Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis.

Hepatocellular carcinoma (HCC) constitutes a major global health threat due to the high incidence and mortality. Sorafenib is known as the first-line medication for advanced HCC; however, it only extends the limited benefit for HCC patients as the development of acquired resistance. Withaferin A exerts broad pharmaceutical applications in several cancers. However, its effects on HCC cell metastatic potential and sorafenib resistance remain elusive. Here, we corroborated that Withaferin A greatly restrained cell viability, invasion, vasculogenic mimicry (VM) formation, and VE-cadherin levels in HepG2 and SNU449 cells. Moreover, Withaferin A sensitized sorafenib (SR)-resistant HCC cells to sorafenib. In striking contrast to the parental cells, lower ferroptosis was observed in SR-resistant cells as the lower ROS, MDA, and higher intracellular GSH levels in SR-resistant cells. Of interest, Withaferin A enhanced ferroptosis in SR-resistant cells, which was reversed by ferroptosis antagonist liproxstation-1. Notably, Withaferin A elevated Keap1 expression to mitigate Nrf2 signaling activation-mediated epithelial to mesenchymal transition (EMT) and ferroptosis-related protein xCT expression. Importantly, blockage of the Keap1/Nrf2 signaling overturned Withaferin A-evoked ferroptosis and facilitated sorafenib resistance. In addition, knockdown of Keap1 antagonized the inhibitory efficacy of Withaferin A on HCC cell viability, invasion, and VM formation. Consequently, Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for HCC therapy, especially for advanced HCC.

Prognostic role of preoperative albumin-bilirubin score in posthepatectomy liver failure and mortality: a systematic review and meta-analysis.

Posthepatectomy liver failure (PHLF) is a life-threatening complication after liver resection, resulting in an increased morbidity and mortality. Epidemiological evidence of the association between preoperative albumin-bilirubin (ALBI) score, a newly established model for assessing liver functional reserve, and the risk of PHLF and mortality remains controversial. A systematical search for relevant literature was performed in PubMed, Embase, and Web of Science databases from December 2014 to September 2020. Odds ratio (OR) value and 95% confidence interval (CI) were extracted or calculated to synthetically estimate the association of preoperative ALBI score with PHLF and mortality. Meta-analyses were performed using a random-effects model. Twelve studies with a total of 21,348 patients were included in this meta-analysis. It was indicated that, compared to patients with a lower preoperative ALBI grade, patients with a higher grade had a significantly elevated risk of PHLF (6 studies, 18,291 patients; OR = 2.48, 95%CI: 2.00-3.07) and mortality (4 studies15, 139 patients; OR = 2.35, 95% CI: 1.38-4.00). In addition, when it was expressed as a continuous variable, ALBI was also a significant predictor of PHLF (6 studies, 3,833 patients; OR = 3.16, 95% CI: 2.07-4.81, per 1-point increase in ALBI score). No significant publication biases were detected as suggested by funnel plots inspection and Begg's tests. The current meta-analysis demonstrates that preoperative elevated ALBI is associated with higher risk of PHLF and mortality after hepatectomy.

The Combination of Age, International Standardized Ratio, Albumin and γ-Glutamyl Transpeptidase (AIAG), Tumor Size and Alpha Fetoprotein (AFP) Stage as the Prognostic Model for Hepatitis B-Related Hepatocellular Carcinoma.

BACKGROUND: Advanced liver fibrosis can lead to cirrhosis, portal hypertension and liver failure. Besides, advanced liver fibrosis and cirrhosis are the major risk factors for hepatocellular carcinoma (HCC). Almost all patients with HCC also have liver cirrhosis. This study aims to predict the survival rate of hepatitis B-related hepatocellular carcinoma (HCC) by age, international standardized ratio, albumin and γ-glutamyl transpeptidase (AIAG), an indicator measuring the degree of cirrhosis. METHODS: A total of 501 hepatitis B-related HCC patients experiencing radical surgery were analyzed, retrospectively. General data about demographics and labs were collected at the date of diagnosis to calculate AIAG [age, international standardized ratio (INR), albumin and gamma-glutamyl transferase (GGT)]. The Kaplan-Meier curves and Cox analysis were used to evaluate overall survival (OS) and recurrence-free survival (RFS). The C-index was calculated in R software (version 4.0.3) to evaluate the accuracy of the prognostic model. RESULTS: During a median follow-up period of 30 months, 31.1% (156/501) of the patients died, and 34.3% (172/501) experienced the recurrence of HCC. Compared with patients with lower AIAG score, patients with higher AIAG score had higher Child-Pugh grade and were at higher Barcelona Clinic Liver Cancer (BCLC) stage (both P<0.05). Multivariate analysis suggested that GGT, alpha fetoprotein (AFP), tumor size, BCLC stage and AIAG grade were independent predictors of OS and RFS. Furthermore, the combined use of tumor size, AFP and AIAG stage could predict survival significantly better (C-index=0.710, 95% CI: 0.669-0.751) than BCLC stage. CONCLUSION: AIAG is significantly associated with survival of HCC patients, and provides additional prognostic information for patients with HCC. Our findings suggest that the combination of AIAG, tumor size and AFP stage has a better predictive value for the prognosis of patients with hepatitis B-related hepatocellular carcinoma. However, it is necessary for more external evidences to determine clinical utility.

Depletion of serotonin relieves concanavalin A-induced liver fibrosis in mice by inhibiting inflammation, oxidative stress, and TGF-ß1/Smads signaling pathway.

Serotonin exerts important functions in several liver pathophysiological processes. In this study, we investigated the role of serotonin in concanavalin A (Con A)-induced liver fibrosis (LF) in mice and the underlying mechanisms. To establish the mouse model of LF, mice of wild-type (WT) and tryptophan hydroxylase 1 (Tph1) knockout (serotonin depletion) received Con A for 8 successive weeks. Degree of fibrosis was assessed by Sirius red staining, as well as the measurements of alpha smooth muscle actin (α- SMA), hydroxyproline (Hyp) and type I collagen in liver tissues. To elucidate the potential mechanisms, we assessed the effect of serotonin depletion on inflammatory, oxidative stress as well as TGF-ß1/Smads signaling pathway. We found that serotonin depletion significantly inhibited collagen deposition as evaluated by less collagenous fiber in Sirus Red staining and reduced contents of Hyp and type I collagen. In addition, the absence of serotonin significantly inhibited the release of several inflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis-alpha (TNF-α), and transforming growth factor ß1 (TGF-ß1). Oxidative stress was also largely mitigated in LF mice with serotonin deficiency as manifested by the decreases of oxidative stress markers (malonaldehyde (MDA) and myeloperoxidase (MPO)), as well as the increases of antioxidant stress indicators (glutathione (GSH), and GSH-px, catalase (CAT), superoxide dismutase (SOD)) in liver tissues. Moreover, the lack of serotonin may provide an antifibrotic role by inhibiting the intrahepatic expressions of TGF-ß1, phosphorylated-smad2 (p-smad2), and phosphorylated-smad3 (p-smad3). These results indicated that, serotonin depletion attenuates Con A-induced LF through the regulation of inflammatory response, oxidative stress injury, and TGF-ß1/Smads signaling pathway.

The Significance of Platelet-Albumin-Bilirubin (PALBI) Grade in Hepatocellular Carcinoma Patients Stratified According to Platelet Count.

BACKGROUND: Platelet-albumin-bilirubin (PALBI) has been demonstrated to be superior to conventional Child-Pugh (C-P) grade in evaluating liver function and prognosis of HCC patients. However, both thrombocytosis and thrombocytopenia are unfavorable for HCC survival. The aim of this study was to preliminarily investigate the prognostic value of PALBI in HCC patients with thrombocytopenia and excluding thrombocytopenia. METHODS: In this retrospective cohort study, we reviewed 465 cases of HCC patients who underwent radical surgery. PALBI grade was calculated based on preoperative serological examinations. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS), which were assessed by Kaplan-Meier method and Cox regression. The prognostic performances of PALBI and other models were estimated by using the concordance index (C-index). RESULTS: During a median follow-up time of 28 months, 31.6% (147/465) of patients died and 33.5% (156/465) experienced recurrence. Multivariate analyses revealed that both thrombocytosis and thrombocytopenia were independently associated with poor OS and RFS compared with normal platelet count (PLT) in HCC patients. Stratified analysis further revealed that PALBI was a significant predictor for HCC survival in patients excluding thrombocytopenia but not in patients with thrombocytopenia. In particular, in HCC patients excluding thrombocytopenia, the combination of tumor size with PALBI (C-index = 0.730, 95% CI: 0.674-0.786) may be superior to the classical Barcelona Clinic Liver Cancer (BCLC) and Cancer of Liver Italian Program (CLIP) staging systems in predicting survival. CONCLUSION: In conclusion, PALBI grade, in particular the combination with tumor size, is an effective model for discriminating survival in HCC patients excluding thrombocytopenia but not in thrombocytopenic HCC patients.