Skip to main content
Download PDF

Protective effect of rutin on the antioxidant genes expression in hypercholestrolemic male Westar rat

BMC Complementary and Alternative Medicine volume 13, Article number: 136 (2013) Cite this article

Abstract

Background

High-cholesterol diet (HCD) increases the oxidative stress in different tissues leading to many diseases. Rutin (RT) is a natural flavonoid (vitamin p), which possesses an antioxidant activity with protective potential. The present study aimed to examine the potential effects of rutin on hypercholesterolemia-induced hepatotoxicity in rat.

Methods

Male Wistar rats were divided into four groups: GI) control (Rat chow), GII) Rutin (0.2% in rat chow), GIII) HCD (1% cholesterol and 0.5% cholic acid in rat chow) and GIV) rutin (0.2%) + HCD.

Results

Rutin in combination with HCD induced a significant protective effect against the hepatotoxicity by reducing the plasma level of alanine transaminase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL). The HCD (GII) showed a decrease in glutathione peroxidase (GPx), glutathione reductase (GR) and increase in glutathione S transferase α (GSTα), sulfiredoxin-1(Srx1), glutamate-cysteine ligase (GCL) and paraoxonase-1(PON-1) genes expression levels.

Conclusion

Treatment with rutin reversed all the altered genes induced by HCD nearly to the control levels. The present study concluded that the HCD feedings altered the expression levels of some genes involved in the oxidative stress pathway resulting in DNA damage and hepatotoxicity. Rutin have a hepatoprotective effect through the mechanism of enhancing the antioxidant effect via amelioration of oxidative stress genes.

Peer Review reports

Background

Hypercholesterolemia is considered as one of the most familiar metabolic disorders and it is closely associated with obesity, diabetes mellitus, and several other metabolic syndromes [1, 2]. It can eventually lead to non-alcoholic fatty liver disease (NAFLD) by depositing the lipids and triglycerides in liver which is usually progress to nonalcoholic steato-hepatitis (NASH), cirrhosis, liver failure and hepatocellular carcinoma [3, 4]. NAFLD is characterized by destruction in liver n-6 and n-3 long-chain polyunsaturated fatty acids [5, 6]. A major factor associated with these liver fatty acids depletion in obesity is the development of prolonged oxidative stress, which may be compounded by defective desaturation activity and dietary imbalance, promoting hepatic steatosis [6, 7]. Earlier studies demonstrated that, even short exposure to HCD is capable of inducing hypercholesterolemia and is significantly associated with oxidative stress [8].

Obesity is increasing worldwide especially in places with high dietary fat intake and is associated with lot of complications including NAFLD [9]. NAFLD is a common disease with an estimated prevalence in unselected population of developed nations around 20–30% [10]. From last three decades, Saudi Arabia has been undergoing massive developments. These developments are causing drastic changes in lifestyles and dietary habitats, like many other developed societies some of these changes tremendously increasing physical disorders such as obesity and NAFLD. The prevalence of overweight in Saudi Arabia is 36.9% and more prevalent in males (42.4%) than females (31.8%) [11] and recently Al-hamoudi et al., reported prevalence of NAFLD is around 17% in Saudi population [12].

Accumulation of lipid in hepatocytes may cause a dysfunction in the synthesis of fatty acids. Transcription factors such as sterol-regulatory-element-binding protein-1c (SREBP) and peroxisome proliferator-activated receptor alpha (PPARs) promote hepatic fatty acid synthesis. Long chain polyunsaturated fatty acids and acyl-CoAs, are metabolic regulators of many transcription factors that motivate the liver lipid metabolism. Fatty acids induce changes in the activity of four transcription factor families: PPARs, LXRs, hepatic nuclear factor 4, and SREBP [13, 14]. Downregulation of gene expression by fatty acids would be restricted to polyunsaturated fatty acids, but the upregulation would be independent of the saturation [15]. These Differences might involve differential metabolism (oxidative pathways, kinetics etc.) and selective transport of fatty acids to the nucleus. Polyunsaturated fatty acids regulates the genes involved in fatty acid oxidation such as PPARa target genes in which suppress SREBP-1c activity, leading to a reduction in liver triacylglycerol content [16]. The liver is a major source of newly synthesized cholesterol. Cholesterol can be derived from newly-absorbed cholesterol, peripheral tissues and cholesterol synthesized within liver. Cholesterol taken up by the liver is in the form of cholesterol esters [17] which can be either stored as esters or hydrolyzed to free cholesterol [18].

Oxidative stress is highly correlated with a wide variety of inflammatory, cancer, brain disorders, and metabolic disease states, including obesity [19, 20]. It is highly correlated with cumulative damage done by reactive oxygen species (ROS) and reactive nitrogen species (RNS) inadequately neutralized by antioxidants mechanisms [21, 22]. It has been shown that free radicals may adversely affect cell survival through the oxidative damage of lipid, protein, and irreversible DNA modification [23, 24]. Damage, at the cellular level by oxidants, is attenuated by antioxidant enzyme [25]. Furthermore oxidative damage is aggravated by the decrease in antioxidant enzymes activities which acts as a free radical scavengers in conditions associated with oxidative stress [26]. Superoxide dismutase is one of the major enzymatic antioxidant mechanisms against superoxide radical, prevents liver toxicity induced by oxidative stress [27]. Catalase and GSHPx catalyze dismutation of the superoxide anion (O2-) into hydrogen peroxide (H2O2) which then converting H2O2 to water thus providing protection against ROS [28]. The reduction in activity of these enzymes may be caused by the increase in free radical induced by HCD [29, 30]. Paraoxonase (PON1) is another antioxidant enzyme closely associated with high-density lipoproteins, which detoxifies lipid peroxides, and is widely distributed in many tissues, such as liver [31]. Sulfiredoxin-1 enzyme, belongs to the family of oxidoreductases, catalyzes reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation [32]. Glutamate–cysteine ligase, composed of catalytic subunit (called GCLC) and regulatory subunit (called GCLM), is important for GSH biosynthesis in combating a variety of oxidative stress-related complications, thereby activating the body’s own protective response [33].

Flavonoids are polyphenolic compounds found in plants and have an important role in detoxification of free radicals [34]. Rutin, flavonoid glycosides, possesses different protective effects such as hepatoprotective against carbon tetrachloride (CCl4)-induced liver injuries in rats, ischemia/reperfusion-associated hemodynamic alteration through antioxidant activity [35–39]. It has an inhibitory effect against membrane lipid peroxidation and oxidative stress-mediated diseases [40]. In order to find out the possible mechanisms mediating the antioxidant effect of RT, the present study evaluate its effect on gene expression of hepatic antioxidant enzymes in male Wistar rats fed with HCD as animal models for NAFLD.

Methods

Animals used

Twenty four young male Wistar albino rats six weeks old with average body weight 80–100 gms, were obtained from the Animal Care Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. The animals were acclimatized to laboratory condition prior ten days to the experiment. They were fed on Purina rat chow diet (Manufactured by Grain Silos &Flour Mills Organization, Riyadh, Saudi Arabia) and water ad libitum and were maintained under standard conditions of temperature (22±1°C), humidity (50-55%) and a 12 h light/dark cycles. All methods including euthanasia procedure were conducted in accordance with Guide for care and use of laboratory animals, institute for laboratory animal research, National Institute of Health (NIH publication No. 80–23; 1996) and it has approved by Research Ethics Committee of Excremental Animal Care Center, College of Pharmacy, King Saud University, Riyadh Saudi Arabia.

Dietary protocol and experimental groups

Dietary protocol

Experimental diets were prepared in pellet form by adding 0.2% rutin (RT) [41] (power, sigma, USA) or 1% cholesterol + 0.5% cholic acid (HCD) [42] or 0.2% RT + 1% cholesterol + 0.5% cholic acid (RT+HCD) in rat chow powder. Rat chow was used as normal diets and was prepared weekly and shade dried.

Experimental group

The Animals were randomly divided into 4 groups of 6 rats in each as follows:

Group (I): Animals received rat chow only and considered as control.

Group (II): Animals received rat chow + 0.2% rutin (RT)

Group (III): Animals received rat chow + {1% cholesterol +0.5% cholic acid }(HCD)

Group (IV): Animals received rat chow + 0.2% rutin (RT) +{1% cholesterol +0.5% cholic acid } (HCD).

The experimental diets were supplemented for 6 consecutive weeks. During whole experimental period, all groups of animals were kept on free access to food and water. At end of the experiment, animals were sacrificed by decapitation and the trunk blood was collected in heparinized tubes. Liver tissues were rapidly excised, weighed and kept in −80°C until used. Plasma samples were collected after centrifugation at 1252 g for 15 min and kept in −20°C until used.

A-Bioassay measurments

  1. I-

    Blood chemistry

    Plasma levels of aspartate aminotransferase (ALT), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL) were estimated by using commercially available diagnostic kits (Human, Wiesbaden, Germany).

  2. II-

    Estimation of Malondialdehyde (MDA) in liver

    The method described by Ohkawa et al., [43] was used to determine MDA concentration in liver. Briefly, 200 mg of liver tissues were homogenized in aqueous 0.15M KCl solution to give 10% homogenate. One ml of homogenate was then mixed with one ml of 10% trichloroacetic acid (TCA) and centrifuged at 704 g for 15 min. one ml of supernatant was suspended into one ml of 0.67% 2-thiobarbutaric acid. Sample tubes were then placed into a boiling water bath for 15 min. Samples were allowed to cool down at room temperature followed by centrifugation at 704 g for 15 min. The optical density of the clear pink supernatants was measured at 532 nm by using spectrophotometer (LKB-Pharmacia, Mark II, Ireland).

  3. III-

    Estimation of (Glutathione) GSH levels in liver

    The concentration of GSH was determined as described by Sedlak and Lindsay [44]. Briefly, 200 gm from liver tissue were dissected out and homogenized in ice-cold 0.02M ethylenediaminetetraacetic acid (EDTA). An aliquots of 0.5ml of tissue homogenate was mixed with 0.2M Tris buffer, pH 8.2 and 0.1 ml of 0.01 M Ellman’s reagent, [5,5’-dithiobis-(2-nitr-benzoic acid)] (DTNB). Each sample tube was centrifuged at 704 g at room temperature for 15 min the absorbance of the clear supernatant was measured using spectrophotometer (LKB-Pharmacia, Mark II, Ireland) at 412 nm.

  4. IV-

    Assessment of plasma hydrogen peroxide concentration

    Plasma H2O2 concentration levels were measured by BioVision assay kit (BioVision, CA, USA). The principles based on the present of horse radish peroxidase, the OxiRed probe react with H2O2 to produce product with color that can be measure.

B- Assessment of gene expression level (GPx, GR, Srx1, GCL, PON-1 and GST-α genes) by real time PCR in liver tissues

  1. I-

    Total RNA extraction

    Total RNA were extracted from liver using RNA Mini kit (Bioline, Taunton,USA) according to the manufacturer's protocol. The quantity and integrity of total RNA were characterized using a UV spectrophotometer (Nanodrop 8000 Thermo Scientific, USA) and ethidium bromide stained agarose gel. The isolated RNA has an A 260/280 ratio of 1.9–2.0.

  2. II-

    cDNA synthesis and real time PCR methods

    First-strand cDNA was synthesized from 1μg of total RNA by reverse transcription with a SuperScript™ first-strand synthesis system kit (Invitrogen, CA, USA), according to the manufacturer's instructions. Real time PCR using ΔΔCT method was done according to previous study [45]. We used GAPDH gene as housekeeping gene. All primers used in this study were synthesized in Metabion Company (Metabion international AG, Germany) and listed in Table 1.

    Table 1 Showing primers and probe used
    Full size table

Statistical analysis

Differences between obtained values (mean ± SEM, n = 6) were carried out by one way analysis of variance followed by the Tukey-Kramer multiple comparison. The differences were considered statistically significant at P<0.05.

Results

Liver enzymes, ALT and AST levels in plasma were used as biochemical markers for the early acute hepatotoxicity. Rats fed with HCD for 6 weeks had significant increase in of AST and ALT levels (p<0.001) compared to control group. Rutin supplementation alone showed no significant changes in biochemical markers. However, administration of rutin in combination with HCD resulted in reversal of hepatic damage biomarker induced by HCD to normal values (Table 2). Lipid parameters of HCD fed rats including TG, TC and LDL levels were significantly increased in plasma by 48%, 89% and 67% respectively and significantly decreased the HDL levels by 17% compared to control group. Rutin supplementation in combination with HCD, significantly decreased TC and LDL levels compared to HCD group. On the other hand there is no effect on TG, TC, HDL and LHL was observed on the supplementation of RT alone (Table 2).

Table 2 Effect of High cholesterol diet, rutin and their combination on plasma levels of AST, ALT, TG, TC, HDL and LDL
Full size table

The effect of HCD, rutin and their combination on the oxidative stress biomarkers and indices of lipid peroxidation, MDA, H2O2 and GSH were shown in Table 3. The HCD feeding was resulted significant increase in liver MDA by 23 % and in plasma H2O2 by 354 %, and decrease in hepatic GSH level by 17% compared to the control group. Rutin administration in combination with HCD resulted in a significant decrease in the levels of MDA and H2O2 and increase the hepatic level of GSH compared to HCD group.

Table 3 Effect of High cholesterol diet, rutin and their combination on levels of MDA, GSH and H2O2
Full size table

The present results showed an insignificant decrease by 23% in the expression of GPX gene and significant decrease by 65% in GR genes in rats fed with HCD compared to control group (Figure 1A & B). Interestingly, administration of rutin in combination with HCD resulted in a significant increase the expression of these genes by 245% and 441% compared to HCD group and by 166% and 90% compared to control group respectively.

Figure 1
figure 1

Showing the Effect of HCD, rutin, and their combination on the expression levels of Glutathione peroxidase (A) and Glutathione reductase (B) in rat liver. Data were presented as mean ± SEM (n = 6). * and # indicate significant change from control and HCD, respectively, at P < 0.05 using ANOVA followed by Tukey–Kramer as a post ANOVA test.

Full size image

The expression of Glutathione S transferase α, paraoxonase-1, sulfiredoxin and glutamate-cystein ligase were significantly increased by 220%, 160%, 250% and 230% respectively, in HCD fed rats compared to the control group (Figures 2A, B, C & D). The rutin supplementation with HCD resulted in significant decrease in the expression of Glutathione S transferase α, PON-1 and sulfiredoxin genes by 63% 130% and 54% respectively and an insignificant decrease in the glutamate-cystein ligase gene expression by 45% as compared with HCD group.

Figure 2
figure 2

Showing the Effect of HCD, rutin, and their combination on the expression levels of Glutathione S transferase α (A), paraoxonase-1 (B), sulfiredoxin (C) and glutamate-cystein ligase (D) in rat liver tissues. Data were presented as mean ± SEM (n = 6). * and # indicate significant change from control and HCD, respectively, at P < 0.05 using ANOVA followed by Tukey–Kramer as a post ANOVA test.

Full size image

Discussion

Obesity is a risk factor for many diseases such as cardiovascular [46] and liver diseases [3, 4]. Rat models fed with HCD can be used as model of the human obesity syndrome [47, 48]. The present study examined the hepatoprotective effect of rutin against hepatotoxicity induced by HCD in rat model and demonstrated that HCD caused hepatotoxicity through increasing plasma levels of liver enzymes ALT and AST. In agreement with earlier studies, the elevated ALT and AST levels are attributed to hepatic damage that may contribute to oxidative stress unbalance [49, 50]. Rutin has reduced the oxidative stress in liver, kidney, and brain tissues of rats [51, 52]. As a result of rutin supplementation, ALT and AST levels were lowered that led to decrease the hepatic damage caused by HCD feeding. The present results showed that rutin can protect hepatocyte against toxicity induced by HCD.

The persistent oxidative stress causes DNA mutation and increases fibroblastic activity, leading to liver cirrhosis and carcinoma. Previous study has demonstrated that rutin has a protective effect against HCD-induced liver cirrhosis [50]. Lipid alterations have been considered as contributory factors to oxidative stress in obesity resulted of increased in the production of ROS as well as reduced antioxidant enzymes [53, 54]. Reactive oxygen species and lipid peroxidation products impaired the respiratory chain in hepatocytes through oxidative damage to the mitochondrial DNA. In the present study, HCD feeding resulted in increasing the levels of TG, TC and LDL and decreasing in HDL as compared with control group; our finding was in agreement with other studies [55, 56].

High cholesterol diet leads to dyslipidemic syndrome and hyperlipidemia that characterized by increasing in TG and decreased in HDL-Cholesterol. [57]. Dyslipidemic syndrome produced anti-inflammatory effects by inhibiting the expressions of proinflammatory cytokines [58, 59]. In the present study, rutin-supplement attenuated HCD-induced hepatotoxicity by lowering the concentrations of TC, TG and LDL. Similarly, rutin lowers the lipid components in the serum of hyper-cholesterolemic rats, probably by reducing the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase [60]. This may be explained on the basis that rutin has a strong ability to chelate multivalent metal ions, especially zinc, calcium and iron [39].

Lipid peroxidation is characterized by imbalance between oxidant-antioxidant and ROS are thought to be a component of obesity-induced pathology [61, 62]. The data of this study showed that HCD increased lipid peroxidation in hepatic tissue as expressed by increased tissue levels of MDA, this will cause an increased accumulation of H2O2 which could further stimulate lipid peroxidation. The present results were convenient with earlier studies [62, 63] showed that obesity is an independent risk factor for increasing lipid peroxidation and decreased activity of cytoprotective enzymes. Damage, at the cellular level by oxidative stress, is attenuated by antioxidant enzyme such as PON-1, GSHPx, GPx, GR and Glutathione S transferase α, sulfiredoxin and glutamate-cystein ligase. When the balance between ROS production and antioxidant defense is lost oxidative stress occurred through a serious of events deregulates the cellular functions leading various pathological conditions [26].

The GSH antioxidant system plays critical role in the detoxification process of liver and is involved in overcoming various hepatotoxins-induced liver injuries [64]. The increasing GSH levels can protect cells against oxidative damage, while depleting cellular GSH can promote such injury [65, 66]. Our results showed that GSH level was decreased in HCD fed rats compared to control which was in agreement with other [67]. The cellular roles of GR have been broadened in various physiological phenomena, especially cellular response against many kinds of stresses by reducing glutathione disulfide (GSSG) to the sulfhydryl form GSH which is an important cellular antioxidant [68]. Glutathione peroxidase is a selenoenzyme, which catalyzes the reduction in hydrogen peroxide to H2O and oxidizing GSH into GSSG [69]. Down-regulation of GR results in cellular GSSG content increase, and reduction of GSH/GSSG ratio is involved in many responses against oxidative stress. Our results showed decrease in GR and GPx genes expression in liver tissues of HCD fed rats and were in agreement with others [70, 71]. Rutin supplementation led to increase the expression of these genes in liver tissues. These data showed that HCD not only increase the free radical formation but also decrease its ability to detoxify ROS, which lead to hepatocellular damage [72].

Paraoxonase-1 (PON-1), an enzyme with lactonase and esterase activities, is synthesized mainly by the liver [73, 74] and it plays a role in the regulation of oxidative stress, fibrosis and hepatic cell apoptosis in chronic liver diseases. [75]. The present results showed that the HCD feeding significantly overexpressed the expression of PON-1 in liver tissues. This increase in the expression enhanced the sensitivity to liver damage development. The increasing in PON-1 hepatic expression in chronic hepatitis and liver cirrhosis, probably as a response to the enhanced oxidative stress observed in the earliest stages of these diseases [75]. Our results were disagreement with Zhang et al., who proposed that PON-1 over expression provides strong protection against the development of experimental liver disease [76]. Rutin supplementation led to decrease the expression of PON-1 gene in liver tissues, and this attributed to its effect as an antioxidant and reduced oxidative stress in plasma, liver and other organs [51, 77]. The present finding was in agreement with recent study who found that rutin administered to High fat diet fed rats attenuated the diet-induced metabolic syndrome, NASH, and cardiovascular abnormalities [78].

Glutamate-cysteine ligase catalyzes the biosynthesis of cellular GSH and is considered one of antioxidant system for counteracting ROS produced during oxidative stress injury. Sulfiredoxin-1 (Srx1), an antioxidant, contains a C-terminal cysteine residue that is highly conserved and crucial for its antioxidant function [79, 80]. It plays a key role in cellular responses to oxidative stress by restoring the activity of over-oxidized peroxiredoxins [80, 81]. The results of the present study show that Srx1, GCL and GSTα expressions are selectively up-regulated in liver tissues of rat fed with HCD. Reactive oxygen species elicit many different responses depending upon the severity of the damage and the duration of the exposure [82].

Low doses of ROS activate c-jun N-terminal Kinase (JNK) transiently thereby promoting cell proliferation. However, persistent JNK activation due to severe oxidative stress ultimately causes cell death via activation of pro-apoptotic signaling pathway [83, 84]. In the current study the activation of GSTα was due to the modulations of GST levels on JNK activation by formation of GSTα-JNK complex integrity in sequence to inhibit its activation. Our results was in agreement with other studies [85, 86], who shows that, besides detoxification of GST-α, it plays an important role in signaling events by modulating stress cell signaling kinases in particular through inhibition of JNK activation. The upregulation of GCL in our data was in agreement with Nishiya et al., who found that, marked upregulation of GCL gene in rats treated with tienilic acid induced hepatotoxicity [87]. Similarly, Wu and his colleague found that Cd-induced oxidative stress increased the mRNA expression of GCL with graded Nrf2 activation. [88]. However, the present data is disagreement with Wang and his colleagues; they found that the downregulation of GCL is confirmed the damage of liver cells in mice treated with Dioscorea bulbifera rhizome [89]. The up-regulation of Sxr1 to maintains the balance between H2O2 production and elimination and then protects liver cells from apoptosis; our finding was in agreement with previous study [90]. In the present study rutin administration reversed the changes induced by HCD feeding in rats to normal levels probably by reducing oxidative stress and inflammation in liver tissue.

Conclusion

The high-cholesterol diet induces symptoms of metabolic syndrome in rat including hepatotoxicity with alteration in the oxidative stress markers. Rutin reversed the changes induced by HCD probably by reducing the oxidative stress and inflammation in the liver. Therefore the administration of rutin may be used as an antioxidant in decreasing the hepatic stress in humans as a treatment.

References

  1. Farrell GC, Teoh NC, McCuskey RS: Hepatic microcirculation in fatty liver disease. Anat Rec (Hoboken). 2008, 291: 684-692. 10.1002/ar.20715.

    Article  Google Scholar 

  2. Trauner M, Arrese M, Wagner M: Fatty liver and lipotoxicity. Biochim Biophys Acta. 1801, 2010: 299-310.

    Google Scholar 

  3. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, Cristanini G, Tiribelli C: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000, 132: 112-117.

    Article  CAS  PubMed  Google Scholar 

  4. Vitaglione P, Morisco F, Mazzone G, Amoruso DC, Ribecco MT, Romano A, Fogliano V, Caporaso N, D'Argenio G: Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology. 2010, 52: 1652-1661. 10.1002/hep.23902.

    Article  CAS  PubMed  Google Scholar 

  5. Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, Poniachik J: Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond). 2004, 106: 635-643. 10.1042/CS20030326.

    Article  CAS  Google Scholar 

  6. Araya J, Rodrigo R, Pettinelli P, Araya AV, Poniachik J, Videla LA: Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring). 2010, 18: 1460-1463. 10.1038/oby.2009.379.

    Article  CAS  Google Scholar 

  7. Videla LA, Rodrigo R, Araya J, Poniachik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med. 2006, 12: 555-558. 10.1016/j.molmed.2006.10.001.

    Article  CAS  PubMed  Google Scholar 

  8. Tomofuji T, Azuma T, Kusano H, Sanbe T, Ekuni D, Tamaki N, Yamamoto T, Watanabe T: Oxidative damage of periodontal tissue in the rat periodontitis model: effects of a high-cholesterol diet. FEBS Lett. 2006, 580: 3601-3604. 10.1016/j.febslet.2006.05.041.

    Article  CAS  PubMed  Google Scholar 

  9. Fried M, Hainer V, Basdevant A, Buchwald H, Dietel M, Finer N, Greve JW, Horber F, Mathus-Vliegen E, Scopinaro N: Interdisciplinary European guidelines on surgery for severe obesity. Rozhl Chir. 2008, 87: 468-476.

    CAS  PubMed  Google Scholar 

  10. Preiss D, Sattar N: Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond). 2008, 115: 141-150. 10.1042/CS20070402.

    Article  CAS  Google Scholar 

  11. Al-Nozha MM, Al-Mazrou YY, Al-Maatouq MA, Arafah MR, Khalil MZ, Khan NB, Al-Marzouki K, Abdullah MA, Al-Khadra AH, Al-Harthi SS: Obesity in Saudi Arabia. Saudi Med J. 2005, 26: 824-829.

    PubMed  Google Scholar 

  12. Al-hamoudi W, El-Sabbah M, Ali S, Altuwaijri M, Bedewi M, Adam M, Alhammad A, Sanai F, Alswat K, Abdo A: Epidemiological, clinical, and biochemical characteristics of Saudi patients with nonalcoholic fatty liver disease: a hospital-based study. Ann Saudi Med. 2012, 32: 288-292.

    PubMed  Google Scholar 

  13. Jump DB: N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol. 2008, 19: 242-247. 10.1097/MOL.0b013e3282ffaf6a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clarke SD, Jump DB: Polyunsaturated fatty acid regulation of hepatic gene transcription. Lipids. 1996, 31 (Suppl): S7-S11.

    Article  CAS  PubMed  Google Scholar 

  15. Pegorier JP, Le May C, Girard J: Control of gene expression by fatty acids. J Nutr. 2004, 134: 2444S-2449S.

    CAS  PubMed  Google Scholar 

  16. Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J, Siliart B, Dumon H: Liver lipid metabolism. J Anim Physiol Anim Nutr. 2008, 92: 272-283. 10.1111/j.1439-0396.2007.00752.x.

    Article  CAS  Google Scholar 

  17. Ikonen E: Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev. 2006, 86: 1237-1261. 10.1152/physrev.00022.2005.

    Article  CAS  PubMed  Google Scholar 

  18. Ho YK, Brown MS, Goldstein JL: Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents. J Lipid Res. 1980, 21: 391-398.

    CAS  PubMed  Google Scholar 

  19. Sonta T, Inoguchi T, Tsubouchi H, Sekiguchi N, Kobayashi K, Matsumoto S, Utsumi H, Nawata H: Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med. 2004, 37: 115-123. 10.1016/j.freeradbiomed.2004.04.001.

    Article  CAS  PubMed  Google Scholar 

  20. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004, 114: 1752-1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Faienza MF, Francavilla R, Goffredo R, Ventura A, Marzano F, Panzarino G, Marinelli G, Cavallo L, Di Bitonto G: Oxidative stress in obesity and metabolic syndrome in children and adolescents. Horm Res Paediatr. 2012, 78: 158-164. 10.1159/000342642.

    Article  CAS  PubMed  Google Scholar 

  22. Park S, Kim M, Paik JK, Jang YJ, Lee SH, Lee JH: Oxidative stress is associated with C-reactive protein in non-diabetic postmenopausal women, independent of obesity and insulin resistance. Clin Endocrinol (Oxf). 2012, 79: 65-70.

    Article  Google Scholar 

  23. Mishra KP: Cell membrane oxidative damage induced by gamma-radiation and apoptotic sensitivity. J Environ Pathol Toxicol Oncol. 2004, 23: 61-66. 10.1615/JEnvPathToxOncol.v23.i1.60.

    Article  CAS  PubMed  Google Scholar 

  24. Bravo E, Palleschi S, Aspichueta P, Buque X, Rossi B, Cano A, Napolitano M, Ochoa B, Botham KM: High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids Health Dis. 2011, 10: 60-10.1186/1476-511X-10-60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koc A, Duru M, Ciralik H, Akcan R, Sogut S: Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats. Mol Cell Biochem. 2005, 278: 79-84. 10.1007/s11010-005-6630-z.

    Article  CAS  PubMed  Google Scholar 

  26. Blokhina O, Virolainen E, Fagerstedt KV: Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot. 2003, 91: Spec No:179-Spec No:194.

    Article  PubMed  Google Scholar 

  27. Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A: Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007, 38: 380-385. 10.1016/j.arcmed.2007.01.007.

    Article  CAS  PubMed  Google Scholar 

  28. Sayed-Ahmed AMA MM, Al-Rejaie SS, Al-Yahya AA, Al-Shabanah OA, Hafez MM, Nagi MN: Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxidative Medicine and Cellular Longevity. 2010, 3: 254-261. 10.4161/oxim.3.4.12714.

    Article  Google Scholar 

  29. Danz ED, Skramsted J, Henry N, Bennett JA, Keller RS: Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radic Biol Med. 2009, 46: 1589-1597. 10.1016/j.freeradbiomed.2009.03.011.

    Article  PubMed  Google Scholar 

  30. Fisher-Wellman K, Bell HK, Bloomer RJ: Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders. Oxid Med Cell Longev. 2009, 2: 43-51. 10.4161/oxim.2.1.7732.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Senti M, Tomas M, Fito M, Weinbrenner T, Covas MI, Sala J, Masia R, Marrugat J: Antioxidant paraoxonase 1 activity in the metabolic syndrome. J Clin Endocrinol Metab. 2003, 88: 5422-5426. 10.1210/jc.2003-030648.

    Article  CAS  PubMed  Google Scholar 

  32. Peltoniemi MJ, Rytila PH, Harju TH, Soini YM, Salmenkivi KM, Ruddock LW, Kinnula VL: Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease. Respir Res. 2006, 7: 133-10.1186/1465-9921-7-133.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lu W, Chen Z, Zhang H, Wang Y, Luo Y, Huang P: ZNF143 transcription factor mediates cell survival through upregulation of the GPX1 activity in the mitochondrial respiratory dysfunction. Cell Death Dis. 2012, 3: e422-10.1038/cddis.2012.156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Potter JD: Cancer prevention: epidemiology and experiment. Cancer Lett. 1997, 114: 7-9. 10.1016/S0304-3835(97)04615-6.

    Article  CAS  PubMed  Google Scholar 

  35. Aleksandrov PN, Speranskaia TV, Bobkov Iu G, Zagorevskii VA, Zykov DA: [Effect of rutin and esculamine on models of aseptic inflammation]. Farmakol Toksikol. 1986, 49: 84-86.

    CAS  PubMed  Google Scholar 

  36. Deschner EE, Ruperto J, Wong G, Newmark HL: Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis. 1991, 12: 1193-1196. 10.1093/carcin/12.7.1193.

    Article  CAS  PubMed  Google Scholar 

  37. Bear WL, Teel RW: Effects of citrus flavonoids on the mutagenicity of heterocyclic amines and on cytochrome P450 1A2 activity. Anticancer Res. 2000, 20: 3609-3614.

    CAS  PubMed  Google Scholar 

  38. Chen S, Gong J, Liu F, Mohammed U: Naturally occurring polyphenolic antioxidants modulate IgE-mediated mast cell activation. Immunology. 2000, 100: 471-480. 10.1046/j.1365-2567.2000.00045.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Khan RA, Khan MR, Sahreen S: CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. BMC Complement Altern Med. 2012, 12: 178-10.1186/1472-6882-12-178.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lopez-Revuelta A, Sanchez-Gallego JI, Hernandez-Hernandez A, Sanchez-Yague J, Llanillo M: Membrane cholesterol contents influence the protective effects of quercetin and rutin in erythrocytes damaged by oxidative stress. Chem Biol Interact. 2006, 161: 79-91. 10.1016/j.cbi.2006.03.004.

    Article  CAS  PubMed  Google Scholar 

  41. Takashi N, Nobuaki T, Yoshiaki I, Naoyuki N: Suppression of early and advanced glycation by dietary water-soluble rutin derivative in diabetic rats. Int Congr Ser. 2002, 1245: 403-405.

    Article  Google Scholar 

  42. Al-Rejaie SS, Abuohashish HM, Alkhamees OA, Aleisa AM, Alroujayee AS: Gender difference following high cholesterol diet induced renal injury and the protective role of rutin and ascorbic acid combination in Wistar albino rats. Lipids Health Dis. 2012, 11: 41-10.1186/1476-511X-11-41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ohkawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979, 95: 351-358. 10.1016/0003-2697(79)90738-3.

    Article  CAS  PubMed  Google Scholar 

  44. Sedlak J, Lindsay RH: Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968, 25: 192-205.

    Article  CAS  PubMed  Google Scholar 

  45. Sayed-Ahmed MM, Al-Shabanah OA, Hafez MM, Aleisa AM, Al-Rejaie SS: Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model. Eur J Pharmacol. 2010, 640: 143-149. 10.1016/j.ejphar.2010.05.002.

    Article  CAS  PubMed  Google Scholar 

  46. Artham SM, Lavie CJ, Milani RV, Ventura HO: The obesity paradox: impact of obesity on the prevalence and prognosis of cardiovascular diseases. Postgrad Med. 2008, 120: 34-41. 10.3810/pgm.2008.07.1788.

    Article  PubMed  Google Scholar 

  47. Madsen AN, Hansen G, Paulsen SJ, Lykkegaard K, Tang-Christensen M, Hansen HS, Levin BE, Larsen PJ, Knudsen LB, Fosgerau K: Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol. 2010, 206: 287-296. 10.1677/JOE-10-0004.

    Article  CAS  PubMed  Google Scholar 

  48. Lopez IP, Marti A, Milagro FI, Zulet Md Mde L, Moreno-Aliaga MJ, Martinez JA, De Miguel C: DNA microarray analysis of genes differentially expressed in diet-induced (cafeteria) obese rats. Obes Res. 2003, 11: 188-194. 10.1038/oby.2003.30.

    Article  CAS  PubMed  Google Scholar 

  49. Tan M, Schmidt RH, Beier JI, Watson WH, Zhong H, States JC, Arteel GE: Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. Toxicol Appl Pharmacol. 2011, 257: 356-364. 10.1016/j.taap.2011.09.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Song HY, Mao ZM, Yang LL, Liu T, Li DF, Zhang L, Ge YL, Zheng PY, Liu P, Zhang XQ: Dangfei liganning capsules attenuate the susceptibility of rat nonalcoholic fatty liver to carbon tetrachloride toxicity. J Tradit Chin Med. 2011, 31: 327-333. 10.1016/S0254-6272(12)60013-2.

    Article  PubMed  Google Scholar 

  51. Kamalakkannan N, Prince PS: Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic wistar rats. Basic Clin Pharmacol Toxicol. 2006, 98: 97-103. 10.1111/j.1742-7843.2006.pto_241.x.

    Article  CAS  PubMed  Google Scholar 

  52. Kamalakkannan N, Stanely Mainzen Prince P: Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Mol Cell Biochem. 2006, 293: 211-219. 10.1007/s11010-006-9244-1.

    Article  CAS  PubMed  Google Scholar 

  53. Tsimikas S, Miller YI: Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des. 2011, 17: 27-37. 10.2174/138161211795049831.

    Article  CAS  PubMed  Google Scholar 

  54. Lavie L, Lavie P: Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J. 2009, 33: 1467-1484. 10.1183/09031936.00086608.

    Article  CAS  PubMed  Google Scholar 

  55. Noeman SA, Hamooda HE, Baalash AA: Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats. Diabetol Metab Syndr. 2011, 3: 17-10.1186/1758-5996-3-17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Amin KA, Nagy MA: Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats. Diabetol Metab Syndr. 2009, 1: 17-10.1186/1758-5996-1-17.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bloomgarden ZT: Dyslipidemia and the metabolic syndrome. Diabetes Care. 2004, 27: 3009-3016. 10.2337/diacare.27.12.3009.

    Article  PubMed  Google Scholar 

  58. Kauss T, Moynet D, Rambert J, Al-Kharrat A, Brajot S, Thiolat D, Ennemany R, Fawaz F, Mossalayi MD: Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther. 2008, 10: R19-10.1186/ar2372.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Guardia T, Rotelli AE, Juarez AO, Pelzer LE: Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco. 2001, 56: 683-687. 10.1016/S0014-827X(01)01111-9.

    Article  CAS  PubMed  Google Scholar 

  60. Ziaee A, Zamansoltani F, Nassiri-Asl M, Abbasi E: Effects of rutin on lipid profile in hypercholesterolaemic rats. Basic Clin Pharmacol Toxicol. 2009, 104: 253-258. 10.1111/j.1742-7843.2008.00368.x.

    Article  CAS  PubMed  Google Scholar 

  61. Park S, Park NY, Valacchi G, Lim Y: Calorie restriction with a high-fat diet effectively attenuated inflammatory response and oxidative stress-related markers in obese tissues of the high diet fed rats. Mediators Inflamm. 2012, 2012: 984643-

    Article  PubMed  PubMed Central  Google Scholar 

  62. Huisamen B, Dietrich D, Bezuidenhout N, Lopes J, Flepisi B, Blackhurst D, Lochner A: Early cardiovascular changes occurring in diet-induced, obese insulin-resistant rats. Mol Cell Biochem. 2012, 368: 37-45. 10.1007/s11010-012-1340-9.

    Article  CAS  PubMed  Google Scholar 

  63. Vincent HK, Powers SK, Dirks AJ, Scarpace PJ: Mechanism for obesity-induced increase in myocardial lipid peroxidation. Int J Obes Relat Metab Disord. 2001, 25: 378-388. 10.1038/sj.ijo.0801536.

    Article  CAS  PubMed  Google Scholar 

  64. Husain K, Somani SM: Interaction of exercise training and chronic ethanol ingestion on hepatic and plasma antioxidant system in rat. J Appl Toxicol. 1997, 17: 189-194. 10.1002/(SICI)1099-1263(199705)17:3<189::AID-JAT431>3.0.CO;2-7.

    Article  CAS  PubMed  Google Scholar 

  65. Ji L, Liu T, Chen Y, Wang Z: Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid clivorine-induced hepatotoxicity. J Cell Biochem. 2009, 108: 424-432. 10.1002/jcb.22269.

    Article  CAS  PubMed  Google Scholar 

  66. Chen L, Pan DD, Zhou J, Jiang YZ: Protective effect of selenium-enriched Lactobacillus on CCl4-induced liver injury in mice and its possible mechanisms. World journal of gastroenterology : WJG. 2005, 11: 5795-5800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sanz N, Diez-Fernandez C, Alvarez A, Cascales M: Age-dependent modifications in rat hepatocyte antioxidant defense systems. J Hepatol. 1997, 27: 525-534. 10.1016/S0168-8278(97)80358-3.

    Article  CAS  PubMed  Google Scholar 

  68. Kim SJ, Jung HJ, Hyun DH, Park EH, Kim YM, Lim CJ: Glutathione reductase plays an anti-apoptotic role against oxidative stress in human hepatoma cells. Biochimie. 2010, 92: 927-932. 10.1016/j.biochi.2010.03.007.

    Article  CAS  PubMed  Google Scholar 

  69. Tappel AL: Glutathione peroxidase and hydroperoxides. Methods Enzymol. 1978, 52: 506-513.

    Article  CAS  PubMed  Google Scholar 

  70. Sekine Y, Osei-Hwedieh D, Matsuda K, Raghavachari N, Liu D, Furuya Y, Koike H, Suzuki K, Remaley AT: High fat diet reduces the expression of glutathione peroxidase 3 in mouse prostate. Prostate. 2011, 71: 1499-1509.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. De Haan JB, Witting PK, Stefanovic N, Pete J, Daskalakis M, Kola I, Stocker R, Smolich JJ: Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet. J Lipid Res. 2006, 47: 1157-1167. 10.1194/jlr.M500377-JLR200.

    Article  CAS  PubMed  Google Scholar 

  72. Pradeep K, Mohan CV, Gobianand K, Karthikeyan S: Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol. 2007, 560: 110-116. 10.1016/j.ejphar.2006.12.023.

    Article  CAS  PubMed  Google Scholar 

  73. Leviev I, Negro F, James RW: Two alleles of the human paraoxonase gene produce different amounts of mRNA. An explanation for differences in serum concentrations of paraoxonase associated with the (Leu-Met54) polymorphism. Arterioscler Thromb Vasc Biol. 1997, 17: 2935-2939. 10.1161/01.ATV.17.11.2935.

    Article  CAS  PubMed  Google Scholar 

  74. Rodrigo L, Gil F, Hernandez AF, Marina A, Vazquez J, Pla A: Purification and characterization of paraoxon hydrolase from rat liver. Biochem J. 1997, 321 (Pt 3): 595-601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ferre N, Marsillach J, Camps J, Mackness B, Mackness M, Riu F, Coll B, Tous M, Joven J: Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases. J Hepatol. 2006, 45: 51-59. 10.1016/j.jhep.2005.12.018.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang C, Peng W, Jiang X, Chen B, Zhu J, Zang Y, Zhang J, Zhu T, Qin J: Transgene expression of human PON1 Q in mice protected the liver against CCl4-induced injury. J Gene Med. 2008, 10: 94-100. 10.1002/jgm.1128.

    Article  CAS  PubMed  Google Scholar 

  77. Curin Y, Ritz MF, Andriantsitohaina R: Cellular mechanisms of the protective effect of polyphenols on the neurovascular unit in strokes. Cardiovasc Hematol Agents Med Chem. 2006, 4: 277-288. 10.2174/187152506778520691.

    Article  CAS  PubMed  Google Scholar 

  78. Panchal SK, Poudyal H, Arumugam TV, Brown L: Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr. 2011, 141: 1062-1069. 10.3945/jn.111.137877.

    Article  CAS  PubMed  Google Scholar 

  79. Findlay VJ, Tapiero H, Townsend DM: Sulfiredoxin: a potential therapeutic agent?. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2005, 59: 374-379. 10.1016/j.biopha.2005.07.003.

    Article  CAS  Google Scholar 

  80. Rhee SG, Jeong W, Chang TS, Woo HA: Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. Kidney Int Suppl. 2007, S3-S8.

    Google Scholar 

  81. Biteau B, Labarre J, Toledano MB: ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin. Nature. 2003, 425: 980-984. 10.1038/nature02075.

    Article  CAS  PubMed  Google Scholar 

  82. Martindale JL, Holbrook NJ: Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002, 192: 1-15. 10.1002/jcp.10119.

    Article  CAS  PubMed  Google Scholar 

  83. Maher P, Schubert D: Signaling by reactive oxygen species in the nervous system. Cell Mol Life Sci. 2000, 57: 1287-1305. 10.1007/PL00000766.

    Article  CAS  PubMed  Google Scholar 

  84. Feinendegen LE: Reactive oxygen species in cell responses to toxic agents. Hum Exp Toxicol. 2002, 21: 85-90. 10.1191/0960327102ht216oa.

    Article  CAS  PubMed  Google Scholar 

  85. Turella P, Cerella C, Filomeni G, Bullo A, De Maria F, Ghibelli L, Ciriolo MR, Cianfriglia M, Mattei M, Federici G: Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res. 2005, 65: 3751-3761. 10.1158/0008-5472.CAN-04-3903.

    Article  CAS  PubMed  Google Scholar 

  86. Burg D, Riepsaame J, Pont C, Mulder G, van de Water B: Peptide-bond modified glutathione conjugate analogs modulate GSTpi function in GSH-conjugation, drug sensitivity and JNK signaling. Biochem Pharmacol. 2006, 71: 268-277. 10.1016/j.bcp.2005.11.003.

    Article  CAS  PubMed  Google Scholar 

  87. Nishiya T, Mori K, Hattori C, Kai K, Kataoka H, Masubuchi N, Jindo T, Manabe S: The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats. Toxicol Appl Pharmacol. 2008, 232: 280-291. 10.1016/j.taap.2008.06.024.

    Article  CAS  PubMed  Google Scholar 

  88. Wu KC, Liu JJ, Klaassen CD: Nrf2 activation prevents cadmium-induced acute liver injury. Toxicol Appl Pharmacol. 2012, 263: 14-20. 10.1016/j.taap.2012.05.017.

    Article  CAS  PubMed  Google Scholar 

  89. Wang J, Ji L, Liu H, Wang Z: Study of the hepatotoxicity induced by Dioscorea bulbifera L. rhizome in mice. Biosci Trends. 2010, 4: 79-85.

    PubMed  Google Scholar 

  90. Baek JY, Han SH, Sung SH, Lee HE, Kim YM, Noh YH, Bae SH, Rhee SG, Chang TS: Sulfiredoxin protein is critical for redox balance and survival of cells exposed to low steady-state levels of H2O2. J Biol Chem. 2012, 287: 81-89. 10.1074/jbc.M111.316711.

    Article  CAS  PubMed  Google Scholar 

Pre-publication history

Download references

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through the research group project no. RGP-VPP-179.

Author information

Authors and Affiliations

  1. Department of pharmacology and toxicology; College of pharmacy, King Saud University, Riyadh, Saudi Arabia

    Salem S Al-Rejaie, Abdulaziz M Aleisa, Mohamed M Sayed-Ahmed, Othman A AL-Shabanah, Hatem M Abuohashish, Mohammed M Ahmed, Khaled A Al-Hosaini & Mohamed M Hafez

Authors
  1. Salem S Al-Rejaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abdulaziz M Aleisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed M Sayed-Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Othman A AL-Shabanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hatem M Abuohashish
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammed M Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Khaled A Al-Hosaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohamed M Hafez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohamed M Hafez.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SA, HA and MA, equally participated in the dietary protocol design of the experimental groups and performed the biochemical assays and their statistical analysis and shared in drafted the manuscript. MH performed all the molecular studies and their statistical analysis and shared in draft the manuscript. AA, MS, OA and KA shared in the draft the manuscript. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Al-Rejaie, S.S., Aleisa, A.M., Sayed-Ahmed, M.M. et al. Protective effect of rutin on the antioxidant genes expression in hypercholestrolemic male Westar rat. BMC Complement Altern Med 13, 136 (2013). https://doi.org/10.1186/1472-6882-13-136

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1472-6882-13-136

Keywords

BMC Complementary Medicine and Therapies

ISSN: 2662-7671

Contact us