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Protective effects of Ginsenoside Rg1 against carbon tetrachloride-induced liver injury in mice through suppression of inflammation.

ABSTRACT

Background: AMP-activated protein kinase (AMPK) is one of the principal cellular energy sensors participating in maintenance of energy balance but recent evidences also suggested that AMPK might be involved in the regulation of inflammation.

Study design/methods: Ginsenoside Rg1 (Rg1) was used to investigate the potential roles of AMPK in carbon tetrachloride (C[Cl.sub.4])-induced hepato-toxicity. The experimental data indicated that treatment with Rg1 significantly decreased the elevation of plasma aminotransferases and alleviated hepatic histological abnormalities in C[Cl.sub.4]- exposed mice. Treatment with Rg1 also inhibited the increase of myeloperoxidase (MPO) and malondialdehyde (MDA), the induction of TNF-[alpha], IL-6, inducible nitric oxide synthase (iNOS), nitric oxide and the upregulation of matrix metalloproteinase 2 (MMP-2), MMP-3 and MMP-9 in mice exposed to C[Cl.sub.4]. These effects were associated with suppressed nuclear accumulation of NF-[kappa]B p65.

Conclusion: These results indicated that Rg1 effectively suppressed the inflammatory responses and alleviated liver damage induced by C[Cl.sub.4], implying that AMPK activation might be beneficial for ameliorating inflammation-based liver damage.

Keywords:

C[Cl.sub.4]-induced hepatotoxicity Ginsenoside Rg1 Inflammation

Introduction

Liver disease has been confirmed as one of the most serious health problems in the world (Williams 2006), which can be caused by many factors including hepatitis virus infection, induction of drugs and toxins. Carbon tetrachloride (C[Cl.sub.4]) is a well-known environmental biohazard, which can cause particularly toxic to the liver. Experimental and clinical studies increasingly show that C[Cl.sub.4] induced hepatic injury, a classic experimental model, has been extensively used to evaluate the potential of drugs and dietary antioxidants against the oxidative damage (Basu 2003). Free radicals, such as trichloromethyl (C[Cl.sub.3] and/or C[Cl.sub.3]OO) and oxygen-centered lipid radicals (LO and/or LOO), are pivotal in C[Cl.sub.4]-induced hepatotoxicity, which are generated during C[Cl.sub.4] metabolism by hepatic cellular cytochrome P450 (Recknagel et al. 1989; Li et al. 2010). In addition, the activation of Kupffer cells also contributes to the liver injury through releasing both direct toxic products and cytokines which promote inflammatory response (Taniguchi et al. 2004). The liver injury may be prevented or treated by blocking or retarding the process of oxidative stress and inflammation (Lin et al. 2012).

Recently, the interplay between energy metabolism pathway and inflammatory response was highly concerned (Delmastro-Greenwood and Piganelli 2013; McGettrick and O'Neill 2013). Several pathways contribute to C[Cl.sub.4]-induced inflammatory response and one of the central pathways is through the induction of AMPK, a conserved cellular energy status sensor. The cellular energy status is monitored by various energy sensors such as AMP-activated protein kinase (AMPK). AMPK is activated by the increased level of adenosine monophosphate (AMP) under falling energy status (Hardie et al. 2012). The activated AMPK helps the cells to restore energy homoeostasis via activating the catabolic pathways that generate ATP while deactivating the anabolic pathways that consume ATP (Dunlop and Tee 2013). AMPK is also a serine-threonine kinase that can phosphorylate and subsequently inactivate sirtuin 1 (Sirt1), thereby attenuating steatosis. Expression of the Sirt1, nicotinamide adenine dinucleotide-dependent class III histone deacetylase, is decreased in mice treated with CCL4, resulting in increased levels of several inflammatory cytokines, in addition, recent studies have found that the induction of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-[alpha]) by lipopolysaccharide (LPS) could be suppressed by over-expression of constitutively active AMPK but could be enhanced by over-expression of dominant-negative AMPK or short hairpin RNA targeting AMPK (Yang et al. 2010). Simultaneously, MAPK may act upstream of NF-[kappa]B signaling because the inhibitors of MAPK activation have a negative effect on NF-[kappa]B activation. NF-[kappa]B activation is largely involved in the gene expression of proinflammatory cytokines and chemokines and is responsible for the expression and activity of inflammatory factor. Therefore, the inhibition of downstream NF-[kappa]B signaling may prevent proinflammatory events. These emerging evidences suggested that AMPK-Sirt1-NF-[kappa]B might be involved in the regulation of inflammation, an energy-intensive pathological response (Pearce et al. 2013).

Nowadays, many hepatoprotective medicines have been widely used, and however, some of them have potential adverse effects (Tian et al. 2012). Natural products from medicinal plants, especially to traditional herbal medicine, have been attracted much attentions as effective and safe alternative treatments for liver diseases (Ma et al. 2009). Panax ginseng C. A. Mey is widely used as a traditional herbal medicine and exhibits many functional activities such as antioxidant, anti-inflammatory, and anti-aging potencies. Ginsenosides, Rg1 is one of the most active and abundant steroid saponin that shares structural similarity with many steroid hormones. The most importantly is that extract of ginkgo biloba injection, which is already available to treat disturbance of blood circulation as prescription drug. Rg1 has been found as an antioxidant substance and attenuated the oxidative damage in liver of thioacetamide treated rats (Deng and Zhang 1991; Geng et al. 2010). In the light of all these bases, the present study was to investigate the hepatoprotective effect of ginsenoside-Rg1 on C[Cl.sub.4]-induced hepatotoxicity in mice and then to explore the possible mechanisms of the action.

Materials and methods

Chemicals and materials

Rg1 (purities > 98%) were purchased from National Institutes of Food and Drug Control of China (Beijing, China). C[Cl.sub.4] was purchased from Kaixing Chemical Industry Co., Ltd. (Tianjin, China). Silymarin was obtained from Sigma Chemical Company (Milan, Italy). The detection kits including alanine transaminase (ALT), aspartate transaminase (AST), myeloperoxidase (MPO), malondialdehyde (MDA), superoxidase dismutase (SOD) and nitric oxide (NO) were all purchased from Nanjing Jiancheng Institute of Biotechnology (Nanjing, China). The enzyme-linked immunosorbent assay (ELISA) kits for determination of 1L-6, TNF-[alpha] and the nuclear and cytoplasmic protein extraction kit were produced by Nanjing KeyGEN Biotech. CO., Ltd. (Nanjing, China). The rabbit anti mouse nuclear factor kappa B (NF-[kappa]B) p65 was purchased from Cell Signaling Technology (Beverly, MA, USA). Horseradish peroxidase-conjugated goat anti-rabbit and goat mouse antibodies were purchased from GE Healthcare (London, UK). PVDF membranes were purchased from Roche (Basel, Switzerland). All other chemicals were of reagent grade.

Animals

50 male Kunming mice (18-22 g) were purchased from the Experimental Animal Center of China Pharmaceutical University (Nanjing, China). The mice were used after one week of acclimatization. They were kept in departmental animal house in well cross ventilated room at 24[degrees]C, relative humidity (45-55%), and a light-dark cycle of 12 h during the experiments. All mice were housed uniformly per cage (free access to tap water and diet) until the end of the study. All experimental procedures were approved by the Animal Care and Use Committee of China Pharmaceutical University, and performed in strict accordance with the PR China Legislation Regarding the Use and Care of Laboratory Animals.

Experimental design

After environmental adaptation, the mice were randomly allocated in to normal group, model group, silymarin-treated group and Rg1-treated groups. Each group contained 10 animals. The mice were received 0.5% CMC-Na distilled water solutions (p.o.) in normal and model groups, Rg1 (20, 40mg/kg dissolved in 0.5 % CMC-Na) in Rg1 treated groups, and the positive drug (20 mg/kg) in silymarin treated group. All administrations were conducted for 7 consecutive days. On the 8th day, all mice except those in normal group was injected intraperitoneally with 0.3% C[Cl.sub.4] (10ml/kg, dissolved in olive oil), whereas the animals in normal group were received olive oil alone (i.p.). Twenty-four hours after injection, the mice were sacrificed under ether anesthesia. The blood was collected and serum was separated immediately. The fresh liver tissues were excised, blotted, weighed and stored at -80[degrees]C for further experiments.

Determination of liver enzymes

The levels of ALT, AST in liver and serum were assayed based on the manufacturer's instruction of the kits. The value of each sample was calculated according to the standard curve.

Histological investigation

Paraffin embedded sections of the livers were cut with 5 [micro]m thicknes sand examined after staining with H&E using alight microscope (Nikon Eclipse TE2000-U, NIKON, Japan) and then photographed at 200 x magnification.

Determination of cytokines by ELISA

The protein levels of TNF-[alpha] and IL-6 in plasma were determined using ELISA kits according to the manufacturer's instructions (NeoBioscience, China).

Determination of NO

The levels of NO in plasma were determined with NO assay kit according to the manufacturer's instructions (Beyotime, China). The values of NO were assessed according to the absorbance measured at 540 nm.

Determination of MPO, SOD and MDA

The frozen liver tissues were homogenized in phosphate buffer containing 0.5% hexadecyltrimethylammonium bromide. The activities of MPO, SOD and MDA were determined with MPO, SOD and MDA assay kit according to the manufacturer's instructions (Nanjing Jiancheng, China).

Quantitative PCR

The mRNA level of TNF-[alpha], IL-6, inducible nitric oxide synthase (iNOS) and matrix metalloproteinases (MMPs) in liver were determined by Quantitative real-time PCR. Briefly, total RNA was isolated from liver samples using Trizol reagent. First-strand complementary DNA (cDNA) was synthesized using oligo-dT primer and the M-MLV reverse transcriptase. Quantitative PCR was performed with SYBR green PCR Master Mix with the following conditions: denaturing at 95[degrees]C for 10 s, annealing at 58[degrees]C for 20 s, and elongation at 72[degrees]C for 20 s. The mRNA level of [beta]-actin. was used as an internal control. The primer sequences were as follows: NF-[kappa]B p65 (forward: 5'-GCGTACACATTCTGGGGAGT-3', reverse: 5'-CCGAAGC AGGAGCTATCAAC-3'), TNF-[alpha] (forward: 5-CTCTTCTCCTTCCTGATCGTGGCA-3, reverse: 5-GTTGGATGTTCGTCC TCCTCACA-3), IL-6 (forward: 5-GAACTCCTTCTCCACAAGCGCCTT-3, reverse: 5-CAAAAGACCAGTGATGATTTTCACCAGG-3), iNOS (forward: 5-CATGGCTTGCCCCTGGAAGTTTCT-3, reverse: 5-CCTCTATGGTGCCAT CGGGCATC-3), MMP-2 (forward: 5-CCGAGGACTATGACCGGGATAA-3, reverse: 5-CTTGTTGCCCAGGAAAGTGAAG-3), MMP-3 (forward: 5-CCACAGACTTGTCCCGTTTCC-3, reverse: 5-GTGCTGACTGCATCAAAG AACAA-3), MMP-9 (forward: 5-CGTGTCTGGAGATTCGACT-3, reverse: 5-TGGAAGATGTCGTGTGAG-3),

[beta]-actin (forward: 5-AGCCATGTACGTAGCCATCC-3, reverse: 5-CTCTCAGCTGTGGTGGTGAA-3).

Western blotting assay

The liver tissues were homogenized, washed with PBS, and incubated in lysis buffer in addition to a protease inhibitor cocktail (Sigma, St. Louis, MO) to obtain extracts of proteins. The samples were loaded to 10% SDS-PAGE gels and were electrotransferred to nitrocellulose. The blots were incubated with the appropriate concentration of specific antibody. After washing, the blots were incubated with horseradish peroxidase-conjugated second antibody. The membranes were stripped and reblotted with anti-actin antibody (Sigma) to verify the equal loading of protein in each lane.

Statistical analysis

All values were expressed as the mean [+ or -] S.D. and analyzed by one-way analysis of variance (ANOVA) followed by Duncan's Multiple Range Test using SPSS version 13.0 software; a P-value of less than 0.05 was considered significant and and P < 0.01 was considered to be statistically very significant.

Results

Effects of Rg1 on AST and ALT in liver and serum

The levels of the AST and ALT in liver and serum were dramatically increased by C[Cl.sub.4] administration, while in Rg1-treated groups and silymarin-treated group, the levels of the AST and ALT in liver and serum were dramatically decreased, as shown in Fig. 1.

Effects of Rg1 on C[Cl.sub.4]-induced activation of inflammation

The contents of MDA and MPO in liver was increased by C[Cl.sub.4] administration, while in Rg1-treated groups and silymarin-treated group, the contents of MDA and MPO in liver were dramatically decreased. The content of SOD in liver were decreased by C[Cl.sub.4] administration, while in Rg1-treated groups and silymarin-treated group the content of SOD in liver was increased, as shown in Fig. 2. The pro-inflammatory cytokines, such as TNF-[alpha] and IL-6, are crucial mediators involved in the progress of C[Cl.sub.4]-induced liver damage, our data indicated that treatment with Rg1 significantly decreased the induction of hepatic mRNA and plasma protein of these two cytokines in C[Cl.sub.4]-exposed mice Fig. 3A-D.

In addition, the upregulation of iNOS and the generation of NO are also critical molecular responses in inflammation and NO plays important roles in C[Cl.sub.4] hepatotoxicity. Consistently, the increased levels of the iNOS mRNA in liver and the NO in plasma in C[Cl.sub.4]-exposed mice were down-regulated by Rg1 Fig. 4A and B.

Effects of Rg1 on liver histology

The histopathological changes induced by C[Cl.sub.4] treatment and by Rg1 are shown in Fig. 5A-E. Compared with the liver tissues of the normal controls, the liver tissue in the C[Cl.sub.4]-treated rats had extensive injuries, characterized by slight to severe necrosis of hepatocytes, cell swelling, and disruption of membranes and contraction of the nucleus. Treatment with Rg1 ameliorated the C[Cl.sub.4]-induced liver injury and markedly diminished the histological alterations.

Effects of Rg1 on MMPs expression

Upregulation of other detrimental factors such as MMPs is one of the mechanisms underlying the cytotoxic actions of inflammatory mediators. The present experiments found that the levels of MMP-2, MMP-3 and MMP-9 increased markedly after C[Cl.sub.4] exposure, but treatment with Rg1 decreased their levels Fig. 6.

Effects of Rg1 on C[Cl.sub.4]-induced NF-[kappa]Bp65 mRNA expression and NF-[kappa]Bp65 activation

The NF-[kappa]B pathways play significant role in the expression and production of IL-6 and TNF-[alpha]. To assess the inhibitory activity of Rg1 on AMPK-Sirt1-NF-[kappa]B pathways, mRNA level and protein expression of NF-[kappa]B p65 were examined by RT-PCR and western blot analysis. As shown in Fig. 7A, in the C[Cl.sub.4] group, the band mRNA of NF-[kappa]B p65 was significantly increased compared to the control group, demonstrating that C[Cl.sub.4] induced NF-[kappa]B p65 signaling pathway activation. The Rg1-treated groups revealed lower density of NF-[kappa]B p65 when compared to the C[Cl.sub.4] group, demonstrating that Rg1 attenuated the NF-[kappa]B p65 induced by C[Cl.sub.4]. Therefore, we performed western blotting to investigate the total expression of NF-[kappa]B p65. As shown in Fig. 7B, compared with the control group, the expressions of NF-[kappa]B p65, AMPK and Sirt1 in C[Cl.sub.4] group was significantly increased, in Rg1-treated groups, the expression of NF-[kappa]B p65, AMPK and Sirt1 were significantly suppressed compared to the model group, respectively. Meanwhile, the immunohistochemical assay result revealed that Rg1 inhibited NF-[kappa]B p65 nuclear translocation induced by C[Cl.sub.4] (Fig. 1C).

Discussion

Anti-inflammatories may serve as potential therapeutic agents for various diseases, including liver injury. The effects of several inflammatories have been tested in patients with liver diseases. However, only some of them have shown promising results in observational and clinical trials. So there is a need to discover new drugs with improved activity and low cost. Ginsenoside Rg1 has recently been further investigated, as a repurposed drug, for new therapeutic uses. Our results shown here revealed that Rg1 has a bona fide anti-inflammation effect in vivo and effectively suppressed the elevation of liver enzymes and alleviated hepatic histological abnormalities in mice with C[Cl.sub.4]-induced liver injury, suggesting Rg1 could provide protective benefits in C[Cl.sub.4] hepatotoxicity.

In the principle of C[Cl.sub.4] hepatotoxicity, the primary damage is induced by the reactive free radicals derived from the hepatic bioconversion of C[Cl.sub.4]. In addition to direct oxidative injury, the inflammatory cells could be secondarily recruited and activated by the free radicals and the toxic debris from the necrotic cells in C[Cl.sub.4]-exposed mice. Once activated, the inflammatory cells might greatly propagate liver damage via releasing various inflammatory mediators (Wang et al. 2010). In the present study, the degree of inflammation activation was evaluated by determining the leukocyte recruitment in liver sections, the MPO activities in liver tissue and the expression of inflammatory mediators including TNF-[alpha], IL-6, iNOS and NO. We found that treatment with Rg1 significantly down-regulated these inflammatory parameters, suggesting that the C[Cl.sub.4]-induced hepatic inflammatory reactions were suppressed by Rg1. Silymarin is a potent antioxidant medicine and has been widely used for the treatment of liver diseases. The aim of this work was to assess the impact of Rg1 on C[Cl.sub.4]-induced hepatic injury, and explore the potential therapeutic mechanisms by compared with the positive drug, silymarin.

The up-regulation of inflammatory mediators such as TNF-[alpha] might induce liver damage via multiple cytotoxic mechanisms (Ding and Yin 2004). For example, TNF-[alpha] might directly activate the intracellular death signals and lead to deleterious outcome (Hatano 2007). TNF-[alpha] could also indirectly injure the liver via up-regulating other deleterious factors such as MMPs, which participating in the degradation of extracellular matrix (ECM) and are involved in a number of pathological processes including inflammation. It was reported that inhibition of MMPs by broad-spectrum inhibitors significantly alleviated liver injury induced by C[Cl.sub.4] or other toxins (de Meijer et al. 2010; Wielockx et al. 2001; Kahraman et al. 2009). In the present study, the up-regulation of MMP-2, MMP-3 and MMP-9 by C[Cl.sub.4] was suppressed after Rg1 treatment, which might lead to compromised disintegration of liver tissue.

The induced expression of pro-inflammatory genes is tightly regulated by complicated signaling pathways, these pathways could signal the activation the several inflammation-related transcriptional factors such as NF-[kappa]B (Kamdar et al. 2013). NF-[kappa]B drives the expression of TNF-[alpha], IL-6 and also involves in the transcriptional regulation of MMPs. NF-[kappa]B is anchored in cytoplasm under resting status, but inflammatory stimuli promote the activation and nuclear translocation of NF-[kappa]B. The nuclear NF-[kappa]B then binds with the promoter of pro-inflammatory genes and initiates transcription. In the present study, the increased nuclear level of NF-[kappa]B in C[Cl.sub.4]-exposed mice was suppressed after Rg1 treatment and this result was consistent with the decreased production of inflammatory mediators and the reduced expression of MMPs.

There are emerging results indicating that AMPK might inhibit the inflammatory responses via suppressing the activity of NF-[kappa]B (Salminen et al. 2011). However, there is currently no evidence indicating that any of the NF-[kappa]B subunits or the upstream kinases of NF-[kappa]B pathway are the direct phosphorylation target of AMPK. It seems that the inhibition of NF-[kappa]B is indirectly mediated by several downstream targets of AMPK. For example, sirtuin 1 (SIRT1) was identified as a negative regulator of NF-[kappa]B via deacetylating NF-[kappa]B p65. The deacetylase activity of SIRT1 largely depends on nicotinamide adenine dinucleotide (NAD+) and nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme in the biosynthesis of NAD+ (Preyat and Leo 2013). Activation of AMPK upregulates NAMPT expression, resulting in increased cellular NAD+ levels, enhanced SIRT1 activity and suppressed NF-[kappa]B signaling (Fulco et al. 2008; Canto et al. 2009). The AMPK-independent anti-oxidative and anti-inflammatory effects of Rg1 might contribute to its protective benefits in C[Cl.sub.4]-induced liver injury. Several studies have revealed that AMPK might participate in antioxidant defenses. These data suggested that AMPK might have anti-oxidative properties under some oxidative circumstance.

On the basis of the results presented in this study, we found that treatment with Rg1 effectively alleviated C[Cl.sub.4]-induced liver injury, these beneficial effects might attribute to the suppression of AMPK-NF-[kappa]B pathway and reduction of inflammatory mediators. Although the potential off target effects of Rg1 might be considered and more specific evidence should be obtained with genetic approaches, our experimental data imply that AMPK activation by Rg1 might be beneficial for ameliorating inflammation-based liver damage.

http://dx.doi.org/10.1016/j.phymed.2016.02.026

ARTICLE INFO

Article history:

Received 10 July 2015

Revised 18 January 2016

Accepted 25 February 2016

Abbreviations: AMPK, AMP-activated protein kinase; Rg1, Ginsenoside Rg1; MPO, myeloperoxidase; MDA, malondialdehyde; NF-[kappa]B, Nuclear factor-kappaB; TNF-[alpha], tumor necrosis factor-[alpha]; IL-6, interleukin-6; iNOS, nitric oxide synthase; MMP-2, metalloproteinase 2.

Conflict of interest

Authors declare that they have not any conflict of interest. Acknowledgments

This work was supported by the Youth Natural Science Foundation of Jiangsu Province (BK20130248). We are also pleased to thank the Department of Pharmacology of Chinese Materia Medica of China Pharmaceutical University for technical support. Cheng Zongqi and Bao Jianan conceived and designed the experiments, Yao Xin, Jiang Wei, Ma Chunhua and Yu Danhong performed the experiments, Yao Xin, Jiang Wei and Zhu Jianguo analyzed the data, Yao Xin wrote the paper.

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Yao Xin (a,1), Jiang Wei (b,1), Ma Chunhua (c), Yu Danhong (d), Zhu Jianguo (a), Cheng Zongqi (a), *, Bao Jian-an (a), **

(a) Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, PR China

(b) Taizhou Institute for Food and Drug Control, Taizhou 225300, PR China

(c) Department of Pharmacology of Chinese Materia Medic a, China Pharmaceutical University, Nanjing 210009, PR China

(d) Soochow University Affiliated Children's Hospital, Suzhou 215003, PR China

* Corresponding author. Tel./fax; +86 512 67780433.

** Corresponding author. Tel./fax: +86 512 67780474.

E-mail addresses: Chengzqsuzhou@163.com (C. Zongqi), Baojasuzhou@126.com (B. Jian-an).

(1) These authors contributed equally.
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Author:Xin, Yao; Wei, Jiang; Chunhua, Ma; Danhong, Yu; Jianguo, Zhu; Zongqi, Cheng; Jian-an, Bao
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9CHIN
Date:Jun 1, 2016
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