Shenpei Liu

Baicalein protects against polymicrobial sepsis-induced liver injury via inhibition of inflammation and apoptosis in mice

Liver dysfunction has been known to occur frequently in cases of sepsis. Baicalein, the main active ingredient of the Scutellaria root, exerts anti-inflammatory and anti-apoptotic properties in endotoxic shock. However, the role of baicalein in polymicrobial sepsis-induced liver injury and its regulatory mechanisms remain unclear. In this study, we aimed to investigate the protective effects of baicalein on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were treated with baicalein (100mg/kg, i.p) at 1h, 6h and 12h following CLP. Baicalein significantly improved the survival of septic mice. Treatment with baicalein ameliorated the CLP-induced liver injury, as indicated by the lower serum aminotransferase levels and the fewer histopathologic abnormalities. Baicalein reduced the neutrophil infiltration and the hepatic inflammatory cytokine expression and release. It also decreased the hepatic and the serum high-mobility group box 1 and macrophage migration inhibitory factor levels in septic mice. Moreover, baicalein significantly inhibited the mitogen-activated protein kinases (MAPKs) activation and suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB). In conclusion, these results suggest that baicalein treatment could protect against the sepsis-induced liver injury, and improve the survival of mice with polymicrobial sepsis. The mechanism of the protective action of baicalein seems to involve its ability to reduce inflammatory response, to inhibit hepatic apoptosis, and to suppress MAPKs and NF-κB activation.

Baicalein pretreatment reduces liver ischemia/reperfusion injury via induction of autophagy in rats

We previously demonstrated that baicalein could protect against liver ischemia/reperfusion (I/R) injury in mice. The exact mechanism of baicalein remains poorly understood. Autophagy plays an important role in protecting against I/R injury. This study was designed to determine whether baicalein could protect against liver I/R injury via induction of autophagy in rats. Baicalein was intraperitoneally injected 1 h before warm ischemia. Pretreatment with baicalein prior to I/R insult significantly blunted I/R-induced elevations of serum aminotransferase levels and significantly improved the histological status of livers. Electron microscopy and expression of the autophagic marker LC3B-II suggested induction of autophagy after baicalein treatment. Moreover, inhibition of the baicalein-induced autophagy using 3-methyladenine (3-MA) worsened liver injury. Furthermore, baicalein treatment increased heme oxygenase (HO)-1 expression, and pharmacological inhibition of HO-1 with tin protoporphyrin IX (SnPP) abolished the baicalein-mediated autophagy and the hepatocellular protection. In primary rat hepatocytes, baicalein-induced autophagy also protected hepatocytes from hypoxia/reoxygenation injury in vitro and the beneficial effect was abrogated by 3-MA or Atg7 siRNA, respectively. Suppression of HO-1 activity by SnPP or HO-1 siRNA prevented the baicalein-mediated autophagy and resulted in increased hepatocellular injury. Collectively, these results suggest that baicalein prevents hepatocellular injury via induction of HO-1-mediated autophagy.

Baicalein pretreatment protects against liver ischemia/reperfusion injury via inhibition of NF-κB pathway in mice.

Ischemia/reperfusion (I/R) is a pathophysiologic process that occurs during hemorrhagic shock, liver resection and liver transplantation. Baicalein, the main active ingredient of the Scutellaria root, exerts anti-inflammatory and anti-apoptotic properties in the setting of I/R injury in the heart and brain. However, the role of baicalein in liver I/R injury and its regulatory mechanisms remain poorly understood. This study was designed to evaluate the effects of baicalein in a model of liver I/R in mice and to explore the possible mechanisms. Baicalein (100mg/kg) was intraperitoneally injected 1h before warm ischemia. Pretreatment with baicalein protected against liver I/R injury, as indicated by the decreased serum aminotransferase levels and the reduced histopathologic abnormalities. Baicalein also significantly reduced cellular hepatic apoptosis in response to I/R injury. Moreover, pretreatment with baicalein significantly inhibited nuclear factor-kappa B (NF-κB) activation and the subsequent proinflammatory cytokine production, and decreased leukocyte infiltration. In vitro studies, baicalein treatment inhibited the proinflammatory cytokine production via the modulation of NF-κB signaling pathway in lipopolysaccharide-stimulated macrophages. Taken together, these results suggest that baicalein could protect against liver I/R injury via inhibition of inflammation by down-regulating NF-κB activity, and suppression of cellular hepatic apoptosis.

GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

1,25(OH)2 D3 attenuates hepatic steatosis by inducing autophagy in mice.

1,25(OH)2D3 has been reported to attenuate liver steatosis; however, its exact mechanism of action remains poorly understood. This study aimed to determine whether 1,25(OH)2D3 can attenuate hepatic steatosis by inducing autophagy.

Ischemic preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: role of heme oxygenase-1-mediated autophagy

Steatotic livers are more susceptible to ischemia/reperfusion (I/R) injury, which is ameliorated by ischemic preconditioning (IPC). Autophagy possesses protective action on liver I/R injury and declines in steatotic livers. The aim of this study was to test the hypothesis that the increased susceptibility of steatotic livers to I/R injury was associated with defective hepatic autophagy, which could be restored by IPC via heme oxygenase-1 (HO-1) signaling. Obesity and hepatic steatosis was induced using a high fat diet. Obesity impaired hepatic autophagy activity and decreased hepatic HO-1 expression. Induction of HO-1 restored autophagy activity and inhibited calpain 2 activity. Additionally, suppression of calpain 2 activity also restored autophagy activity. Mitochondrial dysfunction and hepatocellular injury were significantly increased in steatotic livers compared to lean livers in response to I/R injury. This increase in sensitivity to I/R injury was associated with defective hepatic autophagy activity in steatotic livers. IPC increased autophagy and reduced mitochondrial dysfunction and hepatocellular damage in steatotic livers following I/R injury. Furthermore, IPC increased HO-1 expression. Inhibition of HO-1 decreased the IPC-induced autophagy, increased calpain 2 activity and diminished the protective effect of IPC against I/R injury. Inhibition of calpain 2 restored autophagic defect and attenuated mitochondrial dysfunction in steatotic livers after I/R. Collectively, IPC might ameliorate steatotic liver damage and restore mitochondrial function via HO-1-mediated autophagy.

The fibrin-derived peptide bβ15-42 attenuates liver damage in a rat model of liver ischemia/reperfusion injury.

ABSTRACT The inflammatory response after liver ischemia/reperfusion (I/R) contributes to increased risk of liver failure after liver surgery. Strategies aimed to preventing inflammation could be beneficial in reducing liver I/R injury. Recent studies have demonstrated that peptide B&bgr;15-42 is able to decrease the injury of I/R in heart and kidney by inhibition of leukocyte migration and preserving endothelial barrier function. Prompted by these results, we hypothesized that B&bgr;15-42 could also possess anti-inflammatory abilities to protect from or reduce hepatic I/R injury. Therefore, in this study, we aimed to evaluate the effects of B&bgr;15-42 in a model of liver I/R injury in rats. Rats were treated with B&bgr;15-42 at initiation of reperfusion and 2 h thereafter. Rats were killed at 0.5, 6, 24, and 48 h after reperfusion. Hepatic mRNA levels of fibrinogen-&agr; (Fg&agr;), Fg&bgr;, Fg&ggr; were significantly increased after I/R. Treatment with Fg-derived B&bgr;15-42 ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels and fewer I/R-associated histopathologic changes. B&bgr;15-42 treatment decreased leukocyte infiltration and expression of hepatic inflammatory cytokines. Moreover, B&bgr;15-42 significantly reduced high-mobility group box 1 release and altered mitogen-activated protein kinase activation. In conclusion, B&bgr;15-42 treatment protected against liver warm I/R injury. The mechanism of protective action of B&bgr;15-42 seemed to involve its ability to reduce hepatic inflammatory response through preventing high-mobility group box 1 release and altering mitogen-activated protein kinase activation.

Investigation of Temperature and Strain Rate Behavior of Lead-free Solder Sn96.5Ag3.5

In the late years, many countries will begin to prohibit using the lead-based solders in microelectronic packaging processes in view of inherent toxicity of lead-based solder alloys. The waste electrical and electronic equipment (WEEE) directive by EU has claimed that the use of Pb in consumer electronics will be banned after January 2006. Therefore, the development of lead-free solders replacing Pb-containing solders has been a crucial task for academe and microelectronic packaging industry. Due to the formation of fine Ag3Sn inter-metallic compound precipitates, Sn-Ag binary lead-free solders have some good mechanical properties (ductility, creep resistance and thermal resistance), and they were defined promising candidates substituting Pb-containing solders in microelectronic packaging and interconnecting. However, many mechanical properties of Sn-Ag alloys have not been clarified because Sn-Ag solder alloys used in microelectronic interconnecting process have not a long history. As the interconnecting materials in microelectronic packaging processes, mechanical properties of soldering alloys are important parts to impact the packaging quality, and determine the fracture and thermal fatigue behaviors of solder joint. Recently the trend of higher circuit board component densities results in the decrease of microelectronic packaging dimensions and the solder bump sizes. Therefore, the requirements for mechanical characteristics of lead-free solders will be more rigorous in packaging process. Thus, the research work about the mechanical properties of Sn-Ag binary solders is essential to microelectronic industry and academe. During microelectronic components and devices operating, the packaging and interconnecting materials would be subjected to the thermal-mechanical stress and strain which could affect the reliability and life of microelectronic components. Thus, in this study, it was focused on researching thermal-mechanical properties of the lead-free solder alloy Sn96.5Ag3.5 at different temperature ranging from 25 degC to 125 degC and various strain rate ranging from 10-5 S-1 to 10-1 S-1. Morphology of rupture surface and microstructure of this lead-free solder Sn96.5Ag3.5 were also analyzed by using the scanning electron microscope (SEM)

FK866 attenuates acute hepatic failure through c-jun-N-terminal kinase (JNK)-dependent autophagy

FK866 exhibits a protective effect on D-galactosamine (GaIN)/lipopolysaccharide (LPS) and concanavalin A (ConA)-induced acute liver failure (ALF), but the mechanism by which FK866 affords this benefit has not yet been elucidated. Autophagy has a protective effect on acute liver injury. However, the contribution of autophagy to FK866-conferred hepatoprotection is still unclear. This study aimed to investigate whether FK866 could attenuate GaIN/LPS and ConA-induced ALF through c-jun-N-terminal kinase (JNK)-dependent autophagy. In vivo, Mice were pretreated with FK866 at 24, 12, and 0.5 h before treatment with GaIN/LPS and ConA. 3-methyladenine (3MA) or rapamycin were used to determine the role of autophagy in FK866-conferred hepatoprotection. In primary hepatocytes, autophagy was inhibited by 3MA or autophagy-related protein 7 (Atg7) small interfering RNA (siRNA). JNK was suppressed by SP600125 or Jnk siRNA. FK866 alleviated hepatotoxicity and increased autophagy while decreased JNK activation. Suppression of autophagy abolished the FK866-conferred protection. Inhibition of JNK increased autophagy and exhibited strongly protective effect. Collectively, FK866 could ameliorate GaIN/LPS and ConA-induced ALF through induction of autophagy while suppression of JNK. These findings suggest that FK866 acts as a simple and applicable preconditioning intervention to protect against ALF; autophagy and JNK may also provide therapeutic targets for ALF treatment.

Carbon monoxide ameliorates hepatic ischemia/reperfusion injury via sirtuin 1‐mediated deacetylation of high‐mobility group box 1 in rats

Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion injury (IRI), but the underlying molecular mechanisms are not fully understood. High‐mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic IRI. Here, we investigated whether CO could attenuate hepatic IRI via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with carbon monoxide–releasing molecule (CORM)–2. CORM‐2–delivered CO ameliorated hepatic IRI, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses, and less severe ischemia/reperfusion‐associated histopathologic changes. Treatment with CORM‐2 significantly inhibited IRI‐induced HMGB1 translocation and release. SIRT1 expression was increased by CORM‐2 pretreatment. When CORM‐2–induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic IRI was worsened, whereas SIRT1 activation by resveratrol reversed this trend. In vitro, CORM‐2 reduced hypoxia/reoxygenation–induced HMGB1 translocation and release, these inhibitions were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in alpha mouse liver 12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. IRI increased HMGB1 acetylation, which was abolished by CORM‐2 treatment via SIRT1. In conclusion, these results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic IRI. Liver Transplantation 23 510–526 2017 AASLD.