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Background: Hepatocellular carcinoma (HCC) is an aggressive tumor with limited treatment options, and it is the third leading cause of cancer-related deaths. Hence, novel therapeutic strategies are required to treat HCC. Eupatorium chinense L. is a traditional Chinese medicine (TCM) that can effectively neutralize heat and smoothen the flow of "Qi" through the liver. However, the anti-HCC effects of Eupatorium chinense L. remain unknown., Purpose: The present study investigated the anti-HCC effects and the underlying mechanisms of the electrophilic sesquiterpenes isolated from E. chinense L. (EChLESs) in the regulation of ferroptosis and apoptosis in HCC cells., Study Design/methods: Cell viability was assessed by the MTT assay. Cell apoptosis was confirmed by flow cytometry and western blotting assay. Ferroptosis was assessed by flow cytometry, transmission electron microscopy, and western blotting assay. Ferritinophagy was detected by acridine orange staining and western blotting assay. Small interfering RNA of nuclear receptor coactivator 4 (NCOA4) was used to confirm the role of ferritinophagy in the therapeutic effect of EChLESs on HCC cells. A mouse xenograft model was constructed to determine the inhibitory effect of EChLESs on HCC in vivo., Results: EChLESs induced apoptosis by disrupting mitochondrial membrane potential depolarization and mitochondrial reactive oxygen species. EChLESs induced ferroptosis as noted by a significant increase in mitochondrial disruption, lipid peroxidation, and intracellular iron level and decreased glutathione level. The apoptosis inhibitor Z-VAD-FMK and lipid reactive oxygen species scavenger ferrostatin 1 attenuated EChLESs-induced cell death. NCOA4-mediated ferritinophagy through autophagic flux was the crucial pathway for ferroptosis induced by EChLESs. NCOA4 knockdown alleviated EChLESs-induced cell death. EChLESs controlled the expression of NCOA4 at the transcriptional and post-transcriptional levels. In the in vivo experiment, EChLESs suppressed HCC growth in the xenograft tumor mouse model., Conclusion: EChLESs enhances cell apoptosis through mitochondrial dysfunction and ferroptosis through NCOA4-mediated ferritinophagy. Thus, Eupatorium chinense L. could be a potential TCM for treating HCC., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier GmbH.)

A score model based on clinical characteristics in advanced hepatocellular carcinoma (HCC) patients treated with systemic chemotherapy of oxaliplatin-containing regimens was established to evaluate progression-free survival (PFS) and overall survival (OS). Thirty HCC patients eligible for radical resection were involved in the retrospective study, and these were divided into the good response group (complete response (CR)/partial response (PR) and the poor response group (stable disease (SD)/progression disease (PD). The median PFS and OS were compared in the two groups. PFS and OS combined with clinical characteristics were evaluated by univariate and multivariate analyses. The score model was defined with 1 score for each characteristic, and score model cut-off values were determined by the receiver operating characteristic curve (ROC) which describes treatment response. The median PFS was 10 and 2 months (p<0.001), and the median OS was 13 and 4 months (p=0.011) for the CR/PR and SD/PD groups, respectively. The score of 1 was the optimal cutoff value, with sensitivity ranging from 52.6 to 63.2% and specificity from 81.8 to 100% (AUC= 0.773, p=0.014). The median PFS for good and poor response groups was 9 months and 1month (p<0.001) and the median OS was 22 and 3months at p<0.001, respectively. Patients with scores above 1 had poor response, with median 3 months OS and 1 month PFS, and patients with scores of 0 and 1 established good response, with median 22 months OS and 9 months PFS, respectively.

The long-term survival benefit of treating unresectable hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE) rather than conservative treatment remains controversial. This retrospective case-control study evaluated the survival of patients with unresectable HCC treated with TACE, relative to that of patients who received best supportive care.From January 2002 to December 2010, 522 of 2386 consecutive patients with unresectable HCC were enrolled. Patients were treated with TACE (n = 347) or best supportive care (non-TACE; n = 175). A survival analysis compared the survival of the 2 groups, as well as only those at Barcelona Clinic Liver Cancer Classification (BCLC)-C and Child-Pugh-B (39 TACE, 61 non-TACE).The median follow-up was 5 months (0.15-106 months).The overall median survival of the TACE group (8.0 months) was significantly longer than that of the non-TACE (2.0 months; P ≤ .01). Of the patients at BCLC-C and Child-Pugh-B, the overall median survivals of the TACE and non-TACE patients were 6.0 and 2.0 months, respectively (P ≤ .01); and the 1, 2, 3, 5, and 8-year overall survival rates were significantly superior in the TACE group (P ≤ .01). For all the patients, the independent predictors of survival were treatment modalities, portal vein tumor thrombosis, alpha-fetoprotein, and BCLC stage. Regarding the TACE patients, contributors to prognosis were portal vein tumor thrombosis, alpha-fetoprotein level, and the number of TACE procedures.TACE for unresectable HCC was associated with longer survival compared with best supportive care, especially for patients at BCLC-C and Child-Pugh-B.

Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed, and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds.

Purpose: Alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and Golgi protein 73 (GP73) levels have been widely used as tumor markers for the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether these tumor markers could be used to monitor short-term treatment response and recurrence of HCC in patients undergoing radiofrequency ablation (RFA)., Methods: Between July 2012 and July 2013, 53 consecutive patients with newly diagnosed HCC were prospectively enrolled in this study. Among these, 32 patients underwent RFA, after which they were followed up prospectively at the First Hospital of Jilin University in China., Results: AFP, AFP-L3, and GP-73 values pre-RFA were not associated with tumor size, whereas AFP and GP-73 levels tended to be associated with tumor number, the presence of vascular invasion, deterioration of liver function, advanced-stage disease, and a poor performance status. GP-73 levels were dramatically elevated in the patients with hepatitis C-associated HCC. Neither pre-RFA nor 1-month post-RFA tumor marker values were associated with short-term outcome. The short-term recurrence rate of AFP-positive patients measured 1 month post-RFA was obviously higher than that of AFP-negative patients., Conclusions: AFP and GP-73 values were associated with clinical variables representing tumor growth and invasiveness, and the AFP value measured 1 month post-RFA was a strong predictor of short-term recurrence in patients with HCC.

This experiment was designed to compare the effect of two selenium sources at the dosage of therapeutic level on hepatocarcinogenesis and angiogenic cytokines in DEN-induced hepatocarcinoma rats to further approach their possible anticancer's mechanism. One hundred and seventy-eight Sprague-Dawley (SD) rats (average weight being 100-120g) were randomly divided into 5 groups (I-V). Animals in group I, group II and group III served as the negative control, sodium selenite control (SS) and positive controls respectively, and received 0.1, 3.0, and 0.1mg/kg selenium from sodium selenite supplemented diets during the whole experimental time. Rats in group IV and group V were fed with selenium from selenium-enriched malt (SEM) and sodium selenite (SS) supplemented diets (3mg/kg respectively). To balance the nutritional content among each group, normal malt which was not treated with selenium was added into the diets of the challenge groups. The nutrition contents, except the selenium of the diet in each group, were similar and in accordance with NRC standards. Rats in groups III-V were treated by aqueous diethylnitrosamine solution (100mg/L) at the dosage of 10mg/kg body weight every day for 16 weeks to induce hepatocarcinoma, and drank sterilized water for an additional two weeks. Rats in group I and group II drank sterilized water throughout the experiment. At 4th, 8th, 12th, 16th week, five rats in each group were then sacrificed by cervical decapitation. At the termination of the study, at 18th week, the surplus rats were sacrificed by cervical decapitation. Feed was withheld from the rats for 12h before sampling. The number of hepatoma nodules in liver and mortality of rats were calculated. The values of the following items, including α-fetoprotein (AFP), gamma-glutamyltranspeptidase (GGT), tumor necrosis factor-α (TNF-α), insulin-like growth factors-II (IGF-II), nitric oxide (NO) and total nitric oxide synthase (T-NOS) in plasma were determined. At the same time, the positive numbers of vascular endothelial growth factor (VEGF) and protein kinase C-α (PKCα) staining cells in tumor tissue were analyzed by immunohistochemistry using the Envision two step methods with a kit. The results indicated that SEM could significantly decrease the mortality of rats and the number of hepatoma nodules, values of GGT and AFP, and the levels of IGF-II, NO and NOS and lessen the positive numbers of VEGF and PKCα staining cells in tumor tissue. Moreover, SEM could increase the levels of TNF-α in the initiated time of hepatocarcinogenesis, whereas, decrease the levels of TNF-α in the progressive time of hepatocarcinogenesis. SS could only significantly inhibit the positive numbers of PKCα staining cells in tumor tissue, decrease the levels of GGT, AFP and TNF-α at minority sampling times, and increase the levels of NO. In conclusion, SEM could reduce the mortality. It might be related to deaden significantly the lesion of liver, delay the cause of hepatocarcinogenesis, and inhibit the progress of angiogenesis to increase the livability of DEN-induced hepatocarcinoma rats. SS at the same therapeutic dosage had less effect on the hepatocarcinogenesis by inhibiting angiogenesis and relative cytokines to some extent., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Objective: To explore the clinical value of Fuzheng Yiliu Recipe (FYR) combined with microwave ablation on hepatocellular carcinoma., Methods: Sixty patients with hepatocellular carcinoma were randomly assigned to the control group and the treatment group according to the random digit table, 30 in each group. Patients in the control group received microwave ablation therapy, while those in the treatment group received FYR three days after microwave ablation. The therapeutic course was 6 months. By the end of the treatment, the short-term objective therapeutic efficacy, the liver function, the hepatic fibrosis index, the cellular immune function were statistically analyzed between the two groups., Results: The indices of the liver function, the hepatic fibrosis, and the cellular immune function were more significantly improved in the treatment group than in the control group (P < 0.05). The CD4+ level and the ratio of CD4+/CD8+ of the treatment group were remarkably higher than those of the control group (40.38 +/- 12.47 vs 28. 19 +/- 6.59, 1.49 +/- 0.41 vs 1.22 +/- 0.31). The tubercle recurrence rate of the treatment group (14.0%, 7/50) was significantly lower than that of the control group (33.3%, 15/45) after 6 months of treatment (P < 0.05)., Conclusion: FYR combined with microwave ablation could elevate the therapeutic efficacy, enhance the patients' immunity, improve the liver function and the hepatic fibrosis degree.

One hundred and ninety-three Sprague-Dawley (SD) rats (average body weight being 100-120 g) were randomly divided into 5 groups (I-V). Animals in group I and group II served as the negative control and positive control, respectively, and both received 0.1 mg/kg selenium (Se) from sodium selenite. Animals in groups III-V were fed with Se from Se-enriched malt (SEM) supplemented diets (0.3, 1 and 3 mg/kg, respectively). Simultaneously, hepatocarcinoma were induced in groups II-V by diethylnitrosamine (DEN) solution (100 mg/L) at the dosage of 10 mg/kg body weight every day as drinking water for 16 weeks, then sterilized water for a further two weeks. Rats of group I drank sterilized water during the whole experimental time. At 4th, 8th, 12th, 16th week, five rats in each group were then sacrificed by cervical decapitation. At the termination of the study, at 18th week, the surplus rats were sacrificed by cervical decapitation. Feed was withheld from the rats for 12h before sampling. The values of plasma glucose at different sampling times were measured. The values of the hormones in plasma related to plasma glucose metabolism, including insulin, glucagon, insulin-like growth factors-II (IGF-II), and the ratios of insulin/glucose (IGR(1)), insulin/glucagon (IGR(2)) and glucagon/glucose (GGR) were determined. At the same time, the correlation of plasma glucose concentrations related to hormones was statistically analyzed. The results indicated that the values of plasma glucose, insulin, glucagon and GGR in the groups treated with DEN were decreased significantly as compared with that of the negative control group, however, the values of IGF-II and IGR(2) were increased significantly. SEM showed a significant effect in suppressing the decreased of plasma glucose and glucagons, and delaying the increased of IGF-II and IGR(2) in the DEN-induced hepatocarcinoma rats. The plasma glucose concentrations revealed a significant relation to the hormones. In conclusion, SEM could reduce the development of hypoglycemia in the DEN-induced hepatocarcinoma rats by regulating the relative levels and balances or proportions of hormones.