scholarly journals In vivo siRNA delivery of Keap1 modulates death and survival signaling pathways and attenuates concanavalin-A-induced acute liver injury in mice

2014 ◽  
Vol 7 (9) ◽  
pp. 1093-1100 ◽  
Author(s):  
A. Gonzalez-Rodriguez ◽  
B. Reibert ◽  
T. Amann ◽  
R. Constien ◽  
C. M. Rondinone ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathways ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Sirna Delivery ◽  
Survival Signaling

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

2007 ◽  
Vol 292 (1) ◽  
pp. G253-G261 ◽  
Author(s):  
Cynthia C. Wetzel ◽  
Mike A. Leonis ◽  
Arlene Dent ◽  
Meredith A. Olson ◽  
Angela M. Longmeier ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Ex Vivo ◽  
Short Form ◽  
Cell Receptor ◽  
Ron Receptor ◽  
Ifn Γ

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-γ from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-γ and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.

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.

scholarly journals Fucosterol Protects against Concanavalin A-Induced Acute Liver Injury: Focus on P38 MAPK/NF-κB Pathway Activity

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Wenhui Mo ◽  
Chengfen Wang ◽  
Jingjing Li ◽  
Kan Chen ◽  
Yujing Xia ◽  
...  
Keyword(s):  
Liver Injury ◽  
P38 Mapk ◽  
Concanavalin A ◽  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Acute Liver Injury ◽  
Biological Activities ◽  
Hepatic Necrosis ◽  
Protective Effects ◽  
Eisenia Bicyclis

Objective. Fucosterol is derived from the brown alga Eisenia bicyclis and has various biological activities, including antioxidant, anticancer, and antidiabetic properties. The aim of this study was to investigate the protective effects of fucosterol pretreatment on Concanavalin A- (ConA-) induced acute liver injury in mice, and to understand its molecular mechanisms. Materials and Methods. Acute liver injury was induced in BALB/c mice by ConA (25 mg/kg), and fucosterol (dissolved in 2% DMSO) was orally administered daily at doses of 25, 50, and 100 mg/kg. The levels of hepatic necrosis, apoptosis, and autophagy associated with inflammatory cytokines were measured at 2, 8, and 24 h. Results. Fucosterol attenuated serum liver enzyme levels and hepatic necrosis and apoptosis induced by TNF-α, IL-6, and IL-1β. Fucosterol also inhibited apoptosis and autophagy by upregulating Bcl-2, which decreased levels of functional Bax and Beclin-1. Furthermore, reduced P38 MAPK and NF-κB signaling were accompanied by PPARγ activation. Conclusion. This study showed that fucosterol could alleviate acute liver injury induced by ConA by inhibiting P38 MAPK/PPARγ/NF-κB signaling. These findings highlight that fucosterol is a promising potential therapeutic agent for acute liver injury.

Guavinoside B from Psidium guajava alleviates acetaminophen-induced liver injury via regulating the Nrf2 and JNK signaling pathways

2020 ◽  
Vol 11 (9) ◽  
pp. 8297-8308
Author(s):  
Yuanyuan Li ◽  
Jialin Xu ◽  
Dongli Li ◽  
Hang Ma ◽  
Yu Mu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Phenolic Compound ◽  
Psidium Guajava ◽  
Jnk Signaling ◽  
Nrf2 Signaling Pathway ◽  
Jnk Signaling Pathway

GUB, a main phenolic compound present in guava fruits, could alleviate APAP-induced liver injury in vitro and in vivo by activating the Nrf2 signaling pathway and inhibiting the JNK signaling pathway.

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 A Polyphenol-Rich Fraction from Eugenia uniflora Exhibits Antioxidant and Hepatoprotective Activities In Vivo

2020 ◽  
Vol 13 (5) ◽  
pp. 84
Author(s):  
Mansour Sobeh ◽  
Marwa S. Hamza ◽  
Mohamed L. Ashour ◽  
Mona Elkhatieb ◽  
Mohamed A El Raey ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Ethyl Acetate ◽  
Acute Liver Injury ◽  
Antioxidant Activities ◽  
Biological Effects ◽  
Ethyl Acetate Fraction ◽  
Eugenia Uniflora ◽  
Quercetin Derivatives

Leaves from Eugenia uniflora, the red Brazilian cherry, have a high content of flavonoids that possess several biological effects such as anti-inflammatory, antioxidant, and antidiabetic activities. However, their influence on carbon tetrachloride (CCl4)-induced acute liver injury in rats has not been investigated. In the current study, a bioguided fractionation assay revealed that the ethyl acetate fraction (EAF) of Eugenia uniflora is the safest and most active fraction. LC-MS analysis of the ethyl acetate fraction revealed 22 secondary metabolites, mainly myricetin and quercetin derivatives. EAF did not show toxicity up to 2000 mg/kg, and exhibited antioxidant activities in vitro in DPPH assay with IC50 of 3.35 µg/mL. Additionally, EAF exhibited substantial antioxidant activities in vivo by counteracting the oxidative damage of the prooxidant juglone [80 µM] in Caenorhabditis elegans model organism and increased its survival rate in a dose-dependent fashion through the DAF-16/Foxo pathway. Furthermore, the hepatoprotective activity of EAF (200 mg/kg against carbon tetrachloride (CCl4) intoxicated male Wistar rats was assessed. EAF significantly inhibited CCl4-induced elevation of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB), total cholesterol (TC), and triglycerides (TG), in the blood serum and prevented lipid peroxidation and restored superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissues. The observed hepatoprotective effects of EAF, which were supported by histopathological observations as pretreatment with EAF, effectively attenuated the CCl4-induced histopathological changes. In conclusion, EAF of Eugenia uniflora leaves has substantial hepatoprotective activities against CCl4 induced acute liver injury in rats due to its antioxidant activity.

Protective effect of pterostilbene on concanavalin A-induced acute liver injury

2019 ◽  
Vol 10 (11) ◽  
pp. 7308-7314 ◽  
Author(s):  
Jiayan Wu ◽  
Mengmeng Li ◽  
Jingwen He ◽  
Ke Lv ◽  
Meiyan Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Anti Inflammatory

Pterostilbene (PTE) is broadly found in berries and has antioxidant and anti-inflammatory properties.

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.

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