ABSTRACT
Studies examining the effect of artichoke on liver enzymes have reported inconsistent results. This systematic review and meta-analysis aimed to assess the effects of artichoke administration on the liver enzymes. PubMed, Embase, the Cochrane Library, and Scopus databases were searched for articles published up to January 2022. Standardized mean difference (Hedges’ g) were analyzed using a random-effects model. Heterogeneity, publication bias, and sensitivity analysis were assessed for the liver enzymes. Pooled analysis of seven randomized controlled trials (RCTs) suggested that the artichoke administration has an effect on both alanine aminotransferase (ALT) (Hedges’ g, −1.08; 95% confidence interval [CI], −1.76 to −0.40; p = 0.002), and aspartate aminotransferase (AST) (Hedges’ g, −1.02; 95% CI, −1.76 to −0.28; p = 0.007). Greater effects on ALT were detected in trials that lasted ≤8 weeks. Also, greater effects on AST were detected in trials using > 500 mg artichoke. Overall, this meta-analysis demonstrated artichoke supplementation decreased ALT and AST.
-
Keywords: Artichoke; Liver enzymes; Alanine aminotransferase; Aspartate aminotransferase
INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders in developed countries and its incidence continues to increase [
1,
2]. Furthermore, the general term is known as nonalcoholic steatohepatitis (NASH) which is caused by increasing oxidative stress, hepatocellular inflammation, and insulin resistance [
3,
4]. There are routine approaches for the treatment of this disorder such as weight loss, changes in dietary composition, and lifestyle modifications However, herbal substances have always received a lot of attention as an alternative approach to treating chronic diseases such as NASH [
5,
6].
Based on some evidence, one of the plants used for the protection of hepatocytes is artichoke (
Cynara scolymus) [
7,
8,
9]. It is grown in countries in the Mediterranean region that have a high concentration of natural antioxidants such as mono-caffeoylquinic acid and dicaffeoylquinic acid (cynarin and chlorogenic acid), caffeic acid, and the volatile sesquiterpine and flavonoids [
10] and it also has an antimicrobial [
11] and cholesterol decreasing effects [
12]. Artichoke can have protective effects against NAFLD by reducing the production of reactive oxygen species [
13], lipid peroxidation [
9], and protein oxidation and increasing the activity of glutathione peroxidase [
14].
Some in vitro, animal, and human studies evaluated the potential antioxidant effect of artichoke on hepatocytes [
15,
16,
17,
18]. In a study conducted by Panahi et al. [
17], treatment with artichoke leaf extract (ALE) significantly lowered aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and improved AST/ALT ratio compared with the placebo group. However, Fallah Huseini et al. [
19] did not find any significant effects on ALT and AST for ALE group in comparison with the control group.
Therefore, since studies were inconsistent in this regard, this systematic review and meta-analysis aimed to assess the effect of artichoke on liver enzymes function.
MATERIALS AND METHOD
Literature search and selection
The present study was performed using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [
20]. Electronic databases including PubMed, Cochrane library, Scopus, and Embase were searched for articles published up to January 2022. We used Medical Subject Headings (MeSH) terms, abstracts, and keywords without any limitation in the search.
Supplementary Table 1 provides details of the search terms. The reference lists of the retrieved articles were also reviewed to avoid missing any publication. The literature search procedure was developed and performed by two reviewers (MRA and FS) separately and in duplicate. Any differences were resolved by a discussion with the principal investigator (AH).
Two of the authors identified eligible publications independently via reading titles, abstracts, and their full texts, if necessary. The PICOS model [
21] for the definition of the inclusion criteria was applied: Population (adults aged > 18 years), intervention (artichoke), comparator (placebo), outcome (ALT and AST), and study design (parallel and cross-over clinical trial). Studies were included if they: 1) were RCT studies conducted on the human population; 2) reported mean and standard derivation (SD) of ALT and AST. We also included only English-language publications in the present study. We excluded studies with less than 2 weeks’ intervention duration and publications without any comparing control group. We also excluded letters, books, comments, conference papers, animal and observational studies, non-interventional studies, and reviews. If the same dataset had been published in more than one article, we included the one with the greatest number of participants. Any disagreements about the article choice process were resolved by direct discussion.
Two investigators (MAR and FS) independently extracted data from the studies. The main data were extracted from the included publication using a pre-designed abstraction from general features of studies, reported. When the outcomes were reported at different intervention duration, only the final results were included in the analysis. When necessary, the corresponding author was contacted by the investigators to acquire missing information. Any differences were resolved by a discussion with the principal investigator (AH).
Quality assessment of the studies
We assessed the quality of the included studies using Cochrane Collaboration’s tool [
22]. This tool divided quality into 5 domains: randomization process, deviations from the intended interventions, missing data, outcome measurement, and selection of the reported result (
Table 1). Quality of individual publications were conducted by two independent investigators (MAR and FS). Any differences were resolved by a discussion with the principal investigator (AH).
Table 1Risk of bias for randomized controlled trials, assessed according to the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2)
Table 1
|
Publications |
Year |
Randomization process |
Deviations from the intended interventions |
Missing outcome data |
Measurement of the outcome |
Selection of the reported result |
Overall bias |
|
1. Englisch et al. [27] |
2000 |
L |
L |
L |
L |
L |
L |
|
2. Roghani-Dehkordi and Kamkhah [30] |
2009 |
L |
L |
L |
L |
L |
L |
|
3. Fallah Huseini et al. [19] |
2012 |
L |
L |
L |
L |
S |
L |
|
4. Rangboo et al. [29] |
2016 |
L |
L |
S |
L |
L |
L |
|
5. Panahi et al. [17] |
2018 |
L |
L |
L |
L |
L |
L |
|
6. Musolino et a. [28] |
2020 |
L |
L |
L |
L |
L |
L |
|
7. Rondanelli et al. [31] |
2020 |
L |
L |
L |
L |
L |
L |
Statistical analysis
Bias-corrected standardized mean difference (Hedge’s g method) and its 95% confidence interval (CI) was computed to quantify the effects of artichoke on liver enzymes. Mean and SD values of the baseline and the end of the trials in both intervention and control groups were pooled to estimate the effect of artichoke on ALT and AST. When studies did not report mean and SD, the available statistical data was converted into mean and SD using the suitable formula: SD
difference = square root [(SD
pre-treatment)
2 + (SD
post-treatment)
2 − (2 × R × SD
pre-treatment × SD
post-treatment)], assuming a correlation coefficient (R) 0.8 as it is a conservative estimate for an expected range of 0–1 [
23]. When means (± SD) of outcome measures were not directly available and a standard error of the mean (SEM) was reported in place of SD, we converted it to SD using this formula: SD = SEM × √n, being “n” the number of participants in each group. Numerical data were extracted from graphs GetData Graph Digitizer version 2.24 [
24].
Firstly, we performed a fixed-effect model to determine the effect with a forest plot. The I-squared statistic was used to define the degree of heterogeneity. I
2 values greater than 50% were considered as significant heterogeneity between studies. If there was significant between-study heterogeneity, a random-effects model (DerSimonian and Laird) was applied; otherwise, a fixed-effect model was performed [
25]. Subgroup analysis was performed to detect potential sources of heterogeneity. These analyses were based on intervention and duration of supplementation, sample size, dosage, and mean age. Any publication bias was investigated by visually inspecting funnel plots and quantitatively evaluated using the Egger’s test [
26]. Meta-analysis was conducted using Stata software, version 14.0 (Stata Corp LP, College Station, TX, USA). The p values less than 0.05 were considered to be statistically significant.
RESULTS
Selection and identification of studies
We found 1,507 studies through database searching plus one publication through hand searching, of which 168 records were duplicates. After exclusion of duplicate publications, a total of 1,340 publications were screened by title and abstract. We excluded animal studies (n = 135), unrelated studies (n = 1,074), and reviews (n = 114). Finally, 17 publications remained for full-text review. After a full-text review, ten studies were excluded: 3 with an irrelevant intervention, 1 without a placebo-controlled group, 2 with insufficient data, and 3 with conference abstracts. We also excluded another study with complex intervention. Finally, seven studies were included in the systematic review and meta-analysis [
27,
28,
29,
30,
31,
32,
33].
Figure 1 shows a flow diagram of study selection.
Figure 1Flow chart of the number of studies identified and selected into the meta-analysis.
Characteristics of the studies
In total, 8 effect sizes were extracted from 7 clinical trials conducted on 575 participants (
Table 2). The mean age of participants ranged from 42.5 to 51.5 years. The studies on hypercholesterolemia [
27,
30], NAFLD [
17,
28], type 2 diabetes [
19], NASH [
29] and overweight patients [
31] were included. The clinical trials were released in the period from 2000 to 2020. The studies were conducted in Iran [
17,
19,
29,
30], Italy [
29,
33], and Russia [
27]. The dose of artichoke ranged from 50 mg/day to 2,700 mg/day. The length of supplementations varied from 6 to 16 weeks.
Table 2Demographic characteristics of the included studies
Table 2
|
First author (year) |
Location |
Study design |
Health status |
Sex |
Sample size (male/female) |
Duration (wk) |
Mean age (yr) |
Baseline BMI (kg/m2) |
Intervention |
Outcome |
|
Treatment group |
Control group |
|
Englisch (2000) |
Russia |
Randomized, single-blind, placebo-controlled, parallel trial |
Moderate to severe hypercholesterolemia |
Both |
143 (47/96) |
6 |
44 |
28.2 |
1,800 mg ALE |
Placebo |
ALT/AST |
|
Roghani-Dehkordi (2009) |
Iran |
Randomized, double-blind, placebo-controlled, parallel trial |
Non or mild hypercholesterolemic |
Male |
56 |
12 |
42.5 |
24.5 |
50 mg ALE |
Placebo |
ALT/AST |
|
Roghani-Dehkordi (2009) |
Iran |
Randomized, double-blind, placebo-controlled, parallel trial |
Non or mild hypercholesterolemic |
Male |
51 |
12 |
42.5 |
24.5 |
100 mg ALE |
Placebo |
ALT/AST |
|
Fallah Huseini (2012) |
Iran |
Randomized, double-blind, placebo-controlled, parallel trial |
Mild to moderate hypercholesterolemia in type 2 diabetes |
Both |
76 (18/58) |
8 |
50 |
NA |
1,200 mg ALE |
Placebo |
ALT/AST |
|
Rangboo (2016) |
Iran |
Randomized, double-blind, placebo-controlled, parallel trial |
Non or mild hypercholesterolemic NASH patients |
Both |
60 (42/18) |
8 |
48.9 |
NA |
2,700 mg ALE |
Placebo |
ALT/AST |
|
Panahi (2018) |
Iran |
Randomized, double-blind, placebo-controlled, parallel trial |
Patients with NAFLD |
Both |
89 (50/39) |
8 |
46.2 |
29.1 |
600 mg ALE |
Placebo |
ALT/AST |
|
Musolino (2020) |
Italy |
Randomized, double-blind, placebo-controlled, parallel trial |
Type 2 diabetes and NAFLD |
Both |
40 (NA) |
16 |
50.5 |
25.7 |
300 mg ALE |
Placebo |
ALT/AST |
|
Rondanelli (2020) |
Italy |
Randomized, double-blind, placebo-controlled, parallel trial |
Overweight and obese with newly detected IFG |
Both |
54 (28/26) |
8 |
51.5 |
30 |
500 mg ALE |
Placebo |
ALT/AST |
Meta-analysis of data
Effects of artichoke on ALT
Artichoke administration significantly reduced the serum levels of ALT (Hedges’ g, −1.08; 95% CI, −1.76 to −0.40; p = 0.002). There was evidence of considerable heterogeneity among studies (I
2 = 92.2%; p < 0.001) (
Figure 2).
Figure 2
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of artichoke supplementation on ALT.
SMD, standardized mean difference; CI, confidence interval.
The stratified analyses based on the duration of intervention revealed that the effect of artichoke supplementation on ALT was significantly greater in trials that lasted ≤ 8 weeks (Hedges’ g, −0.69; 95% CI, −0.89 to −0.49; p < 0.001). More subgroup analysis for dosage and mean age did not indicate different results of artichoke supplementation efficacy on ALT (
Table 3).
Table 3Subgroup analysis of included randomized controlled trials in meta-analysis of the effect of artichoke supplementation on liver enzymes
Table 3
|
Group |
No. of trials |
WMD (95% CI) |
p value |
I2 (%) |
P-heterogeneity |
p for between subgroup heterogeneity |
|
ALT |
|
|
|
|
|
|
|
Dosage (mg) |
|
|
|
|
|
0.407 |
|
|
≤ 500 |
3 |
−0.49 (−0.82, −0.16) |
0.003 |
95.5 |
< 0.001 |
|
|
> 500 |
4 |
−0.66 (−0.87, −0.44) |
< 0.001 |
86.3 |
< 0.001 |
|
Duration (wk) |
|
|
|
|
|
0.070 |
|
|
≤ 8 |
5 |
−0.69 (−0.89, −0.49) |
< 0.001 |
82.3 |
< 0.001 |
|
|
> 8 |
2 |
−0.27 (−0.68, 0.13) |
0.184 |
96.9 |
< 0.001 |
|
Mean age (yr) |
|
|
|
|
|
0.079 |
|
|
< 50 |
4 |
−0.51 (−0.72, −0.31) |
< 0.001 |
87.1 |
< 0.001 |
|
|
≥ 50 |
3 |
−0.88 (−1.23, −0.53) |
< 0.001 |
96.4 |
< 0.001 |
|
AST |
|
|
|
|
|
|
|
Dosage (mg) |
|
|
|
|
|
0.001 |
|
|
≤ 500 |
3 |
−0.17 (−0.49, 0.15) |
0.301 |
95.0 |
< 0.001 |
|
|
> 500 |
4 |
−0.81 (−1.02, −0.59) |
< 0.001 |
92.1 |
< 0.001 |
|
Duration (wk) |
|
|
|
|
|
0.448 |
|
|
≤ 8 |
5 |
−0.64 (−0.84, −0.44) |
< 0.001 |
92.6 |
< 0.001 |
|
|
> 8 |
2 |
−0.47 (−0.86, −0.07) |
0.020 |
96.3 |
< 0.001 |
|
Mean age (yr) |
|
|
|
|
|
0.288 |
|
|
< 50 |
4 |
−0.66 (−0.88, −0.45) |
< 0.001 |
91.9 |
< 0.001 |
|
|
≥ 50 |
3 |
−0.45 (−0.79, −0.11) |
0.010 |
96.6 |
< 0.001 |
Effects of artichoke on AST
Compared to that of the control participants, a significant effect of artichoke administration on AST was reached (Hedges’ g, −1.02; 95% CI, −1.76 to −0.28; p = 0.007). An extreme level of heterogeneity was seen in the studies (I
2 = 93.6%; p < 0.001) (
Figure 3). The stratified analysis based on the intervention dose showed that > 500 mg/day of artichoke supplementation significantly reduced the AST levels (Hedges’ g, −0.81; 95% CI, −1.02 to −0.59; p < 0.001). More stratified analysis for the duration and mean age did not indicate different results of artichoke supplementation efficacy on AST (
Table 3).
Figure 3
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of artichoke supplementation on AST.
SMD, standardized mean difference; CI, confidence interval.
Publication bias and sensitivity analysis
To examine the influence of each study on the overall effect estimate, we excluded every single study from the analysis. Sensitivity analysis for ALT and AST indicated that exclusion of each study one at a time did not materially alter the pooled estimate. Egger’s regression test was conducted to find the publication bias. There was no evidence of publication bias for ALT (p = 0.155) and AST (p = 0.315).
DISCUSSION
The current evidence shows that artichoke supplementation significantly affects serum ALT and AST. The prevalence of NAFLD, most commonly caused by sedentary lifestyles and high dietary calorie intakes, is on the rise in industrialized nations [
32]. The American Association for the Study of Liver Diseases [
33] recommends liver biopsy only in patients with elevated serum markers and non-invasive serum markers for screening liver dysfunction, especially in those with metabolic risk factors. The serum markers ALT and AST can be used to diagnose hepatic damage. Severe liver damage was commonly detected by elevated levels of serum ALT and AST [
34]. Due to its multifaceted mechanisms of action, herbal medicine offers possible benefits as an alternative remedy [
5,
6,
35]. Artichoke has been used as a remedy that is rich in natural antioxidants and is frequently grown in Mediterranean countries [
10]. Artichoke extracts have shown antimicrobial, hepatoprotective, choleretic, hypocholesterolemic, hypoglycemic, and anticancer effects in previous in vitro and in vivo studies [
36,
37,
38,
39,
40,
41,
42,
43]. These are the main actions of artichoke that is used as an herbal drug: liver and gallbladder bile stimulation, hepatoprotective, antihepatotoxic, and hypocholesterolemic [
44]. The antioxidative and free radical scavenging ability of artichoke extracts in to protect hepatocytes from oxidative stress has been evaluated in several in vitro and animal studies [
15,
16,
18], but there are limited number of human studies in this area. However, the results are controversial. In line with other findings, in two studies from Iran, ALE supplementation significantly improved the serum levels of ALT and AST in NAFLD [
17] and NASH [
29] patients. Although in another study, Fallah Huseini et al. [
19] showed that artichoke extract supplementation has a significant reduction effect on AST no effect was seen with ALT in hypercholesterolemic type 2 diabetic patients. In return, Rondanelli et al. [
31] study of overweight IFG individuals reported a statistically significant reduction between time and group for ALT level. Meanwhile, the study by Musolino et al. [
28] reported that a combination of bergamot polyphenolic fraction and
Cynara cardunculus significantly increased AST and ALT levels in patients with type 2 diabetes mellitus. Since these studies were conducted on different subjects, direct comparisons of their findings are not possible.
Several studies have documented that artichoke extracts can exert antioxidant activity in the prevention and treatment of oxidative stress related diseases [
14,
45,
46,
47,
48]. The most active antioxidant ingredients in artichoke extract including mono- and dicaffeoylquinic acid (cynarin and chlorogenic acid), caffeic acid, and chlorogenic acid could explain the therapeutic effects of artichoke on biochemical and liver biomarkers [
49]. The main compounds of flavonoids in artichoke extract combinations are glycosides luteolin-7-
β-rutinoside (scolymoside), luteolin-7-
β-D-glucoside, and luteolin-4-
β-D-glucoside that [
50,
51,
52]. The result of Saffa et al. study in determining the efficacy of
Cynara scolymus total methanolic extract (CSM) and its fraction (CSF) in rats showed that CSF is more active in comparison with CSM. Due to the high concentration of chlorogenic acid in CSF [
53]. Several mechanisms could explain the beneficial effects of artichoke supplementation on liver enzymes. Artichoke bioactive compounds inhibit lipid peroxidation [
54], These components also modulate reactive oxygen species (ROS)-dependent cell functional signaling. Intercepting free radicals and ROS at the level of critical signaling pathways involving various protein kinases, phosphatases, and transcription factors may be responsible for the modulation effects [
55]. Finding from a meta-analysis showed that animals with hepatotoxicity compared with animals with other diseases may benefit more from artichoke extract [
56]. However, the high dose and duration of intervention with artichoke extract in patients with hepatitis C did not have a remarkable reduction in serum ALT and AST levels [
57]. Also, the Englisch et al.’s study [
27] which was performed on patients with severe hypercholesterolemia did not show an improvement in AST and ALT levels despite the larger sample size and higher dose of artichoke, than the Roghani-Dehkordi and Kamkhah’s study [
30], which was performed on hypocholesterolemia patients. It seems that the ineffectiveness of artichoke extract on ALT and AST was caused by microbial agents and severe damage to hepatocytes.
A previous meta-analysis revealed Artichoke supplementation reduced liver enzymes, especially among patients with NAFLD [
32]. In comparison to the previous review, we included two more related studies, also we did a subgroup analysis based on dose and duration which showed that artichoke extract in high dosage (> 500 mg) for a short duration (≤ 8 weeks) was suggested as potent antioxidant effect on AST and ALT levels.
Our meta-analysis has several strengths. First, we involved only RCTs in the meta-analysis, therefore the causal inference of our findings is strong. Second, different subgroup analyses were performed to explore the effect of intervention across different subgroups and detect possible sources of heterogeneity. Limitations of our study include the relatively small sample size. Moreover, there was evidence of significant between-study heterogeneity in some of our analyses. Thus, high-quality randomized-controlled trials with different durations and dosages are needed. In addition, most of the included studies was conducted in Asian countries which limits the extrapolation of our findings.
CONCLUSION
In conclusion, this systematic review and meta-analysis of intervention trials suggests that artichoke supplementation may reduce the serum levels of AST and ALT. However, further large, high-quality clinical trials in different regions are needed to provide definite conclusion. Our findings provide additional evidence for physicians and medical researchers on the efficacy of alternative treatments for hepatic patients.
Shahid Beheshti University of Medical Scienceshttps://doi.org/10.13039/501100005851
NOTES
-
Funding: This study supported by “Student Research Committee” and “Research & Technology Chancellor” in Shahid Beheshti University of Medical Sciences.
-
Conflict of Interest: The authors declare that they have no competing interests.
-
Author Contributions:
Conceptualization: Amini MR.
Data curation: Amini MR.
Formal analysis: Amini MR.
Methodology: Sheikhhossein F.
Project administration: Hekmatdoost A.
Supervision: Hekmatdoost A.
Writing - original draft: Djafari F, Bazshahi E, Talebyan A.
Writing - review & editing: Sheikhhossein F, Amini MR.
ACKNOWLEDGEMENTS
This study is related to the project NO. 1400/65026 from Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
We also appreciate the “Student Research Committee” and “Research & Technology Chancellor” in Shahid Beheshti University of Medical Sciences for their financial support of this study.
SUPPLEMENTARY MATERIAL
REFERENCES
- 1. Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 2010;24:695-708.
- 2. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263-2273.
- 3. Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 2014;5:211-218.
- 4. Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014;20:12956-12980.
- 5. Jadeja R, Devkar RV, Nammi S. Herbal medicines for the treatment of nonalcoholic steatohepatitis: current scenario and future prospects. Evid Based Complement Alternat Med 2014;2014:648308.
- 6. Uhl P, Fricker G, Haberkorn U, Mier W. Current status in the therapy of liver diseases. Int J Mol Sci 2014;15:7500-7512.
- 7. Speroni E, Cervellati R, Govoni P, Guizzardi S, Renzulli C, Guerra MC. Efficacy of different Cynara scolymus preparations on liver complaints. J Ethnopharmacol 2003;86:203-211.
- 8. Leung AT, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York (NY): John Wiley & Sons, Inc.; 1996, p 649.
- 9. Barnes J, Anderson LA, Phillipson JD. Herbal medicines: a guide for healthcare professionals. London: The Pharmaceutical Press; 1996.
- 10. Mulinacci N, Prucher D, Peruzzi M, Romani A, Pinelli P, Giaccherini C, Vincieri FF. Commercial and laboratory extracts from artichoke leaves: estimation of caffeoyl esters and flavonoidic compounds content. J Pharm Biomed Anal 2004;34:349-357.
- 11. Zhu X, Zhang H, Lo R. Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities. J Agric Food Chem 2004;52:7272-7278.
- 12. Küskü-Kiraz Z, Mehmetçik G, Doǧru-Abbasoǧlu S, Uysal M. Artichoke leaf extract reduces oxidative stress and lipoprotein dyshomeostasis in rats fed on high cholesterol diet. Phytother Res 2010;24:565-570.
- 13. Zapolska-Downar D, Zapolski-Downar A, Naruszewicz M, Siennicka A, Krasnodębska B, Kołdziej B. Protective properties of artichoke (Cynara scolymus) against oxidative stress induced in cultured endothelial cells and monocytes. Life Sci 2002;71:2897-2808.
- 14. Jiménez-Escrig A, Dragsted LO, Daneshvar B, Pulido R, Saura-Calixto F. In vitro antioxidant activities of edible artichoke (Cynara scolymus L.) and effect on biomarkers of antioxidants in rats. J Agric Food Chem 2003;51:5540-5545.
- 15. Heidarian E, Soofiniya Y, Hajihosseini R. The effect of aerial part of Cynara scolymus extract on the hyperlipidemia, plasma antioxidant capacity, and superoxide dismutase activity in diabetic rats. J Shahrekord Univ Med Sci 2011;13:1-9.
- 16. Mehmetçik G, Özdemirler G, Koçak-Toker N, Cevikbaş 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.
- 17. Panahi Y, Kianpour P, Mohtashami R, Atkin SL, Butler AE, Jafari R, Badeli R, Sahebkar A. Efficacy of artichoke leaf extract in non-alcoholic fatty liver disease: a pilot double-blind randomized controlled trial. Phytother Res 2018;32:1382-1387.
- 18. Miccadei S, Di Venere D, Cardinali A, Romano F, Durazzo A, Foddai MS, Fraioli R, Mobarhan S, Maiani G. Antioxidative and apoptotic properties of polyphenolic extracts from edible part of artichoke (Cynara scolymus L.) on cultured rat hepatocytes and on human hepatoma cells. Nutr Cancer 2008;60:276-283.
- 19. Fallah Huseini H, Kianbakht S, Heshmat R.
Cynara scolymus L. in treatment of hypercholesterolemic type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. J Med Plants 2012;11:58-65.
- 20. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
- 21. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP J Club 1995;123:A12-A13.
- 22. Higgins JPT, Altman DG, Sterne JAC. Chapter 8. Assessing risk of bias in included studies. In Higgins JPT, Green S, eds, ddCochrane handbook for systematic reviews of interventions. London: Cochrane Collaboration; 2008, pp 187-241.
- 23. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Hoboken (NJ): John Wiley & Sons, Ltd; 2011.
- 24. Fedorov S. GetData Graph Digitizer version 2.24 [Internet]. 2002. Available from: www.getdata-graph-digitizer.com
- 25. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 2007;28:105-114.
- 26. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.
- 27. Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittelforschung 2000;50:260-265.
- 28. Musolino V, Gliozzi M, Bombardelli E, Nucera S, Carresi C, Maiuolo J, Mollace R, Paone S, Bosco F, Scarano F, Scicchitano M, Macrì R, Ruga S, Zito MC, Palma E, Gratteri S, Ragusa M, Volterrani M, Fini M, Mollace V. The synergistic effect of Citrus bergamia and Cynara cardunculus extracts on vascular inflammation and oxidative stress in non-alcoholic fatty liver disease. J Tradit Complement Med 2020;10:268-274.
- 29. Rangboo V, Noroozi M, Zavoshy R, Rezadoost SA, Mohammadpoorasl A. The effect of artichoke leaf extract on alanine aminotransferase and aspartate aminotransferase in the patients with nonalcoholic steatohepatitis. Int J Hepatol 2016;2016:4030476.
- 30. Roghani-Dehkordi F, Kamkhah AF. Artichoke leaf juice contains antihypertensive effect in patients with mild hypertension. J Diet Suppl 2009;6:328-341.
- 31. Rondanelli M, Riva A, Petrangolini G, Allegrini P, Bernardinelli L, Fazia T, Peroni G, Gasparri C, Nichetti M, Faliva MA, Naso M, Perna S. The metabolic effects of Cynara supplementation in overweight and obese class I subjects with newly detected impaired fasting glycemia: a double-blind, placebo-controlled, randomized clinical trial. Nutrients 2020;12:3298.
- 32. Moradi S, Shokri-Mashhadi N, Saraf-Bank S, Mohammadi H, Zobeiri M, Clark CC, Rouhani MH. The effects of Cynara scolymus L. supplementation on liver enzymes: a systematic review and meta-analysis. Int J Clin Pract 2021;75:e14726.
- 33. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023.
- 34. Naik SR, Panda VS. Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents. Liver Int 2007;27:393-399.
- 35. Mouzaki M, Allard J. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Ann Gastroenterol 2012;25:207-217.
- 36. Ebrahimi-Mameghani M, Asghari-Jafarabadi M, Rezazadeh K. TCF7L2-rs7903146 polymorphism modulates the effect of artichoke leaf extract supplementation on insulin resistance in metabolic syndrome: a randomized, double-blind, placebo-controlled trial. J Integr Med 2018;16:329-334.
- 37. Al-Ahdab MJ. Protective effect of artichoke (Cynara scolymus L.) leaves and pulp extracts against carbon tetrachloride-induced acute hepatotoxicity in rats. World Appl Sci J 2014;32:1004-1014.
- 38. El Sohaimy SA. Chemical composition, antioxidant and antimicrobial potential of artichoke. Open Nutraceuticals J 2014;7:15-20.
- 39. Vamanu E, Vamanu A, Nita S, Colceriu SJ. Antioxidant and antimicrobial activities of ethanol extracts of Cynara scolymus (Cynarae folium, Asteraceae family). Trop J Pharm Res 2011;10:777-783.
- 40. Gebhardt R, Fausel M. Antioxidant and hepatoprotective effects of artichoke extracts and constituents in cultured rat hepatocytes. Toxicol In Vitro 1997;11:669-672.
- 41. Rezazadeh K, Rahmati-Yamchi M, Mohammadnejad L, Ebrahimi-Mameghani M, Delazar A. Effects of artichoke leaf extract supplementation on metabolic parameters in women with metabolic syndrome: Influence of TCF7L2-rs7903146 and FTO-rs9939609 polymorphisms. Phytother Res 2018;32:84-93.
- 42. Rondanelli M, Opizzi A, Faliva M, Sala P, Perna S, Riva A, Morazzoni P, Bombardelli E, Giacosa A. Metabolic management in overweight subjects with naive impaired fasting glycaemia by means of a highly standardized extract from Cynara scolymus: a double-blind, placebo-controlled, randomized clinical trial. Phytother Res 2014;28:33-41.
- 43. Rondanelli M, Giacosa A, Orsini F, Opizzi A, Villani S. Appetite control and glycaemia reduction in overweight subjects treated with a combination of two highly standardized extracts from Phaseolus vulgaris and Cynara scolymus
. Phytother Res 2011;25:1275-1282.
- 44. Aksu Ö, Altinterim B. Hepatoprotective effects of artichoke (Cynara scolymus). Bilim ve Genclik Dergisi 2013;1:44-49.
- 45. Metwally NS, Kholeif TE, Ghanem KZ, Farrag AR, Ammar NM, Abdel-Hamid AH. The protective effects of fish oil and artichoke on hepatocellular carcinoma in rats. Eur Rev Med Pharmacol Sci 2011;15:1429-1444.
- 46. Brown JE, Rice-Evans CA. Luteolin-rich artichoke extract protects low density lipoprotein from oxidation in vitro. Free Radic Res 1998;29:247-255.
- 47. Goñi I, Jiménez-Escrig A, Gudiel M, Saura-Calixto FD. Artichoke (Cynara scolymus L) modifies bacterial enzymatic activities and antioxidant status in rat cecum. Nutr Res 2005;25:607-615.
- 48. Skarpanska-Stejnborn A, Pilaczynska-Szczesniak L, Basta P, Deskur-Smielcka E, Horoszkiewicz-Hassan M. The influence of supplementation with artichoke (Cynara scolymus L.) extract on selected redox parameters in rowers. Int J Sport Nutr Exerc Metab 2008;18:313-327.
- 49. Gebhardt R. Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke (Cynara scolymus L.) extracts. J Pharmacol Exp Ther 1998;286:1122-1128.
- 50. Azzini E, Bugianesi R, Romano F, Di Venere D, Miccadei S, Durazzo A, Foddai MS, Catasta G, Linsalata V, Maiani G. Absorption and metabolism of bioactive molecules after oral consumption of cooked edible heads of Cynara scolymus L. (cultivar Violetto di Provenza) in human subjects: a pilot study. Br J Nutr 2007;97:963-969.
- 51. Wittemer SM, Ploch M, Windeck T, Müller SC, Drewelow B, Derendorf H, Veit M. Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of artichoke leaf extracts in humans. Phytomedicine 2005;12:28-38.
- 52. Schütz K, Kammerer D, Carle R, Schieber A. Identification and quantification of caffeoylquinic acids and flavonoids from artichoke (Cynara scolymus L.) heads, juice, and pomace by HPLC-DAD-ESI/MS(n). J Agric Food Chem 2004;52:4090-4096.
- 53. Mohamed SH, Ahmed HH, Harrag AR, Abdel-Azim NS, Shahat AA.
Cynara scolymus for relieving on nonalcoholic steatohepatitis induced in rats. Int J Pharm Pharm Sci 2013;5:57-66.
- 54. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
- 55. Leonarduzzi G, Sottero B, Poli G. Targeting tissue oxidative damage by means of cell signaling modulators: the antioxidant concept revisited. Pharmacol Ther 2010;128:336-374.
- 56. Salekzamani S, Ebrahimi-Mameghani M, Rezazadeh K. The antioxidant activity of artichoke (Cynara scolymus): a systematic review and meta-analysis of animal studies. Phytother Res 2019;33:55-71.
- 57. Huber R, Müller M, Naumann J, Schenk T, Lüdtke R. Artichoke leave extract for chronic hepatitis C - a pilot study. Phytomedicine 2009;16:801-804.
, Fatemeh Sheikhhossein2
