Carbon Tetrachloride-induced Liver Injury Research Articles

The regulatory mechanism involved in the prostaglandin E2 disposition in carbon tetrachloride-induced liver injury

Prostaglandin E2 (PGE2) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE2 during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE2 distribution during liver injury. Carbon tetrachloride (CCl4) was used to establish a liver injury mouse model. PGE2 was measured by LC-MS/MS. The plasma and hepatic PGE2 levels were significantly increased at 6 to 48 h after CCl4 treatment. The ratio of plasma levels of 13,14-dihydro-15-ketoPGE2 (PGEM), a major PGE2 metabolite, to PGE2 decreased significantly after CCl4 treatment. PGE2 synthesis and expression of enzymes related to PGE2 production were not induced, while the activity and mRNA expression of 15-prostaglandin dehydrogenase (15-PGDH/Hpgd), a major enzyme for PGE2 inactivation, decreased significantly in the liver of CCl4-treated mice compared to that of vehicle-treated control. The plasma and hepatic PGE2 levels were negatively correlated with the hepatic mRNA expression levels of Hpgd. Although the mRNA expression of organic anion transporting polypeptide 2A1 (OATP2A1/Slco2a1), a major PGE2 transporter, was upregulated, other hepatic OATPs decreased significantly at 24 h after CCl4 treatment. Immunohistochemical analysis indicated that 15-PGDH was mainly expressed in endothelial cells and that OATP2A1 was expressed at least in endothelial cells and Kupffer cells in the liver. These results suggest that the decreased 15-PGDH expression in hepatic endothelial cells is the principal mechanism for the increase in hepatic and plasma PGE2 levels due to the CCl4-induced liver injury.

Curcumin Ameliorates Carbon Tetrachloride-induced Liver Injury in Rats Through Modulating Various Biological Activities

Curcumin Ameliorates Carbon Tetrachloride-induced Liver Injury in Rats Through Modulating Various Biological Activities

Hepatoprotective effect of the unsaponifiable matter from olive, linseed and sesame oils against carbon tetrachloride-induced liver injury in rats

In the present study, the hepatoprotective activity of the unsaponifiable matter (UNSAP) of olive oil, linseed, and sesame oils against CCl4-induced liver toxicity in rats was investigated. In a preliminary antioxidant study, UNSAP showed pronounced DPPH radical scavenging activity (IC50 6.2-10.8 mg/mL). The constituents of UNSAP were determined by GC-MS. The subcutaneous administration of CCl4, caused liver injury. The hepatoprotective effect of UNSAP was comparable to that of α-tocopherol, a standard antioxidant agent. The co-administration of the investigated UNSAP normalized the activities of serum marker enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Furthermore, the serum alkaline phosphatase (ALP) activity and hepatic malondialdehyde (MDA) level were found to be alleviated by pre-treatment with the UNSAP. A histopathological evaluation showed marked improvement in the liver of UNSAP- and α-Tocopherol-treated animals. The hepatoprotective effect could be attributed to the antioxidant characteristics of UNSAP.

Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis.

Our understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this context, especially when considering their contribution in dampening liver inflammation. Liver macrophages were studied in mouse models of prolonged diet-induced liver steatohepatitis and carbon tetrachloride-induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non-alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co-inhibitory protein CD274 (Programmed-death ligand 1) and major histocompatibility complex (MHC) class II. Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co-inhibitory signalling. Liver macrophages circumscribed endotoxin-mediated inflammatory response by upregulating anti-inflammatory genes arginase 1 and interleukin-10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH-like parenchymal abnormalities. Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune-mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.

Preventive effect of lemon seed flavonoids on carbon tetrachloride-induced liver injury in mice.

The aim of this study was to determine the preventive effect of lemon seed flavonoids (LSF) on carbon tetrachloride-induced liver injury in mice. Liver injury was induced by injection with 2 mL kg−1 of carbon tetrachloride after administration of LSF by gavage. Liver index, serological parameters, and expression intensities of related mRNA and protein in the liver tissue were observed. The results indicated that LSF reduced liver weight and liver index, downregulated serum levels of AST, ALT, ALP, TG, TC, BUN, NO, and MDA, and upregulated levels of ALB, SOD, CAT, and GSH-Px in the mice with liver injury. It also downregulated serum cytokines, such as IL-6, IL-12, TNF-α, and IFN-γ in these mice. qPCR and western blot confirmed that LSF upregulated mRNA and protein expression of Mn-SOD, Cu/Zn-SOD, CAT, GSH-Px, and IκB-α, and downregulated expression of NF-κB-p65, iNOS, COX-2, TNF-α, IL-1β, and IL-6 in the liver tissue of mice with liver injury. The preventive effect on carbon tetrachloride-induced liver injury was attributed to (−)-epigallocatechin, caffeic acid, (−)-epicatechin, vitexin, quercetin, and hesperidin, which were active substances that were detected in LSF by HPLC. Moreover, the effect of LSF is similar to that of silymarin, but the synergistic effect of the five active substances working in concert acted to produce a more robust liver-protecting effect.

Polysaccharides from Enteromorpha prolifera protect against carbon tetrachloride-induced acute liver injury in mice via activation of Nrf2/HO-1 signaling, and suppression of oxidative stress, inflammation and apoptosis.

To investigate whether polysaccharides from Enteromorpha prolifera (EPP) could protect against acute hepatic injury induced by CCl4, ICR mice were pretreated with EPP (150, 300, and 450 mg kg-1) and silymarin (100 mg kg-1) for 28 days before CCl4 induction. Pretreatment with EPP attenuated CCl4-induced elevated serum transaminase activities and histopathological alterations in the liver. In addition, EPP prevented CCl4-induced reduction of protein levels of phosphorylated nuclear factor E2-related factor 2 (p-Nrf2)/Nrf2, heme oxygenase-1 (HO-1), and mRNA levels of NADPH quinineoxidoreductase-1 (NQO-1), which, in turn, reduced hepatic oxidative stress injury. Furthermore, the hepatic protein levels of inflammatory mediators and the phosphorylation of nuclear factor-kappaB p65 (NF-κB p65) and I kappaB alpha (IκBα), and the mRNA levels of Toll-like receptor 2 (TLR2), TLR4, and prolyl-isomerase-1 (Pin-1) in the inflammatory signaling pathway were recovered in the EPP pretreated groups. Moreover, EPP prevented the hepatocellular apoptotic changes with inhibition of B-cell lymphoma 2 (Bcl-2), and the induction of Bcl-2-associated X (Bax) and Cleaved caspase-3 caused by CCl4. Taken together, these results indicated that EPP protected against hepatic injury induced by CCl4-derived reactive intermediates through the activation of Nrf2/HO-1 signaling, and suppression of oxidative stress, inflammation and apoptosis.

Investigation of hepatoprotective effect of some algae species on carbon tetrachloride-induced liver injury in rats

The aim of this study was to investigate hepatoprotective effect of some algae species such as Spirulina platensis, Chlorella vulgaris, Laminaria japonica, Sargassum sp. on experimental acute hepatotoxicity model that induced with carbon tetrachloride (CCl4) in rats. Algaes at a dose of 200 mg/kg and Silymarin at a dose of 25 mg/kg were orally administered for 7 days followed by CCl4 at a single dose (0.5 ml/kg), at the 8th day to cause experimental acute hepatotoxicity. Levels of biochemical (AST, ALT etc.), lipid peroxidation (MDA), antioxidant (GSH, CAT, GPx) parameters and histopathological examination were carried out to investigate the hepatoprotective effects of algae. In Sp group ALT and ALP levels were significantly decreased compared with CCl4 (p < .05). Histological liver structures of Sp group were similar to the control group. MDA, GPx and CAT levels of Sp and La groups were significantly different compared with CCl4 (p < .05). Based on these results, algae species able to minimise the toxic effects of CCl4 and especially S. platensis could be used in the purpose of protection against chemical-induced hepatotoxicity.

Genipin Ameliorates Carbon Tetrachloride-Induced Liver Injury in Mice via the Concomitant Inhibition of Inflammation and Induction of Autophagy.

Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl4-) induced acute liver injury (ALI) and its underlying molecular machinery. Our results indicated that treatment with genipin significantly reduced CCl4-induced hepatotoxicity by ameliorating histological liver changes, decreasing the aspartate aminotransferase and alanine transaminase levels, alleviating the secretion of inflammatory cytokines, and promoting autophagic flux. Moreover, genipin effectively induced the conversion of LC3 and inhibition of p62 accumulation. The liver expressions of ATG5, ATG7, and ATG12 were significantly increased by genipin pretreatment in the ALI mice model. This protective effect may be mediated by the inhibition of mTOR and the activation of p38 MAPK signaling pathways. Meanwhile, genipin attenuated CCl4-induced inflammatory response by inhibiting the NF-κB and STAT3 signaling pathway. In addition, pretreatment with autophagy inhibitor 3-methyladenine (3-MA) or inhibition of p38 MAPK by SB203580 abolished the hepatoprotective effect of genipin. Taken together, our study implicates that genipin has a protective potential against CCl4-induced hepatotoxicity, which might be strongly associated with the induction of autophagy and the attenuation of inflammatory response.

Hepatoprotective effect of crude polysaccharides extracted from Ganoderma lucidum against carbon tetrachloride-induced liver injury in mice.

Background and Aim:Natural products are currently widely used as alternative treatments for liver disease. The study aimed to determine the hepatoprotective effect of crude polysaccharides extracted from Ganoderma lucidum against liver injury induced by carbon tetrachloride (CCl4).Materials and Methods:Twenty-four male BALB/C mice were randomly divided into six groups. Serum and liver samples were taken on day 10 after G. lucidum administration. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured using enzyme-linked immunosorbent assays, and the histology of the liver was evaluated using light microscopy.Results:G. lucidum extract significantly decreased the levels of ALT, AST, and MDA and significantly increased the levels of SOD and CAT. In the histological evaluation, the liver tissue of CCl4-treated mice exhibited hydropic degeneration, necrosis, and sinusoidal dilatation. G. lucidum extract administration improved this liver tissue histopathology.Conclusion:Crude polysaccharides extracted from G. lucidum showed a hepatoprotective effect, regenerating damaged liver tissue.

Design, Preparation, and Characterization of Dioscin Nanosuspensions and Evaluation of Their Protective Effect against Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

The purpose of this study was to prepare a dioscin nanosuspension (Dio-NS) that has a better distance and high solubility for oral administration and to evaluate its hepatoprotective effects. Optimal primary manufacture parameters, including shear time, shear speed, emulation temperature, pressure, and cycles of homogenization, were determined by single-factor experiments. The concentrations of dioscin, SDS, and soybean lecithin were optimized using the central composite design-response surface method, and their effects on the mean particle size (MPS) and particle size distribution of Dio-NS were investigated. Characterization of the Dio-NS formulations included examinations of the surface morphology and physical status of dioscin in Dio-NS, the stability of Dio-NS at different temperatures, in vitro solubility, and liver protective effect in vivo. Under optimal conditions, Dio-NS had an MPS of 106.72 nm, polydispersity index of 0.221, and zeta potential of −34.27 mV. Furthermore, the proportion of dioscin in Dio-NS was approximately 21.26%. The observation of particles with a spherical shape and the disappearance of crystalline peaks indicated that the physical and chemical properties of Dio-NS were altered. Furthermore, we observed that the dissolution of Dio-NS was superior to that of a physical mixture and Dio-GZF. Moreover, Dio-NS was demonstrated to have a protective effect against CCl4-induced acute liver damage in mice that was equivalent to that of silymarin (a positive control drug) at the same dose. The good hepatoprotective effect of our Dio-NS preparation can provide a theoretical basis for investigating its absorption mechanisms in the body.

Hepatoprotective Mechanisms of Taxifolin on Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

Objective: To investigate the hepatoprotective mechanisms of taxifolin in mice with acute liver injury induced by CCl4. Methods: ICR (Institute of Cancer research) mice were orally pretreated using taxifolin for 7 consecutive days and were then given single intraperitoneal (i.p.) injections of 0.2% CCl4 (10 mL/kg body weight, i.p.). Liver injury was then determined using assays of serum alanine aminotransferase (sALT) and serum aspartate aminotransferase (sAST). Further, to investigate the hepatoprotective mechanisms of taxifolin, we determined malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) activities. Results: CCl4-induced liver injury led to significant increases in sALT and sAST activities, and these increases were limited by taxifolin and silymarin (Sily) pretreatments. Histological analyses also indicated that taxifolin and Sily decreased the range of liver lesions in CCl4-treated mice and vacuole formation, neutrophil infiltration, and necrosis were visibly reduced. In addition, SOD, GPx, and GRd activities were increased and MDA levels were decreased after taxifolin and Sily treatments. Conclusion: The hepatoprotective mechanisms of taxifolin and Sily are related to decreases in MDA levels presumably due to increased antioxidant enzyme activities. These outcomes suggest that taxifolin mitigates acute liver injury resulted from CCl4 in mice, demonstrating the hepatoprotective effects of taxifolin.

Protective Effects of Propolis and Probiotic Lactobacillus acidophilus against Carbon Tetrachloride-Induced Hepatotoxicity in Rats

Background: Propolis (PRS) and probiotic bacteria Lactobacillus are natural products used as dietary supplement for their therapeutic benefits. This study was performed to examine the possible hepatoprotective effect of PRS and probiotics (PRCs) against carbon tetrachloride-induced liver injury. Methods: Experimentally, intoxicated rats received 0.5 ml/kg CCl4 (i.p.) daily for six days, pretreated rats received per os PRS 100 mg/kg or PRCs 109 CFU for six days followed by a single dose of 0.5 ml/kg CCl4. Control groups received either PRS, PRCs or olive oil for six days. Then, serum biochemistry (total protein, cholesterol, triglycerides and albumin) and oxidative stress parameters were measured. Results: We showed that CCl4 treatment was associated with an increase of the serum aspartate amino transferase (AST), alanine aminotransferase (ALT), cholesterol and triglycerides levels. In parallel, serum total protein, albumin and blood sugar levels were significantly decreased. Regarding the oxidative stress parameters, catalase and glutathione S-transferase (GST) levels were lower, conversely to the lipid peroxidation (MDA). Conclusion: Our results strongly support that administration of PRS and PRCs may significantly protect liver against CCl4-induced toxicity by enhancing antioxidative stress pathway and preventing lipid peroxidation.

Effects of Ethanol Leaf Extract of Lawsonia inermis Linn. on Carbon Tetrachloride-Induced Liver Injury In Adult Wistar Rats

Effects of Ethanol Leaf Extract of Lawsonia inermis Linn. on Carbon Tetrachloride-Induced Liver Injury In Adult Wistar Rats

Morin Hydrate Inhibits TREM-1/TLR4-Mediated Inflammatory Response in Macrophages and Protects Against Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

This study aims to investigate the protective effects of morin hydrate (MH) against acute liver injury induced by carbon tetrachloride (CCl4) in mice and to elucidate the possible molecular mechanism of action. Mice were pretreated with MH (50 mg/kg body weight) or vehicle by oral gavage once daily for 5 days, followed by intraperitoneal injection of a single dose of CCl4 (1 ml/kg in olive oil). Mice were sacrificed 24 h later; the blood and liver samples were harvested for analysis. We also used the model of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in vitro and examined the effects of MH and its mechanism of action on the inflammatory response. Our results revealed that MH remarkably attenuated liver histopathological alterations, serum transaminases, hepatocytes death, and inflammatory response induced by CCl4. Importantly, MH reduced expression of the triggering receptor expressed on myeloid cells-1 (TREM-1) and toll-like receptor 4 (TLR4) both in vivo and in vitro experiments. This inhibitory effect MH on expression of the TREM-1 and TLR4 in cell culture was further heightened after TREM-1 knockdown with small interfering RNA (siRNA). Moreover, MH dramatically suppressed the inhibitor of kappa B α (IκBα) degradation and subsequent nuclear factor-kappa B (NF-κB) p65 translocation into the nucleus and NF-κB-mediated cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6. Additionally, MH also ameliorated CCl4-induced oxidative stress by enhancing the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in the injured livers. Taken together, MH has hepatoprotective activity, and this effect may be elicited by attenuating macrophage-mediated inflammatory responses via inhibition TREM-1/TLR4/NF-κB signaling and by regulating hepatic oxidative stress via enhancement Nrf2/HO-1 antioxidant pathway.

Protective Effect of Selenium-Enriched Red Radish Sprouts on Carbon Tetrachloride-Induced Liver Injury in Mice.

This study aimed to investigate the effect of Se (Selenium) treatment on nutritional quality in radish sprouts. The results showed that 15 µM sodium selenite significantly increased phenolics compounds, flavonoids compounds, anthocyanins, and some essential amino acid content, while improving the total antioxidant capacity of radish sprouts. Besides, the Se-enriched radish sprouts significantly alleviated the liver damage caused by carbon tetrachloride (CCl4 ) in mice and improved the antioxidant capacity of the liver in mice, whereas the Se-enriched radish sprouts alleviated the inflammatory reaction and apoptosis caused by CCl4 . These results imply that Se-enriched radish sprouts have a positive impact on mice with CCl4 -induced liver injury, and that in future Se-enriched radish sprouts could be developed into an effective food and health care product for the liver injury prevention. PRACTICAL APPLICATION: Because selenium is an essential trace element in the human body, selenium-enriched sprouts can help eliminate free radicals in the body, relieve aging, and selenium-deficient diseases. They are easy to grow and have low costs. Hence, selenium-enriched sprouts have a great potential of being widely consumed.

Amelioration of Carbon Tetrachloride-Induced Liver Injury by Citrus Leaf Extract

The main purpose of this study is to investigate the role of citrus leaf extract in carbon tetrachloride-induced hepatic injury and its potential molecular mechanism. Carbon tetrachloride was used to construct hepatic injury animal model. To this end, rats were randomly divided into 4 groups: control, carbon tetrachloride-treated, and two carbon tetrachloride + citrus leaf extract-treated groups. The results show that citrus leaf extract treatment significantly reversed the effects of carbon tetrachloride on the body weight changes and liver index. Besides, treatment with citrus leaf extract also reduced the levels of serum liver enzymes and oxidative stress in a dose-dependent manner. H&amp;E staining and western blotting suggested that citrus leaf extract could repair liver histological damage by regulating AMPK and Nrf-2.

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo.

Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar-tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM-producing myofibroblasts. Involvement of the Janus kinase (JAK)-2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride-induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF-β-induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF-β-induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α-smooth muscle actin). In LPS- and IFN-γ-stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C-C motif chemokine ligand 2, IL-1β, IL-6, and C-C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.-Akcora, B. O., Dathathri, E., Ortiz-Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo.

Inhibition of the mitochondrial complex-1 protects against carbon tetrachloride-induced acute liver injury

Mitochondrial dysfunction has been documented to play a crucial role in the pathogenesis of liver injury. In the present study, we investigated the role of rotenone, a mitochondrial complex-1 inhibitor, in carbon tetrachloride (CCl4) -induced acute liver injury, as well as the underlying mechanisms. Before CCl4 administration, the mice were pretreated with rotenone at a dose of 250 ppm in food for three days. Then CCl4 was administered to the mice for 16 h by intraperitoneal injection. The liver injury, mitochondrial status, oxidative stress, and inflammation were examined. Strikingly, CCl4 treatment markedly induced liver injury as shown by enhanced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and morphological lesions (HE stating), which was significantly attenuated by rotenone treatment in line with the reduced activity of mitochondrial complex-1. Meanwhile, oxidative stress markers of malondialdehyde (MDA), 4-hydroxynonenal (HNE), and dihydroethidium (DHE) and the inflammatory markers of IL-1β, MCP-1, TNF-α, TLR-4, and IL-6 were also significantly suppressed by rotenone. More importantly, the mitochondrial abnormalities shown by the reduction of SOD2, mitochondrial transcription factor A (TFAM), mitochondrial NADH dehydrogenase subunit 1 (mtND1), and Cytb were significantly restored, indicating that rotenone protected against mitochondrial damage induced by CCl4 in liver. Moreover, rotenone treatment alone did not significantly alter liver morphology and liver enzymes ALT and AST. CYP2E1, a metabolic enzyme of CCl4, was also not significantly affected by rotenone. In conclusion, rotenone protected the liver from CCl4-induced damage possibly by inhibiting the mitochondrial oxidative stress and inflammation.

Protective effect of the glucagon-like peptide-1 analogue liraglutide on carbon tetrachloride-induced acute liver injury in mice

Acute liver injury seriously endangers human health. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has antioxidative effects in addition to being widely used in the treatment of type 2 diabetes and was reported to ameliorate liver diseases. The aim of this study was to evaluate the hepatoprotective effects of liraglutide on carbon tetrachloride (CCl4)-induced acute liver injury in mice and to investigate the mechanisms involved in this protective effect. Male BALB/c mice were pre-treated with liraglutide (200 μg/kg/day) by hypodermic injection for 3 days before a 0.1% (v/v) CCl4 (10 ml/kg, dissolved in olive oil) intraperitoneal injection, or post-treated with liraglutide once immediately after a CCl4 intraperitoneal injection. The experimental data showed that liraglutide treatment significantly decreased the serum ALT and AST levels and ameliorated the liver histopathological changes induced by CCl4. In addition, liraglutide pre-treatment dramatically increased the number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and significantly reduced hepatocyte apoptosis after CCl4 treatment. As a consequence, liraglutide pre-treatment significantly prevented CCl4-induced malondialdehyde (MDA) production and increased the activity of the antioxidant superoxide dismutase (SOD) enzyme. In addition, liraglutide pre-treatment significantly ameliorated mitochondrial respiratory functions and ultrastructural features. Furthermore, liraglutide pre-treatment enhances the activation of the NRF2/HO-1 signaling pathway. In summary, liraglutide protects against CCl4-induced acute liver injury by protecting mitochondrial functions and inhibiting oxidative stress, which may partly involve the activation of NRF2/HO-1 signaling pathway.

Hepatoprotective effects of ginseng saponins in a mouse model of carbon tetrachloride-induced liver injury

Purpose: To investigate the effects of ginsenosides Rg1 and Rb1 on carbon tetrachloride (CCl4)-induced liver injury in mice.Methods: Thirty-two mice were randomly divided into four groups. In control group, mice were administered sodium carboxymethylcellulose (CMC-Na) by intraperitoneal injection for seven days. In CCl4 treatment group, mice were treated as control group for the first seven days and then intraperitoneally injected with CCl4 in olive oil on day 8. In Rb1- and Rg1-treatment group, the mice were intraperitoneally injected with Rb1 or Rg1 (each 30 mg/kg, dissolved in 0.5 % CMC-Na), respectively for seven days, followed by intraperitoneal injection with CCl4 in olive oil on day 8. Histological damage was examined by haematoxylin and eosin (H&amp;E) staining. Serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) were assessed enzymatically. Tissue IL-6 and IL-8 levels were measured by ELISA. Gene and protein levels of transforming growth factor (TGF)-β, Smad2, and Smad3 were analyzed by real-time PCR (RT-PCR) and western blotting, respectively.Results: CCl4 treatment caused histological damage in mouse liver, and increased the levels of ALT, AST (five-fold), IL-6 (three-fold), and IL-8 (five-fold), and elevated expressions of TGF-β, Smad2, and Smad3. Ginsenosides Rg1 or Rb1 pre-treatment attenuated liver injury by decreasing the serum levels of ALT (from 700 to 200 UI/L) AST (from 550 pg/mL to 250 pg/ml), IL-6 (from 1,100 to 750 pg/mL), and IL-8 (from 600 to 200 pg/mL), and inhibiting the expressions of TGF-β, Smad2, and Smad3.Conclusion: Ginsenosides (Rg1 and Rb1) attenuate CCl4-induced liver injury and inflammation by regulating TGF-β/Smad signalling pathway.Keywords: Ginseng saponin, Ginsenosides, Rg1, Rb1, Hepatoprotective effect, TGF-β/Smad signalling pathway