Traditional & Integrative Medicine TRADITIONAL AND INTEGRATIVE MEDICINE Trad Integr Med, Volume 6, Issue 2, Spring 2021 Original Research Beneficial Hypoglycemic, Hypolipidemic Effects of Aerial Branches and Roots Extract of Eryngium caeruleum M. Bieb on Streptozotocin-Induced Diabetes Model in Rats Aryaneh Sardarbandeh1, Mohammad Reza Delnavazi1,2, Mohammad Sharifzadeh3, Masoumeh Ghajarieh Sepanlou4, Zahra Tamiji5, Seyede Nargess Sadati Lamardi4* 1School of Pharmacy, Tehran University of Medical Sciences, Tehran, 2Department of Pharmacognosy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 3Department of Pharmacology and Toxicology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 4Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran 5Food and Drug Administration, Tehran University of Medical Sciences, Tehran, Iran

Received: 20 Feb 2021 Revised: 19 May 2021 Accepted: 23 May 2021

Abstract

Eryngium caeruleum (Apiacea) is native to the northern forests of Iran. The anti-diabetic effect of other species of the genus Eryngium has already been reported in previous studies. In this study, the anti-diabetic effect of this extract and their effect on animal blood lipid factors was investigated. Hy- droalcoholic extract was obtained from different parts of the , including roots, leaves, and aerial branches with fruits were prepared by maceration with 70% ethanol. Oral acute toxicity of the extracts was assayed in different doses of 2000, 4000, and 8000 mg/kg in rats. To induce diabetes in the studied animals, 60-70 mg/kg of streptozotocin (STZ) was injected intraperitoneally (IP). For the purpose of this study, 72 male Wistar rats were randomly divided into different groups of normal, diabetic, and positive controls (metformin 500 mg/kg) as well as 9 diabetic groups that orally received 200, 400, and 800 mg/kg of extracts. The effects of the treatment with extracts for a 14-day period were inves- tigated on weight, blood glucose, and lipid profile. By comparing the control groups with the groups of hydroalcoholic extracts of E. caeruleum showed that the most effective sample on weight gain and also on reducing blood glucose was the group receiving 800 mg/kg of the aerial branches extract (P < 0.01 and P < 0.001, respectively) after 14 days. As well, the most effective sample on lowering the blood lipid factors was the hydroalcoholic extract of the root of E. coareleum with a dose of 200 mg/kg, which showed a significant effect on lowering total cholesterol in diabetic rats compared to the diabetic controls (P < 0.05). Hydroalcoholic extract of leaves with 200 mg/kg also showed a better effect on low- ering the LDL and VLDL levels compared to the diabetic control group (P < 0.001). The results of pan- creatic histology in the samples showed that the extracts of the aerial branch and root (800 mg/kg) had

Citation: Sardarbandeh A, Delnavazi MR, Sharifzadeh M, Ghajarieh Sepanlou M, Tamiji Z, Sadati Lamardi SN. Beneficial Hypogly- cemic, Hypolipidemic Effects of Aerial Branches and Roots Extract of Eryngium caeruleum M. Bieb on Streptozotocin-Induced Diabetes Model in Rats. Trad Integr Med 2021;6(2):92-102. *Corresponding Author: Seyede Nargess Sadati Lamardi Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran E-mail: [email protected]

Copyright © 2021 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International license (https://creativecommons. org/licenses/by-nc/4.0/). Noncommercial uses of the work are permitted, provided the original work is properly cited.

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significant effects on the regeneration of the islets of Langerhans compared to the diabetic control group. In conclusion, E. caeruleum could significantly improve glycemic and lipid profiles in diabetic rats.

Keywords: Eryngium; Diabetes mellitus; Blood glucose; Streptozotocin (STZ); Rats

Introduction caucasicum Trautv.) is one of the with Diabetes mellitus (DM) is a group consisting of many applications in the traditional Persian metabolic disorders that have appearance sim- medicine (TPM), which recommended its roots ilar to hyperglycemia. Epidemiological studies usage besides the aerial parts of the . Re- reported that DM can become an epidemic asso- searchers in the field of Persian medicine con- ciated with metabolic and endocrine disorders sider that E. caeruleum belongs to the genus Er- worldwide [1]. The important issue is alarm yngium, which was also called “Qaracaane” in increasing in type-2 diabetes mellitus (T2DM) the book "Makhzan Al-.", as one of the among adults and children. Additionally, met- sources of TPM. The genus Eryngium belongs abolic dysregulation with type-1 diabetes caus- to the family, and with 274 accepted es some secondary pathophysiological changes species, it is considered as the largest genus of in many organs, which consequently impose this family. The herbs of this genus have spread a huge burden on the affected individuals and in all over the world, especially in Asia, Europe, health systems [2]. America, Africa, and Australia [4]. Nowadays, due to the ineffectiveness of chemi- Different parts of the genus Eryngium has been cal drugs on controlling blood glucose and their used for the treatment of various diseases such subsequent side effects, one of the main goals as diarrhea and gastrointestinal problems, blad- of the effective diabetes treatment with minimal der and kidney disorders, kidney stones, tu- side effects is the need for systematic search in mors, infections, skin diseases, anemia, sexual- order to find natural resources, including herbs, ly transmitted diseases, women's reproductive as blood glucose lowering agents. Other bene- problems such as infertility, menstrual cramps, fits of using herbs to treat diseases are low side eliminating and facilitating labor problems, effects, low cost, high effectiveness, and avail- postpartum abdominal pain, vaginal infections, ability. In recent years, the anti-T2DM proper- various inflammatory diseases, colds, flu, fever, ties of many herbs and natural compounds have asthma, cough, sinusitis, rheumatism, hyper- been identified and many studies have been tension, eye disorders, poisoning, liver disease, conducted to elucidate possible mechanisms in diabetes, malaria, and snake bites in traditional this regard [3]. medicines from various ethnic groups and vari- Eryngium caeruleum M.Bieb. (Syn. Eryngium ous countries in all parts of the world, including

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Asia, Europe, and Central and South America THE-6610. Thereafter, different parts of this from ancient times to the present day. These herb, including its roots, leaves, and aerial parts herbs also have some properties, including fit- (fruiting branches), were dried at the ambient ness enhancing, pain relief, constipation treat- temperature away from light and moisture. ment, wound healing, anthelmintic, analgesic, anti-malarial and antibacterial, diuretic, appe- Hydroalcoholic Extraction tizing, sedative, and sexual stimulating proper- The extraction process was performed on 300 g ties in ethnobotanical treatments performed in of dried powder of the studied samples via 70% different countries [5]. ethanol using maceration method for 3 days (72 Several pharmacological studies have also prov- h). Accordingly, this process was repeated three en the effects of herbs of different species of times and the extracts were then concentrated this genus on bacteria and fungi, malaria, leish- using a rotary evaporator. maniasis and worms, venom, and bite of snakes and scorpions, as well as analgesic and anti-in- Animal studies flammatory, anti-diabetic, anti-seizure, anti-hy- At this stage, the experiment was performed on poxic, anti-cancer, anti-mutagenicity, cytotoxic male Wistar rats weighing between 250 and 300 effects, renal protective effects, anti-hemolytic g. These rats were purchased from the Facul- activity, antioxidant activity, skin effects, and ty of Pharmacy, Tehran University of Medical the increased skin permeability, food preser- Sciences. Thereafter, the animals were placed in vation effect, and their high nutritional values their cages in a temperature-controlled environ- [6,7]. ment (24 ± 1 ° C), with 12:12 light–dark (LD) In the present study, considering the anti-diabet- cycle. The animals were then fed with standard ic effects of different species of Eryngium genus, food and water. Afterward, they were placed in the anti-diabetic effects of its different parts, in- the laboratory for one week prior to the exper- cluding roots, leaves, and fruiting branches of iment in order to be accustomed to the experi- Eryngium caereleum in streptozotocin-induced mental conditions. In the current study, all the diabetic rats were investigated. experimental protocols were approved by the Research Ethics Committee of the Faculty of Methods Science, University of Tehran (IR.TUMS.TIPS. REC.1398.112). Plant material E. caeruleum samples were collected from Gi- Oral acute toxicity lan province, north of Iran. As well, its species Acute oral toxicity was assessed by gavage in and genus were identified in the herbarium of ten groups, each one consisting of three rats, in- the Faculty of Pharmacy, Tehran University cluding three different doses of extracts (2000, of Medical Sciences with the voucher number 4000, 8000 mg/kg), as well as the normal saline

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http://jtim.tums.ac.ir Hypoglycemic effects of Eryngium caeruleum A. Sardarbandeh et al. as the control group. Subsequently, animal mor- and at the end of the second week of this ex- tality, and behavioral and nutritional symptoms periment. At the end of the study on the 15th were evaluated for 24-72 h. day, heart blood samples were collected from the rats under deep anesthesia of xylazine (15 mg/ Induction of diabetes kg) (Alfasan, Netherlands) as well as ketamine After the time of 24 h fasting in rats, intraperito- (80 mg/kg) (Alfasan, Netherlands). The obtained neal (IP) streptozotocin (STZ) (Sigma, USA) at blood samples were centrifuged at 4000 revo- a dose of 60-70 mg/kg was used. Accordingly, lutions per minute (RPM) for 10 min and then STZ was dissolved in 0.05 mol/L cold sodium the separated serum was stored at -70°C until citrate buffer at pH 4.5 proximately before use. biochemical analysis [8]. Subsequently, Lipid After 72 h, hyperglycaemia was defined using a profiles, including ventricular blood low densi- glucometer (Glucotrend, Germany) in the blood ty lipoprotein (LDL), high density lipoprotein samples obtained from the tail veins of the study (HDL), very-low-density lipoprotein (VLDL), rats. Finally, only those animals with non-fast- and cholesterol lipid indices, were measured. ing blood glucose levels higher than 200 mg/dL Finally, the animal's abdomen was opened and were selected and then studied in this research. the histology sample of rat pancreas was isolated from the five groups of normal and diabetic con- Experimental design trols as well as 800 mg/kg groups of RE, AE and The rats were randomly divided into the follow- metformin for performing the pathology study. ing 12 groups, each one consisting of 6 rats: 1. Normal control (normal saline 5 ml/kg, n = 6); Statistical analysis 2. Diabetic control (normal saline 5 ml/kg, n = All the obtained data were compared using SPSS 6); 3. Diabetic + metformin 500 mg/kg, (n = 6); software. Data were first analyzed for normal 4, 5, and 6. Diabetic + hydroalcoholic extract of distribution and equal variance. One-way ANO- E. caeruleum (HEC) root (RE) (200, 400, 800 VA and post hoc (Tukey's multiple comparisons mg/kg, respectively, n = 6); 7, 8, and 9. Dia- test) tests were also used to determine the statis- betic + hydroalcoholic extract of E. caeruleum tically significant differences among the groups. (HEC) leave (LE) (200, 400, and 800 mg/kg, Finally, the data were expressed as mean±SEM respectively, n = 6); and 10, 11, and 12. Diabetic and P<0.05 was considered as statistically sig- + hydroalcoholic extract of E. caeruleum aerial nificant. part (AE) (200, 400, and 800 mg/kg, respective- ly, n = 6). Results All the study animals were treated daily for a 2-week duration by oral gavage. Non-fasting Acute toxicity test blood glucose level and weight of the rats were Administration of doses of 2000, 4000, 8000 measured at the baseline, at the end of the first, mg/kg of 70% hydroalcoholic extracts (RE, LE,

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http://jtim.tums.ac.ir Hypoglycemic effects of Eryngium caeruleum A. Sardarbandeh et al. and AE) showed no death or change in the ani- Additionally, at the end of the experiment (day mals after 24 and 48 h. Based on these results, 14), root extract at dose of 800 mg/kg led to a the LD50 is considered higher than 8 g / kg. significant improvement in the weight of the di- abetic rats in the RE (P < 0.001) and AE groups Body weight measurement (P < 0.01), respectively. Figure 1 shows the effect of the repeated ad- Treatment with metformin at a dose of 500 mg/ ministration of RE, LE, and AE of E. caeruleum kg (as the standard anti-diabetic drug) led to a on body weight in diabetic rats. In both the first significant increase in the weight of the diabetic and second weeks of the treatment protocol, no rats in the second week (P < 0.05). significant difference was found between the di- abetic control and normal control rats in terms Blood glucose assay of body weight. By analyzing the results, it was Figure 2 shows the effects of hydroalcoholic ex- shown that root extract (RE) at a dose of 800 tract of E. caeruleum leaf, root, and aerial parts mg/kg led to a significant improvement in the on the STZ-induced diabetic rats. STZ injection weight of diabetic rats on the day 7 (p < 0.05). at a dose of 60 mg/kg significantly increased

Figure 1: Effect of hydroalcoholic extract of E. caeruleum (EC) root (RE), leave (LE) and aerial part (AE) on body weight changes in rats with STZ-induced diabetes (mean ± SEM) (n = 6). Data expressed as means ± SEM. *** P < 0.001, ** p < 0.01, * p < 0.05 com- pared to DC. NC: Normal control; DC: Diabetic control; Met: metformin 500 mg/kg of animal weight; LE: Hydroalcoholic extract of EC leave; RE: Hydroalcoholic extract of EC root; AE: Hydroalcoholic extract of EC aerial part; weight of rats (gram) blood glucose levels in rats in the diabetic con- kg resulted in a significant hypoglycemic effect trol group compared to the normal control group on days 7 (P < 0.05) and 14 of the experiment (P < 0.001). (P < 0.001). Moreover, daily administration of Notably, daily administration of hydroalcoholic metformin at a dose of 500 mg/kg showed a extract of E. caeruleum AE at a dose of 800 mg/ significant hypoglycemic effect on diabetic rats

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Figure 2. Effect of hydroalcoholic extract of E. = (EC) root (RE), leave (LE) and aerial part (AE) on blood glucose level in rats with STZ-induced diabetes (mean ± SEM) (n = 6). Data expressed as means ± SEM. *** P < 0.001, ** p < 0.01, * p < 0.05 compared to DC. ### P < 0.001 compared to NC. NC: Normal control; DC: Diabetic control; Met: metformin 500 mg/kg of animal weight; LE: Hydroalcoholic extract of EC leave; RE: Hydroalcoholic extract of EC root; AE: Hydroalcoholic extract of EC aerial pars.

Blood lipid profile assay < 0.05). Although the TC level was lower in the The effect of the hydroalcoholic extracts of other extract-treated groups than the diabetic E. caeruleum obtained from leaf, aerial part, control group, this difference was not statistical- and root on the lipid profile (TG, TC, LDL, ly significant. Of note, there was no significant and HDL) are shown in table 1. In this regard, difference in terms of TC levels between other the results showed no significant difference in extract-treated groups and the normal control terms of the total cholesterol (TC) level be- group. The results of investigating the effects of tween the diabetic control group and normal the extracts as well as metformin on the blood control group. However, TC level was signifi- triglyceride (TG) level of the studied animals cantly higher in the metformin–treated group showed no significant difference between the compared to the normal control (P < 0.05) and TG levels in all the experiment groups and the the diabetic control groups (P < 0.01). normal control group after the two weeks of The treatment with hydroalcoholic root extract treatment. As it was found, the administration (RE) at a dose of 200 mg/kg for a 2-week du- of extracts and metformin for 14 days led to no ration resulted in a significant reduction in TC significant changes in HDL levels in the treat- level compared to the diabetic control group (P ment groups compared to the control groups.

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Additionally, the plasma LDL level in all the significant increase in both the metformin and groups, except the LE group 200 mg/kg in the LE groups (200 mg/kg) compared to the normal diabetic group (P <0.001), was not changed and diabetic controls (P < 0.001). significantly. While the VLDL level showed a

Table 1: Effects of Eryngium caeroleum hydroalcoholic extract on the lipid profile in the serum of streptozotocin induced diabetic rats (mean ± SEM, n = 6).

Treatment Dose (mg/kg) TC (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) VLDL (mg/dl)

Normal control Normal saline (5 53.5±10.3 49.67±13.7 30.17±6.3 5.67±1.6 9.83±2.7 (NC) mL/kg)

Dabetic control Normal saline (5 50.2±11.4 43.67±7.3 26.5±4.7 5.33±2.2 8.83±1.5 (DC) mL/kg)

500 mg/kg Metformin 73.2±6.8#,* 83.5±20.5* 39.67±4.5 8.67±1.4 19.83±3.4###,***

57.2±5.6 77.0±52.1 31.17±7.2 11.67±1.5###,*** 24.83±10.2###,*** 200 mg/kg 48.3±12.0 46.67±10.1 32.83±8.5 7.67±3.3 10.0±2.4 LE 400 53.0±6.3 42.33±14.1 26.83±5.8 6.17±1.2 11.17±3.1 800

42.7±8.3 33.83±7.4 37.33±6.4 5.0±2.7 6.67±1.6 200 mg/kg 40.8±10.8 38.33±7.2 32.0±9.2 6.0±1.5 8.17±0 AE 400 47.5±7.8 48.5±14.9 31.33±3.3 6.7±1.4 9.67±3.2 800

29.5±14.1* 25.17±5.0 25.0±13.3 3.67±1.8 5.17±1.2 200 mg/kg 35.5±7.1 30.0±7.2 28.17±4.7 3.67±1.2 6.17±1.5 RE 400 44.5±10.5 33.67±10.9 37.5±7.7 6.67±1.8 6.83±2.2 800

The one-way ANOVA and post hoc test were used to determine statistically significant differences between the groups. #P < 0.05, ###P < 0.001 significant compared with Normal control, *P < 0.05, ***P < 0.001 significant compared with Diabetic control. TC: Total cho- lesterol; TG: Triglyceride; HDL: High density lipoprotein; LDL: Low-density lipoprotein; VLDL: Very low density lipoprotein; LE: Leaf extract; AE: Aerial (fruiting) part extract; RE: Root extract.

Histopathological analysis As shown in figure 3, in the diabetic control treated with aerial AE (800 mg/kg) showed the rats, size and β cells in the islets of Langerhans regenerated pancreatic islet cells as well as the have significantly reduced, some islet’s were reduced pancreatitis. Furthermore, the diabetic found to have degraded. On the other hand, the rat group treated with RE (800 mg/kg) showed metformin-treated diabetic group with normal the regenerated pancreatic islet cells as well as cells showed a change in the size of the islets. the reduced pancreatitis. In this study, histolog- Apoptotic changes were also seen in the form ical and biochemical evaluations showed the of a small picnotic nucleus and a deeply acido- possibility of regenerating the islets using both philic cytoplasm. In addition, the diabetic group AE and RE (800 mg/kg) of E. caeruleum.

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Figure 3: Pancreas histopathology. Control rats shows endocrine glands with normal histological features of islets of Langerhans. Pancreatic acini are normal in the exocrine part with pyramidal cells and represents basal basophils and apical acidophilic cyto- plasm (H&E, x200). Diabetic rats: The islets of Langerhans have been significantly reduced in size and in terms of β cells, some of the islet cells have been shown to be destroyed by the cytoplasm (H&E, x200, 400). Metformin 500 mg/kg: The metformin-treated diabetic group with regular cells shows a change in the size of the islets. Apoptotic changes are seen in the form of a small picnotic nucleus and a deeply acidophilic cytoplasm (H&E, x200, 400) .AE (800 mg/kg) sample: A diabetic group treated with aerial part extract showed regenerated pancreatic islet cells and reduced pancreatitis (H&E, x200).RE (800 mg/kg): A diabetic rat group was treated with root extract and showed regenerated pancreatic islet cells and reduced pancreatitis (H&E, x400).

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Discussion and Conclusion be better controlled than the other groups us- Considering the confirmed anti-diabetic effects ing a dose of 800 extracts of the fruiting branch of different species of Eryngium, the hydroal- (AE) of this plant. coholic extract of E. caereleum was evaluated In another study conducted by Abdul Sadiq for the anti-diabetic effects of its different parts, et al., the chloroform fraction obtained from including roots (RE), leaves (LE), and fruiting the methanolic extract of the aerial parts of E. branches (AE) in the STZ-induced diabetic rats. caeruleum showed a better effect compared to According to the data obtained from weight the other fractions by applying α-glucosidase measurements in the current study, RE and AE inhibition test. Correspondingly, this fraction in at the dose of 800 mg/kg led to a significant in- the diabetic mice by passing 24 h from the intra- crease in rat’s weight as about 2% and 25% after peritoneal injection of different doses showed 14 days of treatment, respectively, compared to a significant reducing effect compared to the the diabetic control group. Additionally, daily control group. In this study, blood sugar levels treatment with AE (800 mg/kg) significantly re- were measured in different hours after the first duced the blood glucose level on days 7 and 14 injection of the extract [10]. of the experiment. Thus, no significant differ- Many studies have been previously conducted ence was observed with the metformin group. on hypoglycemia in animal models using var- The results of the pancreatic histology also ious extracts of Eryngium species. As well, the showed that the AE and RE (800 mg/kg) had hypoglycemic activity of the aqueous branch significant effects on controlling blood glucose extract of Eryngium creticum has been tested in level compared to the diabetic control group, the STZ-induced diabetic rats. The results indi- which may possibly be due to the regeneration cate that this extract could significantly reduce of the islets of Langerhans. the blood glucose concentration [11]. In a study by Afshari et al., the hypoglycemic A study performed on diabetic rats in 2012 and lipid-lowering effects of the leaf extract of showed that blood glucose, creatinine, uric E. caeruleum on streptozotocin-nicotinamide acid, and TC levels have elevated in diabetic induced type 2 diabetes in male rats were in- rats treated by ethanolic extract of E. carlinae. vestigated. In this study, it was observed that Accordingly, the results showed that the herb the extract at doses of 200 and 300 mg/kg sig- extract could significantly reduce TG, uric acid, nificantly reduced the fasting blood sugar level and TC levels. This herb can also be effective compared to the control group. Moreover, this on lowering blood lipids in patients with car- improved serum insulin levels. LDL levels were diovascular diseases and even in patients with also decreased significantly by administrating a diabetes mellitus [12]. dose of 300 mg/kg [9]. In our study, a random Norouzi and Valipour (2021) in their study in- blood glucose measurement was performed, in vestigated the effects of E. campestre extract which the animal's blood glucose was found to on blood sugar levels and blood lipid indices

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http://jtim.tums.ac.ir Hypoglycemic effects of Eryngium caeruleum A. Sardarbandeh et al. in diabetic male rats. Their results showed that an inhibitory effect on hormone-sensitive lipase the treatment with different doses of E. campes- (HSL) activity. Considering the fact that high tre extract for two weeks significantly reduced levels of fatty acids and triglycerides play im- blood sugar (p < 0.001), triglyceride (p < 0.001), portant roles in the development of type 2 di- and VLDL (p < 0.001) levels; however, LDL abetes and insulin resistance, so this enzyme level was significantly increased (p < 0.001). In plays key roles in both fat metabolism and ener- addition, E. campestre extract significantly in- gy homeostasis in mammals [17]. Furthermore, creased total cholesterol (p < 0.05) at 100 mg/ in a previous study conducted on rats with nor- kg dose and HDL at both 100 mg/kg (p < 0.05) mal blood glucose as well as diabetic rats, the and 200 (p < 0.001) doses [13]. oral administration of a single dose of E. foeti- Rehman et al. (2017) showed that two new fla- dum leaf extract showed no significant effect on vonol glycosides obtained from the aerial parts lowering blood glucose levels [18]. The results of E. caeruleum represented an inhibitory effect of the present study show that aerial part (fruit- on the aldose reductases (ALR1 and ALR2) and ing) (AE) and root extracts at the dose of 800 glucosidases (α and β) enzymes under in vi- mg/kg could have a significant effect on weight tro condition. It was also found that these two control in diabetic rats. Moreover, AE (800 mg/ flavonoids had stronger effects on inhibiting kg) indicated a significant hypoglycemic effect. ALR1, rather than ALR2 [14]. According to this result, it can be concluded that Dehghan et al. (2016) reported that methano- the administration of hydroalcoholic extract of lic, hexane, and ethyl acetate extracts derived E. caeroleum aerial parts could be effective on from the aerial parts of E. caeruleum by inhib- lowering blood glucose in STZ-induced dia- iting the α-amylase and α-glucosidase enzymes betes. Additionally, none of the extract doses showed anti-diabetic effects. In this regard, the had a significant effect on reducing LDL and highest inhibitory effect was found to be related VLDL, except the leaf extract at dose of 200 to methanolic extract, followed by ethyl acetate mg; however, this requires further studies to be and hexane extracts, respectively [15]. confirmed. Histological results showed that the Another study showed that the oral adminis- treatment with AE and RE (800 mg/kg) had sig- tration of aqueous extract of E. creticum aerial nificant effects on the regeneration of pancreatic parts could reduce blood glucose levels in rats cells in this group in comparison with the dia- with normal blood glucose (20%) and also in betic control group. streptozocin-induced diabetic rats (64.2%). Considering the presence of some effective Moreover, a study reported that the aqueous compounds such as flavonoids, triterpenes, and extract of this herb has a strong hypoglycemic saponins in different parts of this medicinal effect on rats under starch diet [16]. Besides, plant [5], so its beneficial hypoglycemic effects some laboratory studies have previously shown can be attributed to various mechanisms, in- that the methanolic extract of E. creticum has cluding the inhibition of alpha and beta-gluco-

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http://jtim.tums.ac.ir Hypoglycemic effects of Eryngium caeruleum A. Sardarbandeh et al. sidase enzymes as well as antioxidants effects, droalcoholic extract on insulin, serum anti-oxidant enzymes, glucose, and lipid profiles in alloxan-induced diabetic rats. and playing a role in the regeneration of pancre- IJMS 2020;45:199-206. atic cells. [9] Afshari M, Mohammadshahi M, Malayeri A, Zaheri L. An- tidiabetic, Hepato-Protective and Hypolipidemic Effects The results of the present study can be used as of Eryngium caucasicum extract in streptozotocin-nico- a starting point for further usages of different tinamide induced type 2 diabetes in male rats. Iraq Med J 2019;3:2521-8492. parts of this herb in the preparation of food [10] Sadiq A, Rashid U, Ahmad S, Zahoor M, Al Ajmi MF et products as well as the production of herbal me- al. Treating Hyperglycemia From Eryngium caeruleum M. Bieb: in-vitro α-glucosidase, antioxidant, in-vivo antidiabet- dicinal supplements in the future. ic and molecular docking-based approaches. Front Chem 2020;8:558641. [11] Jaghabir M. Hypoglycemic effects of Eryngium creticum. Conflict of Interest Arch Pharm Res 1991;14:295-297. None. [12] Noriega-Cisneros R, Ortiz-Avila O, Esquivel-Gutiérrez E, Clemente-Guerrero M, Manzo-Avalos S et al. Hypolipidem- ic activity of Eryngium carlinae on streptozotocin-induced Acknowledgment diabetic rats. Biochem Res Int 2012;2012. This research has been supported by Interna- [13] Norouzi M, Valipour Chahardah Charic S. The effect of Er- yngium campestre hydroalcoholic extract on glucose and tional Campus, Tehran University of Medical lipid indices of the blood in streptozotocin-induced diabetic Sciences(IC-TUMS), Grant No: 98-01-169- male rats. JAR 2021. In Press. [14] Rehman AU, Hashmi MA, Tehseen Y, Khan A, Khan SS et 41438. al. Antidiabetic flavonol glycosides from Eryngium caeru- leum. Rec Nat Prod 2017;11:229-234. [15] Dehghan H, Sarrafi Y, Salehi P. Antioxidant and antidiabet- References ic activities of 11 herbal from Hyrcania region, Iran. [1] Mathers CD, Loncar D. Projections of global mortality JFDA 2016;24:179-188. and burden of disease from 2002 to 2030. PLoS medicine [16] Kasabri V, Afifi FU, Hamdan I. Evaluation of the acute -an 2006;3:e442. tihyperglycemic effects of four selected indigenous plants [2] Kasper DLFA, Hauser S, Longo D. Harrison's Principles of from Jordan used in traditional medicine. Pharm Biol Internal Medicine. 19th ed. McGraw-Hill Companies. New 2011;49:687-695. York 2015. [17] Bustanji Y, Issa A, Moulay A, Hudaib M, Tawaha K et al. [3] Xu L, Li Y, Dai Y, Peng J. Natural products for the treatment Hormone sensitive lipase inhibition by selected medicinal of type 2 diabetes mellitus: Pharmacology and mechanisms. plants. JMPR 2011;5:4405-4410. Pharmacol Res 2018;130:451-465. [18] Paul JH, Seaforth CE, Tikasingh T. L.: A [4] Ghajarieh Sepanlou M, Salami F, Mirabzadeh Ardakani M, review. Fitoterapia 2011; 82:302-308. Sadati Lamardi SN, Sadrai S et al. The proximate, mineral and amino acid composition of spring, autumn leaves and roots of Eryngium caeruleum M. Bieb. RJP 2019;6:1-7. [5] Sepanlou MG, Ardakani MM, Hajimahmoodi M, Sadrai S, Amin GR et al. Ethnobotanical and traditional uses, phyto- chemical constituents and biological activities of Eryngium species growing in Iran. TMR 2019;4:148. [6] Wang P, Su Z, Yuan W, Deng G, Li S. Phytochemical constit- uents and pharmacological activities of Eryngium L.(Apia- ceae). Pharm Crops 2012;3:99. [7] Kikowska M, Dworacka M, Kędziora I, Thiem B. Eryngium creticum-ethnopharmacology, phytochemistry and pharma- cological activity. A review. Revista Brasileira de Farmacog- nosia 2016;26:392-399. [8] Majidi Z, Sadati Lamardi SN, Mohajjel-Nayebi A, Vatankhah AM, Asnaashari S et al. Effects of persicum hy-

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