Amelioration of Carbon Tetrachloride - Induced Liver Injury by p-Coumaric Acid

We investigated the protective and in vivo antioxidant effects of p-coumaric acid on carbon tetrachloride-induced hepatotoxicity in Sprague-Dawley rats. The rats were orally pre-treated with p-coumaric acid (at 50 and 100 mg/kg body weight) for 15 days before the subcutaneous injection of carbon tetrachloride (1.5 mL/kg). Silymarin served as a positive control for hepatoprotection. Blood and tissue samples were obtained and used to assess the effects of p-coumaric acid using quantitative and qualitative histological evaluation, glutathione levels, protein determination, and liver enzymes. p-Coumaric acid treatment did not demonstrate any toxicological abnormalities in mice. p-Coumaric acid and silymarin reduced the extent of carbon tetrachloride-induced liver damage and preserved normal hepatic enzymes (P < 0.05). p-Coumaric acid pre-treatment led to a diminution in increased malondialdehyde and decreased glutathione following carbon tetrachloride administration (P < 0.05). Furthermore, p-coumaric acid restored changes in superoxide dismutase and caspase-3 gene expression as a result of carbon tetrachloride exposure. In conclusion, p-coumaric acid helps restore toxicant-induced liver injury in rats via avoidance of lipid peroxidation, inhibition of cell death and preservation of antioxidant mechanism.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/5941263 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 4

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.

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

Pharmaceuticals ◽

10.3390/ph13050084 ◽

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.

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

Marine Drugs ◽

10.3390/md16090300 ◽

2018 ◽

Vol 16 (9) ◽

pp. 300 ◽

Cited By ~ 8

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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Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

Toxicologic Pathology ◽

10.1177/0192623320968716 ◽

2020 ◽

Vol 48 (8) ◽

pp. 994-1007

Author(s):

Timothy P. LaBranche ◽

Anna K. Kopec ◽

Srinivasa R. Mantena ◽

Brett D. Hollingshead ◽

Andrew W. Harrington ◽

...

Keyword(s):

Metabolic Syndrome ◽

Pharmaceutical Industry ◽

Liver Injury ◽

Hepatic Steatosis ◽

Sprague Dawley ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Sd Rats ◽

Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

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Grape-Leaf Extract Attenuates Alcohol-Induced Liver Injury via Interference with NF-κB Signaling Pathway

Biomolecules ◽

10.3390/biom10040558 ◽

2020 ◽

Vol 10 (4) ◽

pp. 558 ◽

Cited By ~ 1

Author(s):

Yhiya Amen ◽

Asmaa E. Sherif ◽

Noha M. Shawky ◽

Rehab S. Abdelrahman ◽

Michael Wink ◽

...

Keyword(s):

Liver Injury ◽

Secondary Metabolites ◽

Nuclear Factor Κb ◽

Sprague Dawley ◽

Leaf Extracts ◽

Underlying Mechanisms ◽

Grape Leaf ◽

Factor Α ◽

Antioxidant Effects

Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC–PDA–ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-κB) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-κB signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.

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Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90435.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. G572-G581 ◽

Cited By ~ 46

Author(s):

Ji-Young Hong ◽

Margitta Lebofsky ◽

Anwar Farhood ◽

Hartmut Jaeschke

Keyword(s):

Liver Injury ◽

Caspase 3 ◽

Oxidant Stress ◽

Positive Control ◽

Terminal Deoxynucleotidyl Transferase ◽

Kinase Activation ◽

Superoxide Formation ◽

Apoptotic Morphology ◽

High Doses

Oxidant stress is critically involved in various liver diseases. Superoxide formation causes c-Jun NH2-terminal kinase (JNK)- and caspase-dependent apoptosis in cultured hepatocytes. To verify these findings in vivo, male Fisher rats were treated with diquat and menadione. The oxidant stress induced by both compounds was confirmed by increased formation of glutathione disulfide and 4-hydroxynonenal protein adducts. Plasma alanine aminotransferase activities increased from 46 ± 4 U/l in controls to 955 ± 90 U/l at 6 h after diquat treatment. Hematoxylin and eosin staining of liver sections revealed large areas of necrotic cells at 3 and 6 h. DNA strandbreaks, evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, showed clusters of TUNEL-positive cells, where the staining was predominantly cytosolic and the cells were swollen, indicating oncotic necrosis. There was no significant increase in caspase-3 activities or relevant release of DNA fragments into the cytosol at any time between 0 and 6 h after diquat treatment. Despite the activation of JNK after high doses of diquat, the JNK inhibitor SP-600125 did not protect against diquat-induced necrosis. Menadione alone did not cause liver injury, but, in combination with phorone and FeSO4, induced moderate oncotic necrosis. On the other hand, if animals were treated with galactosamine/endotoxin as positive control for apoptosis, caspase-3 activities were increased by 259%, the number of TUNEL-positive cells with apoptotic morphology was increased 103-fold, and DNA fragmentation was enhanced 6-fold. The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation.

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HEPATOPROTECTIVE EFFECTS ETHANOL EXTRACT OF MAGROVE PROPAGULE (Rhizophora mucronata) IN WHITE RAT STRAIN Sprague Dawley INDUCED CARBON TETRACHLORIDE (CCL4)

KnE Life Sciences ◽

10.18502/kls.v1i0.98 ◽

2015 ◽

Vol 2 (1) ◽

pp. 141

Author(s):

Sri Purwaningsih ◽

Ekowati Handharyani ◽

Aditya Yudha Prawira Sukarno

Keyword(s):

Carbon Tetrachloride ◽

Antioxidant Activities ◽

Ethanol Extract ◽

Positive Control ◽

Rhizophora Mucronata ◽

Sprague Dawley ◽

Cell Recovery ◽

Group I ◽

Best Value ◽

Histopathological Studies

Prevalence of liver disease more increased. Imfflamation in liver tissue caused by free radical metabolism results of toxic compounds such as alcohol, paracetamol, and carbon tetrachloride (CCL4). Rhizophora mucronata has been higher antioxidant activities and reported as hepatoprotector. This research was aimed to investigate activity of mangrove propagule (R.mucronata) as a hepatoprotector and determined the effect levels of specific liver enzymes, liver MDA, and histopathological studies. Rhizophora mucronata was extracted by ethanol 95% solvent (b:v)(1:5). There were 21 rats randomly divided into 7 following groups (n=3), they were group I allowed fed with standard pellet, group II was positive control induced CCL4 dose 2 ml/kg BW, group III, IV, V, and VI were induced by CCL dose 2 ml/kg BW and given consecutively the mangrove extract 1 mg/kg BW, 5 mg/kg BW, 15 mg/kg BW, and 25 mg/kg BW. Result showed the extract did not affect significantly (p>0.05) to decreased level of AST enzyme and the best value owned of 15 mg/kg BW treatment with AST levels as 187 U/L. In contrast, extract R.mucronata effected significantly different (p<0.05) on ALT levels with the best value in 5 mg/kg BW treatment. R.mucronata did not effect significantly (p>0.05) of MDA level in liver, and decreased with the best result in 5 mg/kg BW treatment. Histopatological studies showed a protective effect and cell recovery of the liver induced CCL4. Keywords: Antoxidant, Hepatoprotective, Mangrove propagule (R.mucronata)

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A Practical Noncontact Model to Create Standardized Experimental Burn Wounds of Any Thickness: Blue Beam Laser Pointer for Burn Induction

Journal of Burn Care & Research ◽

10.1093/jbcr/irz088 ◽

2019 ◽

Vol 40 (6) ◽

pp. 805-808

Author(s):

Uğur Anıl Bingöl ◽

Sinan Öksüz ◽

Anıl Demiröz ◽

Hakan Arslan

Keyword(s):

Histological Evaluation ◽

Dorsal Skin ◽

Laser Pointer ◽

Sprague Dawley ◽

Burn Wound ◽

Tissue Samples ◽

Burn Wounds ◽

The Third ◽

Beam Laser ◽

Degree Burn

Abstract The objective of this study was to describe a predictable and easy-to-use model that can create standardized burn wounds. A 450-nm 1000-mW blue beam laser pointer was used to create burn wounds on the dorsal skin of 24 Sprague Dawley rats. Twelve distinct areas of dorsal skin were pulsed for 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 seconds with the help of a punched plastic card template. Three groups of 8 animals were killed immediately after on the third day and on the seventh day of the procedure and tissue samples were taken for histological evaluation and measurements. A second-degree burn was obtained in all animals with 3 and 5 seconds of laser application on the same day, third day, and seventh day measurements. Seven seconds of application resulted in a burn depth of 84.87% of dermis on the application day which deepened to involve the whole dermal layer on the third and seventh day. Nine seconds and longer application times resulted in third-degree burn wounds. Burn induction with blue beam laser pointer is an easy-to-use, predictable and safe model to create a standardized burn wound of desired thickness.

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Effects and Mechanisms of Acremoniumterricola milleretal mycelium on Liver Fibrosis Induced by Carbon Tetrachloride in Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x11009019 ◽

2011 ◽

Vol 39 (03) ◽

pp. 537-550 ◽

Cited By ~ 10

Author(s):

Xiao-Peng Tian ◽

Yan-Yan Yin ◽

Xia Li

Keyword(s):

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Liver Injury ◽

Chinese Herb ◽

Immunoblot Analysis ◽

Hepatoprotective Activity ◽

Protective Effects ◽

Sprague Dawley ◽

Procollagen Type ◽

Tgf Β1

Acremoniumterricola milleretal mycelium (AMM) is one of the most precious traditional Chinese medicines. It has numerous protective effects on organs, and has been used in Chinese herb prescription to treat refractory diseases. Our preliminary studies demonstrated that AMM had hepatoprotective activity in acute liver injury. We further investigated the effects of AMM on liver fibrosis in rats induced by carbon tetrachloride ( CCl 4) and explore its possible mechanisms. The animal model was established by injection with 50% CCl 4 subcutaneously in male Sprague-Dawley rats twice a week for eight weeks. Meanwhile, AMM (175, 350 and 700 mg/kg) was administered intragastrically per day until sacrifice. We found that treatment with AMM (175, 350 and 700 mg/kg) decreased CCl 4-induced elevation of serum transaminase activities, hyaluronic acid, laminin and procollagen type III levels, and contents of hydroxyproline in liver tissues. It also restored the decreased SOD and GSH-Px activities and inhibited the formation of lipid peroxidative products during CCl 4 treatment. Moreover, AMM (350 and 700 mg/kg) decreased the elevation of TGF-β1 by 19.6% and 34.3%, respectively. In the pathological study, liver injury and the formation of liver fibrosis in rates treated by AMM were improved significantly. Immunoblot analysis showed that AMM (175, 350 and 700 mg/kg) inhibited Smad 2/3 phosphorylation, and elevated inhibitor Smad 7 expression. These results suggested that AMM could protect liver damage and inhibit the progression of hepatic fibrosis induced by CCl 4, and its mechanisms might be associated with its ability to scavenge free radicals, decrease the level of TGF-β1 and block TGF-β/Smad signaling pathway.

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