scholarly journals 5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction

2021 ◽  
Vol 22 (3) ◽  
pp. 1083
Author(s):  
Sukkum Ngullie Chang ◽  
Se Ho Kim ◽  
Debasish Kumar Dey ◽  
Seon Min Park ◽  
Omaima Nasif ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Elevated Serum ◽  
In Vitro Study ◽  
Biological Properties ◽  
Autophagic Flux ◽  
Serum Aminotransferase ◽  
Ccl4 Treatment

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.

Human umbilical cord blood-derived cells differentiate into hepatocyte-like cells in the Fas-mediated liver injury model

2005 ◽  
Vol 289 (6) ◽  
pp. G1091-G1099 ◽  
Author(s):  
Kazunobu Nonome ◽  
Xiao-Kang Li ◽  
Terumi Takahara ◽  
Yusuke Kitazawa ◽  
Naoko Funeshima ◽  
...  
Keyword(s):  
Liver Injury ◽  
Umbilical Cord Blood ◽  
Fas Ligand ◽  
In Vitro Study ◽  
Cell Types ◽  
Human Umbilical Cord Blood ◽  
Specific Gene ◽  
Human Umbilical Cord

Human umbilical cord blood (HUCB) contains stem/progenitor cells, which can differentiate into a variety of cell types. In this study, we investigated whether HUCB cells differentiate into hepatocytes in vitro and in vivo. We also examined whether CD34 could be the selection marker of stem cells for hepatocytes. HUCB cells were obtained from normal full-term deliveries, and CD34+/−cells were further separated. For in vitro study, HUCB cells were cultured for 4 wk, and expressions of liver-specific genes were examined. For the in vivo study, nonobese diabetic/severe combined immunodeficient mice were subjected to liver injury by a Fas ligand-carried adenoviral vector or only radiated. Mice were treated simultaneously with or without cell transplantation of HUCB, CD34+, or CD34−cells. After 4 wk, human-specific gene/protein expression was examined. In the in vitro study, human liver-specific genes were positive after 7 days of culture. The immunofluorescent study showed positive staining of α-fetoprotein, cytokeratin 19, and albumin in round-shaped cells. In the in vivo study, immunohistochemical analysis showed human albumin-positive, hepatocyte-specific antigen-positive cells in mouse livers of the Fas ligand/transplantation group. Fluorescence in situ hybridization analysis using the human Y chromosome also showed positive signals. However, no difference between transplanted cell types was detected. In contrast, immunopositive cells were not detected in the irradiated/transplantation group. The RT-PCR result also showed human hepatocyte-specific gene expressions only in the Fas ligand/transplantation group. HUCB cells differentiated into hepatocyte-like cells in the mouse liver, and liver injury was essential during this process. The differences between CD34+and CD34−cells were not observed in human hepatocyte-specific expression.

scholarly journals Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Weitao Ji ◽  
Hongyun Shi ◽  
Hailin Shen ◽  
Jing Kong ◽  
Jiayi Song ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Acute Liver Injury ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Klf4 Expression ◽  
Mrna And Protein Expression

Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.

scholarly journals Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 300 ◽  
Author(s):  
Shulan Li ◽  
Juan Liu ◽  
Mengya Zhang ◽  
Yuan Chen ◽  
Tianxing Zhu ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Protective Effect ◽  
Acute Liver Injury ◽  
Treated Group ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Enhanced Expression ◽  
Pre Treatment

Several in vitro studies have shown the potential hepatoprotective properties of eckol, a natural phlorotannin derived from the brown alga. However, the in vivo hepatoprotective potential of eckol has not been determined. In this study, we performed an in vivo study to investigate the protective effect of eckol and its possible mechanisms on the carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Results revealed that eckol pre-treatment at the dose of 0.5 and 1.0 mg/kg/day for 7 days significantly suppressed the CCl4-induced increases of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum and meliorated morphological liver injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) analysis showed that the number of positive apoptotic hepatocytes in the eckol-treated group was lower than that in the CCl4 model group. Western blotting analysis also demonstrated the enhanced expression of bcl-2 and suppressed expression of cleaved caspase-3 by eckol. The CCl4-induced oxidative stress in liver was significantly ameliorated by eckol, which was characterized by reduced malondialdehyde (MDA) formations, and enhanced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and glutathione (GSH) content. Moreover, the CCl4-induced elevations of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were markedly suppressed in the eckol-treated group. However, eckol enhanced the level of IL-10, a potent anti-inflammatory cytokine, and recruited CD11c+ dendritic cells into the liver tissues of CCl4-treated mice. These results indicated that eckol has the protective effect on CCl4-induced acute liver injury via multiple mechanisms including anti-apoptosis, anti-oxidation, anti-inflammation and immune regulation.

Salvianolic acid B exerts a protective effect in acute liver injury by regulating the Nrf2/HO-1 signaling pathway

2020 ◽  
Vol 98 (3) ◽  
pp. 162-168 ◽  
Author(s):  
Yong-mei Jin ◽  
Xiang-ming Tao ◽  
Yi-ning Shi ◽  
Youjin Lu ◽  
Jin-yu Mei
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Acute Liver Injury ◽  
Damage Model ◽  
Underlying Mechanism ◽  
Salvianolic Acid B ◽  
Salvianolic Acid ◽  
Injury Model

Salvianolic acid B (Sal B) exerts strong antioxidant activity and eliminates the free radical effect. However, how it affects the antioxidant pathway is not very clear. The objective of this study was to investigate the underlying mechanism of Sal B in CCl4-induced acute liver injury, especially its effect on the Nrf2/HO-1 signaling pathway. For the in vivo experiment, an acute liver injury model was induced using CCl4 and treated with Sal B. For the in vitro experiment, an oxidative damage model was established followed by Sal B treatment. Serum biochemical indicators and reactive oxygen species activity were detected using corresponding kits. Oxidant/antioxidant status was determined based on the levels of malondialdehyde, glutathione, and superoxide dismutase. Nrf2 and HO-1 levels were analyzed by Western blotting and immunohistochemical staining. Sal B treatment improved liver histology, decreased the aminotransferase levels, and attenuated oxidative stress in the acute liver injury model. Nrf2 and HO-1 levels were increased both in vivo and in vitro. Sal B suppresses acute liver injury and Nrf2/HO-1 signaling plays a key role in this process.

Dendrobium officinale polysaccharides protected against ethanol-induced acute liver injury in vivo and in vitro via the TLR4/NF-κB signaling pathway

Cytokine ◽  
2020 ◽  
Vol 130 ◽  
pp. 155058 ◽  
Author(s):  
Ke Yang ◽  
Lianghui Zhan ◽  
Tingting Lu ◽  
Cong Zhou ◽  
Xue Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Acute Liver Injury ◽  
Dendrobium Officinale

The Proton Pump Inhibitor Lansoprazole Has Hepatoprotective Effects in In Vitro and In Vivo Rat Models of Acute Liver Injury

2019 ◽  
Vol 64 (10) ◽  
pp. 2854-2866 ◽  
Author(s):  
Richi Nakatake ◽  
Hidehiko Hishikawa ◽  
Masaya Kotsuka ◽  
Morihiko Ishizaki ◽  
Kosuke Matsui ◽  
...  
Keyword(s):  
Liver Injury ◽  
Proton Pump Inhibitor ◽  
Proton Pump ◽  
Acute Liver Injury ◽  
Rat Models ◽  
Hepatoprotective Effects

scholarly journals SDF-1/CXCR4 Augments the Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells in the Treatment of Lipopolysaccharide-Induced Liver Injury by Promoting Their Migration Through PI3K/Akt Signaling Pathway

2020 ◽  
Vol 29 ◽  
pp. 096368972092999 ◽  
Author(s):  
Guanghui Xiu ◽  
Xiuling Li ◽  
Yunyu Yin ◽  
Jintao Li ◽  
Bingqin Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Acute Liver Injury ◽  
Akt Signaling ◽  
Akt Signaling Pathway

Mesenchymal stem cells (MSCs) are thought to have great potential in the therapy of acute liver injury. It is possible that these cells may be regulated by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling axis, which has been shown to promote stem cells migration in the inflammation-associated diseases. However, the effects of SDF-1/CXCR4 axis on the MSCs-transplantation-based treatment for acute liver injury and the underlying mechanisms are largely unknown. In this study, we sought to determine whether SDF-1/CXCR4 would augment the therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) by promoting their migration, which may result from activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in a rat acute liver injury model induced by lipopolysaccharide (LPS). We found that BMSCs transplantation markedly attenuated liver injury and improved the survival of LPS-treated rats. Of interest, overexpression of CXCR4 in BMSCs could substantially promote their migration both in vitro and in vivo, and result in even better therapeutic effects. This might be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4, as demonstrated by the use of the CXCR4 antagonist AMD3100 and PI3K pathway inhibitor LY294002 assays in vitro and in vivo. Together, our results unraveled a novel molecular mechanism for the therapeutic effect of BMSCs for the treatment of acute liver injury, which may shed a new light on the clinical application of BMSCs for acute liver failure.

scholarly journals IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Lujing Shao ◽  
Xi Xiong ◽  
Yucai Zhang ◽  
Huijie Miao ◽  
Yuqian Ren ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Mrna Levels ◽  
Protective Effects ◽  
Activating Transcription Factor 4 ◽  
Pre Treatment ◽  
Underlying Mechanisms

Abstract Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593–0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/−) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.

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