Xiya Lu

The protective effects of shikonin on hepatic ischemia/reperfusion injury are mediated by the activation of the PI3K/Akt pathway

Hepatic ischemia/reperfusion (I/R) injury, which can result in severe liver injury and dysfunction, occurs in a variety of conditions such as liver transplantation, shock, and trauma. Cell death in hepatic I/R injury has been linked to apoptosis and autophagy. Shikonin plays a significant protective role in ischemia/reperfusion injury. The purpose of the present study was to investigate the protective effect of shikonin on hepatic I/R injury and explore the underlying mechanism. Mice were subjected to segmental (70%) hepatic warm ischemia to induce hepatic I/R injury. Two doses of shikonin (7.5 and 12.5 mg/kg) were administered 2 h before surgery. Balb/c mice were randomly divided into four groups: normal control, I/R, and shikonin preconditioning at two doses (7.5 and 12.5 mg/kg). The serum and liver tissues were collected at three time points (3, 6, and 24 h). Shikonin significantly reduced serum AST and ALT levels and improved pathological features. Shikonin affected the expression of Bcl-2, Bax, caspase 3, caspase 9, Beclin-1, and LC3, and upregulated PI3K and p-Akt compared with the levels in the I/R group. Shikonin attenuated hepatic I/R injury by inhibiting apoptosis and autophagy through a mechanism involving the activation of PI3K/Akt signaling.

The long noncoding RNA TUG1 acts as a competing endogenous RNA to regulate the Hedgehog pathway by targeting miR-132 in hepatocellular carcinoma

Emerging evidence shows that the Hedgehog pathway and the long noncoding RNA TUG1 play pivotal roles in cell proliferation, migration, and invasion in tumors. However, the mechanism underlying the effect of TUG1 and the Hedgehog pathway in hepatoma remains undefined. In the present study, we showed that the expression of TUG1 was negatively correlated with that of microRNA (miR)-132, and depletion of TUG1 inhibited the activation of the Hedgehog pathway in vitro and in vivo. We showed that TUG1 functions as a competing endogenous (ceRNA) by competing with miR-132 for binding to the sonic hedgehog protein in HCC, thereby suppressing the activation of Hedgehog signaling and its tumorigenic effect. These data indicate that targeting the TUG1-miR132-Hedgehog network could be a new strategy for the treatment of HCC.

Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways

The aim of this study was to investigate the effect of quercetin on hepatic fibrosis, a characteristic response to acute or chronic liver injury. Mice were randomized to bile duct ligation (BDL) or carbon tetrachloride (CCl4) cirrhosis models. Quercetin (100 mg/kg or 200 mg/kg daily) was administered by gavage for 2 or 4 weeks. Liver tissue and blood samples were collected for histological and molecular analysis. The results of our experiments showed that quercetin reduced BDL or CCl4 liver fibrosis, inhibited extracellular matrix formation, and regulated matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Quercetin attenuated liver damage by suppressing the TGF-β1/Smads signaling pathway and activating the PI3K/Akt signaling pathway to inhibit autophagy in BDL- or CCl4- induced liver fibrosis. Quercetin prevented hepatic fibrosis by attenuating hepatic stellate cell activation and reducing autophagy through regulating crosstalk between the TGF-β1/Smads and PI3K/Akt pathways.

Pretreatment with propylene glycol alginate sodium sulfate ameliorated concanavalin A-induced liver injury by regulating the PI3K/Akt pathway in mice

Aims: Propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide possesses anti‐inflammatory effects. Here, we investigated the effect of PSS on concanavalin A (Con A)‐induced liver injury in mice and examined the underlying mechanisms. Main methods: Balb/C mice were injected intravenously with Con A (25 mg/kg) to generate a model of acute liver injury. PSS (25 or 50 mg/kg) was injected intraperitoneally 1 h before the Con A administration. The levels of serum liver enzymes, inflammatory cytokines, and other marker proteins were determined, and liver injury was assessed histopathologically 2, 8, and 24 h after Con A injection. Key findings: Pretreatment with PSS reduced the levels of serum liver enzymes, inflammatory cytokines such as tumor necrosis factor (TNF)‐&agr; and interleukin (IL)‐1&bgr;, and attenuated histopathological damage in Con A‐induced liver injury in mice. The effects of Con A were mediated by apoptosis and autophagy, as indicated by changes in protein and gene expression of related factors after Con A injection. PSS activated the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway and showed a protective function against apoptosis and autophagy. Significance: PSS ameliorated Con A‐induced liver injury by downregulating inflammatory cytokines including TNF‐&agr; and IL‐1&bgr; and regulating apoptosis and autophagy via the PI3K/Akt pathway.

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib‐resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.

Hepatoprotective effect of quercetin via TRAF6/JNK pathway in acute hepatitis

Quercetin, as a member of the flavonoids family, has many beneficial properties. The aim of our study was to evaluate the protective effect of quercetin in ConA-induced hepatitis in mice, and to clarify its mechanism of action. Hepatitis was induced by using ConA (25 mg/kg), and quercetin was administered intragastrically at the dose of 100 mg/kg or 200 mg/kg for 5 days before ConA injection. The serum levels of liver enzymes, inflammatory cytokines and other marker proteins were determined at 2 h, 8 h and 24 h after ConA injection. Following ConA injection, serum levels of liver enzymes and inflammatory cytokines were significantly increased. Quercetin ameliorated liver damage and histopathological changes, and suppressed the release of inflammatory cytokines. The expression of Bax, Bcl-2, Beclin-1, LC3, P62 and caspase 9 were markedly affected by quercetin pretreatment. The expression of TRAF6 and p-JNK were decreased in the quercetin groups. Quercetin attenuated apoptosis and autophagy in ConA-induced autoimmune hepatitis by inhibiting TRAF6/JNK pathway.

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death

Background:Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear.Methods:Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib.Results:Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice.Conclusions:Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

The liver protection of propylene glycol alginate sodium sulfate preconditioning against ischemia reperfusion injury: focusing MAPK pathway activity

Hepatic ischemia reperfusion (IR) injury contributes to the morbidity and mortality associated with liver surgery. This study investigated the protective function and mechanism of propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide, in a mouse hepatic IR injury model. PSS (25 or 50 mg/kg) or saline were injected intraperitoneally to male Balb/c mice 1 h before 45 min of 70% warm hepatic ischemia and 2, 8, and 24 h of reperfusion. Serum and liver tissue samples were collected for evaluation of hepatocellular damage, liver histology, and assay of inflammatory cytokines, apoptosis- and autophagy-related proteins, and proteins in the mitogen-activated protein kinase (MAPKs). Histological injury and release of transaminases, and inflammatory cytokine production were significantly reduced by PSS pretreatment. The expression of apoptosis- and autophagy-related proteins, and the activation of MAPK signal, including jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and P38 were all affected by PSS treatment compared with IR model controls. PSS protected the liver from IR injury by suppressing the MAPK signaling and down-regulating inflammation, apoptosis, and autophagy.

Quercetin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy by Inhibiting ERK/NF-κB Pathway

Background Hepatic ischemia reperfusion (IR) injury is a common phenomenon in transplantation or trauma. The aim of the present study was to determine the protective effect of quercetin (QE) on hepatic IR injury via the ERK/NF-κB pathway. Methods Mice were randomized into the sham, IR, QE100 + IR, and QE200 + IR groups. Quercetin was administered intragastrically daily at two doses (100 mg/kg and 200 mg/kg) for 5 days prior to IR injury. The expression levels of liver enzymes, inflammatory cytokines, and other marker proteins were determined at 2, 8, and 24 hours after IR. And they were compared among these groups. Results Compared with the IR group, the treatment of QE reduced the release of cytokines, leading to inhibition of apoptosis and autophagy via downregulation of the ERK/NF-κB pathway in this model of hepatic IR injury. Conclusion Apoptosis and autophagy caused by hepatic IR injury were inhibited by QE following a reduction in the release of inflammatory cytokines, and the relationship between the two may be associated with inactivation of the ERK/NF-κB pathway.

Cerebral Hemodynamics and Cognitive Function in Cirrhotic Patients with Hepatic Encephalopathy

Aims. To investigate cerebral hemodynamics in cirrhotic patients with HE and to observe effects of treatment in cerebral hemodynamics and correlations among ammonia, cerebral hemodynamics, and cognitive function. Methods. There were four groups: healthy controls (group 1), cirrhosis without HE (group 2), cirrhosis with MHE (group 3), and cirrhosis with OHE (group 4). Ammonia and cerebral hemodynamics (by TCD) were assessed. Patients in group 3 were subsequently randomized to two subgroups: the control (group A) and the treated (group B, treated with lactulose for two months), and they were retested for ammonia and TCD after treatment. Results. Ammonia, Vm, Vd, PI, and RI were statistically different before treatment, and ammonia, PI, and RI levels paralleled the severity of HE (P < 0.05). In group B, Vd increased and ammonia, PI, and RI declined following treatment (P < 0.05), while there were no differences in group A (P > 0.05). Correlations were found between ammonia and Vd, PI, RI, NCT-A, and DST and also found between Vd, PI, RI, and NCT-A and DST (P < 0.05). Conclusions. This study revealed that cerebral hemodynamics were related to the severity of HE and cerebral autoregulation was impaired. There were tight correlations among ammonia, cerebral hemodynamics, and cognitive function, and, following treatment, cerebral hemodynamics improved.