The Open Medicinal Chemistry Journal




ISSN: 1874-1045 ― Volume 15, 2021
RESEARCH ARTICLE

Anethum graveolens L‎. Alleviates Sperm ‎Damage by Limiting Oxidative Stress ‎and Insulin ‎Resistance ‎in ‎Diabetic Rats ‎



Ebrahim Abbasi-Oshaghi1, 2, Iraj Khodadadi2, Fatemeh Mirzaei3, Mehrdad Ahmadi1, Heidar Tayebinia2, Mohammad Taghi Goodarzi4, *
1 Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
2 Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
3 Department of Anatomy, Hamadan University of Medical Sciences, Hamadan, Iran
4 Department of Biochemistry, Islamic Azad University, Shahrood Branch, Shahrood, Iran

Abstract

Background:

It has been reported that diabetes is associated with sperm ‎damage and infertility.

Objective:

The purpose of this experiment was to survey the effect of Anethum graveolens L. (Dill) powder on sperm profiles, oxidative stress, insulin resistance, and histological changes in male diabetic rats.

Methods:

Male rats were randomly divided into 6 groups (n=7); group 1: normal rats, 2: normal rats + 100mg/kg Dill, 3: normal rats + 300mg/kg Dill, 4: diabetic rats, 5: diabetic rats + 100mg/kg Dill, and 6: diabetic rats + 300mg/kg Dill. After 2 months of treatments, the sperm profile, anti-oxidant activity, superoxide dismutase (SOD) activity, and malondialdehyde were measured. The histopathology of testis was evaluated. Hormonal changes and tumor necrosis factor-α (TNF-α) levels were measured by ELISA.

Results:

Total anti-oxidant and SOD activity in diabetic rats significantly decreased, while MDA concentration was significantly increased in the testis and pancreas of diabetic rats compared with control. However, the use of Dill significantly normalized these profiles. The treatment of diabetic rats with Dill changed the sperm parameters. The levels of testosterone, FSH, and LH in diabetic rats were significantly reduced, but the treatment with Dill did not alter the level of these hormones. Dill also significantly normalized testis morphological changes, insulin resistance, and inflammation.

Conclusion:

The use of Dill normalized oxidative stress, inflammation, and insulin resistance in diabetic rats that correlated with sperm profile and testis histological changes. The treatment of diabetic rat models with Dill did not show harmful effects on sperm profiles.

Keywords: Dill, Diabetes, Insulin resistance, Herbal medicine, Anti-oxidant, ELISA, Anethum graveolens L.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 35
Last Page: 44
Publisher Id: TOMCJ-14-35
DOI: 10.2174/1874104502014010035

Article History:

Received Date: 14/02/2020
Revision Received Date: 29/05/2020
Acceptance Date: 18/06/2020
Electronic publication date: 31/07/2020
Collection year: 2020

© 2020 Abbasi-Oshaghi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Biochemistry, Islamic Azad University, Shahrood Branch, Shahrood, Iran, E-mail:Mtgoodarzi@yahoo.com





1. INTRODUCTION

Diabetes is a metabolic disorder that is related to a disturbance in carbohydrate, lipid, and protein metabolisms [1Moridi, H.; Karimi, J.; Sheikh, N.; Goodarzi, M. T.; Saidijam, M.; Yadegarazari, R.; Khazaei, M.; Khodadadi, I.; Tavilani, H.; Piri, H. Resveratrol-dependent down-regulation of receptor for advanced glycation end-products and oxidative stress in kidney of rats with diabetes. Int. J. endo. Met, 2015, 13(2)]. Obesity, inactivity, and consumption of high calorie diet significantly raise the prevalence of type 2 diabetes (T2D) worldwide. In this respect, the World Health Organization (WHO) reported that the prevalence of this disorder would reach 552 million by the year 2030 [2Whiting, D.R.; Guariguata, L.; Weil, C.; Shaw, J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract., 2011, 94(3), 311-321.
[http://dx.doi.org/10.1016/j.diabres.2011.10.029] [PMID: 22079683]
]. In diabetes, increasing inflammation and oxidative stress lead to dysfunction of pancreatic β-cells and a decline in insulin secretion [3Amirrasouli, H.; Asefy, Z.; Taghikhani, M. Study of serum cystatin C as a reliable marker for metabolic syndrome. J. Diabetes Metab. Disord., 2011, 10, 6.]. Furthermore, inflammation and oxidative stress are related to all diabetic complications [4Mirzaei, F.; Khazaei, M. Role of nitric oxide in biological systems: a systematic review. Majallah-i Danishgah-i Ulum-i Pizishki-i Mazandaran, 2017, 27(150), 192-222.].

It has been reported that high free radicals and cytokines levels have potentially harmful effects on male fertility by inducing damages in lipids, DNA, testicular cells, and spermatozoa structure [5Fattahi, A.; Latifi, Z.; Ghasemnejad, T.; Nejabati, H.R.; Nouri, M. Insights into in vitro spermatogenesis in mammals: Past, present, future. Mol. Reprod. Dev., 2017, 84(7), 560-575.
[http://dx.doi.org/10.1002/mrd.22819] [PMID: 28436137]
]. Consequently, reducing free radicals and inflammatory factors has a central role in the management of blood glucose, insulin levels, and diabetes complications [3Amirrasouli, H.; Asefy, Z.; Taghikhani, M. Study of serum cystatin C as a reliable marker for metabolic syndrome. J. Diabetes Metab. Disord., 2011, 10, 6., 6Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med., 2011, 50(5), 567-575.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.006] [PMID: 21163346]
, 7Ilghari, D.; Piri, H.; Seyyed, A. F.; Gheibi, N. Expression and purification of the recombinant kinase domain of fgfr2b and study of its structural changes due to the ‎interaction with gallic acid. Mol. Biol. Res. Commun. , 2014, 3, 282.]. In spite of various hypoglycemic medicines, patients tend to use herbal medicine for the treatment of diabetes due to low adverse effects and low cost. About 300 hypoglycemic and anti-oxidant herbal medicines have been recognized for diabetes management [8El-Refaei, M.F.; Abduljawad, S.H.; Alghamdi, A.H. Alternative Medicine in Diabetes - Role of Angiogenesis, Oxidative Stress, and Chronic Inflammation. Rev. Diabet. Stud., 2014, 11(3-4), 231-244.
[http://dx.doi.org/10.1900/RDS.2014.11.231] [PMID: 26177484]
]. One of them is Dill (Anethum graveolens L.), which is a native plant of Asia and Europe. Interestingly, 5000 years ago, this plant was used by Egypt and Roman pharmacologists. Greeks covered their heads with this plant for the treatment of sleep disorders [9Heamalatha, S.; Swarnalatha, S.; Divya, M.; Gandhi Lakshmi, R.; Ganga Devi, A.; Gomathi, E. Pharmacognostical, pharmacological, investigation on Anethum graveolens Linn: A review. Res. J. Pharm. Biol. Chem. Sci., 2011, 2, 564-574.]. Many studies have shown useful effects of Dill on in vitro and in vivo experiments [9Heamalatha, S.; Swarnalatha, S.; Divya, M.; Gandhi Lakshmi, R.; Ganga Devi, A.; Gomathi, E. Pharmacognostical, pharmacological, investigation on Anethum graveolens Linn: A review. Res. J. Pharm. Biol. Chem. Sci., 2011, 2, 564-574.]. Different pharmacological effects of Dill, such as anti-diabetic, anti-secretory, and anti-ulcer activities, anti-hyperlipidemic, anti-hypercholesterolemic, anti-oxidant, anti-spasmodic, anti-microbial, and anti-inflammation have been established [10Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
-14Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
]. Some flavonoids isolated from Dill have potential anti-oxidant effects and could counteract with reactive oxygen species (ROS) and therefore, are capable of preventing diabetic complications [11Jana, S.; Shekhawat, G.S. Anethum graveolens: An Indian traditional medicinal herb and spice. Pharmacogn. Rev., 2010, 4(8), 179-184.
[http://dx.doi.org/10.4103/0973-7847.70915] [PMID: 22228959]
]. Previous phytochemical studies, along with other reports indicated that Dill is a rich source of phenolic components, saponins, tannin, and flavonoids [10Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
-14Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
]. The aim of this study was to evaluate the effects of Dill consumption in testicular and pancreatic oxidative stress, insulin resistance, sperm profile, and hormonal changes in streptozotocin-induced diabetic animals. It was postulated that Dill administration could reduce insulin resistance and oxidative stress in the pancreas and testes of diabetic rats and prevent the harmful effects of diabetes on fertility.

2. METHODS AND MATERIALS

2.1. Animals

In this experiment, 42 adult male Wistar rats weighing about 220 g were adapted to the laboratory environment for one week and randomly divided to 6 groups of 7 rats as: group 1: normal rats, group 2: normal rats + 100mg/kg Dill, group 3: normal rats + 300mg/kg Dill, group 4: diabetic rats, group 5: diabetic rats + 100mg/kg Dill, group 6: diabetic rats + 300mg/kg Dill.

2.2. Induction of Diabetes

T2D was induced in overnight fasted rats using intraperitoneal (IP) injection of streptozotocin (STZ in citrate buffer pH 4.5) at the dose of 60 mg/kg followed by the injection of nicotinamide at the dose of 110 mg/kg after 15 min, to prevent up to 40% β-cells from STZ toxicity and to induce type-2 diabetic models instead of type-1 diabetes [15Masiello, P.; Broca, C.; Gross, R.; Roye, M.; Manteghetti, M.; Hillaire-Buys, D.; Novelli, M.; Ribes, G. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes, 1998, 47(2), 224-229.
[http://dx.doi.org/10.2337/diab.47.2.224] [PMID: 9519717]
]. Blood glucose was measured after 72h and the levels more than 250 mg/dL were considered diabetic [16Javad, H.; Seyed-Mostafa, H.Z.; Farhad, O.; Mehdi, M.; Ebrahim, A.O.; Nader, R.G.; Ramin, G.S.; Behrooz, H. Hepatoprotective effects of hydroalcoholic extract of Allium hirtifolium (Persian shallot) in diabetic rats. J. Basic Clin. Physiol. Pharmacol., 2012, 23(2), 83-87.
[http://dx.doi.org/10.1515/jbcpp-2012-0017] [PMID: 23104823]
].

2.3. Experimental Design

The rats were housed in an animal house with good ventilation and a period of 12-h light/12-h dark cycle with ad libitum access to standard chow diet and water during the experiment.

Two months after the Dill treatment, rats were anesthetized, and blood was taken from the heart of the animals after overnight fasting. Serum samples were prepared and kept at -20°C for biochemical analysis. All treatments were performed daily for eight weeks to evaluate Dill effects.

2.4. Evaluation of Fertility Hormones

The serum levels of Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), and testosterone was measured by the Enzyme-linked Immunosorbant Assay (ELISA)‎ method using the rat commercial enzyme immunoassay kits, according to the manufacturer’s protocols (Zellbio, Germany) [17Tavilani, H.; Setarehbadi, R.; Fattahi, A.; Nasrollahi, S.; Karimi, J.; Shafiee, G.; Hosseinipanah, M. The Relationship between Plasma Antioxidant Enzymes Activity and Sex Hormones during the Menstrual Cycle. Med. Lab. J., 2014, 7(4), 34-40.].

2.5. Sperm Profile

Epididymal spermatozoon was achieved by a puncture of cauda epididymidis with surgical blades in one ml Hams F'10. The sample was then thoroughly mixed to evaluate the progressive motility and viability by microscope within about 2 min of their isolation. The result was expressed as percentages. For determination of sperm count, the caudal epididymis sperm was diluted 10 times in normal saline. The spermatozoa were counted by hemocytometer, according to the previously published method [18Farombi, E.O.; Adedara, I.A.; Abolaji, A.O.; Anamelechi, J.P.; Sangodele, J.O. Sperm characteristics, antioxidant status and hormonal profile in rats treated with artemisinin. Andrologia, 2014, 46(8), 893-901.
[http://dx.doi.org/10.1111/and.12170] [PMID: 24079412]
]. The smear of the sperm suspension also was used for morphological evaluation and viability tests according to the previous method [18Farombi, E.O.; Adedara, I.A.; Abolaji, A.O.; Anamelechi, J.P.; Sangodele, J.O. Sperm characteristics, antioxidant status and hormonal profile in rats treated with artemisinin. Andrologia, 2014, 46(8), 893-901.
[http://dx.doi.org/10.1111/and.12170] [PMID: 24079412]
].

2.6. Anti-oxidant Activity

Total Anti-oxidant Capacity (TAC) in seminal plasma was determined according to Ferric reducing Anti-oxidant Power (FRAP) assay using small modifications [19Haghdoost-Yazdi, H.; Piri, H.; Faraji, A.; Fraidouni, N.; Dargahi, T.; Mahmudi, M.; Alipour Heidari, M. Pretreatment with potassium channel blockers of 4-aminopyridine and tetraethylammonium attenuates behavioural symptoms of Parkinsonism induced by intrastriatal injection of 6-hydroxydopamine; the role of lipid peroxidation. Neurol. Res., 2016, 38(4), 294-300.
[http://dx.doi.org/10.1080/01616412.2015.1114290] [PMID: 27098232]
]. Briefly, ferric tripyridyltriazine (Fe3+-TPTZ) complex was reduced to ferrous form (Fe2+-TPTZ) by the anti-oxidants in the sample at acidic pH [20Bahabadi, M.; Mohammadalipour, A.; Karimi, J.; Sheikh, N.; Solgi, G.; Goudarzi, F.; Hashemnia, M.; Khodadadi, I. Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease. Immunopharmacol. Immunotoxicol., 2017, 39(4), 233-242.
[http://dx.doi.org/10.1080/08923973.2017.1327965] [PMID: 28555525]
, 21Sharifi, S.; Mohseni, R.; Amiri, I.; Tavilani, H. Sperm matrix metalloproteinase-2 activity increased in pregnant couples treated with intrauterine insemination: a prospective case control study. J. Obstet. Gynaecol., 2019, 39(5), 675-680.
[http://dx.doi.org/10.1080/01443615.2018.1558189] [PMID: 30917742]
]. FeSO4, at the 100-1000 μmol/L concentration, was used as a standard and the results were calculated as μmol/L of FeSO4. The levels of Malondialdehyde (MDA) in seminal plasma and pancreas homogenate were determined by a colorimetric method based on Thiobarbituric Acid Reactive Substances (TBARS), as previously described [22Ravan, A.P.; Bahmani, M.; Ghasemi Basir, H.R.; Salehi, I.; Oshaghi, E.A. Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats. J. Basic Clin. Physiol. Pharmacol., 2017, 28(5), 463-471.
[http://dx.doi.org/10.1515/jbcpp-2016-0181] [PMID: 28467312]
, 23Abbasi-Oshaghi, E.; Mirzaei, F.; Pourjafar, M. NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study. Int. J. Nanomedicine, 2019, 14, 1919-1936.
[http://dx.doi.org/10.2147/IJN.S192382] [PMID: 30936694]
]. The SOD activity in seminal plasma and pancreas homogenate was determined using a commercial kit, according to the manufacturer's instructions (ZellBio, Germany) [24Abbasi-Oshaghi, E.; Mirzaei, F.; Mirzaei, A. Effects of ZnO nanoparticles on intestinal function and structure in normal/high fat diet-fed rats and Caco-2 cells. Nanomedicine (Lond.), 2018, 13(21), 2791-2816.
[http://dx.doi.org/10.2217/nnm-2018-0202] [PMID: 30394178]
].

2.7. TNF-α Cytokine Assay

The inflammatory marker TNF-α was determined in serum by commercial kit using the ELISA method (BioLegend, UK) following the manufacturer's protocol [25Mohammadalipour, A.; Karimi, J.; Khodadadi, I.; Solgi, G.; Hashemnia, M.; Sheikh, N.; Bahabadi, M. Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism. Immunopharmacol. Immunotoxicol., 2017, 39(1), 19-27.
[http://dx.doi.org/10.1080/08923973.2016.1263860] [PMID: 27908221]
].

2.8. Insulin Resistance

Fasting blood glucose and serum insulin were measured in order to calculate the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Fasting blood glucose concentration was determined enzymatically by the glucose oxidase method using a commercial kit (Pars Azmun, Iran). Blood insulin levels were determined by the ELISA method using the kits purchased from Biocompare Co. with a detection limit of 28pg/mL. The HOMA-IR was calculated by the following formula: HOMA-IR = serum insulin (mmol/L)× blood glucose (mmol/L)/22.5.

2.9. Histopathology

One of the testes and a small part of the pancreas were removed, washed with PBS, and then fixed in 10% formalin solution. After the dehydration process, the testes and pancreas were blocked in paraffin, sections of 5µm were prepared, and stained with hematoxylin and eosin (H & E) and slides were examined under a light microscope [24Abbasi-Oshaghi, E.; Mirzaei, F.; Mirzaei, A. Effects of ZnO nanoparticles on intestinal function and structure in normal/high fat diet-fed rats and Caco-2 cells. Nanomedicine (Lond.), 2018, 13(21), 2791-2816.
[http://dx.doi.org/10.2217/nnm-2018-0202] [PMID: 30394178]
, 26Karimi, J.; Mohammadalipour, A.; Sheikh, N.; Khodadadi, I.; Hashemnia, M.; Goudarzi, F.; Khanjarsim, V.; Solgi, G.; Hajilooi, M.; Bahabadi, M.; Kheiripour, N.; Hedayatyanfard, K. Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Drug Chem. Toxicol., 2018, 1-11.
[http://dx.doi.org/10.1080/01480545.2018.1504960] [PMID: 30207194]
].

2.10. Statistical Analysis

Data are expressed as mean ± SD and statistical analysis was performed using a one-way analysis of variance, followed by Tukey test to compare the factors in various groups. The results were considered significant at P < 0.05.

3. RESULTS

3.1. Hormonal Profile

The findings showed that luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone significantly reduced in diabetic rats compared with the control group (p<0.05). Treatment with Dill had no significant effect on LH, FSH, and testosterone and estradiol levels of rats in the various treatment groups (Fig.1). However, treatment of normal rat with Dill significantly reduced testosterone levels as compared to untreated control animals.

3.2. Semen Analysis

Abnormal morphology, viability, motility, and count of sperms markedly reduced in diabetic animals in comparison with those of control rats (p<0.05); whereas, the administration of Dill significantly normalized these profiles compared to diabetic rats (p<0.05, Table 1).

3.3. Cytokine Assay

A significant rise in serum TNF-α was observed in the T2D rats compared with normal animals. Nevertheless, oral administration of Dill to T2D rats significantly decreased (p<0.05) TNF-α level when compared with untreated diabetic rats (Fig. 2).

3.4. Anti-oxidant Capacity and Malondialdehyde (MDA) Levels

TAC in the seminal plasma and pancreas of treated groups were significantly reduced in T2D animals compared to healthy group (P<0.05). Treatment of T2D animals with Dill markedly increased TAC levels compared with untreated diabetic rats (P<0.05). Compared with normal rat, SOD activity was significantly lower in T2D rats (P<0.05). Treatment of diabetic rats with Dill increased the SOD activity when compared with diabetic group (Fig. 3).

T2D animals showed significantly higher MDA levels compared with the normal control group (p <0.05). After 2 months of treatment of T2D animals with Dill, the MDA levels significantly decreased compared to diabetic control (Fig. 4).

3.5. Serum Levels of Glucose, Insulin, and HOMA-IR

Serum insulin and glucose concentration were markedly higher in diabetic rats compared to normal rats (P<0.05). The treatment with Dill normalized insulin and glucose concentration. HOMA-IR was found markedly higher in the T2D animals comparing to normal rat; nevertheless, it was completely normalized after treatment of the rats with Dill (Fig. 5).

3.6. Histological Results

Fig. (4) displays histological changes in testis in different groups. Significant histological changes were observed in diabetic rats and in rats treated with Dill. Diabetic rats showed a significant decline in the diameter of the tubules and their epithelial heights concurrent with irregular seminiferous tubules, intertubular hemorrhage, and cytoplasmic vacuolization. These changes were significantly reduced in treated animals. Testicular tissues in treated animals exhibited marked raise in the spermatogenic activity. As illustrated in Fig. (4), most of the seminiferous tubules were repaired to the normal structure in Dill groups (Fig. 6).

4. DISCUSSION

It has been reported that diabetes is accompanied by augmented levels of apoptosis of germ cells in testes and disturbance of spermatogenesis [27Ricci, G.; Catizone, A.; Esposito, R.; Pisanti, F.A.; Vietri, M.T.; Galdieri, M. Diabetic rat testes: morphological and functional alterations. Andrologia, 2009, 41(6), 361-368.
[http://dx.doi.org/10.1111/j.1439-0272.2009.00937.x] [PMID: 19891634]
, 28Nejabati, H.R.; Mota, A.; Farzadi, L.; Ghojazadeh, M.; Fattahi, A.; Hamdi, K.; Nouri, M. Follicular fluid PlGF/sFlt-1 ratio and soluble receptor for advanced glycation end-products correlate with ovarian sensitivity index in women undergoing A.R.T. J. Endocrinol. Invest., 2017, 40(2), 207-215.
[http://dx.doi.org/10.1007/s40618-016-0550-5] [PMID: 27664102]
], which are associated with hormonal alterations, oxidative stress and hyperglycemia [29Mansour, R.; El-Faissal, Y.; Kamel, A.; Kamal, O.; Aboulserour, G.; Aboulghar, M.; Fahmy, I. Increased insulin resistance in men with unexplained infertility. Reprod. Biomed. Online, 2017, 35(5), 571-575.
[http://dx.doi.org/10.1016/j.rbmo.2017.08.020] [PMID: 28888863]
]. Diabetic subjects have reduced anti-oxidant capacity and/or raised oxidative damage in different tissues. High blood glucose in diabetes leads to oxidative stress because of increased ROS generation [6Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med., 2011, 50(5), 567-575.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.006] [PMID: 21163346]
]. In this context, it is vital to find potential agents that scavenge free radicals and prevent the onset and/or development of diabetes or other diseases [30Mohseni, R.; Karimi, J.; Tavilani, H.; Khodadadi, I.; Hashemnia, M. Carvacrol Downregulates Lysyl Oxidase Expression and Ameliorates Oxidative Stress in the Liver of Rats with Carbon Tetrachloride-Induced Liver Fibrosis. Indian J. Clin. Biochem., 2019, 1-7.
[http://dx.doi.org/10.1007/s12291-019-00845-w]
-34Fattahi, A.; Darabi, M.; Farzadi, L.; Salmassi, A.; Latifi, Z.; Mehdizadeh, A.; Shaaker, M.; Ghasemnejad, T.; Roshangar, L.; Nouri, M. Effects of dietary omega-3 and -6 supplementations on phospholipid fatty acid composition in mice uterus during window of pre-implantation. Theriogenology, 2018, 108, 97-102.
[http://dx.doi.org/10.1016/j.theriogenology.2017.10.031] [PMID: 29207295]
]. Dill has been established to have a variety of beneficial effects in diabetes [10Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
]. In the recent experiments, Dill showed hypolipidemic and strong anti-oxidant properties [12Oshaghi, E.A.; Khodadadi, I.; Mirzaei, F.; Khazaei, M.; Tavilani, H.; Goodarzi, M.T. Methanolic Extract of Dill Leaves Inhibits AGEs Formation and Shows Potential Hepatoprotective Effects in CCl4 Induced Liver Toxicity in Rat. J. Pharm. (Cairo), 2017, 20176081374
[http://dx.doi.org/10.1155/2017/6081374] [PMID: 28182107]
, 14Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
, 35Abbasi Oshaghi, E.; Khodadadi, I.; Saidijam, M.; Yadegarazari, R.; Shabab, N.; Tavilani, H.; Goodarzi, M.T. Lipid Lowering Effects of Hydroalcoholic Extract of Anethum graveolens L. and Dill Tablet in High Cholesterol Fed Hamsters. Cholesterol, 2015, 2015958560
[http://dx.doi.org/10.1155/2015/958560] [PMID: 26823981]
]. Here Dill showed increased sperm quality and testis morphological change that was related to insulin sensitivity in diabetic animals. Herein, we studied the useful properties of Dill administration in T2D rats.

Table 1
Semen profiles in different animal groups.


Fig.(1)
Effect of Dill on testosterone (A) luteinizing hormone (LH) (B), and follicle stimulating hormone (FSH) (C) levels in treated animals. Data are expressed as mean ± SEM. ###P<0.001, ##P<0.01 and #P<0.05 compared with the normal control animals and ***P<0.001, **P<0.01 and *P<0.05 compared with diabetic group.


Fig.(2)
Effect of Dill on Tumor necrosis factor alpha (TNFα) level in treated animals. Data are presented as mean ± SEM. ###P<0.001, ##P<0.01 and #P<0.05 compared with the normal control animals and ***P<0.001, **P<0.01 and *P<0.05 compared with diabetic group.


Fig.(3)
Effect of Dill on malondialdehyde (MDA) level in seminal plasma (A) and pancreas (B). Data are expressed as mean ± SEM. ###P<0.001, ##P<0.01 and #P<0.05 compared with the normal control animals and ***P<0.001, **P<0.01 and *P<0.05 compared with diabetic group.


Fig. (4)
Effect of Dill on total anti-oxidant capacity (TAC) in seminal plasma (A) and pancreas (B). Data are expressed as mean ± SEM. ###P<0.001, ##P<0.01 and #P<0.05 compared with the normal control animals and ***P<0.001, **P<0.01 and *P<0.05 compared with diabetic group.


In this experiment, Dill treated animals showed reduced blood glucose levels and improved insulin resistance. In line with this study, various experiments established that Dill or its main constituents normalized hyperglycemia. Dill phytochemicals, such as quercetin, limonene, α-pinene, and isoliquiritigenin, ameliorate hyperglycemia by enhancing insulin action and anti-oxidant activity. Several experiments have reported that these agents declined blood glucose, triglycerides, cholesterol, HOMA-IR, inflammation, and oxidative stress [10Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
-14Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
]. Hence, it is suggested that an anti-hyperglycemic property of Dill is due to reducing insulin resistance and improving anti-oxidant capacity, mainly because of its high concentration of quercetin, limonene, α-pinene, and isoliquiritigenin. Various experiments showed that quercetin and limonene normalized β-cells structure and insulin secretion [10Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
-14Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
]. Quercetin content of Dill may attribute to protective and regenerative effects in β-cells. Quercetin administration also increases sperm motility and viability [36Kanter, M.; Aktas, C.; Erboga, M. Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis. Food Chem. Toxicol., 2012, 50(3-4), 719-725.
[http://dx.doi.org/10.1016/j.fct.2011.11.051] [PMID: 22166789]
]. In Dill treated animals, the morphological changes of β-cells significantly normalized in diabetic rats. Dill also increased TAC, SOD activity and reduced MDA levels in the pancreas. In this study, Dill also ameliorated HOMA-IR in T2D rats. Notably, insulin resistance is of extreme importance in spermatogenesis since insulin controls the metabolic co-operation between testis and its need for normal testicular action [29Mansour, R.; El-Faissal, Y.; Kamel, A.; Kamal, O.; Aboulserour, G.; Aboulghar, M.; Fahmy, I. Increased insulin resistance in men with unexplained infertility. Reprod. Biomed. Online, 2017, 35(5), 571-575.
[http://dx.doi.org/10.1016/j.rbmo.2017.08.020] [PMID: 28888863]
].

The authors of this study showed that Dill increases total anti-oxidant in seminal plasma. High levels of testicular oxidative stress have harmful effects on male fertility [37Adewoyin, M.; Ibrahim, M.; Roszaman, R.; Isa, M.L.M.; Alewi, N.A.M.; Rafa, A.A.A.; Anuar, M.N.N. Male Infertility: The Effect of Natural Antioxidants and Phytocompounds on Seminal Oxidative Stress. Diseases, 2017, 5(1)E9
[http://dx.doi.org/10.3390/diseases5010009] [PMID: 28933362]
]. Elevated oxidative stress in diabetes is accompanied by DNA damage causing infertility in animal models. Oxidative stress can also lead to damage to testicular lipids and proteins and especially spermatozoa. Previous studies showed that diabetes is associated with high oxidative stress-derived damage [6Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med., 2011, 50(5), 567-575.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.006] [PMID: 21163346]
, 38Shi, G.J.; Li, Z.M.; Zheng, J.; Chen, J.; Han, X.X.; Wu, J.; Li, G.Y.; Chang, Q.; Li, Y.X.; Yu, J.Q. Diabetes associated with male reproductive system damages: Onset of presentation, pathophysiological mechanisms and drug intervention. Biomed. Pharmacother., 2017, 90, 562-574.
[http://dx.doi.org/10.1016/j.biopha.2017.03.074] [PMID: 28407577]
], and consequently reduced testicular anti-oxidant capacity [38Shi, G.J.; Li, Z.M.; Zheng, J.; Chen, J.; Han, X.X.; Wu, J.; Li, G.Y.; Chang, Q.; Li, Y.X.; Yu, J.Q. Diabetes associated with male reproductive system damages: Onset of presentation, pathophysiological mechanisms and drug intervention. Biomed. Pharmacother., 2017, 90, 562-574.
[http://dx.doi.org/10.1016/j.biopha.2017.03.074] [PMID: 28407577]
]; while, treatment of diabetic animals with Dill normalized anti-oxidant activity in testis tissue. In oxidative stress, the membrane lipids are oxidized and MDA (the end-product of lipid peroxidation) is increased that is determined by the TBARS assay [39Mazloomi, S.; Alimohammadi, S.; Khodadadi, I.; Ghiasvand, T.; Shafiee, G. Evaluation of methylenetetrahydrofolate reductase (MTHFR) activity and the levels of homocysteine and malondialdehyde (MDA) in the serum of women with preeclampsia. Clin. Exp. Hypertens., 2020, 42(7), 590-594.
[http://dx.doi.org/10.1080/10641963.2020.1739700] [PMID: 32174183]
]. MDA formation has vigorous harmful effects on male fertility which is caused by oxidative stress in diabetes. In this experiment, testicular MDA levels significantly increased in T2D animals; while, treatment with Dill markedly reduced MDA in T2D animals to their normal levels. SOD is known as a main anti-oxidant defense in the different tissue and its activity in seminal plasma correlates with sperm quality [40Ghiasvand, T.; Goodarzi, M.T.; Shafiee, G.; Zamani, A.; Karimi, J.; Ghorbani, M.; Amiri, I. Association between seminal plasma neopterin and oxidative stress in male infertility: A case-control study. Int. J. Reprod. Biomed. (Yazd), 2018, 16(2), 93-100.
[http://dx.doi.org/10.29252/ijrm.16.2.93] [PMID: 29675493]
]. In this study, SOD activity significantly increased in the testis and pancreas of Dill treated group. Furthermore, sperm count, sperm viability, and motility significantly reduced in diabetic animals. Whereas, these factors were normalized in T2D animals treated with Dill. A large number of studies have established that sperm quality is significantly reduced in diabetes in comparison with controls [27Ricci, G.; Catizone, A.; Esposito, R.; Pisanti, F.A.; Vietri, M.T.; Galdieri, M. Diabetic rat testes: morphological and functional alterations. Andrologia, 2009, 41(6), 361-368.
[http://dx.doi.org/10.1111/j.1439-0272.2009.00937.x] [PMID: 19891634]
]. This plant ameliorates sperm count, viability, and motility chiefly by inhibiting oxidative stress and insulin resistance. Monsefi et al. [41Monsefi, M.; Zahmati, M.; Masoudi, M.; Javidnia, K. Effects of Anethum graveolens L. on fertility in male rats. Eur. J. Contracept. Reprod. Health Care, 2011, 16(6), 488-497.
[http://dx.doi.org/10.3109/13625187.2011.622815] [PMID: 22066892]
] reported that administration of the aqueous and ethanol extracts of Dill seed in normal Wistar rats (0.5 and 5 g/kg) could not change sperm count, sperm motility or testosterone levels. However, in this experiment, dill tablets were used to treat diabetic animals, which contains dill (68%), Cichorium intybus (5%), Fumaria parviflora (5%), and Citrus aurantifolia (4%) [42Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Effect of dill tablet (Anethum graveolens L) on antioxidant status and biochemical factors on carbon tetrachloride-induced liver damage on rat. Int. J. Appl. Basic Med. Res., 2016, 6(2), 111-114.
[http://dx.doi.org/10.4103/2229-516X.179019] [PMID: 27127740]
]. The results of Iamsaard et al. [43Iamsaard, S.; Prabsattroo, T.; Sukhorum, W.; Muchimapura, S.; Srisaard, P.; Uabundit, N.; Thukhammee, W.; Wattanathorn, J. Anethum graveolens Linn. (dill) extract enhances the mounting frequency and level of testicular tyrosine protein phosphorylation in rats. J. Zhejiang Univ. Sci. B, 2013, 14(3), 247-252.
[http://dx.doi.org/10.1631/jzus.B1200287] [PMID: 23463768]
] showed that Dill extract increased protein phosphorylation in testis, proposing that Dill may motivate tyrosine phosphorylation of testicular proteins involved in spermatogenesis. They also showed that Dill extract has no effects on sperm physiology, particularly acrosome exocytosis, indicating that Dill is harmless to sperm profile. In this study, the levels of testosterone, LH, and FSH in diabetic animals significantly reduced compared with the normal control group. However, these hormonal changes in Dill treated groups were not statistically significant. On the other hand, testosterone levels significantly reduced in control groups. In diabetic animals, a declined pituitary response to gonadotropin-releasing hormone (GnRH) has been reported in diabetes [44Seethalakshmi, L.; Menon, M.; Diamond, D. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat. J. Urol., 1987, 138(1), 190-194.
[http://dx.doi.org/10.1016/S0022-5347(17)43042-4] [PMID: 3599211]
]. Dill reduced serum TNF-α level in diabetic animals. TNF-α has a main role in the impairment of the insulin signaling cascade and leads to insulin resistance [45Krogh-Madsen, R.; Plomgaard, P.; Møller, K.; Mittendorfer, B.; Pedersen, B.K. Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am. J. Physiol. Endocrinol. Metab., 2006, 291(1), E108-E114.
[http://dx.doi.org/10.1152/ajpendo.00471.2005] [PMID: 16464907]
]. This marker also significantly reduced sperm function [46Micu, M.C.; Micu, R.; Surd, S.; Gîrlovanu, M.; Bolboacă, S.D.; Ostensen, M. TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology (Oxford), 2014, 53(7), 1250-1255.
[http://dx.doi.org/10.1093/rheumatology/keu007] [PMID: 24599921]
].

Fig(5)
Effect of Dill on fasting glucose (A), insulin (B) and homeostasis model assessment of insulin resistance (HOMA-IR) (C). Data are expressed as mean ± SEM. ###P<0.001, ##P<0.01 and #P<0.05 compared with the normal control animals and ***P<0.001, **P<0.01 and *P<0.05 compared with diabetic group.


Fig.(6)
Testis histological changes in different groups. Diabetic animals showed significant decline in the diameter of the tubules and their epithelial heights, irregular seminiferous tubules and cytoplasmic vacuolization. These changes were restored by Dill (300 mg/kg body weight) (magnification 400×).


Diabetic animal models showed apoptosis in the testicular germ cell, abnormal spermatozoa, and low testosterone concentration [27Ricci, G.; Catizone, A.; Esposito, R.; Pisanti, F.A.; Vietri, M.T.; Galdieri, M. Diabetic rat testes: morphological and functional alterations. Andrologia, 2009, 41(6), 361-368.
[http://dx.doi.org/10.1111/j.1439-0272.2009.00937.x] [PMID: 19891634]
]. In this study, testis tissue of diabetic animals showed irregular seminiferous tubules, intertubular hemorrhage, maturation arrest, and giant cell formation, and many of the spermatogonia displayed cytoplasmic vacuolization. In diabetic rats, the spermatogenic cells are also degenerated and exfoliated in the lumen of the tubules. These changes observed in diabetic rats were significantly normalized after 2 months of treatment with Dill. The augmented anti-oxidant capacity and reduced total oxidant and MDA levels were observed; also, unpleasant morphological changes were ameliorated in treated groups. In fact, it can be concluded that the increased oxidative environment in the testis of diabetic rats causes cellular damage.

CONCLUSION

Dill alleviated oxidative stress, insulin resistance, and improved sperm profile in diabetic rats. Therefore, Dill, which is used as a hypolipidemic agent, may show beneficial effects on sperm profile by reducing inflammatory markers, scavenging free radicals, and mitigating insulin resistance.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All experiments were carried out according to the animal ethical committee of Hamadan University of Medical Sciences, Hamadan, Iran (ethical code: IR. UMSHA.REC.1394.578). All process of this experiment was done in accordance with the principles expressed in the Declaration of Helsinki.

HUMAN AND ANIMAL RIGHTS

Humans did not participate in this research.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

This work was supported by a Hamadan University of Medical Sciences grant (Project number: ‎9503251543‎).

REFERENCES

[1] Moridi, H.; Karimi, J.; Sheikh, N.; Goodarzi, M. T.; Saidijam, M.; Yadegarazari, R.; Khazaei, M.; Khodadadi, I.; Tavilani, H.; Piri, H. Resveratrol-dependent down-regulation of receptor for advanced glycation end-products and oxidative stress in kidney of rats with diabetes. Int. J. endo. Met, 2015, 13(2)
[2] Whiting, D.R.; Guariguata, L.; Weil, C.; Shaw, J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract., 2011, 94(3), 311-321.
[http://dx.doi.org/10.1016/j.diabres.2011.10.029] [PMID: 22079683]
[3] Amirrasouli, H.; Asefy, Z.; Taghikhani, M. Study of serum cystatin C as a reliable marker for metabolic syndrome. J. Diabetes Metab. Disord., 2011, 10, 6.
[4] Mirzaei, F.; Khazaei, M. Role of nitric oxide in biological systems: a systematic review. Majallah-i Danishgah-i Ulum-i Pizishki-i Mazandaran, 2017, 27(150), 192-222.
[5] Fattahi, A.; Latifi, Z.; Ghasemnejad, T.; Nejabati, H.R.; Nouri, M. Insights into in vitro spermatogenesis in mammals: Past, present, future. Mol. Reprod. Dev., 2017, 84(7), 560-575.
[http://dx.doi.org/10.1002/mrd.22819] [PMID: 28436137]
[6] Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med., 2011, 50(5), 567-575.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.006] [PMID: 21163346]
[7] Ilghari, D.; Piri, H.; Seyyed, A. F.; Gheibi, N. Expression and purification of the recombinant kinase domain of fgfr2b and study of its structural changes due to the ‎interaction with gallic acid. Mol. Biol. Res. Commun. , 2014, 3, 282.
[8] El-Refaei, M.F.; Abduljawad, S.H.; Alghamdi, A.H. Alternative Medicine in Diabetes - Role of Angiogenesis, Oxidative Stress, and Chronic Inflammation. Rev. Diabet. Stud., 2014, 11(3-4), 231-244.
[http://dx.doi.org/10.1900/RDS.2014.11.231] [PMID: 26177484]
[9] Heamalatha, S.; Swarnalatha, S.; Divya, M.; Gandhi Lakshmi, R.; Ganga Devi, A.; Gomathi, E. Pharmacognostical, pharmacological, investigation on Anethum graveolens Linn: A review. Res. J. Pharm. Biol. Chem. Sci., 2011, 2, 564-574.
[10] Goodarzi, M.T.; Khodadadi, I.; Tavilani, H.; Abbasi Oshaghi, E. The Role of Anethum graveolens L. (Dill) in the Management of Diabetes. J. Trop. Med., 2016, 20161098916
[http://dx.doi.org/10.1155/2016/1098916] [PMID: 27829842]
[11] Jana, S.; Shekhawat, G.S. Anethum graveolens: An Indian traditional medicinal herb and spice. Pharmacogn. Rev., 2010, 4(8), 179-184.
[http://dx.doi.org/10.4103/0973-7847.70915] [PMID: 22228959]
[12] Oshaghi, E.A.; Khodadadi, I.; Mirzaei, F.; Khazaei, M.; Tavilani, H.; Goodarzi, M.T. Methanolic Extract of Dill Leaves Inhibits AGEs Formation and Shows Potential Hepatoprotective Effects in CCl4 Induced Liver Toxicity in Rat. J. Pharm. (Cairo), 2017, 20176081374
[http://dx.doi.org/10.1155/2017/6081374] [PMID: 28182107]
[13] Hajhashemi, V.; Abbasi, N. Hypolipidemic activity of Anethum graveolens in rats. Phytother. Res., 2008, 22(3), 372-375.
[http://dx.doi.org/10.1002/ptr.2329] [PMID: 18058989]
[14] Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Aqueous Extract of Anethum Graveolens L. has Potential Antioxidant and Antiglycation Effects. Iran. J. Med. Sci., 2016, 41(4), 328-333.
[PMID: 27365555]
[15] Masiello, P.; Broca, C.; Gross, R.; Roye, M.; Manteghetti, M.; Hillaire-Buys, D.; Novelli, M.; Ribes, G. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes, 1998, 47(2), 224-229.
[http://dx.doi.org/10.2337/diab.47.2.224] [PMID: 9519717]
[16] Javad, H.; Seyed-Mostafa, H.Z.; Farhad, O.; Mehdi, M.; Ebrahim, A.O.; Nader, R.G.; Ramin, G.S.; Behrooz, H. Hepatoprotective effects of hydroalcoholic extract of Allium hirtifolium (Persian shallot) in diabetic rats. J. Basic Clin. Physiol. Pharmacol., 2012, 23(2), 83-87.
[http://dx.doi.org/10.1515/jbcpp-2012-0017] [PMID: 23104823]
[17] Tavilani, H.; Setarehbadi, R.; Fattahi, A.; Nasrollahi, S.; Karimi, J.; Shafiee, G.; Hosseinipanah, M. The Relationship between Plasma Antioxidant Enzymes Activity and Sex Hormones during the Menstrual Cycle. Med. Lab. J., 2014, 7(4), 34-40.
[18] Farombi, E.O.; Adedara, I.A.; Abolaji, A.O.; Anamelechi, J.P.; Sangodele, J.O. Sperm characteristics, antioxidant status and hormonal profile in rats treated with artemisinin. Andrologia, 2014, 46(8), 893-901.
[http://dx.doi.org/10.1111/and.12170] [PMID: 24079412]
[19] Haghdoost-Yazdi, H.; Piri, H.; Faraji, A.; Fraidouni, N.; Dargahi, T.; Mahmudi, M.; Alipour Heidari, M. Pretreatment with potassium channel blockers of 4-aminopyridine and tetraethylammonium attenuates behavioural symptoms of Parkinsonism induced by intrastriatal injection of 6-hydroxydopamine; the role of lipid peroxidation. Neurol. Res., 2016, 38(4), 294-300.
[http://dx.doi.org/10.1080/01616412.2015.1114290] [PMID: 27098232]
[20] Bahabadi, M.; Mohammadalipour, A.; Karimi, J.; Sheikh, N.; Solgi, G.; Goudarzi, F.; Hashemnia, M.; Khodadadi, I. Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease. Immunopharmacol. Immunotoxicol., 2017, 39(4), 233-242.
[http://dx.doi.org/10.1080/08923973.2017.1327965] [PMID: 28555525]
[21] Sharifi, S.; Mohseni, R.; Amiri, I.; Tavilani, H. Sperm matrix metalloproteinase-2 activity increased in pregnant couples treated with intrauterine insemination: a prospective case control study. J. Obstet. Gynaecol., 2019, 39(5), 675-680.
[http://dx.doi.org/10.1080/01443615.2018.1558189] [PMID: 30917742]
[22] Ravan, A.P.; Bahmani, M.; Ghasemi Basir, H.R.; Salehi, I.; Oshaghi, E.A. Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats. J. Basic Clin. Physiol. Pharmacol., 2017, 28(5), 463-471.
[http://dx.doi.org/10.1515/jbcpp-2016-0181] [PMID: 28467312]
[23] Abbasi-Oshaghi, E.; Mirzaei, F.; Pourjafar, M. NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study. Int. J. Nanomedicine, 2019, 14, 1919-1936.
[http://dx.doi.org/10.2147/IJN.S192382] [PMID: 30936694]
[24] Abbasi-Oshaghi, E.; Mirzaei, F.; Mirzaei, A. Effects of ZnO nanoparticles on intestinal function and structure in normal/high fat diet-fed rats and Caco-2 cells. Nanomedicine (Lond.), 2018, 13(21), 2791-2816.
[http://dx.doi.org/10.2217/nnm-2018-0202] [PMID: 30394178]
[25] Mohammadalipour, A.; Karimi, J.; Khodadadi, I.; Solgi, G.; Hashemnia, M.; Sheikh, N.; Bahabadi, M. Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism. Immunopharmacol. Immunotoxicol., 2017, 39(1), 19-27.
[http://dx.doi.org/10.1080/08923973.2016.1263860] [PMID: 27908221]
[26] Karimi, J.; Mohammadalipour, A.; Sheikh, N.; Khodadadi, I.; Hashemnia, M.; Goudarzi, F.; Khanjarsim, V.; Solgi, G.; Hajilooi, M.; Bahabadi, M.; Kheiripour, N.; Hedayatyanfard, K. Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Drug Chem. Toxicol., 2018, 1-11.
[http://dx.doi.org/10.1080/01480545.2018.1504960] [PMID: 30207194]
[27] Ricci, G.; Catizone, A.; Esposito, R.; Pisanti, F.A.; Vietri, M.T.; Galdieri, M. Diabetic rat testes: morphological and functional alterations. Andrologia, 2009, 41(6), 361-368.
[http://dx.doi.org/10.1111/j.1439-0272.2009.00937.x] [PMID: 19891634]
[28] Nejabati, H.R.; Mota, A.; Farzadi, L.; Ghojazadeh, M.; Fattahi, A.; Hamdi, K.; Nouri, M. Follicular fluid PlGF/sFlt-1 ratio and soluble receptor for advanced glycation end-products correlate with ovarian sensitivity index in women undergoing A.R.T. J. Endocrinol. Invest., 2017, 40(2), 207-215.
[http://dx.doi.org/10.1007/s40618-016-0550-5] [PMID: 27664102]
[29] Mansour, R.; El-Faissal, Y.; Kamel, A.; Kamal, O.; Aboulserour, G.; Aboulghar, M.; Fahmy, I. Increased insulin resistance in men with unexplained infertility. Reprod. Biomed. Online, 2017, 35(5), 571-575.
[http://dx.doi.org/10.1016/j.rbmo.2017.08.020] [PMID: 28888863]
[30] Mohseni, R.; Karimi, J.; Tavilani, H.; Khodadadi, I.; Hashemnia, M. Carvacrol Downregulates Lysyl Oxidase Expression and Ameliorates Oxidative Stress in the Liver of Rats with Carbon Tetrachloride-Induced Liver Fibrosis. Indian J. Clin. Biochem., 2019, 1-7.
[http://dx.doi.org/10.1007/s12291-019-00845-w]
[31] Mohseni, R.; Arab Sadeghabadi, Z.; Goodarzi, M.T.; Karimi, J. Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl4-induced liver fibrosis in rats. Immunopharmacol. Immunotoxicol., 2019, 41(6), 644-651.
[http://dx.doi.org/10.1080/08923973.2019.1688829] [PMID: 31724452]
[32] Piri, H.; Seyyed-Attaran, F.; Gheibi, N.; Najafipour, R.; Sirati-Sabet, M.; Asl-Fallah, S.; Ilghari, D. Structural Characterization of the Recombinant Human Fibroblast Growth Factor Receptor 2b Kinase Domain Upon Interaction with Flavonoids. Jundishapur J. Nat. Pharm. Prod., 2018, 14(2)
[http://dx.doi.org/10.5812/jjnpp.12499]
[33] Ghorbani, M.; Amiri, I.; Khodadadi, I.; Fattahi, A.; Atabakhsh, M.; Tavilani, H. Influence of BHT inclusion on post-thaw attributes of human semen. Syst Biol Reprod Med, 2015, 61(1), 57-61.
[http://dx.doi.org/10.3109/19396368.2014.968267] [PMID: 25285571]
[34] Fattahi, A.; Darabi, M.; Farzadi, L.; Salmassi, A.; Latifi, Z.; Mehdizadeh, A.; Shaaker, M.; Ghasemnejad, T.; Roshangar, L.; Nouri, M. Effects of dietary omega-3 and -6 supplementations on phospholipid fatty acid composition in mice uterus during window of pre-implantation. Theriogenology, 2018, 108, 97-102.
[http://dx.doi.org/10.1016/j.theriogenology.2017.10.031] [PMID: 29207295]
[35] Abbasi Oshaghi, E.; Khodadadi, I.; Saidijam, M.; Yadegarazari, R.; Shabab, N.; Tavilani, H.; Goodarzi, M.T. Lipid Lowering Effects of Hydroalcoholic Extract of Anethum graveolens L. and Dill Tablet in High Cholesterol Fed Hamsters. Cholesterol, 2015, 2015958560
[http://dx.doi.org/10.1155/2015/958560] [PMID: 26823981]
[36] Kanter, M.; Aktas, C.; Erboga, M. Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis. Food Chem. Toxicol., 2012, 50(3-4), 719-725.
[http://dx.doi.org/10.1016/j.fct.2011.11.051] [PMID: 22166789]
[37] Adewoyin, M.; Ibrahim, M.; Roszaman, R.; Isa, M.L.M.; Alewi, N.A.M.; Rafa, A.A.A.; Anuar, M.N.N. Male Infertility: The Effect of Natural Antioxidants and Phytocompounds on Seminal Oxidative Stress. Diseases, 2017, 5(1)E9
[http://dx.doi.org/10.3390/diseases5010009] [PMID: 28933362]
[38] Shi, G.J.; Li, Z.M.; Zheng, J.; Chen, J.; Han, X.X.; Wu, J.; Li, G.Y.; Chang, Q.; Li, Y.X.; Yu, J.Q. Diabetes associated with male reproductive system damages: Onset of presentation, pathophysiological mechanisms and drug intervention. Biomed. Pharmacother., 2017, 90, 562-574.
[http://dx.doi.org/10.1016/j.biopha.2017.03.074] [PMID: 28407577]
[39] Mazloomi, S.; Alimohammadi, S.; Khodadadi, I.; Ghiasvand, T.; Shafiee, G. Evaluation of methylenetetrahydrofolate reductase (MTHFR) activity and the levels of homocysteine and malondialdehyde (MDA) in the serum of women with preeclampsia. Clin. Exp. Hypertens., 2020, 42(7), 590-594.
[http://dx.doi.org/10.1080/10641963.2020.1739700] [PMID: 32174183]
[40] Ghiasvand, T.; Goodarzi, M.T.; Shafiee, G.; Zamani, A.; Karimi, J.; Ghorbani, M.; Amiri, I. Association between seminal plasma neopterin and oxidative stress in male infertility: A case-control study. Int. J. Reprod. Biomed. (Yazd), 2018, 16(2), 93-100.
[http://dx.doi.org/10.29252/ijrm.16.2.93] [PMID: 29675493]
[41] Monsefi, M.; Zahmati, M.; Masoudi, M.; Javidnia, K. Effects of Anethum graveolens L. on fertility in male rats. Eur. J. Contracept. Reprod. Health Care, 2011, 16(6), 488-497.
[http://dx.doi.org/10.3109/13625187.2011.622815] [PMID: 22066892]
[42] Oshaghi, E.A.; Khodadadi, I.; Tavilani, H.; Goodarzi, M.T. Effect of dill tablet (Anethum graveolens L) on antioxidant status and biochemical factors on carbon tetrachloride-induced liver damage on rat. Int. J. Appl. Basic Med. Res., 2016, 6(2), 111-114.
[http://dx.doi.org/10.4103/2229-516X.179019] [PMID: 27127740]
[43] Iamsaard, S.; Prabsattroo, T.; Sukhorum, W.; Muchimapura, S.; Srisaard, P.; Uabundit, N.; Thukhammee, W.; Wattanathorn, J. Anethum graveolens Linn. (dill) extract enhances the mounting frequency and level of testicular tyrosine protein phosphorylation in rats. J. Zhejiang Univ. Sci. B, 2013, 14(3), 247-252.
[http://dx.doi.org/10.1631/jzus.B1200287] [PMID: 23463768]
[44] Seethalakshmi, L.; Menon, M.; Diamond, D. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat. J. Urol., 1987, 138(1), 190-194.
[http://dx.doi.org/10.1016/S0022-5347(17)43042-4] [PMID: 3599211]
[45] Krogh-Madsen, R.; Plomgaard, P.; Møller, K.; Mittendorfer, B.; Pedersen, B.K. Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am. J. Physiol. Endocrinol. Metab., 2006, 291(1), E108-E114.
[http://dx.doi.org/10.1152/ajpendo.00471.2005] [PMID: 16464907]
[46] Micu, M.C.; Micu, R.; Surd, S.; Gîrlovanu, M.; Bolboacă, S.D.; Ostensen, M. TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology (Oxford), 2014, 53(7), 1250-1255.
[http://dx.doi.org/10.1093/rheumatology/keu007] [PMID: 24599921]
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2021 Bentham Open