Troxerutin Chronic Treatment Protects Against Fructose-Induced Metabolic

International Journal of Medical Laboratory 2017;4(3):201-210.

Original Article

Troxerutin Chronic Treatment Protects against Fructose- induced Metabolic Syndrome in Male Rats

Mitra Jalali1M.Sc., Mahsa Hassanipour2,3Pharm D., Ph.D., Mohammadreza Hajizadeh1,4Ph.D., Soudeh Khanamani Falahati Pour4Ph.D., Alireza Khoshdel1Ph.D., Farzad Roustai1M.Sc., Marzieh Rezai1M.Sc., Mehdi Mahmoodi1,4*Ph.D.

1Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 2Department of Physiology and Pharmacology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 3Physiology and Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 4Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. A B S T R A C T Article history Background and Aims: Metabolic syndrome, a common metabolic Received 21 Apr 2017 disorder, for the serious health consequences such as insulin resistance and Accepted 29 Jul 2017 lipid abnormalities has been considered as a major clinical challenge with Available online 30 Aug 2017 obscure causes. Oxidative stress is an important component of metabolic Key words syndrome, contributing in its development. Troxerutin, a semi-synthetic Fructose derivative of natural bioflavonoid rutin, exerts various pharmacological Insulin resistance activities, which among all, strong anti-oxidative property is of great Metabolic syndrome importance. The aim of the current study was to evaluate the effects of Oxidative stress Troxerutin troxerutin on metabolic parameters and oxidative stress in metabolic syndrome induced by fructose in male rats. Materials and Methods: In order to induce metabolic syndrome, animals

Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 received the water containing 20% fructose for 8 weeks. Troxerutin was administered to animals with the dose of 150 mg/kg orally for 4 weeks after induction of metabolic syndrome following biochemical analysis and oxidative stress marker assessment. Results: Data showed that high-fructose diet leads to elevation of blood glucose and insulin resistance and causes abnormalities in lipid profile as well as oxidative stress enhancement (signs of a metabolic syndrome) (p<0.001). Troxerutin administration improved the detrimental effects of metabolic syndrome on biochemical factors and diminished oxidative stress (p<0.001). Conclusions: Troxerutin administration reverses the deleterious effect of metabolic syndrome in rats with high-fructose diet.

*Corresponding Author: Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Tel: +9835234003-5, Email: [email protected] M. Jalali et al.

Introduction

Metabolic syndrome (MS), a constellation of rutin is capable for attenuation of metabolic conditions and metabolic irregularities, is a changes and cardiovascular remodeling in rats common health challenge worldwide with under high-carbohydrate and high-fat diet, the characterization of visceral obesity, suggesting a non-nutritive effect of rutin in hypertension, hyperglycemia and dyslipidaemia metabolic syndrome chronic changes [15]. (increased low-density lipoprotein (LDL) Recent investigations report the ability of particles and triglyceride-rich lipoproteins as cell protection for troxerutin, which is well as decreased high-density lipoprotein mediated via radical scavenging mechanism (HDL)), which enhances the individual risk for and inhibition of oxidative stress-induced cell development of type 2 diabetes, cardiovascular death [16]. Data demonstrated that troxerutin events and atherogenesis [1-3]. MS is the result has a regulatory role in lipid metabolism. of increasing the obesity prevalence due to Geetha et al., (2014) showed that this sedentary lifestyle and Western type diet and derivative suppresses lipid abnormalities in the several factors play a role in its heart of mice, which were fed with high-fat– pathophysiology such as insulin resistance, high-fructose diet [12]. Troxerutin has the chronic inflammation, perturbations in cell capability to inhibit obesity, hyperglycemia signaling and ectopic fat accumulation [4-6]. A and hyperlipidemia normalization in high- new insight into the MS pathophysiology cholesterol diet-induced diabetic animals and points to the role of oxidative stress and protects against atherosclerosis through plasma contribution of reactive oxygen species (ROS) lipid reduction and homocysteine levels [17- overproduction, which induces insulin 19]. Several mechanisms have been proposed Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 resistance and exerts key function in MS for the protective effects of troxerutin, through salt-sensitive hypertension induction, including a decrease in advanced glycation affecting mineralocorticoid receptors as well as end products, protein carbonyl levels and sympathetic excitation in brain [7-10]. Several reactive oxygen species and enhancement studies showed that MS induced by high- phosphoinositide 3-kinase/Akt activation [18]. fat, high-refined sugar diet is accompanied The formation of advanced glycation end by oxidative stress and nitric oxide synthase products, which trigger oxidative stress and dysregulation [11]. Troxerutin (vitamin P4, contribute in early phases of age-related a derivative of rutin with more hydroxyl groups), disorders such as diabetes is inhibited by a pharmacologically active flavonoid, has troxerutin [20, 21]. Data reported that been studied for its protective properties in troxerutin could diminish high-fat diet-induced chronic venous insufficiency disease, neural enhancement of hepatic gluconeogenesis by its disorders, diabetes and inflammation [12-14]. inhibitory role for endoplasmic reticulum Studies showed that supplementation with stress-mediated nucleotide oligomerization

International Journal of Medical Laboratory 2017;4(3): 201-210. 202 TROXERUTIN PROTECTION AGAINST METABOLIC SYNDROME

domain activation and the consequent metabolic syndrome induced animals (MS) inflammation [22]. Moreover, troxerutin and MS animals, which were treated with promotes insulin sensitivity, possibly via troxerutin (MS+TXR). Animals received modifying peroxisome proliferator-activated water containing 20% fructose (purchased receptors [23]. Considering the seriousness from Sigma, USA) for 8 continual weeks in and prevalence of MS finding new therapeutic order to induce metabolic syndrome, but the strategy to encounter this common problem in control animals received tap water only. The modern society and a method for metabolic weight of the animal was measured using a dysregulation reversal are of great importance, digital scale (FEW, Japan) for body mass so in this study, we investigated the protective index calculation. To measure biochemical effects of troxerutin on lipids profile and parameters, including triglycerides, fasting oxidative stress in male MS rats. blood glucose, total cholesterol (TC), HDL and LDL the blood samples were taken after Materials and Methods 12 hours fasting with retro-orbital sampling. Subjects Troxerutin (purchased from Sigma, USA) 32 male Wistar rats weighing 200-250 g were was prepared in distilled water and used throughout this study (from animal house administered orally for 4 weeks with the dose of Rafsanjan University of Medical Sciences). of 150 mg/kg after induction of MS [22-24]. Rats were housed in polycarbonate and Biochemical assessment, insulin resistance standard cages in a temperature-controlled and oxidative stress evaluation room (22±2◦C, 12 hour light/12 hour dark Blood samples were obtained through cycle) with free access to laboratory pellet penetrating the retro-orbital plexus with a chow and water. All experiments were capillary tube. The samples were centrifuged Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 conducted between 10:00 A.M to 14:00 P.M at 1000×g for 10 min. to separate the serum and were carried out in accordance with and then stored at −20°C until the assay. Rafsanjan University of Medical Sciences Quantitative detection of HDL, LDL, TC and guidelines for animal care and use with triglycerides and the blood glucose was minimizing the number of animals as well performed by relevant kits (Pars Azmoun, as animals’ discomfort such as immediate Iran) and expressed as mg/dl. The markers of euthanasia after experimental procedures. The oxidative stress, including malondialdehyde groups consisted of 8 rats and each animal was serum level (µM), total antioxidant activity used only once. (mM), glutathione peroxidase, catalase and Experimental design and induction of superoxide dismutase enzyme activities (U/ml) metabolic syndrome were measured using specific kits (Zelbio, Animals were randomly divided into four Germany) based on manufacturer procedures. groups: control (C), control animals, which After determining the appropriate amount of were treated with troxerutin (C+TXR), insulin to the appropriate kit (Mercodia,

203 International Journal of Medical Laboratory 2017;4(3):201-210. M. Jalali et al.

Sweden) the Homeostatic Model Assessment administration with the dose of 150 mg/kg did (HOMA) was used for insulin resistance not alter the abovementioned parameters in the assessment [25-27]. Homeostatic Model control group (p>0.05) but this dose could Assessment has been widely used as an insulin decrease the blood glucose and insulin resistance index in the clinical or resistance in metabolic syndrome-induced epidemiological studies based on following animals in troxerutin treatment in comparison formula: fasting insulin (micro U/L) x fasting with control group (p<0.001 and p<0.01 glucose (nmol/L) /22.5 [27]. respectively) and metabolic syndrome group Statistical analysis (p<0.001). Data are expressed as mean±standard Lipid profile and body mass index deviation. The one-way analysis of variance alterations in animals under troxerutin (ANOVA) followed by Tukey multiple treatment comparisons was used to analyze the data of Induction of metabolic syndrome by fructose body mass index, biochemical and oxidative resulted in a significant elevation in the body stress assessment. The computations were mass index, LDL, triglyceride and TC in done by SPSS software package (version 16) comparison with control, but the HDL level and Excel (Microsoft Excel, 2010, Microsoft revealed a reduction (all p<0.001) as Corporation, USA). P<0.05 was considered as shown in Table 2. Troxerutin (150 mg/kg) the significance level between the groups. administration did not alter these factors in the control group (p>0.05), but significantly Results reduced all parameters compared to metabolic Troxerutin attenuates blood glucose and syndrome group (p<0.001) and led to an insulin resistance in metabolic syndrome- enhancement in HDL cholesterol (p<0.01). Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 induced animals Table 1 illustrated that blood glucose and insulin resistance in the animals with metabolic syndrome increases in comparison with control (p<0.001). Troxerutin

Table 1. Troxerutin effects on blood glucose and insulin resistance

Variables C C+TXR MS MS+TXR

Fasting blood glucose (mg/dl) 79.87±5.05 79±4.34 138.12±6.85*** 108.62±7.89***,###

Insulin resistance 0.39±0.11 0.37±0.10 1.20±0.22*** 0.66±0.17**,### Data are expressed as mean±SD. Each group consists of 8 animals. *** p<0.001 and ** p <0.01 compared to control group. ### p<0.001 compared to the metabolic syndrome group. C= control group; C+TXR= control group treated with troxerutin; MS= metabolic syndrome group; MS+TXR= metabolic syndrome treated with troxerutin

International Journal of Medical Laboratory 2017;4(3): 201-210. 204 TROXERUTIN PROTECTION AGAINST METABOLIC SYNDROME

Table 2. Troxerutin effect on the lipid profile and body mass index

Variables C C+TXR MS MS+TXR Body mass index (Kg/m2) 7.29±0.53 7.02±0.43 9.34±0.45*** 7.44±0.32### High-density lipoprotein (mg/dl) 45.87±4.96 46.5±2.44 32.75±1.98*** 37.37±2.13***,## Low-density lipoprotein (mg/dl) 23.87±9.23 24.12±4.41 48.57±5.78*** 31.02±4.19### Triglyceride (mg/dl) 82.5±4.03 83.75±3.84 116.5±9.85*** 98±8.65### Total cholesterol (mg/dl) 86.25±5.06 87.37±2.66 104.12±5.66*** 88±2.66### Data are expressed as mean±SD. Each group consists of 8 animals. *** p<0.001 compared to the control group. ### p<0.001 and ## p<0.01 compared to the metabolic syndrome group. C= control group; C+TXR= control group treated with troxerutin; MS= metabolic syndrome group; MS+TXR= metabolic syndrome treated with troxerutin

Troxerutin effects on oxidative stress activities (catalase, superoxide dismutase indices and glutathione peroxidase) compared to the To investigate the role of troxerutin on control animals (all p<0.001). Treatment with oxidative stress due to metabolic syndrome troxerutin (150 mg/kg) did not affect these induction, it was determined the total indices in the control group (p>0.05), but antioxidant capacity and malondialdehyde significantly decreased malondialdehyde content as well as catalase, superoxide and led to the increase in total antioxidant dismutase and glutathione peroxidase capacity and glutathione peroxidase, activities. Data showed a rise in superoxide dismutase and catalase activities in malondialdehyde content besides a reduction comparison with the metabolic syndrome in total antioxidant capacity and enzyme group (all p<0.001) (Table 3).

Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 Table 3. Troxerutin effects on oxidative stress indices

Variables C C+TXR MS MS+TXR Antioxidant capacity (mM) 0.91±0.10 0.94±0.11 0.30±0.041*** 0.82±0.16### Malondialdehyde (Mµ) 0.98±0.11 0.95±0.08 2.75±0.43*** 1.19±0.35### Catalase (U/ml) 12.72±2.37 12.96±2.14 5.34±1.081*** 10.31±2.83### Superoxid dismutase (U/ml) 33.78±3.81 35.58±2.83 23.27±4.67*** 33.48±2.96### Glutathion peroxidase (U/ml) 192.20±28.65 193.02±33.13 73.83±18.81*** 191.37±53.90### Data are expressed as mean±SD. Each group consists of 8 animals. *** p<0.001 compared to the control group. ### p<0.001 compared to the metabolic syndrome group. C= control group; C+TXR= control group treated with troxerutin; MS= metabolic syndrome; MS+TXR= metabolic syndrome treated with troxerutin.

Discussion

Our results showed that long-term fructose diet which is accompanied by enhanced body mass (in drinking water, 20%) induces MS in rats, index and blood glucose, insulin resistance,

205 International Journal of Medical Laboratory 2017;4(3):201-210. M. Jalali et al.

lipid profile abnormalities (increase in LDL, resistance) were significantly observed. In TC and triglycerides levels and decrease in metabolic syndrome, there is a dysregulation HDL content) as well as oxidative stress in adipokines (leptin, adiponectin, apelin) dysregulation (decrease in total antioxidant action and secretion and adipocytes show capacity, lower enzyme activity of catalase, significant changes and glucose homeostasis superoxide dismutase and glutathione has been affected [33, 34]. Obesity- initiated peroxidase and elevated malondialdehyde MS exhibit a complex linkage with serum level). Chronic treatment with inflammatory responses and inflammation troxerutin for one month exerted protection causes metabolic dysregulation through and significantly reversed the disadvantageous several molecular signaling pathways and effects of MS. Blood glucose was diminished anti-inflammatory agents are considered as and insulin resistance was blocked following therapy in this proinflammatory state [35-37]. troxerutin administration. Moreover, lipid Moreover, the role of oxidative stress has profile and oxidative stress markers were been explored in MS development. Data regulated and balanced after 4 weeks treatment indicated a poor antioxidants status in MS with troxerutin. Metabolic syndrome, subjects with an increased oxidative stress, previously known as syndrome X, is on the which is positively correlated with insulin rise due to the increased incidence of obesity resistance [38]. In regard to Furukawa et al., manifesting raised fasting glucose (>110 hypothesis increased NADPH oxidase as mg/dl) or blood pressure (≥130/85 mmHg), well as decreased antioxidant enzymes in dyslipidemia (such as low HDL cholesterol accumulated fat resulted from obesity not only (women <50 mg/dl and men <40 mg/dl) or leads to a dysregulation in adipocytokines hypertriglyceridemia (≥150 mg/dl)) and a locally but also leads to other organ oxidative Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 hallmark of insulin resistance, which leads stress and eventually diabetes, insulin towards cardiovascular diseases, diabetes resistance and atherosclerosis (signs of MS) mellitus and chronic kidney diseases [28, 29]. [39]. Devaraj et al. (2008) reported that fatty In order to study the pathophysiology of meal consumption leads to postprandial MS and finding new drugs, different animal oxidative stress in MS [40]. In line with models have been used for induction of MS previous reports, our data on oxidative stress such as high-fat/sugar diet or transgenic biomarkers (decrease total antioxidant capacity models (overexpressing the enzyme 11β and enzyme activity of catalase, superoxide hydroxysteroid dehydrogenase type 1), in this dismutase and glutathione peroxidase and study, we added fructose 20% to the animal’s increased malondialdehyde serum level) water for 8 weeks, which is considered as a demonstrated that oxidative stress is a pivotal standard and valid method [5, 30-32] and key component of MS. features of MS (body mass index (BMI) and A number of studies showed that oxidative blood biochemical alteration and insulin stress along with chronic inflammation leads

International Journal of Medical Laboratory 2017;4(3): 201-210. 206 TROXERUTIN PROTECTION AGAINST METABOLIC SYNDROME

to the development of metabolic diseases and neuroprotection against high-cholesterol- enhanced systemic oxidative stress is induced cognitive deficits (through blocking associated with metabolic syndrome. There is the endoplasmic reticulum stress pathways and a positive correlation between oxidative stress activating the PI3K/Akt/CREB pathway in presence and increased LDL and low levels of brain) and suggested that troxerutin may be a HDL. Studies indicated that oxidative stress in possible candidate for the cognitive deficits metabolic disorders may lead to different therapy in Alzheimer’s disease and type 2 pathologies such as diabetes [41, 42]. This diabetes [18]. Geetha et al. (2014) showed that study showed that fructose administration to troxerutin blocks lipid abnormalities in the animals leads to oxidative imbalance and heart of high-fat/high-fructose diet-fed mice it was aimed to examine whether troxerutin is [12]. There is not enough evidence in the able to re-establish the oxidative balance literature review elucidating the possible and to prevent oxidative stress. Troxerutin, protective effects of troxerutin on MS; our trihydroxyethylated derivative of the natural study was designed to address this issue in a

bio-flavonoid rutin (C33H42O19), is considered rat model. Studies indicated that troxerutin as a fascinating target for disease prevention displays reversal effects on insulin resistance, and therapy for its multiple pharmacological lipid accumulation, oxidative damage effects and anti-inflammatory, anti-oxidative, and hypertension as well as decreasing anti-thrombotic, anti-neoplastic, hepatoprotective, reactive oxygen species and apoptosis [12, 18]. antihyperlipidemic, nephroprotective, cardioprotective The results obtained in our study reported that and neuroprotective properties have been reported troxerutin treatment improves BMI, blood [17, 43-48]. Safety profile and tolerability of glucose, insulin resistance, lipid profile and troxerutin have been investigated in pre- oxidative stress indices to normal or near Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 clinical or clinical studies and no serious normal levels in MS, but does not affect these adverse reactions were observed even at high parameters in healthy animals. doses [49]. Troxerutin administration exerted Data demonstrated that troxerutin exerts anti-diabetic effects in high fat and sucrose- significant therapeutic potential against liver induced type 2 diabetes mellitus in rats or high cancer via modulating the liver function cholesterol-induced insulin resistance in enzymes, oxidative damage, xenobiotic mice and type 2 diabetic patients with enzymes, blocking cell proliferation, different mechanisms, including blood glucose inflammatory response suppression and or glycosylated hemoglobin reduction, apoptosis induction [51]. Studies suggested normalizing serum insulin and lipid profile, that troxerutin can serve as a novel agent improving the insulin signaling molecules, for colon cancer chemoprevention via affecting glucose transporter4 proteins and modulating lipid peroxidation and antioxidant regulating skeletal muscle glucose utilization status. Troxerutin can act as a free radical [14, 24, 50]. Lu et al. showed troxerutin quencher and a growth inhibitor [52].

207 International Journal of Medical Laboratory 2017;4(3):201-210. M. Jalali et al.

Conclusion Conflict of Interest The authors declared that there is no conflict of It is concluded from this study that troxerutin may interest. play a therapeutic role in metabolic syndrome Acknowledgement The present article was financially supported by via modulating the insulin resistance, blood Rafsanjan University of Medical Sciences. biochemical and oxidative stress parameters. References [1]. Alberti KG, Zimmet P, Shaw J. The metabolic kidney from d-galactose-caused injury through syndrome-a new worldwide definition. Lancet. anti-inflammation and anti-oxidation. Int 2005; 366(9491): 1059-1062. Immunopharmacol. 2009; 9(1): 91-6. [2]. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC [14]. Chung HK, Choi SM, Ahn BO, Kwak HH, Jr, Lenfant C. Definition of metabolic syndrome. Kim JH, Kim WB. Efficacy of troxerutin on Circul. 2004; 109(3): 433-38. streptozotocin-induced rat model in the early stage [3]. Ruotolo G, Howard BV. Dyslipidemia of the of diabetic retinopathy. Arzneimittelforschung. 2005; metabolic syndrome. Curr Cardiol Rep. 2002; 55(10): 573-80. 4(6): 494-500. [15]. Panchal SK, Poudyal H, Arumugam TV, [4]. Wisse BE. The inflammatory syndrome: the role Brown L. Rutin attenuates metabolic changes, of adipose tissue cytokines in metabolic disorders nonalcoholic steatohepatitis, and cardiovascular linked to obesity. J Am Soc Nephrol. 2004; remodeling in high-carbohydrate, high-fat diet- 15(11): 2792-800. fed rats. J Nutr. 2011; 141(6): 1062-1069. [5]. Rutledge AC, Adeli K. Fructose and the metabolic [16]. Panat NA, Maurya DK, Ghaskadbi SS, Sandur syndrome: pathophysiology and molecular SK. Troxerutin, a plant flavonoid, protects cells mechanisms. Nutr Rev. 2007; 65(suppl 1): S13-S23. against oxidative stress-induced cell death [6]. Laclaustra M, Corella D, Ordovas JM. through radical scavenging mechanism. Food Metabolic syndrome pathophysiology: the role of Chem. 2016; 194: 32-45. adipose tissue. Nutr Metab Cardiovasc Dis. 2007; [17]. Zhang ZF, Fan SH, Zheng YL, Lu J, Wu DM, 17(2): 125-39. Shan Q, et al. Troxerutin improves hepatic lipid [7]. Hopps E1, Noto D, Caimi G, Averna MR. A homeostasis by restoring NAD+-depletion- novel component of the metabolic syndrome: the mediated dysfunction of lipin 1 signaling in high- oxidative stress. Nutr Metab Cardiovasc Dis. fat diet-treated mice. Biochem Pharmacol. 2014; 2010; 20(1): 72-77. 91(1): 74-86. [8]. Ando K, Fujita T. Fujita, Metabolic syndrome [18]. Lu J, Wu DM, Zheng ZH, Zheng YL, Hu B, and oxidative stress. Free Radic Biol Med. 2009; Zhang ZF. Troxerutin protects against high

Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 47(3): 213-18. cholesterol-induced cognitive deficits in mice. [9]. Roberts CK, Sindhu KK. Oxidative stress and Brain 2011; 134(Pt 3): 783-97. metabolic syndrome. Life Sci. 2009; 84(21): 705- [19]. Olszewski AJ, Szostak WB, Bialkowska M, 712. Rudnicki S, McCully KS. Reduction of plasma [10]. Hansel B, Giral P, Nobecourt E, Chantepie S, lipid and homocysteine levels by pyridoxine, Bruckert E, Chapman MJ, et al. Metabolic folate, cobalamin, choline, riboflavin, and syndrome is associated with elevated oxidative troxerutin in atherosclerosis. Atherosclerosis stress and dysfunctional dense high-density 1989; 75(1): 1-6. lipoprotein particles displaying impaired [20]. Tian J, Ishibashi K, Ishibashi K, Reiser K, antioxidative activity. J Clin Endocrinol Metab. Grebe R, Biswal S, et al. Advanced glycation 2004; 89(10): 4963-971. endproduct-induced aging of the retinal pigment [11]. Roberts CK, Barnard RJ, Sindhu RK, Jurczak epithelium and choroid: a comprehensive M, Ehdaie A, Vaziri ND. Oxidative stress transcriptional response. Proc Natl Acad Sci U S and dysregulation of NAD(P)H oxidase and A. 2005; 102(33): 11846-1851. antioxidant enzymes in diet-induced metabolic [21]. Lommel M, Cirak S, Willer T, Hermann R, syndrome. Metabolism. 2006; 55(7): 928-34. Uyanik G, van Bokhoven H, et al. Chronic [12]. Geetha R, Yogalakshmi B, Sreeja S, Bhavani administration of troxerutin protects mouse brain K, Anuradha CV. Troxerutin suppresses lipid against D-galactose-induced impairment of abnormalities in the heart of high-fat–high- cholinergic system. Neurol. 2010; 93(2): 157-64. fructose diet-fed mice. Mol Cell Biochem. 2014; [22]. Zhang Z, Wang X, Zheng G, Shan Q, Lu J, Fan 387(1-2): 123-34. S, et al. Troxerutin Attenuates Enhancement of [13]. Fan SH, Zhang ZF, Zheng YL, Lu J, Wu DM, Hepatic Gluconeogenesis by Inhibiting NOD Shan Q, et al. Troxerutin protects the mouse

International Journal of Medical Laboratory 2017;4(3): 201-210. 208 TROXERUTIN PROTECTION AGAINST METABOLIC SYNDROME

Activation-Mediated Inflammation in High-Fat [34]. Putnam K, Shoemaker R, Yiannikouris F, Diet-Treated Mice. Int J Mol Sci. 2016; 18(1): 31. Cassis LA. The renin-angiotensin system: a target [23]. Ranjith V, Radika M, Anuradha C. Effect of of and contributor to dyslipidemias, altered Troxerutin on Insulin Resistance Induced by Post- glucose homeostasis, and hypertension of the Natal Administration of Monosodium Glutamate: metabolic syndrome. Am J Physiol Heart Circ A Comparative Study with Rosiglitazone. J Clin Physiol. 2012; 302(6): H1219-H1230. Lab Investiga Updat. 2013; 1: 36-47. [35]. Lumeng CN, Saltiel AR. Inflammatory links [24]. Sampath S, Karundevi B. Effect of troxerutin between obesity and metabolic disease. J Clin on insulin signaling molecules in the Invest. 2011; 121(6): 2111-117. gastrocnemius muscle of high fat and sucrose- [36]. Wisse BE. The inflammatory syndrome: the induced type-2 diabetic adult male rat. Mol Cell role of adipose tissue cytokines in metabolic Biochem. 2014; 395(1-2): 11-27. disorders linked to obesity. J Am Soc Nephrol. [25]. Haffner SM, Kennedy E, Gonzalez C, Stern 2004; 15(11): 2792-800. MP, Miettinen H. A prospective analysis of the [37]. Chandalia M, Abate N. Metabolic complications HOMA model: the Mexico City Diabetes Study. of obesity: inflated or inflamed? J Diabet Complica. Diabet Care 1996; 19(10): 1138-141. 2007; 21(2): 128-36. [26]. Matthews DR, Hosker JP, Rudenski AS, Naylor [38]. Sharma P, Mishra S, Ajmera P, Mathur S. BA, Treacher DF, Turner RC. Homeostasis model Oxidative stress in metabolic syndrome. Indian J assessment: insulin resistance and β-cell Clin Biochem. 2005; 20(1): 145-49. function from fasting plasma glucose and insulin [39]. Furukawa S, Fujita T, Shimabukuro M, Iwaki concentrations in man. Diabetol. 1985; 28(7): M, Yamada Y, Nakajima Y, et al. Increased 412-19. oxidative stress in obesity and its impact on [27]. Salgado AL, Carvalho Ld, Oliveira AC, Santos metabolic syndrome. J Clin Invest. 2004; VN, Vieira JG, Parise ER. Insulin resistance 114(12): 1752-761. index (HOMA-IR) in the differentiation of [40]. Devaraj S, Wang-Polagruto J, Polagruto J, patients with non-alcoholic fatty liver disease and Keen CL, Jialal I. High-fat, energy-dense, healthy individuals. Arq Gastroenterol. 2010; fast-food-style breakfast results in an increase 47(2): 165-69. in oxidative stress in metabolic syndrome. [28]. Alberti KG, Eckel RH, Grundy SM, Zimmet Metabolism 2008; 57(6): 867-70. PZ, Cleeman JI, Donato KA, et al. Harmonizing [41]. Rani V, Deep G, Singh RK, Palle K, Yadav the metabolic syndrome: a joint interim statement UC. Oxidative stress and metabolic disorders: of the International Diabetes Federation Task Pathogenesis and therapeutic strategies. Life Sci. Force on Epidemiology and Prevention; National 2016; 148: 183-93. Heart, Lung, and Blood Institute; American Heart [42]. Reuter S, Gupta SC, Chaturvedi MM, Association; World Heart Federation; International Aggarwal BB. Oxidative stress, inflammation, Atherosclerosis Society; and International and cancer: how are they linked? Free Radic Biol Association for the Study of Obesity. Circulation Med. 2010; 49(11): 1603-616.

Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021 2009; 120(16): 1640-645. [43]. Babri S, Mohaddes G, Feizi I, Mohammadnia [29]. Wahba IM, Mak RH. Obesity and obesity- A, Niapour A, Alihemmati A, et al. Effect of initiated metabolic syndrome: mechanistic links troxerutin on synaptic plasticity of hippocampal to chronic kidney disease. Clin J Am Soc dentate gyrus neurons in a β-amyloid model of s disease: An electrophysiological׳Nephrol. 2007; 2(3): 550-62. Alzheimer [30]. Aleixandre de Artiñano A, Miguel Castro M. study. Eur J Pharmacol. 2014; 732: 19-25. Experimental rat models to study the metabolic [44]. Blasig IE, Löwe H, Ebert B. Radical trapping syndrome. Br J Nutr. 2009; 102(09): 1246-253. and lipid peroxidation during myocardial [31]. Fraulob JC, Ogg-Diamantino R, Fernandes- reperfusion injury-radical scavenging by Santos C, Aguila MB, Mandarim-de-Lacerda CA. troxerutin in comparison to mannitol. Biomed A mouse model of metabolic syndrome: insulin Biochim Acta. 1986; 46(8-9): 539-44. resistance, fatty liver and non-alcoholic fatty [45]. Ping X, Junqing J, Junfeng J, Enjin J. pancreas disease (NAFPD) in C57BL/6 mice fed Radioprotective effects of troxerutin against a high fat diet. J Clin Biochem Nutr. 2010; 46(3): gamma irradiation in V79 cells and mice. Asian 212-23. Pac J Cancer Prev. 2011; 12(10): 2593-596. [32]. Masuzaki H, Paterson J, Shinyama H, Morton [46]. Boisseau MR, Taccoen A, Garreau C, Vergnes NM, Mullins JJ, Seckl JR, et al. A transgenic C, Roudaut MF, Garreau-Gomez B. Fibrinolysis model of visceral obesity and the metabolic and hemorheology in chronic venous syndrome. Science. 2001; 294(5549): 2166-170. insufficiency: a double blind study of troxerutin [33]. Maury E, Brichard SM. Adipokine dysregulation, efficiency. J Cardiovasc Surg (Torino). 1995.; adipose tissue inflammation and metabolic 36(4): 369-74. syndrome. Mol Cell Endocrinol. 2010; 314(1): 1-16.

209 International Journal of Medical Laboratory 2017;4(3):201-210. M. Jalali et al.

[47]. Perk AA, Shatynska-Mytsyk I, Gerçek YC, [51]. Thomas NS, George K, Arivalagan S, Mani V, Boztaş K, Yazgan M, Fayyaz S, et al. Rutin Siddique AI, Namasivayam N. The in vivo mediated targeting of signaling machinery in antineoplastic and therapeutic efficacy of cancer cells. Cancer Cell Int. 2014; 14(1): 124. troxerutin on rat preneoplastic liver: biochemical, [48]. Chahar MK, Sharma N, Dobhal MP, Joshi YC. histological and cellular aspects. Eur J Nutr. Flavonoids: a versatile source of anticancer drugs. 2016; 1-14. Pharmacogn Rev. 2011; 5(9): 1-12. [52]. Vinothkumar R, Vinoth Kumar R, Karthikkumar [49]. Maurya DK, Balakrishnan S, Salvi VP, Nair V, Viswanathan P, Kabalimoorthy J, Nalini CK. Protection of cellular DNA from γ-radiation- N. Oral supplementation with troxerutin induced damages and enhancement in DNA (trihydroxyethylrutin), modulates lipid peroxidation repair by troxerutin. Mol Cell Biochem. 2005; and antioxidant status in 1, 2-dimethylhydrazine- 280(1): 57-68. induced rat colon carcinogenesis. Environ Toxicol [50]. Adam BS, Pentz R, Siegers CP, Strubelt O, Pharmacol. 2014; 37(1): 174-84. Tegtmeier M. Troxerutin protects the isolated perfused rat liver from a possible lipid peroxidation by coumarin. Phytomedicine. 2005; 12(1): 52-61. Downloaded from ijml.ssu.ac.ir at 11:04 IRST on Monday October 11th 2021

International Journal of Medical Laboratory 2017;4(3): 201-210. 210