whether TRZ exposure alters epigenetic regulation and DNA integrity, potentially implicating its role in carcinogenesis. Methods: The selected human cell lines were exposed to different concentrations of TRZ (20 µM, 40 µM, and 80 µM), with DMBA serving as a positive control. After treatment, we quantified the expression levels of DNMT1, DNMT3a, DNMT3b, HDAC5, and HDAC6 using quantitative real-time PCR. Additionally, we assessed DNA fragmentation via the alkaline comet assay to determine the extent of DNA damage resulting from TRZ exposure. Results: Our findings indicate that TRZ significantly upregulates the expression of HDAC5, HDAC6, DNMT1, DNMT3a, and DNMT3b in comparison to the control group. Furthermore, TRZ exposure leads to a notable increase in DNA damage, as evidenced by elevated tail moments across all examined human cell lines. Conclusions: These results suggest that TRZ may play a role in carcinogenesis and epigenetic modifications. The observed upregulation of DNMTs and HDACs, coupled with increased DNA damage, highlights the potential risks associated with TRZ exposure. Further research is necessary to explore these mechanisms and assess their implications for human health. 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

Background/Objectives: The Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma (HCC) was updated in 2022 to refine patient stratification, particularly in patients with intermediate-stage (BCLC B) HCC. Although transarterial chemoembolization (TACE) remains a key treatment for these patients, there is no prognostic model for survival outcomes based on the pretreatment factors of patients who meet the updated 2022 BCLC indications for TACE. The aim of this study was to develop a pretreatment risk model predicting overall survival (OS) in patients with intermediate-stage HCC and reclassified as candidates for TACE according to the updated 2022 BCLC criteria. Methods: This retrospective study included 658 HCC patients treated with first-line TACE according to the updated BCLC 2022 guidelines. Pretreatment factors such as the Child–Pugh score, tumor burden (up-to-11 criteria), bilobar tumor involvement, and serum alpha-fetoprotein (AFP) levels were analyzed. Cox proportional hazards models were used to identify significant predictors of OS, with these factors subsequently incorporated into a risk prediction model. Results: Significant predictors of OS included Child–Pugh score ≥ 7, bilobar tumor involvement, beyond up-to-11 criteria, and AFP ≥ 400 ng/mL. A risk model was developed using these factors, stratifying patients into low-, intermediate-, and high-risk groups. The median OS in the low-, intermediate-, and high-risk groups was 53, 35, and 21 months, respectively. Conclusions: The proposed pretreatment risk prediction model may be useful for predicting OS and guiding TACE candidacy in intermediate-stage HCC patients based on the updated 2022 BCLC guidelines. Full article

Background/Objectives: To develop a decision framework integrating computed tomography (CT) radiomics and clinical factors to guide the selection of transarterial chemoembolization (TACE) technique for optimizing treatment response in non-resectable hepatocellular carcinoma (HCC). Methods: A retrospective analysis was performed on 151 patients [33 conventional TACE (cTACE), 69 drug-eluting bead TACE (DEB-TACE), 49 degradable starch microsphere TACE (DSM-TACE)] who underwent TACE for HCC at a single tertiary center. Pre-TACE contrast-enhanced CT images were used to extract radiomic features of the TACE-treated liver tumor volume. Patient clinical and laboratory data were combined with radiomics-derived predictors in an elastic net regularized logistic regression model to identify independent factors associated with early response at 4–6 weeks post-TACE. Predicted response probabilities under each TACE technique were compared with the actual techniques performed. Results: Elastic net modeling identified three independent predictors of response: radiomic feature “Contrast” (OR = 5.80), BCLC stage B (OR = 0.92), and viral hepatitis etiology (OR = 0.74). Interaction models indicated that the relative benefit of each TACE technique depended on the identified patient-specific predictors. Model-based recommendations differed from the actual treatment selected in 66.2% of cases, suggesting potential for improved patient–technique matching. Conclusions: Integrating CT radiomics with clinical variables may help identify the optimal TACE technique for individual HCC patients. This approach holds promise for a more personalized therapy selection and improved response rates beyond standard clinical decision-making. Full article

Background: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two distinct types of primary liver cancer (PLC) characterized by considerable extents of cellular and molecular heterogeneities. We recently developed a web-based cell atlas called LiverSCA that possesses a user-friendly interface and comprehensive functionalities. It facilitates the exploration of gene expression patterns, cellular compositions, and intercellular communication within the microenvironments of liver and PLC tumors. Methods: To further enhance the documentation of data pinpointing different phenotypes/subtypes of liver and PLC, we extended the catalog of LiverSCA with additional datasets, e.g., ICC and metabolic dysfunction-associated steatotic liver disease/steatosis (MASLD/MASH). Results: The current enhanced version of the LiverSCA cell atlas encompasses six phenotypes (normal, HBV-HCC, HCV-HCC, non-viral HCC, ICC, and MASH), 63 patients, and over 248,000 cells. Furthermore, we have incorporated comparative visualization methods that allow users to simultaneously examine and compare gene expression levels between two different phenotypes. Conclusions: We are committed to the continuous development of LiverSCA and envision that it will serve as a valuable resource to support researchers in convenient investigations into the cellular and molecular landscapes of liver and PLC. Full article

Background/Objectives: Natural substances have been a widely studied source of both pharmaceutical excipients and drugs. Berberine (BRB) is a benzylisoquinoline alkaloid isolated from different plant sources. It possesses various pharmacological properties including antibacterial, antitumor, antidiabetic, neuroprotective, hepatoprotective, anti-inflammatory, antioxidant, etc. However, the limited aqueous solubility hinders its application. Nanosized drug delivery systems are an innovative approach for addressing various challenges regarding drug delivery via different routes of administration. Their utilization could improve the solubility of active constituents. Methods: A melt-emulsification and ultrasonication technique was applied for the preparation of nanostructured lipid carriers (NLCs). They were thoroughly physicochemically characterized by the means of Dynamic Light Scattering, TEM, FTIR, DSC, TGA, and In Vitro release. The In Vitro efficacy and safety were evaluated on cholangiocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, lymphoma, fibroblast, and cardioblast cells, as well as rat liver microsomes by means of cytotoxicity assays and the comet assay. Results: The obtained nanoparticles had a spherical shape and size around 158.2 ± 1.8 nm with negative zeta potential. They revealed successful drug loading and improved dissolution of berberine in physiological conditions. The In Vitro safety studies showed that loading BRB in NLCs resulted in improved or retained cytotoxicity to tumor cell lines and reduced cytotoxicity to normal cell lines and liver microsomes. The NLC itself increased microsomal malondialdehyde (MDA) and comet formation. Conclusions: A successful preparation of NLCs with berberine is presented. The nanocarriers show favorable physicochemical and biopharmaceutical properties. The cellular experiments show that the NLC loading of berberine could improve its anticancer efficacy and safety. These findings highlight the potential applicability of berberine in gastrointestinal neoplasms and build the foundation for future practical translation. Full article

The transcription factor carbohydrate response element binding protein (ChREBP) has emerged as a crucial regulator of hepatic glucose and lipid metabolism. The increased ChREBP activity involves the pro-oncogenic PI3K/AKT/mTOR signaling pathway that induces aberrant lipogenesis, thereby promoting hepatocellular carcinomas (HCC). However, the molecular pathogenesis of ChREBP-related hepatocarcinogenesis remains unexplored in the high-fat diet (HFD)-induced mouse model. Male C57BL/6J (WT) and liver-specific (L)-ChREBP-KO mice were maintained on either a HFD or a control diet for 12, 24, and 48 weeks, starting at the age of 4 weeks. At the end of the feeding period, mice were perfused, and liver tissues were formalin-fixed, paraffin-embedded, sectioned, and stained for histological and immunohistochemical analysis. Biochemical and gene expression analysis were conducted using serum and frozen liver tissue. Mice fed with HFD showed a significant increase (p < 0.05) in body weight from 8 weeks onwards compared to the control. WT and L-ChREBP-KO mice also demonstrated a significant increase (p < 0.05) in liver-to-body weight ratio in the 48-week HFD group. HFD mice exhibited a gradual rise in hepatic lipid accumulation over time, with 24-week mice showing a 20–30% increase in fat content, which further advanced to 80–100% fat accumulation at 48 weeks. Both dietary source and the increased expression of lipogenic pathways at transcriptional and protein levels induced steatosis and steatohepatitis in the HFD group. Moreover, WT mice on a HFD exhibited markedly higher inflammation compared to the L-ChREBP-KO mice. The enhanced lipogenesis, glycolysis, persistent inflammation, and activation of the AKT/mTOR pathway collectively resulted in significant metabolic disturbances, thereby promoting HCC development and progression in WT mice. In contrast, hepatic loss of ChREBP resulted in reduced hepatocyte proliferation in the HFD group, which significantly contributed to the impaired hepatocarcinogenesis and a reduced HCC occurrence in the L-ChREBP-KO mice. Our present study implicates that prolonged HFD feeding contributes to NAFLD/NASH, which in turn progresses to HCC development in WT mice. Collectively, hepatic ChREBP deletion ameliorates hepatic inflammation and metabolic alterations, thereby impairing NASH-driven hepatocarcinogenesis. Full article

Exosomes are nanosized extracellular vesicles secreted by various cells, including natural killer (NK) cells, and are known for their low toxicity, high permeability, biocompatibility, and strong targeting ability. NK cell-derived exosomes (NK-exos) contain cytotoxic proteins that enhance tumor-targeting efficiency, making them suitable for treating solid tumors such as hepatocellular carcinoma (HCC). Despite their potential in drug delivery, the mechanisms of drug-loaded NK-exos, particularly those loaded with doxorubicin (NK-exos-Dox), remain unclear in HCC. This study explored the anti-tumor effects of NK-exos-Dox against Hep3B cells in vitro. NK-exos-Dox expressed exosome markers (CD9 and CD63) and cytotoxic proteins (granzyme B and perforin) and measured 170–220 nm in size. Compared to NK-exos, NK-exos-Dox enhanced cytotoxicity and apoptosis in Hep3B cells by upregulating pro-apoptotic proteins (Bax, cytochrome c, cleaved caspase 3, and cleaved PARP) and inhibiting the anti-apoptotic protein (Bcl-2). These findings suggest that NK-exos-Dox significantly boost anti-tumor effects by activating specific cytotoxic molecules, offering promising therapeutic opportunities for solid tumor treatment, including HCC. Full article