Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related mortality worldwide. The expression of nitric oxide synthase (NOS) and the inhibition of autophagy have been linked to cancer cell death. However, the involvement of serum nitric oxide (NO), the expression of NOS and autophagy have not been investigated in HCC. In the present study, we first established that the NO level was significantly higher in hepatitis B virus‐related HCC than in the liver cirrhosis control (53.60 ± 19.74 vs 8.09 ± 4.17 μmol/L, t = 15.13, P < 0.0001). Using immunohistochemistry, we found that the source of NO was at least partially attributed to the expression of inducible NOS and endothelial NOS but not neuronal NOS in the liver tissue. Furthermore, in human liver cancer cells, NO‐induced apoptosis and inhibited autophagy. Pharmacological inhibition of autophagy also induced apoptosis, whereas the induction of autophagy could ameliorate NO‐induced apoptosis. We also found that NO regulates the switch between apoptosis and autophagy by disrupting the Beclin 1/Vps34 association and by increasing the Bcl‐2/Beclin 1 interaction. Overall, the present findings suggest that increased NOS/NO promotes apoptosis through the inhibition of autophagy in liver cancer cells, which may provide a novel strategy for the treatment of HCC.

Liver sinusoids serve as the first line of defense against extrahepatic stimuli from the intestinal tract. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space that integrate cytokine-mediated inflammatory responses in the sinusoids and relay these signals to the liver parenchyma. Oxidative stress has been shown to promote inflammation during acute liver failure (ALF). Whether and how oxidative stress is involved in HSC inflammation during ALF remains unclear. Level of systemic oxidative stress is reflected by superoxide dismutase (SOD). Thus, ALF patients were recruited to investigate the correlation between plasma SOD levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from ALF patients who had undergone liver transplantation. SOD2 expression and HSCs activation were investigated by immunohistochemistry. Inflammation, mitophagy, and apoptosis were investigated by immunoblot analysis and flow cytometry in HSCs treated with lipopolysaccharide (LPS) and reactive oxygen species (ROS) donors. The plasma SOD level was significantly increased in patients with ALF compared with those with cirrhosis (444.4 ± 23.58 vs. 170.07 ± 3.52 U/ml, P < 0.01) and was positively correlated with the Model for End-Stage Liver Disease-Na score ( R² = 0.4720, P < 0.01). In vivo observations revealed that SOD2 immunostaining was increased in ALF patients and mice models, and in vitro experiments demonstrated that LPS/ROS promoted inflammation via inhibiting mitophagy. Moreover, the regulation of inflammation was apoptosis independent in HSCs. LPS-induced increases in oxidative stress promote inflammation through inhibiting mitophagy in HSCs during the process of ALF, providing a novel strategy for the treatment of patients with ALF. NEW & NOTEWORTHY Here we demonstrate that the serum superoxide dismutase (SOD) level is significantly increased in patients with acute liver failure (ALF), and, correlated with the Model for End-Stage Liver Disease-Na score, SOD level dropped in the remission stage of ALF. We identify that, in liver tissue from ALF patients and mice models, manganese-dependent SOD was overexpressed, and show lipopolysaccharide/H₂O₂ inhibits mitophagy via reactive oxygen species in hepatic stellate cells (HSCs). We show that inhibited mitophagy promotes inflammation in HSCs, whereas mitophagy inducer rescues HSCs from lipopolysaccharide-induced inflammation.

Background & Aims: There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. Methods: Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. Results: Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. Conclusions: TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. Trial registration: This study is ongoing and is registered with ClinicalTrials.gov, NCT03640728 (05/02/2019).

Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.

Background: Acute liver failure (ALF) is marked by a substantial generation of reactive oxygen species (ROS), which can induce both cellular senescence and a pronounced inflammatory response. Senescent cells secrete factors collectively termed the senescence-associated secretory phenotype (SASP), which exacerbate inflammation, while inflammation can reciprocally promote cellular senescence. Quercetin (Que), recognized for its ROS-scavenging capabilities, holds the potential for anti-inflammatory and anti-senescent effects. However, its extremely low aqueous solubility constrains its clinical efficacy in treating inflammation.