The Matrine Derivate MASM Inhibits Recruitment of Gr1hi Monocyte and Alleviates Liver Injury

Pharmacology ◽  
2019 ◽  
Vol 104 (5-6) ◽  
pp. 235-243 ◽  
Author(s):  
Wei-Heng Xu ◽  
Jing Xu ◽  
Fang-Yuan Xie ◽  
Ying-Hua Li ◽  
Zhen-Lin Hu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Protective Role ◽  
Chronic Liver ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nonparenchymal Cells ◽  
Hepatic Expression ◽  
Injury Models ◽  
Vitro Effect

Backgrounds: (6aS, 10S, 11aR, 11bR, 11cS)-10-methylaminododecahydro-3a, 7a-diaza-benzo (de) anthracene-8-thione (MASM), a novel derivative of matrine, exhibits better anti-inflammatory activity. This study was designed to evaluate the protective effect of MASM on acute and chronic liver injuries and explore the possible mechanisms. Methods: Acute and chronic liver injury models were established by the CCl4 intraperitoneal injection and the protective effect of MASM was assessed by biochemical and histological examination. The infiltration of different monocyte subsets into the liver was characterized and analyzed by flow cytometry. The in vitro effect of MASM on liver nonparenchymal cells was evaluated by real-time PCR and transwell chemotaxis assays. Results: Administration of MASM markedly attenuated acute liver injury and liver fibrosis induced by CCl4 injection. Meanwhile, the infiltrations of Gr1hi monocytes in injured livers and induced hepatic expression of monocyte chemoattractant protein-1 (MCP-1) were greatly inhibited. Cellular experiments demonstrated that MASM not only decreased the expression of MCP-1 but also inhibited its chemotactic activity. Conclusions: This study demonstrates that the protective effect of MASM on liver injury could be contributed to the suppression of Gr1hi monocyte infiltration to the liver and the inhibition of MCP-1 production and activity. These findings provide new insights into the protective role of MASM in liver injury.

scholarly journals Protective Role of Coenzyme Q10 in Acute Sepsis-Induced Liver Injury in BALB/c Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Qian-wei Li ◽  
Qin Yang ◽  
Hong-Yang Liu ◽  
Yu-ling Wu ◽  
Yu-Hua Hao ◽  
...  
Keyword(s):  
Liver Injury ◽  
Coenzyme Q10 ◽  
Cecal Ligation ◽  
Protective Role ◽  
Hepatic Tissue ◽  
Control Group ◽  
Cecal Ligation And Puncture ◽  
Sequestosome 1

Sepsis increases the risk of the liver injury development. According to the research works, coenzyme Q10 exhibits hepatoprotective properties in vivo as well as in vitro. Current work aimed at investigating the protective impacts of coenzyme Q10 against liver injury in septic BALB/c mice. The male BALB/c mice were randomly segregated into 4 groups: the control group, the coenzyme Q10 treatment group, the puncture and cecal ligation group, and the coenzyme Q10+cecal ligation and puncture group. Cecal ligation and puncture was conducted after gavagaging the mice with coenzyme Q10 during two weeks. Following 48 h postcecal ligation and puncture, we estimated hepatic biochemical parameters and histopathological changes in hepatic tissue. We evaluated the expression of factors associated with autophagy, pyroptosis, and inflammation. Findings indicated that coenzyme Q10 decreased the plasma levels in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in the cecal ligation and puncture group. Coenzyme Q10 significantly inhibited the elevation of sequestosome-1, interleukin-1β, oligomerization domain-like receptor 3 and nucleotide-binding, interleukin-6, and tumor necrosis factor-α expression levels; coenzyme Q10 also increased beclin 1 levels. Coenzyme Q10 might be a significant agent in the treatment of liver injury induced by sepsis.

scholarly journals Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice

2004 ◽  
Vol 286 (1) ◽  
pp. G60-G67 ◽  
Author(s):  
Yoshiya Ito ◽  
Edward R. Abril ◽  
Nancy W. Bethea ◽  
Robert S. McCuskey
Keyword(s):  
Nitric Oxide ◽  
Liver Injury ◽  
Cell Injury ◽  
Parenchymal Cell ◽  
Protective Role ◽  
Hepatic Expression ◽  
Inos Inhibitor ◽  
Microcirculatory Disturbances

Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l- N6-(1-iminoethyl)-lysine (l-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. l-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas l-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. l-NIL, but not l-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. l-NIL restored the sinusoidal perfusion, but l-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. l-NIL tended to minimize this infiltration, whereas l-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by l-NIL, whereas l-NAME further elevated it. l-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. l-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.

scholarly journals Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Zhengyu Jiang ◽  
Yan Meng ◽  
Lulong Bo ◽  
Changli Wang ◽  
Jinjun Bian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Great Part ◽  
Protective Role ◽  
Stress Indicators ◽  
Oxidative Reaction ◽  
Hepatic Expression ◽  
Jnk Cascade ◽  
Oxidative Stress Indicators

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H2O2, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia.

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.

scholarly journals Mycelium Polysaccharides from Termitomyces albuminosus Attenuate CCl4-Induced Chronic Liver Injury Via Inhibiting TGFβ1/Smad3 and NF-κB Signal Pathways

2019 ◽  
Vol 20 (19) ◽  
pp. 4872 ◽  
Author(s):  
Zhao ◽  
Li ◽  
Feng ◽  
Zhang ◽  
Yuan ◽  
...  
Keyword(s):  
Liver Injury ◽  
Chronic Liver ◽  
Molar Ratio ◽  
Gas Chromatography Mass Spectrometry ◽  
Signal Pathways ◽  
Chronic Liver Injury ◽  
Potential Health ◽  
Anti Inflammatory

A major fraction (MPT-W), eluted by deionized water, was extracted from mycelium polysaccharides of Termitomyces albuminosus (MPT), and its antioxidant, anti-fibrosis, and anti-inflammatory activities in CCl4-induced chronic liver injury mice, as well as preliminary characterizations, were evaluated. The results showed that MPT-W was a polysaccharide of α- and β-configurations containing xylose (Xyl), fucose (Fuc), mannose (Man), galactose (Gal), and glucose (Glc) with a molar ratio of 0.29:8.67:37.89:35.98:16.60 by gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared (FT-IR) spectroscopy. Its molecular weight (Mw), obtained by high-performance gel permeation chromatography (HPGPC), was 1.30 × 105 Da. The antioxidant assays in vitro showed that MPT-W displayed scavenging free-radical abilities. Based on the data of in vivo experiments, MPT-W could inhibit TGFβ1/Smad3 and NF-κB pathways; decrease the level and activity of cytochrome P4502E1 (CYP2E1), malonaldehyde (MDA) and serum enzyme; activate the HO-1/Nrf2 pathway; and increase antioxidant enzymes to protect the liver in CCl4-induced chronic liver injury mice. Therefore, MPT-W could be a potentially natural and functional resource contributing to antioxidant, hepatoprotective, and anti-inflammatory effects with potential health benefits.

scholarly journals Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

2015 ◽  
Vol 309 (12) ◽  
pp. G965-G974 ◽  
Author(s):  
Xiaoying Liu ◽  
Anne S. Henkel ◽  
Brian E. LeCuyer ◽  
Matthew J. Schipma ◽  
Kristy A. Anderson ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fatty Liver ◽  
Cell Injury ◽  
Binding Protein ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Huh7 Cells

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient ( Xbp1−/−) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1−/− mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1−/− mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1−/− mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1−/− compared with Xbp1fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

Weak Inhibitors Protect Cholinesterases from Stronger Inhibitors (Dichlorvos): In Vitro Effect of Tiapride

2005 ◽  
Vol 24 (2) ◽  
pp. 79-86 ◽  
Author(s):  
G. A. Petroianu ◽  
A. Schmitt ◽  
K. Arafat ◽  
M. Y. Hasan
Keyword(s):  
Protective Effect ◽  
Protective Action ◽  
Reversible Inhibitor ◽  
Protective Agent ◽  
Dimethyl Phosphate ◽  
Prokinetic Drug ◽  
In Vivo Testing ◽  
Vitro Effect

Metoclopramide is a benzamide dopamine receptor antagonist and serotonine receptor agonist widely used as an antiemetic and gastric prokinetic drug. In addition, metoclopramide is a weak and reversible inhibitor of cholinesterases. The authors have previously shown that metoclopramide has a cholinesterase protective effect against inhibition by organophosphates (OPs). The putative mode of protective action of metoclopramide is, when administered in excess, competion for the active site of the enzyme with the more potent OP. In the present paper the authors present their results using another benzamide with weak cholinesterase inhibitory properties, tiapride (TIA). The purpose of the study was to quantify in vitro the extent of TIA-conferred protection, using dichlorvos (dichlorovinyl dimethyl phosphate; DDVP) as an inhibitor. DDVP is a moderately toxic (LD50 in rats in the milligram range), non-neuropathic OP. The substance is responsible for a large number of accidental or suicidal exposures. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different DDVP and TIA concentrations and IC50 was calculated. Determinations were repeated in the presence of increasing TIA concentrations. The IC50 of DDVP increases with the TIA concentration in a linear manner. The protective effect of TIA on cholinesterase could be of practical relevance in the treatment of OP poisoning. The authors conclude that in vivo testing of TIA as an OP protective agent is warranted.

scholarly journals Magnesium Isoglycyrrhizinate Ameliorates Concanavalin A-Induced Liver Injury by Inhibiting Autophagy

2022 ◽  
Vol 12 ◽  
Author(s):  
Zihao Fan ◽  
Yuxian Li ◽  
Sisi Chen ◽  
Ling Xu ◽  
Yuan Tian ◽  
...  
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Concanavalin A ◽  
Severe Liver ◽  
Cytokine Levels ◽  
Therapeutic Mechanism ◽  
Severe Liver Dysfunction ◽  
Hepatocyte Death ◽  
Magnesium Isoglycyrrhizinate

Background and Aims: Acute liver failure (ALF) is a type of liver injury that is caused by multiple factors and leads to severe liver dysfunction; however, current treatments for ALF are insufficient. Magnesium isoglycyrrhizinate (MgIG), a novel glycyrrhizin extracted from the traditional Chinese medicine licorice, has a significant protective effect against concanavalin A (ConA)-induced liver injury, but its underlying therapeutic mechanism is unclear. Hence, this study aims to explore the potential therapeutic mechanism of MgIG against ConA-induced immune liver injury.Methods: ConA (20 mg/kg, i. v.) was administered for 12 h to construct an immune liver injury model, and the treatment group was given MgIG (30 mg/kg, i. p.) injection 1 h in advance. Lethality, liver injury, cytokine levels, and hepatocyte death were evaluated. The level of autophagy was evaluated by electron microscopy, RT-PCR and western blotting, and hepatocyte death was assessed in vitro by flow cytometry.Results: MgIG significantly increased the survival rate of mice and ameliorated severe liver injury mediated by ConA. The decrease in the number of autophagosomes, downregulation of LC3b expression and upregulation of p62 expression indicated that MgIG significantly inhibited ConA-induced autophagy in the liver. Reactivation of autophagy by rapamycin (RAPA) reversed the protective effect of MgIG against ConA-induced liver injury. Compared with MgIG treatment, activation of autophagy by RAPA also promoted the expression of liver inflammation markers (IL-1β, IL-6, TNF-α, CXCL-1, CXCL-2, CXCL-10, etc.) and hepatocyte death. In vitro experiments also showed that MgIG reduced ConA-induced hepatocyte death but did not decrease hepatocyte apoptosis by inhibiting autophagy.Conclusion: MgIG significantly ameliorated ConA-induced immune liver injury in mice by inhibiting autophagy. This study provides theoretical support for the ability of MgIG to protect against liver injury in clinical practice.

scholarly journals Raf Kinase Inhibitory Protein Down-Expression Exacerbates Hepatic Fibrosis In Vivo and In Vitro

2016 ◽  
Vol 40 (1-2) ◽  
pp. 49-61 ◽  
Author(s):  
Quanfang Huang ◽  
Chunhong Liang ◽  
Ling Wei ◽  
Jinlan Nie ◽  
Shengjuan Lu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Chronic Liver ◽  
Chronic Liver Injury ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein ◽  
Liver Tissues

Background/Aims: Raf kinase inhibitory protein (RKIP) is closely associated with numerous tumors and participates in their development through regulating the growth, apoptosis, invasion and metastasis of tumor cells. However, the role of RKIP in chronic liver injury and particularly in liver fibrosis is still unclear. Methods: In the present study, hepatic fibrosis was induced by porcine serum (PS) in rats and primary hepatic stellate cells (HSCs) were isolated from rat livers. Moreover, locostatin was used to interfere with RKIP expression. Results: RKIP expression was significantly inhibited by locostatin in both liver tissues of rats and primary HSCs. Down-regulating RKIP expression resulted in serious liver injury, extensive accumulation of collagen, and significant increase in the levels of ALT, AST and TNF-α during liver fibrosis in rats. Moreover, down-regulating RKIP significantly promoted HSCs proliferation and colony formation in vitro. Reduced RKIP significantly increased the production of collagen and the level of α-SMA as well as the expression of MMP-1 and MMP-2 in both liver tissues and primary HSCs. Furthermore, down-regulating RKIP promoted the activation of the ERK and TLR4 signaling pathways. Conclusion: Our findings clearly indicate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. The decrease in RKIP expression may exacerbate chronic liver injury and liver fibrosis.

scholarly journals Matrine Inhibits Infiltration of the InflammatoryGr1hiMonocyte Subset in Injured Mouse Liver through Inhibition of Monocyte Chemoattractant Protein-1

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Duo Shi ◽  
Jinjin Zhang ◽  
Lei Qiu ◽  
Jianzhong Li ◽  
Zhenlin Hu ◽  
...  
Keyword(s):  
Acute Liver Injury ◽  
Stellate Cells ◽  
Sophora Flavescens ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nonparenchymal Cells ◽  
Monocyte Chemoattractant ◽  
Hepatic Expression ◽  
Single Intraperitoneal Injection ◽  
Anti Inflammatory ◽  
The Impact

Matrine (Mat) is a major alkaloid extracted fromSophora flavescensAit, an herb which is used in the traditional Chinese medicine for treatment of inflammation, cancer, and other diseases. The present study examined the impact of Mat on the CCl4-induced hepatic infiltration ofGr1himonocytes to explore the possible mechanisms underlying its anti-inflammatory and antifibrotic effects. The results indicated that Mat protected mice from acute liver injury induced by single intraperitoneal injection of CCl4and attenuated liver fibrosis induced by repeated CCl4injection. Meanwhile, the infiltrations ofGr1himonocytes in both acute and chronic injured livers were all inhibited, and the enhanced hepatic expression of MCP-1 was suppressed. Cellular experiments demonstrated that Mat directly inhibited MCP-1 production in both nonparenchymal cells and hepatic stellate cells derived from CCl4-injured livers. Transwell chemotaxis assays showed that Mat significantly inhibited the chemotactic activity of MCP-1. These results suggest that the anti-inflammatory and antifibrotic effects of Mat could be contributed, at least in part, to its prevention ofGr1himonocyte infiltration into the injured livers and inhibition of MCP-1 production and activity. These findings extend our understanding of the mechanisms underlying the anti-inflammatory and antifibrotic effects of Mat.

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