scholarly journals Alcoholic hepatitis and metabolic disturbance in female mice: a more tractable model than Nrf2−/− animals

2020 ◽  
Vol 13 (12) ◽  
pp. dmm046383
Author(s):  
Lozan Sheriff ◽  
Reenam S. Khan ◽  
Raquel Saborano ◽  
Richard Wilkin ◽  
Nguyet-Thin Luu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Alcoholic Hepatitis ◽  
Myeloid Cell ◽  
Related Factor ◽  
Murine Models ◽  
Hepatic Inflammation ◽  
Hepatocyte Regeneration ◽  
Regulatory Frameworks ◽  
Novel Model ◽  
Transcription Factor Nuclear Factor

ABSTRACTAlcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 15% mortality rate within 28 days in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of ad libitum delivery of alcohol but without any additional insult, and is associated with relatively mild liver injury. The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) protects against oxidative stress, and mice deficient in this molecule are suggested to be more sensitive to alcohol-induced injury. We have established a novel model of AH in mice and compared the nature of liver injury in C57/BL6 wild-type (WT) versus Nrf2−/− mice. Our data showed that both WT and Nrf2−/− mice demonstrate robust weight loss, and an increase in serum transaminase, steatosis and hepatic inflammation when exposed to diet and ethanol. This is accompanied by an increase in peripheral blood and hepatic myeloid cell populations, fibrogenic response and compensatory hepatocyte regeneration. We also noted characteristic disturbances in hepatic carbohydrate and lipid metabolism. Importantly, use of Nrf2−/− mice did not increase hepatic injury responses in our hands, and female WT mice exhibited a more-reproducible response. Thus, we have demonstrated that this simple murine model of AH can be used to induce an injury that recreates many of the key human features of AH – without the need for challenging surgical procedures to administer ethanol. This will be valuable for understanding of the pathogenesis of AH, for testing new therapeutic treatments or devising metabolic approaches to manage patients whilst in medical care.This article has an associated First Person interview with the joint first authors of the paper.

scholarly journals Lemon Balm and Dandelion Leaf Extracts Synergistically Protect against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

2021 ◽  
Vol 11 (1) ◽  
pp. 390
Author(s):  
Beom-Rak Choi ◽  
Il-Je Cho ◽  
Su-Jin Jung ◽  
Jae-Kwang Kim ◽  
Dae-Geon Lee ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Acute Liver Injury ◽  
Antioxidant Activities ◽  
Body Weight Gain ◽  
Histopathological Analysis ◽  
Related Factor ◽  
Mrna Levels ◽  
Protective Effects ◽  
Lemon Balm

Lemon balm and dandelion are commonly used medicinal herbs exhibiting numerous pharmacological activities that are beneficial for human health. In this study, we explored the protective effects of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (MLD) on carbon tetrachloride (CCl4)-induced acute liver injury in mice. CCl4 (0.5 mL/kg; i.p.) injection inhibited body weight gain and increased relative liver weight. Pre-administration of MLD (50–200 mg/kg) for 7 days prevented these CCl4-mediated changes. In addition, histopathological analysis revealed that MLD synergistically alleviated CCl4-mediated hepatocyte degeneration and infiltration of inflammatory cells. MLD decreased serum aspartate aminotransferase and alanine transferase activities and reduced the number of liver cells that stained positive for cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting that MLD protects against CCl4-induced hepatic damage via the inhibition of apoptosis. Moreover, MLD attenuated CCl4-mediated lipid peroxidation and protein nitrosylation by restoring impaired hepatic nuclear factor erythroid 2-related factor 2 mRNA levels and its dependent antioxidant activities. Furthermore, MLD synergistically decreased mRNA and protein levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the liver. Together, these results suggest that MLD has potential for preventing acute liver injury by inhibiting apoptosis, oxidative stress, and inflammation.

scholarly journals Hepatoprotective Effect of Polysaccharides Isolated from Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Guosheng Lin ◽  
Dandan Luo ◽  
Jingjing Liu ◽  
Xiaoli Wu ◽  
Jinfen Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Hepatoprotective Effect ◽  
Dendrobium Officinale ◽  
Regulatory Subunit ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Glutamate Cysteine Ligase ◽  
Nrf2 Signaling Pathway

The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2−Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate–cysteine ligase catalytic (GCLC) subunit, glutamate–cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2−Keap1 signaling pathway.

scholarly journals Renal control of disease tolerance to malaria

2019 ◽  
Vol 116 (12) ◽  
pp. 5681-5686 ◽  
Author(s):  
Susana Ramos ◽  
Ana Rita Carlos ◽  
Balamurugan Sundaram ◽  
Viktoria Jeney ◽  
Ana Ribeiro ◽  
...  
Keyword(s):  
Control Mechanism ◽  
Damage Control ◽  
Kidney Injury ◽  
Resistance Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Disease Tolerance ◽  
Host Protection ◽  
Ferritin H ◽  
Transcription Factor Nuclear Factor

Malaria, the disease caused byPlasmodiumspp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that killPlasmodium. However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not targetPlasmodiumdirectly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage ofPlasmodiuminfection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.

scholarly journals CCl4-Induced Liver Injury Was Ameliorated by Qi-Ge Decoction through the Antioxidant Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Chong Peng ◽  
Zun-ming Zhou ◽  
Jing Li ◽  
Yan Luo ◽  
Yun-song Zhou ◽  
...  
Keyword(s):  
Liver Injury ◽  
High Performance ◽  
Mucosal Damage ◽  
Positive Control ◽  
Chinese Herbs ◽  
Gastric Mucosal Damage ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Mechanism ◽  
Cyp 2E1

Qi-Ge decoction (QGD), which is derived from the Huangqi Gegen decoction, contains three traditional Chinese herbs: Astragalus membranaceus (Huangqi), Pueraria lobata (Gegen), and Citri Reticulatae Blanco Pericarpium (Chenpi). Gastric mucosal damage caused by ethanol was prevented and alleviated by QGD. However, the role of QGD in protecting the liver from toxins has not been reported. High-performance liquid chromatography with diode-array detection was used to qualitatively analyze QGD. Positive control (silymarin 100 mg/kg/day), QGD (20, 10, or 5 g/kg/day), and Nrf2 inhibitor brusatol (0.4 mg/kg/2 d) were administered to rats for 7 days, and then, liver injury was induced by injecting 2 mL/kg 25% CCl4. After 24 h, blood and liver were collected for analysis and evaluation. QGD was found to contain 12 main components including calycosin, puerarin, and hesperidin. QGD treatment significantly reduced liver damage and decreased serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities. QGD increased superoxide dismutase and catalase activities, and glutathione levels, but decreased malondialdehyde levels in livers from CCl4-treated rats. Compared to rats treated with CCl4 alone, after QGD administration, mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 were increased, while those of Kelch-like ECH-related protein 1 (Keap1) and cytochrome P450 (CYP)2E1 were decreased. However, these improvements in QGD were reversed by brusatol. In conclusion, QGD can achieve its hepatoprotective effect through an antioxidant mechanism by activating the Nrf2 pathway.

scholarly journals Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yaru Xue ◽  
Qiangqiang Deng ◽  
Qingli Zhang ◽  
Zhenghua Ma ◽  
Binfan Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Nordihydroguaiaretic Acid ◽  
Hepatic Inflammation ◽  
Cpla2 Activation ◽  
Inflammatory Processes ◽  
Mrna And Protein Expression ◽  
Lox Inhibitors ◽  
Jnk Activation

AbstractArachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.

Cpt1a promoted ROS-induced oxidative stress and inflammation in liver injury via the Nrf2/HO-1 and NLRP3 inflammasome signaling pathway

2020 ◽  
Author(s):  
Xigang Luo ◽  
Dapeng Sun ◽  
Yinxiang Wang ◽  
Fengxiang Zhang ◽  
Yi Wang
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Over Expression ◽  
Vitro Model

Various liver diseases caused by liver damage seriously affect people’s health. The purpose of this study was to clarify that the effects and mechanism of Carnitine palmitoyltransferase 1 (Cpt1a) on oxidative stress and inflammation in liver injury. It was found that the expression of Cpt1a mRNA was up-regulated in model mice of liver injury. So, over-expression of Cpt1a increased reactive oxygen species (ROS) production and malondialdehyde (MDA) levels, and reduced superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-px) levels in vitro model of liver injury. It was also shown that over-expression of Cpt1a suppressed the Nuclear factor-erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway. In summary, these data indicate that Cpt1a promotes ROS-induced oxidative stress in liver injury via the Nrf2/HO-1 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome signaling pathway.

scholarly journals Bamboo Stems (Phyllostachys nigra variety henosis) Containing Polyphenol Mixtures Activate Nrf2 and Attenuate Phenylhydrazine-Induced Oxidative Stress and Liver Injury

Nutrients ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 114 ◽  
Author(s):  
Ji Hye Yang ◽  
Moon-Hee Choi ◽  
Chang-Su Na ◽  
Sam Seok Cho ◽  
Jae Hoon Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Iron Overload ◽  
Liver Damage ◽  
Hepg2 Cells ◽  
Hepatoprotective Effect ◽  
Glutathione Depletion ◽  
Related Factor ◽  
Nrf2 Target Gene ◽  
Phyllostachys Nigra

This study was designed to investigate the hepatoprotective effect of bamboo stems using in vitro and in vivo experimental liver damage models. Ethyl acetate fraction of 80% ethanol extract of Phyllostachys nigra stem (PN3) containing polyphenols had a higher NQO1-ARE reporter gene activity as monitored by the activity of the NF-E2-related factor (Nrf2) antioxidant pathway in cells in comparison to extracts from other species and under other conditions. The Nrf2 was translocated from the cytosol to the nucleus in response to PN3, followed by induction of the Nrf2 target gene expression, including HO-1, GCL, and NQO-1 in HepG2 cells. Phosphorylation of Nrf2 in HepG2 cells was enhanced in PN3, which was mediated by PKCδ, ERK, and p38 MAPK. Consequently, PN3 inhibited arachidonic acid (AA) + iron-induced reactive oxygen species generation and glutathione depletion, and, thus, highlighted their role in cytotoxicity. Treatment with major polyphenols of PN3, including catechin, chlorogenic acid, caffeic acid, and p-coumaric acid, also improved AA + iron-mediated oxidative stress and, thus, improved cell viability. Treatment with phenylhydrazine in mice, i.e., the iron overload liver injury model, increased plasma alanine aminotransferase and aspartate aminotransferase levels and changed histological features in mice—a response that was almost completely blocked by PN3 administration. Moreover, PN3 extract mitigated phenylhydrazine-induced oxidative stress and inflammatory responses. Conclusively, PN3 can exert a hepatoprotective effect against iron overload-induced acute liver damage due to its antioxidant properties.

scholarly journals Protective Effects of Nutria Bile against Thioacetamide-Induced Liver Injury in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Joo-Yeon Kong ◽  
Seong-Chan Yeon ◽  
Hu Jang Lee ◽  
Changkeun Kang ◽  
Jin-Kyu Park ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Function ◽  
Alien Invasive Species ◽  
Protective Effects ◽  
Marker Protein ◽  
Hepatic Inflammation ◽  
Myocastor Coypus ◽  
Liver Injuries ◽  
Hepatoprotective Effects ◽  
Bear Bile

Several eradication programs have been developed and executed to curb alien invasive species that tend to damage the ecological environments they colonize; however, only few studies have evaluated the utilization of carcasses of these species after eradication. Nutria (Myocastor coypus) is an invasive rodent species targeted by eradication programs in many countries. We noted that nutria produce large amounts of ursodeoxycholic acid (UDCA) in their bile. UDCA is a unique component responsible for the anti-inflammatory and hepatoprotective effects exerted by bear bile. Therefore, we sought to examine the medicinal utility of nutria carcasses by investigating the hepatoprotective effect of their bile in mice. C57BL/6 mice were injected with thioacetamide (TAA), which induced liver damage by increasing Kupffer cell infiltration. Administration of nutria bile reduced hepatic inflammation, improved hepatic function, and increased the levels of senescence marker protein 30 (an indicator of hepatocyte viability). Our results show that nutria bile exerts protective effects against TAA-induced liver injury in mice, suggesting that nutria carcasses may be used for the treatment of liver injuries.

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