Effects of citral on serum antioxidant status and liver genes expressions of paraoxonase 1 and nitric oxide synthase in a rat model of streptozotocin-induced diabetes mellitus

Document Type : Full paper (Original article)


1 Resident of Clinical Pathology, Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

3 Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran


Background: Citral (C10H16O) is the main ingredient of Cymbopogon citratus (lemongrass oil) and can reduce the side effects of oxidative stress. Diabetes caused by insulin deficiency induces oxidative stress in the liver. Aims: This study aimed to investigate the ameliorative effects of citral on selected oxidative parameters and the gene expression of paraoxonase 1 (PON1) and endothelial nitric oxide synthase (eNOS) in a rat model of streptozotocin (STZ)-induced diabetes mellitus. Methods: Forty rats were divided into four groups at random: control (C), control citral (CC), and two STZ-induced diabetic groups (diabetic (D) and citral diabetic (CD)). After diabetes confirmation (day 7), gavage treatment with citral (300 mg/kg body weight (BW)) was started in the CD and CC groups and continued for two weeks. Results: On day 21 of the study, following treatment with citral for 14 days, the serum levels of total antioxidant capacity (TAC), and PON1 in the CD group were significantly increased compared to those in the D group (P<0.05). While treatment with citral caused a significant decrease in the Malondialdehyde (MDA), and eNOS in the CD group compared to those of the D group (P<0.001). The expression rate of liver PON1 gene was considerably upregulated in the CD group compared to that in the D group (P<0.001); while the opposite was observed for eNOS gene expression. However, there was no significant difference between the CC and C groups in terms of all examined parameters (P>0.05). Conclusion: This study showed positive effects of citral on serum antioxidant status and liver gene expression of PON1 and eNOS in diabetic rats.


Main Subjects

Al-Sagheer, AA; Daader, AH; Gabr, HA and Abd El-Moniem, EA (2017). Palliative effects of extra virgin olive oil, gallic acid, and lemongrass oil dietary supplementation on growth performance, digestibility, carcass traits, and antioxidant status of heat-stressed growing New Zealand White rabbits. Environ. Sci. Pollut. Res., 24: 6807-6818.
Badr, G; Hozzein, WN; Badr, BM; Al Ghamdi, A; Saad Eldien, HM and Garraud, O (2016). Bee venom accelerates wound healing in diabetic mice by suppressing activating transcription factor 3 (ATF 3) and inducible nitric oxide synthase (iNOS) mediated oxidative stress and recruiting bone marrow derived endothelial progenitor cells. J. Cell. Physiol., 231: 2159-2171.
Bhattacharya, SK (1995). Shilajit attenuates streptozotocin induced diabetes mellitus and decrease in pancreatic islet superoxide dismutase activity in rats. Phytother. Res., 9: 41-44.
Campos, J; Schmeda-Hirschmann, G; Leiva, E; Guzman, L; Orrego, R; Fernandez, P; González, M; Radojkovic, C; Zuñiga, F and Lamperti, L (2014). Lemon grass (Cymbopogon citratus (DC) Stapf) polyphenols protect human umbilical vein endothelial cell (HUVECs) from oxidative damage induced by high glucose, hydrogen peroxide and oxidised low-density lipoprotein. Food Chem., 151: 175-181.
De Vries, A; Verbeuren, T; Van de Voorde, J; Lameire, N and Vanhoutte, P (2000). Endothelial dysfunction in diabetes. Brit. J. Pharmacol., 130: 963-974.
Flekac, M; Skrha, J; Zidkova, K; Lacinova, Z and Hilgertova, J (2008). Paraoxonase 1 gene polymorohisms and enzyme activities in diabetes mellitus. Physiol. Res., 57: 717-726.
Förstermann, U; Xia, N and Li, H (2017). Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res., 120: 713-735.
Giteru, SG; Coorey, R; Bertolatti, D; Watkin, E; Johnson, S and Fang, Z (2015). Physicochemical and antimicrobial properties of citral and quercetin incorporated kafirin-based bioactive films. Food Chem., 168: 341-347.
Gross, D; Fogg, L; Webster-Stratton, C; Garvey, C; Julion, W and Grady, J (2003). Parent training of toddlers in day care in low-income urban communities. J. Consult. Clin. Psych., 71: 261-278.
Hossein-Nia, B; Khorram, S; Rezazadeh, H; Safaiyan, A; Ghiasi, R and Tarighat-Esfanjani, A (2018). The effects of natural clinoptilolite and nano-sized clinoptilolite supplementation on lipid profile, food intakes and body weight in rats with streptozotocin-induced diabetes. Can. J. Diabetes. 8: 211-216.
James, RW; Leviev, I; Ruiz, J; Passa, P; Froguel, P and Garin, MC (2000). Promoter polymorphism T (-107) C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes. 49: 1390-1393.
Kaneto, H; Katakami, N; Kawamori, D; Miyatsuka, T; Sakamoto, K; Matsuoka, T; Matsuhisa, M and Yamasaki, Y (2007). Involvement of oxidative stress in the pathogenesis of diabetes. Antiox. Redox. Sign., 9: 355-366.
Kao, Y; Donaghue, K; Chan, A; Knight, J and Silink, M (1998). A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J. Clin. Endocr. Metab., 83: 2589-2592.
Kota, SK; Meher, LK; Kota, SK; Jammula, S; Krishna, S and Modi, KD (2013). Implications of serum paraoxonase activity in obesity, diabetes mellitus, and dyslipidemia. Indian J. Endocr. Metab., 17: 402-412.
Lai, YS; Lee, WC; Lin, YE; Ho, CT; Lu, KH; Lin, SH; Panyod, S; Chu, YL and Sheen, LY (2016). Ginger essential oil ameliorates hepatic injury and lipid accumulation in high fat diet-induced nonalcoholic fatty liver disease. J. Agri. Food Chem., 64: 2062-2071.
Li, H; Horke, S and Förstermann, U (2014). Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 237: 208-219.
Li, CC; Yu, HF; Chang, CH; Liu, YT and Yao, HT (2018). Effects of lemongrass oil and citral on hepatic drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in rats. J. Food Drug Anal., 26: 432-438.
Mackness, B; Durrington, P; Boulton, A; Hine, D and Mackness, M (2002). Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controls. Eur. J. Clin Invest., 32: 259-264.
Magenta, A; Greco, S; Capogrossi, MC; Gaetano, C and Martelli, F (2014). Nitric oxide, oxidative stress, and p66Shc interplay in diabetic endothelial dysfunction. Bio. Med. Res. Int., 2014: 1-16.
Maritim, A; Dene, B; Sanders, R and Watkins III, J (2003). Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats. J. Biochem. Mol. Toxcic., 17: 193-199.
Nakamura, Y; Miyamoto, M; Murakami, A; Ohigashi, H; Osawa, T and Uchida, K (2003). A phase II detoxification enzyme inducer from lemongrass: identification of citral and involvement of electrophilic reaction in the enzyme induction. Biochem. Bioph. Res. Co., 302: 593-600.
Perrault, DP; Lee, GK; Bouz, A; Sung, C; Yu, R; Pourmoussa, AJ; Park, SY; Kim, GH; Jiao, W and Patel, KM (2020). Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps. PLoS One. 15: e0227599.
Rahim, SM; Taha, EM; Al-Janabi, MS; Al-Douri, BI; Simon, KD and Mazlan, AG (2014). Hepatoprotective effect of Cymbopogon citratus aqueous extract against hydrogen peroxide-induced liver injury in male rats. Afr. J. Tradit. Complem., 11: 447-445.
Rashed, L; Gharib, DM; Hussein, RE; Tork, O and Abusree, A (2016). Combined effect of bone marrow derived mesenchymal stem cells and nitric oxide inducer on
injured gastric mucosa in a rat model. Tissue Cell., 48: 644-652.
Saenthaweesuk, S; Munkong, N; Parklak, W; Thaeomor, A; Chaisakul, J and Somparn, N (2017). Hepato-protective and antioxidant effects of Cymbopogon citratus Stapf (Lemon grass) extract in paracetamolinduced hepatotoxicity in rats. Trop. J. Pharm. Res., 16: 101-107.
Scott, JA and King, GL (2004). Oxidative stress and antioxidant treatment in diabetes. Ann. NY. Acad. Sci., 1031: 204-213.
Sharma, A; Sellers, S; Stefanovic, N; Leung, C; Tan, SM; Huet, O; Granville, DJ; Cooper, ME; de Haan, JB and Bernatchez, P (2015). Direct endothelial nitric oxide synthase activation provides atheroprotection in diabetes-accelerated atherosclerosis. Diabetes. 64: 3937-3950.
Siewert, S; Gonzalez, II; Lucero, RO and Ojeda, MS (2015). Association of cholesteryl ester transfer protein genotypes with paraoxonase 1 activity, lipid profile and oxidative stress in type 2 diabetes mellitus: A study in SanLuis, Argent. J. Diabetes Invest., 6: 67-77.
Tajidin, N; Ahmad, S; Rosenani, A; Azimah, H and Munirah, M (2012). Chemical composition and citral content in lemongrass (Cymbopogon citratus) essential oil at three maturity stages. Afr. J. Biotech., 11: 2685-2693.
Uchida, NS; Silva Filho, SE; Aguiar, RP; Wiirzler, LAM; Cardia, GFE; Cavalcante, HAO; Silva Comar, FMDS; Becker, TCA; Silva, EL and Bersani Amado, CA (2017a). Protective effect of Cymbopogon citratus essential oil in experimental model of acetaminophen-induced liver injury. Am. J. Chinese Med., 45: 515-532.
Uchida, NS; Silva Filho, SE; Cardia, GFE; Cremer, E; Silva Comar, FMDS; Silva, EL; Bersani Amado, CA and Cuman, RKN (2017b). Hepatoprotective effect of citral on acetaminophen-induced liver toxicity in mice. Evid. Based. Comp. Alt. Med., 22: 1-9.
Ülker, S; McKeown, PP and Bayraktutan, U (2003). Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD (P) H oxidase activities. Hypertension. 41: 534-539.
Xu, L; Zhu, J; Yin, W and Ding, X (2015). Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. Int. J. Clin. Exp. Patho., 8: 6083-6094.
Yamagishi, Si and Imaizumi, T (2005). Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr. Pharm., 11: 2279-2299.
Yang, SM; Hua, KF; Lin, YC; Chen, A; Chang, JM; Chao, LK; Ho, CL and Ka, SM (2013). Citral is renoprotective for focal segmental glomerulosclerosis by inhibiting oxidative stress and apoptosis and activating Nrf2 pathway in mice. PLoS One. 8: e74871.
Zaki, ME; El Bassyouni, H; Kamal, S; El Gammal, M and Youness, E (2014). Association of serum paraoxonase enzyme activity and oxidative stress markers with dyslipidemia in obese adolescents. Indian J. Endocrinol. Metab., 18: 340-344.