CP is a prodrug that undergoes hydroxylation in the liver to become 4-hydroxy-cyclophosphamide, which is the active form. 4-hydroxy-cyclophosphamide and aldophosphamide, its tautomeric counterpart, are in equilibrium. It is often believed that aldophosphamide is converted into the alkylating agent phosphoramide mustard through the spontaneous β-elimination of acrolein. Phosphoramide mustard is thought to stop cell development by alkylating DNA. Apart from the processes triggered by phosphoramide mustard, acrolein and the hydroxylation reaction's byproduct, chloroacetaldehyde, are thought to be the primary sources of CP toxicity³.

According to reports, the use of CP results in reactive oxygen species (ROS) and free radical generation, which can lead to oxidative stress⁴. The metabolic activation of CP by the cytochrome P-450 mixed functional oxidase system results in the formation of two metabolites, phosphoramide mustard and acrolein, which promote oxidative stress⁵. Acrolein exerts its effect by passing through the uroepithelium and stimulating some ROS. Overproduction of ROS causes oxidative stress⁶. Due to excessive free radical production, administration of CP has been shown to chance glutathione (GSH) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity, as well as raise malondialdehyde (MDA) levels in the kidney⁷.

Today, prevention or reduction of oxidative stress due to toxications resulting from exposure to chemical toxic substances and carcinogens is one of the most studied subjects. For this purpose, studies on the research and development of substances with antioxidant properties are needed now as in the past, and there have been several in vitro and in vivo models employed^1,2,6,8,9. Artichoke is one of these ingredients.

Artichoke (Cynara scolymus L.) has strong antioxidant properties and it has been stated that it has liver protective, antimicrobial, cholesterol-lowering properties thanks to its flavonoids (luteolin, apigenin) and caffeoyl quinic acid derivatives (cynarin and chlorogenic acid). However, it is also frequently used in conditions such as dyspepsia and intestinal syndrome. Owing to the active compounds' water solubility and bitter flavor, the majority of teas and aqueous extracts of dried leaves are utilized medicinally¹⁰. Numerous research efforts have concentrated on the antioxidant and liver-protective properties of artichoke, demonstrating its efficacy in these areas^11-15.

Thus, early therapies and an understanding of the pathogenic pathways are necessary for the successful prevention of kidney injury. The mechanisms and goals for reducing CP-induced nephrotoxicity are the main topics of this study. Therefore, the purpose of this study was to use certain histopathological and biochemical data to examine how artichokes affected oxidative damage and stress and CP-induced nephrotoxicity in rats.

Experimental Animals: Twenty eight male Wistar Albino rats, weighing an average of 250–300 g and 8–10 weeks old, were used in the investigation. The Fırat University, Center for Experimental Research and Application (Elazığ, Türkiye) provided the rats that were bought. Before the application, the rats spent a week getting used to their new surroundings. The outside temperature was 24±1°C with a 45±5% relative humidity. There was also a 12-hour cycle of light and dark in the rats' surroundings. Rats were given a regular pellet diet and unlimited access to tap water.

Experimental Protocol: There were four different groups of rats, each including seven rats. There are three experimental groups and a control in the experimental design. The first group, referred to as the control group, did not receive any medicine; second group received artichoke treatment for seven days; third group received a single dose of CP by injection; and fourth group received artichoke treatment for five days following administration of single dose of CP, in addition to seven days of treatment prior to it. One intraperitoneal dosage of CP (Cas No: 6055-19-2, C3250000, Merck, Germany) (150 mg/kg) (16, 17) was administered and artichoke extract (1 g/kg/day) (Arı Engineering, Ankara/Türkiye)^15,18 was given using oral gavage and artichoke was prepared by dissolving in distilled water. The rats were decapitated 24 hours following the final administration, and their blood kidney tissues were subsequently collected for biochemical and histopathological analyses.

Determination of MDA, GSH Levels and Some Antioxidant Enzyme Activities: Following the applications, the rats were killed, and samples of kidney tissue were collected. A Potter-Elvehjem homogenizer was used to homogenize the kidney tissues, which were then diluted 1:10 with distilled water, and cleaned with physiological serum before to the analyses. The homogenate was centrifuged for 15 min at 3.500 rpm in a refrigerated centrifuge (NÜVE NF 800R) for MDA, GSH, CAT and GST analyses and the supernatants were taken^18,19.

This study used a spectrophotometer and a modified Placer et al.²⁰ method to detect the levels of MDA in tissue samples. The process involves the interaction of MDA, an LPO byproduct, with thiobarbituric acid. The method described by Ellman et al.²¹ was used to quantify the GSH levels. Spectrophotometric study of the yellow coloration that results from the introduction of 5,5'-dithiobis (2-nitrobenzoic acid) to sulfhydryl groups is the basis for the procedure. Since hydrogen peroxide (H2O2) can absorb light at 240 nm, the methodology established by Aebi in 1974 was employed to assess the activity of CAT²². This method uses spectrophotometry to measure the rate of H2O2 breakdown by the CAT enzyme. The Beutler method²³ was used to calculate the GSH-Px activity. This method entails using H2O2 to catalyze. The conversion of GSH to its oxidized form, known as oxidized glutathione (GSSG), which is done by GSH-Px. The glutathione reductase (GR) reaction was used to calculate the rate at which GSSG formed. The Habig et al.²⁴ technique was used to measure GST activity. GSH and 1-chloro-2,4-dinitrobenzene (CDNB) were used to measure the quantity of enzyme catalyzing 1 μmol of 1-(S-gluthathionyl)-2,4-dinitrobenzene produced at 340 nm at 37°C per minute in order to evaluate enzyme activity using spectrophotometry. Using a modified version of Sun et al.'s²⁵ approach, the SOD activity was measured by measuring the color of the reduction product, which was obtained by reducing nitroblue tetrazolium with the superoxide anion (O2-) generated by the xanthine oxidase (XO) system. The Lowry et al.²⁶ technique was used to calculate the protein concentration. Protein levels were used to calculate the specific activity of enzymes.

Histopathological Analyses: At the end of experimental study, kidney tissue specimen of all group were removed and fixed in 10% formaldehyde solution. The samples were serially sectioned at 5 μm after being embedded in parafin. Sections of tissue stained using Masson's Trichrome and Hematoxylin & Eosin methods to determine structıral changes due to CP. All stained tissue sections were examined with an Olympus BH2 photomicroscope²⁷.

Statistical Analysis: The SPSS 22 program was used to assess the statistical significance between the different groups. To determine if the raw values of all measured parameters displayed a normal distribution, the Shapiro-Wilk normality test was employed. The outcomes of the test demonstrated that every parameter value was normally distributed. Based on the outcomes of this test, group differences were assessed utilizing post hoc Tukey testing and one-way analysis of variance (ANOVA), it was utilized to compare the groups. All values were derived using the mean and the standard error of the mean. The mean and standard error were used to illustrate the study's conclusions. p-values that fell below 0.05 were considered to be statistically significant.

Büyütmek İçin Tıklayın

Table 1: Effects of artichoke on kidney MDA, GSH levels and CAT, GSH-Px, GST, SOD activities in CP-applied rats

Histopathologically, the kidney section of control rats showed normal structural integrity (Figure 1A). In the section of kidneys of artichoke group that received only artichoke group, histological appearances of cortex and medulla closely resembled those of the controls except obvious peritubular congestion (Figure 1B). Hyalin-like material accumulation was observed both of cortical and medullar tubules in the CP administered group (Figure 1C). In addition, distal tubule dilatation and foamy appearanced tubular cells were observed in the renal cortex of CP group (Figure 1D, E).

Büyütmek İçin Tıklayın

Figure 1: (A) Control Group. Glomerulus (*), distal convoluted tubule (black arrow), proximal convoluted tubule (red arrow) are exhibiting normal structure. (B) Artichoke Group. Peritubular congestion (arrow) in the cortex. (C) CP Group. Cortical distal convoluted tubules containing eosinophilic hyalin-like material. (D) CP Group. Dilatation of distal convoluted tubule (*). (E) CP Group. Foamy appearanced tubules in the cortex (arrow). (F) CP + Artichoke Group. Peritubular congestion (arrow) in the cortex. (A) and (C), Hematoxylin & Eosin x 400. (B), (D), (E), (F), Masson’s Trichrome x 400.

In the section of kidney of the CP group that recevied artichoke group, foamy appearanced tubular cells were absent. Structural integrity of kidney tissue better than CP group. However, there was peritubular congestion prominently in this group (Figure 1F). Moreover, there were fewer dilated tubules and hyalin-like material containing tubule.

Although CP has been used in the treatment of malignancy, cumulative dose-dependent toxicity is the main limiting factor. Many researchers have reported that CP can cause gastrointestinal^31, bone marrow³² and cardiac³³ toxicity, as well as nephrotoxicity³⁴ and hepatotoxicity³⁵. The basic mechanism underlying the kidney damage caused by CP is oxidative stress. It leads to an increase in the levels of H2O2, ROS and hydroxyl radicals. Variations in the activity of some antioxidant enzymes and lipid peroxidation were determined by many researchers in rats given CP, and it was determined that antioxidants reversed the process and protected the cell with the addition of antioxidants. In our study, we observed that artichoke, an antioxidant born in rats given CP, improved the biochemical and histological results.

Prior research has demonstrated that CP results in toxicity and oxidative stress by causing changes in some indicators (blood urea nitrogen (BUN) and creatinine (Cr)) MDA, GSH concentration, and antioxidant enzyme activity (e.g., GSH-Px, SOD, CAT)^18,19,33,36. In their studies, researchers have reached results such as increased MDA levels^18,19,33,36, decreased³⁶ or increased^18,33 in GSH levels, increased³³ or decreased^18,19 in CAT activities, decreased^18,19,33 in GST activities, increased ¹⁹ or decreased³³ in SOD activities, decreased (33) in GSH-Px activities, increased³⁶ in BUN and Cr levels when compared to the control group after CP application. Our findings showed that CP increases the level of lipid peroxidation (MDA) and changes some antioxidant enzyme activities, which is consistent with the literature. In their investigation into the potential preventive impact of selenium against CP-induced acute nephrotoxicity, Gunes et al.^37, found that after CP applied at the same dose as the current study, creatinine, cystatin C, The levels of the oxidative stress index (OSI) and total oxidant status (TOS) rose, as did the levels of TAS decreased in rats treated only with CP. In addition, the researchers found that Localized shedding of tubular epithelial cells, glomerular compression, hyaline material accumulation in the renal tubules, restricted Bowman's capsule space, inflammatory foci, congested blood vessels, and tiny hemorrhagic regions were all visible in animals treated only with CP. In the current study, significant changes were detected in biomarkers related to oxidative damage and stress and in the histopathology of the kidney.

Many studies have been done to determine whether adding antioxidants to cancer chemotherapy improves treatment outcomes or lessens unwanted side effects. Antioxidants are likely to interfere with a cancer chemotherapeutic agent's anti-neoplastic effectiveness if the drug's production of ROS contributes significantly to its cytotoxicity. Antioxidants, however, can actually lessen the severity of adverse effects without compromising the efficacy of the medication if ROS is the main cause of them. Therefore, it is essential to differentiate between the role that free radicals play in a drug's mode of action and its ability to induce oxidative stress in biological systems. Since CP is an alkylating chemical, DNA alkylation is primarily responsible for its ability to kill tumor cells. Nevertheless, acrolein's generation of free radicals is frequently linked to harmful outcomes that are not desired^18,19,33.

Reducing CP side effects may improve medication tolerance and make therapy more efficient and comfortable for those who need it. The antioxidant system in cells reduces the amount of tissue damage brought on by ROS. Generally speaking, some antioxidants might be helpful in reducing the harmful side effects of anticancer medications. Antioxidants and oxidative stress inhibitors such as selenium^37, propolis^18,19,33, artichoke^18, sesamin^17, resveratrol^30, lycopene³¹ have been demonstrated to guard against renal damage and oxidative stress brought on by CP.

Studies conducted both in vitro and in vivo have demonstrated that artichokes contain a variety of biological properties, including the ability to scavenge free radicals and act as an efficient antioxidant^38,39.

Many antioxidants have been tested to prevent CP-induced nephrotoxicity to date, but there is no study in rats where artichoke treatment was applied in CP-induced nephrotoxicity models. In our previous study, artichoke application was encountered in the CP-induced hemorrhagic cystitis model ¹⁸. The antitumoral activity of artichoke leaf extract was demonstrated by experimental tests due to its effect on signaling pathways with oncogenic importance. The bladder damage in the study occured due to cell membrane damage by CP metabolites. Because propolis and artichoke, when combined with CP, lower MDA levels and boost antioxidant enzyme activity, bladder tissue were prevented from oxidative injury. Various in vitro studies have shown that the antioxidant effect of artichoke is due to the metallic ion chelating and radical scavenging effects of components such as flavonoids, chlorogenic acid and cynarin. The antioxidant effect of artichoke is associated with the induction of antioxidant enzyme synthesis, which results in the intervention of inflammatory pathways gene expression and reduction of oxidative stress. Thus, the antioxidative function of artichokes is likely linked to CP's protective impact against H2O2 toxicity.

When the studies in recent years are examined, it has been observed that the number of studies examining the antioxidant effects of artichoke has increased. In this context, the effects of artichoke against many harmful substances or effects have been examined^13-15.

In a study examining the protective effect of chicory and/or artichoke leaf extracts against chronic nephrotoxicity caused by carbon tetrachloride and gamma irradiation in rats, researchers observed that the levels of lipid peroxidation indicator MDA, which increased after artichoke application, decreased, and the levels of GSH and the activities of antioxidant enzymes SOD and CAT improved⁴⁰. Artichoke administration reduced renal histological abnormalities, attenuated renal function, oxidative stress biomarkers, and up-regulated Bcl-2 and p53 mRNA gene expressions in rats treated with diethylnitrosamine (DEN) / acetylaminofluorene (2AAF) in a study designed to estimate the preventive effects of artichoke extracts from Cynara scolymus⁴¹. Artichokes (Cynara scolymus L.) were found to improve altered MDA, GSH levels and SOD, GSH-Px activities after high-fat diet application. Additionally, artichoke application improved the kidney histopathologically by reducing the size of Bowman's space and preserving the glomerular structure, according to another study looking at the preventive effect of artichokes against high-fat diet-induced obesity in rats and renal dysfunction⁴². In our current study, lipid peroxidation levels (MDA levels) in kidney tissue were lower in the group given artichoke together with CP compared to CP group. Also, GSH levels, GSH-PX, SOD and GST activities also showed changes in the group administered with artichoke+CP compared to the group administered only CP. The change in CAT activities remained statistically insignificant between CP and artichoke+CP groups. Histopathologically, foamy-looking tubular cells were not observed in the kidney section of the CP group receiving artichoke, and the structural integrity of the kidney tissue was better than the CP group. In addition, fewer dilated tubules and tubules containing hyaline-like material were observed. All these are consistent with the results of the studies mentioned above. It was shown that artichoke administration reduced oxidative damage in the kidney tissue of rats administered CP, and these results are consistent with our research hypothesis.

In Wistar rats, artichoke significantly reduces the renal damage caused by CP. According to the results, artichoke may lessen the negative effects of CP, indicating a possible therapeutic use for it in the treatment of drug-induced organ damage. To clarify the particular processes underlying these protective effects and investigate their potential therapeutic importance in human subjects, more research is necessary.

1) Ijaz MU, Mustafa S, Batool R, et al. Ameliorative effect of herbacetin against cyclophosphamide-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Hum Exp Toxicol 2022; 41: 1-13.

2) Alabi QK, Akomolafe RO, Omole JG, et al. Polyphenol-rich extract of Ocimum gratissimum leaves prevented toxic effects of cyclophosphamide on the kidney function of Wistar rats. BMC Complement Med Ther 2021; 21: 1-14.

3) Voelcker G. The mechanism of action of cyclophosphamide and its consequences for the development of a new generation of oxazaphosphorine cytostatics. Sci Pharma 2020; 88: 42.

4) McDermott EM, Powell RJ. Incidence of ovarian failure in systemic lupus erythematosus after treatment with pulse cyclophosphamide. Ann Rheum Dis 1996; 55: 224-229.

5) Ludeman SM. The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des 1999; 5: 627-644.

6) Senthilkumar S, Devaki T, Manohar BM, Babu MS. Effect of squalene on cyclophosphamide-induced toxicity. Clin Chim Acta 2006; 364: 335-342.

7) Gunes S, Ayhanci A, Sahinturk V, Altay DU, Uyar R. Carvacrol attenuates cyclophosphamide-induced oxidative stress in rat kidney. Can J Physiol Pharmacol 2017; 95: 844-849.

8) Chen YT, Yang CC, Sun CK, et al. Extracorporeal shock wave therapy ameliorates cyclophosphamide-induced rat acute interstitial cystitis though inhibiting inflammation and oxidative stress-in vitro and in vivo experiment studies. Am J Trans Res 2014; 6: 631.

9) Nie Z, Zhang L, Chen W, et al. The protective effects of pretreatment with resveratrol in cyclophosphamide-induced rat ovarian granulosa cell injury: In vitro study. Reprod Toxicol 2020; 95: 66-74.

10) Holtmann G, Adam B, Haag S, et al. Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: A six‐week placebo‐controlled, double‐blind, multicentre trial. Alim Pharmacol Therap 2003; 18: 1099-1105.

11) Adzet T, Camarasa J, Laguna JC. Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in isolated rat hepatocytes. J Nat Prod 1987; 50: 612-617.

12) Speroni E, Cervellati R, Govoni P, et al. Efficacy of different Cynara scolymus preparations on liver complaints. J Ethnopharmacol 2003; 86: 203-211.

13) Mehmetçik G, Özdemirler G, Koçak-Toker N, Çevikbaş U, Uysal M. Effect of pretreatment with artichoke extract on carbon tetrachloride-induced liver injury and oxidative stress. Exp Toxicol Pathol 2008; 60: 475-480.

14) Kaymaz MB, Kandemir FM, Pamukcu E, Eröksüz Y, Özdemir N. Effects of aqueous artichoke (Cynara scolymus) leaf extract on hepatic damage generated by alpha-amanitin. Kafkas Univ Vet Fak Derg 2017; 23: 155-160.

15) Kaya E, Yılmaz S. Nitrozomorfolin uygulanmış ratlarda enginar (Cynara scolymus l.)’ın lipid peroksidasyon düzeyleri ve bazı antioksidan enzim aktiviteleri üzerine etkisinin araştırılması. Fırat Üniversitesi Sağlık Bilimleri Veteriner Dergisi 2020; 34: 23-27.

16) Akomolafe SF, Olasehinde TA, Oyeleye SI, et al. Curcumin administration mitigates cyclophosphamide-induced oxidative damage and restores alteration of enzymes associated with cognitive function in rats’ brain. Neurotoxi Res 2020; 38: 199-210.

17) Alshahrani S, Ali Thubab HM, Ali Zaeri AM, et al. The protective effects of sesamin against cyclophosphamide-induced nephrotoxicity through modulation of oxidative stress, inflammatory-cytokines and apoptosis in rats. Int J Mol Sci 2022; 23: 11615.

18) Yılmaz S, Kaya E. Ratlarda siklofosfamid ile oluşturulmuş hemorajik sistitte propolis ve enginarın koruyucu etkileri. Fırat Üniversitesi Sağlık Bilimleri Veteriner Dergisi 2018; 32: 93-98.

19) Kaya E, Yılmaz S, Altay Z, et al. Protective effect of propolis on the antioxidant enzymes activities, characteristics of epididymal spermatozoa and histopathological structure of testis from rats treated with cyclophosphamide. Rev Cient Fac Vet 2024; 34: e34365.

20) Placer ZA, Cushmann LL, Johnson BG. Estimation of products of lipid peroxidation in biological systems. Anal Biochem 1960; 16: 359-364.

21) Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7: 88-95.

22) Aebi H. Catalase. In: Bergmeyer HU (Editor). Methods of Enzymatic Analysis. 2nd Edition, Weinheim: Verlag Chemie, 1974: 673-678.

23) Beutler E. Red Cell Metabolism. A Manual of Biochemical Methods, 3rd. Edition. Orlando: Grune & Stratton; 1984: 310-311.

24) Habig WH, Pabst MJ, Jakoby WB. Glutathione S–transferases: The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 1974; 249:7130-7139.

25) Sun Y, Oberly LW, Ying LA. Simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34: 497-500.

26) Lowry O, Rosebrough N, Farr AL, Randall R. Protein measurement with the Folin phenol reagent. J. Biol. Chem 1951; 193: 265-275.

27) Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. 5th Edition, London, England: Churchill Livingstone Publishing, 2002.

28) McCarroll N, Keshava N, Cimino M, et al. An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide. Env Mol Mut 2008; 49: 117-131.

29) Senthilkumar S, Yogeeta SK, Subashini R, Devaki T. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact 2006; 160: 252-260.

30) Alghamdi A, Alissa M, Alghamdi SA, et al. Suppression of glomerular damage, inflammation, apoptosis, and oxidative stress of acute kidney injury induced by cyclophosphamide toxicity using resveratrol in rat models. Tissue Cell 2024; 91: 102548.

31) Pan X, Niu X, Li Y, Yao Y, Han L. Preventive mechanism of lycopene on intestinal toxicity caused by cyclophosphamide chemotherapy in mice by regulating TLR4-MyD88/TRIF-TRAF6 signaling pathway and gut-liver axis. Nutrients 2022; 14: 4467.

32) Deng J, Zhong YF, Wu YP, et al. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage. Redox Biol 2018; 14: 1-6.

33) Kaya E, Yılmaz S, Çolakoğlu N. The protective role of propolis in cyclophosphamide-induced cardiotoxicity in rats. Ankara Üniversitesi Veteriner Fakültesi Dergisi, 2019; 66: 13-20.

34) Ayza MA, Zewdie KA, Yigzaw EF, et al. Potential Protective Effects of Antioxidants against Cyclophosphamide‐Induced Nephrotoxicity. International Journal of Nephrology 2022; 1: 5096825.

35) Akamo AJ, Rotimi SO, Akinloye DI, et al. Naringin prevents cyclophosphamide-induced hepatotoxicity in rats by attenuating oxidative stress, fibrosis, and inflammation. Food Chem Toxicol 2021; 153: 112266.

36) Goudarzi M, Esmaeilizadeh M, Dolatshahi M, et al. Protective effect of elaeagnus angustifolia L. Fruit hydroalcoholic extract on cyclophosphamide-induced nephrotoxicity in mice. Shiraz E-Med J 2018; 19: e55075.

37) Gunes S, Sahinturk V, Uslu S, et al. Protective effects of selenium on cyclophosphamide-induced oxidative stress and kidney injury. Biolo Trace Elem Res 2018; 185: 116-123.

38) Mejri F, Baati T, Martins A, et al. Phytochemical analysis and in vitro and in vivo evaluation of biological activities of artichoke (Cynara scolymus L.) floral stems: Towards the valorization of food by-products. Food Chem 2020; 333: 127506.

39) Shallan MA, Ali MA, Meshrf WA, Marrez DA. In vitro antimicrobial, antioxidant and anticancer activities of globe artichoke (Cynara cardunculus var. scolymus L.) bracts and receptacles ethanolic extract. Bio Agr Biotech 2020; 29: 101774.

40) Eassawy MM, Ismail AF. Protective effect of chicory and/or artichoke leaves extracts on carbon tetrachloride and gamma‐irradiation‐induced chronic nephrotoxicity in rats. Env Toxicol 2024; 39: 1666-1681.

41) Bakry LN, El-Hameed AMA, El-Twab SMA, Ahmed OM, Abel-Moneim A. The preventive effects of Cynara scolymus leaf and flower extracts on diethylnitrosamine / acetylaminoflourene induced nephrotoxicity in male wistar rats. Adv Anim Vet Sci 2020; 8: 74-81.

42) Ben Salem M, Affes H, Dhouibi R, et al. Preventive effect of Artichoke (Cynara scolymus L.) in kidney dysfunction against high fat-diet induced obesity in rats. Archives of Physiology and Biochemistry 2022; 128: 586-592.