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Hormoznejad R, Mohammad Shahi M, Mahboobi S, Rahim F, Helli B, Alavinejad P, et al . The Impact of Combined Cranberry Supplementation and Weight Loss Diet on Inflammatory, Antioxidant, and Apoptosis Biomarkers in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized, Double-Blinded, Controlled Clinical Trial. JNFS 2024; 9 (4) :692-701
URL: http://jnfs.ssu.ac.ir/article-1-843-en.html
URL: http://jnfs.ssu.ac.ir/article-1-843-en.html
Razie Hormoznejad 
, Majid Mohammad Shahi * , Sepideh Mahboobi , Fakher Rahim , Bijan Helli , Pezhman Alavinejad , Narges Dehghanseresht , Narges Sadeghi , Asaad Sharhani
, Majid Mohammad Shahi * , Sepideh Mahboobi , Fakher Rahim , Bijan Helli , Pezhman Alavinejad , Narges Dehghanseresht , Narges Sadeghi , Asaad Sharhani
Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Keywords: Vaccinium macrocarpon, Non-alcohlic fatty liver diseases, Inflammation, Oxidative stress, Apoptosis.
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The Impact of Combined Cranberry Supplementation and Weight Loss Diet on Inflammatory, Antioxidant, and Apoptosis Biomarkers in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized, Double-Blinded, Controlled Clinical Trial
Razie Hormoznejad; PhD1, Majid Mohammad Shahi; PhD*1, Sepideh Mahboobi; PhD2,
Fakher Rahim; PhD3, 4, Bijan Helli; MD1, Pezhman Alavinejad; MD5, Narges Dehghanseresht; MSc6,
Narges Sadeghi; MSc6 & Asaad Sharhani; PhD7
Razie Hormoznejad; PhD1, Majid Mohammad Shahi; PhD*1, Sepideh Mahboobi; PhD2,
Fakher Rahim; PhD3, 4, Bijan Helli; MD1, Pezhman Alavinejad; MD5, Narges Dehghanseresht; MSc6,
Narges Sadeghi; MSc6 & Asaad Sharhani; PhD7
1 Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;
2 Department of Clinical Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran; 3 Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 4 Research Center of Thalassemia & Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 5 Alimentary Tract Research Center, Ahvaz Imam Hospital, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 6 Department of Nutrition, Faculty of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 7 Department of Epidemiology, and Biostatistics, School of Public Health, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran.
2 Department of Clinical Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran; 3 Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 4 Research Center of Thalassemia & Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 5 Alimentary Tract Research Center, Ahvaz Imam Hospital, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; 6 Department of Nutrition, Faculty of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 7 Department of Epidemiology, and Biostatistics, School of Public Health, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The aim of this study is to evaluate the effect of combined weight loss diet and cranberry supplementation on anthropometric measurements, inflammation and antioxidant biomarkers in patients with NAFLD. Methods: In this randomized, double-blinded, and controlled clinical trial, 41 NAFLD patients were supplemented with either cranberry or placebo tablets for 12 weeks. Both groups followed a diet of 500-1000 calories less than the estimated energy requirements. Serum levels of total antioxidant capacity (TAC), malondialdehyde (MDA), cytokeratin 18 M30 (CK-18 M30), chemokine C-C motif ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α) were measured at both baseline and the end of the study. Results: Significant improvements in TAC were observed in the cranberry group and between the two groups (P=0.006 and P=0.011, respectively), but the changes in the placebo group were not significant (P=0.325). There were no statistically significant differences in the serum levels of MDA, CK-18 M30, CCL2 and TNF-α between the cranberry and the placebo groups (P>0.05). Conclusions: It seems that daily consumption of cranberry supplement would be beneficial in increasing serum levels of TAC. Further studies are needed to investigate the effects of anti-inflammatory and antioxidant properties of cranberry on NAFLD. | |
| Article history: Received: 5 Mar 2023 Revised: 14 Feb 2023 Accepted:21 Feb 2023 |
||
| *Corresponding author: shahi334@gmail.com Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Postal code: 61357-15794 Tel: + 98 6133738253 |
||
| Keywords: Vaccinium macrocarpon; Non-alcohlic fatty liver diseases; Inflammation; Oxidative stress; Apoptosis. |
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a condition in which excessive accumulation of triglycerides in the cytoplasm of hepatocytes
(>0.5%) without the over-consumption of alcohol (Benedict and Zhang, 2017). NAFLD that embrace a broad spectrum of physio-pathological conditions from simple steatosis to non-alcoholic steatohepatitis (NASH), is highly related to obesity, diabetes, insulin resistance, hypertension, hyperlipidemia, and metabolic syndrome (Asrih and Jornayvaz, 2015). The prevalence of NAFLD is currently estimated to be about 25-30% (Le et al., 2022). In terms of pathogenesis of NAFLD, it has been shown in both “two-hit” model and “multi-parallel hit” hypothesis that hepatic inflammation, oxidative stress, necrosis, apoptosis, and finally, fibrosis are caused by excessive fat accumulation in hepatocytes (Abenavoli et al., 2017). A fundamental intervention for the management of NAFLD is lifestyle modification such as having healthy eating patterns and regular exercise (Friedman et al., 2018, Kwon et al., 2023). An increased serum content of free-radical oxidation products and a decreased total antioxidant capacity (TAC) in patients with NAFLD have been detected (Abenavoli et al., 2017). It is recommended that antioxidant and anti-inflammatory supplements may be beneficial as adjuvant therapy along with healthy eating patterns in oxidative stress and inflammation among patients with NAFLD (Mansoori et al., 2020). Available evidence shows that food ingredients such as phytochemicals, vitamins and minerals exhibit anti-inflammatory, antioxidant and immune-regulating activity in body (Hormoznejad et al., 2021). One of the classes of phytochemicals are phenolics compounds, which include flavonoids and polyphenol (Nisar, 2022). Researchers have shown that these phytochemicals have the ability to scavenge free radicals, reduce inflammation, and modify the lipid profile. Cranberries (Vaccinium Macrocarpon) are rich in polyphenols such as flavonols, catechins, anthocyanins, resveratrol, organic acids, B-type proanthocyanidins (PACs) and a high amount of rare A-type PACs (Flammer et al., 2013), and according to the United States Department of Agriculture (USDA), they have the highest free radical scavenging ability (Abenavoli et al., 2016). The previous studies have shown that cranberry bio-actives have various beneficial effects, such as reducing inflammation in humans and in vitro. They also help in reducing blood markers of oxidative stress in humans (Glisan et al., 2016) and hepatic inflammation and steatosis in mice that are fed a high-fat diet and hepatic inflammation and steatosis in mice fed a high-fat diet (Shimizu et al., 2019). Impact of consumption of low-calorie cranberry juice on several cardiometabolic risk factors in overweight middle-aged population was investigated. There was a significant improvement in C-reactive protein (CRP) for intervention group after 8 weeks of evaluation (Novotny et al., 2015).
This placebo-controlled, double-blind, randomized clinical trial study was designed to explore the possible role of combined weight loss diet and cranberry supplementation on inflammatory, antioxidant, and apoptosis biomarkers in patients with NAFLD because of the anti-inflammatory and antioxidant properties of cranberry and role of inflammation and oxidative stress in pathogenesis of NAFLD.
Materials and Methods
Samples and study design
In this randomized double-blind and placebo-controlled clinical trial, the patients with NAFLD were recruited from Ahvaz Golestan Hospital. Totally, 50 eligible patients were recruited. A signed consent form was collected by all participants. The recruited participants were randomly allocated to control (n=25) and intervention (n=25) groups based on the block design. The type of treatment was selected by numbering it in the envelope without the person studied, and the researcher was responsible for the intervention being aware of it. Elsewhere, the numbers were computerized to determine whether the number was a cranberry supplement or placebo. Being 18 or older, having body mass index (BMI) of 25–35 kg/m2, and having confirmed NAFLD (the grade of steatosis higher or equal to 2 at ultrasonography) were the inclusion criteria; having a history of significant alcohol intake (more than 10 mL/day for women and 20 ml/d for men), smoking habits, being affected by other liver diseases, cardiovascular, respiratory, kidney disorders, malignancies, hypertension, dyslipidemia, hypothyroidism, and diabetes mellitus, pregnancy or breastfeeding, being under medication in the previous 6 months, having supplementation with antioxidants or vitamins, having weight loss over the past 3 months, and having metabolism and endocrine disorders pregnancy or breastfeeding, were the exclusion criteria. The placebo and cranberry groups received either placebo or cranberry tablets (two tablets; one tablet after lunch and another one after dinner) for 12 weeks. Cranberry tablets were purchased from Shari Nutraceutical Co., Tehran, Iran. Each tablet contained 144 mg of vaccinium macrocarpon extract with at least 36 mg proanthocyanidine (equal to 13 g dried cranberry fruit), while composition of the remaining 144 mg was unknown. Placebo tablets contained 288 mg starch. The cranberry and placebo tablets were similar in color, size, and weight. Both groups followed a diet of 500-1000 calories less than the estimated energy requirement. Energy requirements were calculated by Mifflin Jeor St equation. The distribution of macronutrients content in relation to the diet was as follows: 15% to 18% protein, 52% to 55% carbohydrate, and ≤ 30% fat (Bellentani et al. 2008). Dietary intakes were obtained from three 24 h dietary recalls (1 weekend day and 2 weekdays). Physical activity levels were assessed by metabolic equivalent of task (MET) questionnaire (Ainsworth et al., 2000).
Biochemical and anthropometric measurements
At baseline, 6th weeks and after 12 weeks, all participants underwent anthropometric measurements: Height was measured to the nearest 0.1 cm using a non-stretched tape measure. Weight, body fat (BF), and BMI were measured using a bioelectrical impedance analysis (OMRON device BF-511). Waist circumference (WC) (the widest area between the lower rib and the superior iliac crest) was also measured to the nearest 0.1 cm. A fasting blood sample (12 ml) was collected from participants at baseline and the end of intervention. Blood samples were centrifuged at 3500 rpm for 10 min, and then, the supernates were stored at -70 °C until analysis. The serum samples were used to analyze TAC, tumor necrosis factor alpha (TNF-α), Malondialdehyde (MDA), Cytokeratin 18 M30 (CK-18 M30), and C-C Motif Chemokine Ligand 2 (CCL2). Serum levels of CCL2, CK-18 M30, TNF-α and TAC were measured using ELISA method by laboratory kits (Biotech Day Crystal for CCL2, CK-18 M30, TNF-α; and LDN, PLabor Diagnostika Nord GmbH, Germany for TAC). Serum MDA levels were assessed utilizing thiobarbituric acid reactive substances (TBARS).
Ethical considerations
The research protocol was approved by the ethics committee of the Research Deputy of Ahvaz Jundishapur University of Medical Sciences (IR.AJUMS.REC.1397.678). This clinical trial study was registered in “Iranian Registry of Clinical Trials” with IRCT number IRCT20150124020765N2.
Data analysis
Considering 95% confidence interval with an estimated standard deviation and difference in fasting blood glucose (Shidfar et al., 2012), the sample size was calculated, and 25 subjects in each group were determined. Statistical analyses were performed using IBM SPSS (version 19.0, SPSS Inc., Chicago, IL, USA). The results were presented as mean±SD, and P-value of lower than 0.05 was considered significant. Kolmogorov-Smirnov test was used to assess the normal distribution of variables. Independent samples comparisons in terms of quantitative variables were performed using two independent samples t-tests and repeated measures ANOVA. In order to analyze nutrient intakes, “Nutritionist IV” software was applied.
Results
In this study, 9 out of 50 patients were excluded due to non-adherence to diet and medication. Therefore, 21 participants in the group received cranberry supplements, and 20 in the placebo group remained in the study (Figure 1). Patients’ compliance with this randomized clinical trial study was 82%. The characteristics of participants are shown in Table 1. No statistically significant difference was seen between the two groups in terms of their demographic characteristics or their baseline biomedical, and anthropometric measurements. Table 2 shows dietary intake and anthropometric indices of the two groups. Statistical analysis showed that after 12 weeks, weight, BF, BMI, and WC significantly decreased in both groups. There was no significant difference in weight, BMI, BF, and WC between the two groups. No significant differences were also observed between two groups for dietary data including the intakes of energy and macronutrients at the end of the study.
Table 3 shows the inflammatory, antioxidant and apoptosis biomarkers at baseline after 12 weeks for the two groups. Significant improvements in TAC were observed in the cranberry group and between the two groups (P=0.006 and P=0.011, respectively), but the changes in the placebo group were not significant (P=0.325). The mean MDA was reduced (but not significantly) in the cranberry group after intervention; moreover, no significant differences were seen in serum levels of MDA between the cranberry and the placebo groups. Also, both within cranberry and placebo groups, there were no significant changes in the mean levels of CK-18 M30 in post-intervention compared with baseline. There were no statistically significant differences in the serum levels of CCL2 and TNF-α between the cranberry and the placebo groups.
(>0.5%) without the over-consumption of alcohol (Benedict and Zhang, 2017). NAFLD that embrace a broad spectrum of physio-pathological conditions from simple steatosis to non-alcoholic steatohepatitis (NASH), is highly related to obesity, diabetes, insulin resistance, hypertension, hyperlipidemia, and metabolic syndrome (Asrih and Jornayvaz, 2015). The prevalence of NAFLD is currently estimated to be about 25-30% (Le et al., 2022). In terms of pathogenesis of NAFLD, it has been shown in both “two-hit” model and “multi-parallel hit” hypothesis that hepatic inflammation, oxidative stress, necrosis, apoptosis, and finally, fibrosis are caused by excessive fat accumulation in hepatocytes (Abenavoli et al., 2017). A fundamental intervention for the management of NAFLD is lifestyle modification such as having healthy eating patterns and regular exercise (Friedman et al., 2018, Kwon et al., 2023). An increased serum content of free-radical oxidation products and a decreased total antioxidant capacity (TAC) in patients with NAFLD have been detected (Abenavoli et al., 2017). It is recommended that antioxidant and anti-inflammatory supplements may be beneficial as adjuvant therapy along with healthy eating patterns in oxidative stress and inflammation among patients with NAFLD (Mansoori et al., 2020). Available evidence shows that food ingredients such as phytochemicals, vitamins and minerals exhibit anti-inflammatory, antioxidant and immune-regulating activity in body (Hormoznejad et al., 2021). One of the classes of phytochemicals are phenolics compounds, which include flavonoids and polyphenol (Nisar, 2022). Researchers have shown that these phytochemicals have the ability to scavenge free radicals, reduce inflammation, and modify the lipid profile. Cranberries (Vaccinium Macrocarpon) are rich in polyphenols such as flavonols, catechins, anthocyanins, resveratrol, organic acids, B-type proanthocyanidins (PACs) and a high amount of rare A-type PACs (Flammer et al., 2013), and according to the United States Department of Agriculture (USDA), they have the highest free radical scavenging ability (Abenavoli et al., 2016). The previous studies have shown that cranberry bio-actives have various beneficial effects, such as reducing inflammation in humans and in vitro. They also help in reducing blood markers of oxidative stress in humans (Glisan et al., 2016) and hepatic inflammation and steatosis in mice that are fed a high-fat diet and hepatic inflammation and steatosis in mice fed a high-fat diet (Shimizu et al., 2019). Impact of consumption of low-calorie cranberry juice on several cardiometabolic risk factors in overweight middle-aged population was investigated. There was a significant improvement in C-reactive protein (CRP) for intervention group after 8 weeks of evaluation (Novotny et al., 2015).
This placebo-controlled, double-blind, randomized clinical trial study was designed to explore the possible role of combined weight loss diet and cranberry supplementation on inflammatory, antioxidant, and apoptosis biomarkers in patients with NAFLD because of the anti-inflammatory and antioxidant properties of cranberry and role of inflammation and oxidative stress in pathogenesis of NAFLD.
Materials and Methods
Samples and study design
In this randomized double-blind and placebo-controlled clinical trial, the patients with NAFLD were recruited from Ahvaz Golestan Hospital. Totally, 50 eligible patients were recruited. A signed consent form was collected by all participants. The recruited participants were randomly allocated to control (n=25) and intervention (n=25) groups based on the block design. The type of treatment was selected by numbering it in the envelope without the person studied, and the researcher was responsible for the intervention being aware of it. Elsewhere, the numbers were computerized to determine whether the number was a cranberry supplement or placebo. Being 18 or older, having body mass index (BMI) of 25–35 kg/m2, and having confirmed NAFLD (the grade of steatosis higher or equal to 2 at ultrasonography) were the inclusion criteria; having a history of significant alcohol intake (more than 10 mL/day for women and 20 ml/d for men), smoking habits, being affected by other liver diseases, cardiovascular, respiratory, kidney disorders, malignancies, hypertension, dyslipidemia, hypothyroidism, and diabetes mellitus, pregnancy or breastfeeding, being under medication in the previous 6 months, having supplementation with antioxidants or vitamins, having weight loss over the past 3 months, and having metabolism and endocrine disorders pregnancy or breastfeeding, were the exclusion criteria. The placebo and cranberry groups received either placebo or cranberry tablets (two tablets; one tablet after lunch and another one after dinner) for 12 weeks. Cranberry tablets were purchased from Shari Nutraceutical Co., Tehran, Iran. Each tablet contained 144 mg of vaccinium macrocarpon extract with at least 36 mg proanthocyanidine (equal to 13 g dried cranberry fruit), while composition of the remaining 144 mg was unknown. Placebo tablets contained 288 mg starch. The cranberry and placebo tablets were similar in color, size, and weight. Both groups followed a diet of 500-1000 calories less than the estimated energy requirement. Energy requirements were calculated by Mifflin Jeor St equation. The distribution of macronutrients content in relation to the diet was as follows: 15% to 18% protein, 52% to 55% carbohydrate, and ≤ 30% fat (Bellentani et al. 2008). Dietary intakes were obtained from three 24 h dietary recalls (1 weekend day and 2 weekdays). Physical activity levels were assessed by metabolic equivalent of task (MET) questionnaire (Ainsworth et al., 2000).
Biochemical and anthropometric measurements
At baseline, 6th weeks and after 12 weeks, all participants underwent anthropometric measurements: Height was measured to the nearest 0.1 cm using a non-stretched tape measure. Weight, body fat (BF), and BMI were measured using a bioelectrical impedance analysis (OMRON device BF-511). Waist circumference (WC) (the widest area between the lower rib and the superior iliac crest) was also measured to the nearest 0.1 cm. A fasting blood sample (12 ml) was collected from participants at baseline and the end of intervention. Blood samples were centrifuged at 3500 rpm for 10 min, and then, the supernates were stored at -70 °C until analysis. The serum samples were used to analyze TAC, tumor necrosis factor alpha (TNF-α), Malondialdehyde (MDA), Cytokeratin 18 M30 (CK-18 M30), and C-C Motif Chemokine Ligand 2 (CCL2). Serum levels of CCL2, CK-18 M30, TNF-α and TAC were measured using ELISA method by laboratory kits (Biotech Day Crystal for CCL2, CK-18 M30, TNF-α; and LDN, PLabor Diagnostika Nord GmbH, Germany for TAC). Serum MDA levels were assessed utilizing thiobarbituric acid reactive substances (TBARS).
Ethical considerations
The research protocol was approved by the ethics committee of the Research Deputy of Ahvaz Jundishapur University of Medical Sciences (IR.AJUMS.REC.1397.678). This clinical trial study was registered in “Iranian Registry of Clinical Trials” with IRCT number IRCT20150124020765N2.
Data analysis
Considering 95% confidence interval with an estimated standard deviation and difference in fasting blood glucose (Shidfar et al., 2012), the sample size was calculated, and 25 subjects in each group were determined. Statistical analyses were performed using IBM SPSS (version 19.0, SPSS Inc., Chicago, IL, USA). The results were presented as mean±SD, and P-value of lower than 0.05 was considered significant. Kolmogorov-Smirnov test was used to assess the normal distribution of variables. Independent samples comparisons in terms of quantitative variables were performed using two independent samples t-tests and repeated measures ANOVA. In order to analyze nutrient intakes, “Nutritionist IV” software was applied.
Results
In this study, 9 out of 50 patients were excluded due to non-adherence to diet and medication. Therefore, 21 participants in the group received cranberry supplements, and 20 in the placebo group remained in the study (Figure 1). Patients’ compliance with this randomized clinical trial study was 82%. The characteristics of participants are shown in Table 1. No statistically significant difference was seen between the two groups in terms of their demographic characteristics or their baseline biomedical, and anthropometric measurements. Table 2 shows dietary intake and anthropometric indices of the two groups. Statistical analysis showed that after 12 weeks, weight, BF, BMI, and WC significantly decreased in both groups. There was no significant difference in weight, BMI, BF, and WC between the two groups. No significant differences were also observed between two groups for dietary data including the intakes of energy and macronutrients at the end of the study.
Table 3 shows the inflammatory, antioxidant and apoptosis biomarkers at baseline after 12 weeks for the two groups. Significant improvements in TAC were observed in the cranberry group and between the two groups (P=0.006 and P=0.011, respectively), but the changes in the placebo group were not significant (P=0.325). The mean MDA was reduced (but not significantly) in the cranberry group after intervention; moreover, no significant differences were seen in serum levels of MDA between the cranberry and the placebo groups. Also, both within cranberry and placebo groups, there were no significant changes in the mean levels of CK-18 M30 in post-intervention compared with baseline. There were no statistically significant differences in the serum levels of CCL2 and TNF-α between the cranberry and the placebo groups.
| Table 1. Baseline characteristics and dietary intakes of study participants. | |||
| Variable | Placebo group (n=21) | Cranberry group (n=20) | P-valuea |
| Age (years) | 40.00 ± 9.91 | 43.55 ± 11.51 | 0.296 |
| Gender Female Male |
7 (38.9)b 14 (60.9) |
11 (61.1) 9 (39.1) |
0.215 |
| Weight (kg) | 89.66±13.39 | 89.94±11.58 | 0.944 |
| Height (m) | 1.68±0.08 | 1.67±0.12 | 0.758 |
| Body mass index (kg/m2) | 31.67±4.72 | 32.46±6.09 | 0.645 |
| Waist circomference (cm) | 105.64±9.19 | 106.52±11.15 | 0.783 |
| Body fat (%) | 40.12±11.01 | 39.46±10.72 | 0.847 |
| MET (min/d) | 35.77±4.81 | 33.68±2.44 | 0.090 |
| Total antioxidant capacity (mmol/l) | 1.42±0.50 | 1.21±0.47 | 0.197 |
| Malondialdehyde (nmol/ml) | 13.14±7.11 | 12.28±6.33 | 0.686 |
| CK-18 M30 (ngl/ml) | 16.01±7.88 | 18.76±7.06 | 0.248 |
| CCL2 (ng/l) | 851.05±875.96 | 916.94±374.78 | 0.669 |
| TNF-α (ng/l) | 433.98±300.22 | 547.13±242.38 | 0.193 |
| Energy (kcal/day) | 2714.98±799.72 | 2743.85±706.31 | 0.903 |
| Carbohydrate (g/day) | 340.15±90.84 | 364.51±121.15 | 0.469 |
| Protein (g/day) | 96.94±33.76 | 83.66±35.69 | 0.228 |
| Fat (g/day) | 104.10±55.04 | 95.90±19.40 | 0.535 |
| MET: Metabolic equivalent of task; CK-18 M30: Cytokeratin 18-M30; CCL2: Chemokine C-C motif ligand 2; TNF-α: Tumor necrosis factor alpha; a: Student t-test and Ch-square test used for quantitative and categorical variables, respectively; b: n(%). | |||
Discussion
The present study was conducted to evaluate the effects of cranberry supplementation and weight loss diet on markers of inflammation (TNF-α and CCL-2), oxidative stress (MDA and TAC) and hepatic cell apoptosis (CK-18 M30) in NAFLD patients. Supplementing a weight loss diet with cranberry for a period of 12 weeks could significantly increase TAC. However, changes in other variables remained insignificant. Different studies have been conducted on the effects of cranberry with or without dietary interventions on these markers with different intervention types (extract, juice, tablet, etc), variable doses, and different findings.
Cytokine imbalances occur in the “second hit” of NAFLD. Therefore, the issue has gained a considerable attention as a target for therapeutic interventions (Speliotes and George, 2022). Glisan et al. evaluated the effects of polyphenol enriched cranberry extract (CBE) on markers of hepatic inflammation in HFD-fed obese rats and found that CBE can decrease hepatic protein levels of TNF-α and CCL-2, as well as hepatic mRNA levels of toll like receptor-4 (TLR-4) and nuclear factor κB (NFκB) (Glisan et al., 2016). Another study was performed to evaluate possible anti-fibrotic effects of cranberry nutraceuticals in high fat cholesterol diet induced (HFCD)-NAFLD rats.
The present study was conducted to evaluate the effects of cranberry supplementation and weight loss diet on markers of inflammation (TNF-α and CCL-2), oxidative stress (MDA and TAC) and hepatic cell apoptosis (CK-18 M30) in NAFLD patients. Supplementing a weight loss diet with cranberry for a period of 12 weeks could significantly increase TAC. However, changes in other variables remained insignificant. Different studies have been conducted on the effects of cranberry with or without dietary interventions on these markers with different intervention types (extract, juice, tablet, etc), variable doses, and different findings.
Cytokine imbalances occur in the “second hit” of NAFLD. Therefore, the issue has gained a considerable attention as a target for therapeutic interventions (Speliotes and George, 2022). Glisan et al. evaluated the effects of polyphenol enriched cranberry extract (CBE) on markers of hepatic inflammation in HFD-fed obese rats and found that CBE can decrease hepatic protein levels of TNF-α and CCL-2, as well as hepatic mRNA levels of toll like receptor-4 (TLR-4) and nuclear factor κB (NFκB) (Glisan et al., 2016). Another study was performed to evaluate possible anti-fibrotic effects of cranberry nutraceuticals in high fat cholesterol diet induced (HFCD)-NAFLD rats.
| Table 2. Anthropometric measurements and dietary intakes at the baseline, 6 weeks and after 12 weeks. | |||
| Variable | Placebo group (n=21) | Cranberry group (n=20) | P-valueb |
| Weight (kg) Baseline 6 weeks 12 weeks P-valuea |
89.66±13.39c 86.20±11.98 84.50±11.65 < 0.001 |
89.94±11.58 88.19±11.60 85.85±10.64 <0.001 |
0.984 0.858 0.341 |
| Body mass index (kg/m2) Baseline 6 weeks 12 weeks P-value |
31.67±4.72 30.44±4.12 29.87±4.32 <0.001 |
32.46±6.09 31.85±6.20 31.04±6.02 < 00.1 |
0.749 0.493 0.551 |
| Waist circumference Baseline 6 weeks 12 weeks P-value |
105.64±9.19 102.19±8.39 101.04±8.24 <0.001 |
106.52±11.15 105.55±12.95 103.60±11.33 <0.001 |
0.888 0.378 0.429 |
| Body fat (%) Baseline 6 weeks 12 weeks P-value |
40.12±11.01 37.13±9.96 34.19±9.39 <0.001 |
39.46±10.72 37.76±10.38 34.54±10.27 <0.001 |
0.704 0.676 0.721 |
| Energy (kcal/day) Baseline 6 weeks 12 weeks P-value |
2714.9±799.0 1956.5±344.0 1749.5±395.0 <0.001 |
2743.8±706.0 2063.3±569.0 1794.0±329.0 <0.001 |
0.067 0.612 0.406 |
| Carbohydrate (%) Baseline 6 weeks 12 weeks P-value |
51.18 ± 7.60 52.84 ± 6.40 52.94 ± 6.48 <0.001 |
52.54 ± 6.64 52.25 ± 6.37 56.23 ± 7.25 <0.001 |
0.124 0.387 0.500 |
| Protein (%) Baseline 6 weeks 12 weeks P-value |
15.54±4.69 16.68±4.86 16.08±5.28 0.005 |
14.86±4.02 14.97±4.77 14.31±3.70 0.007 |
0.180 0.472 0.486 |
| Fat (%) Baseline 6 weeks 12 weeks P-value |
33.28±10.49 30.48±11.82 30.98±8.53 <0.001 |
32.60±7.28 32.78±6.44 29.46±6.52 <0.001 |
0.069 0.308 0.364 |
| a: Kruskal-Wallis test; b: student t-test; c: Means±SD | |||
| Table 3. Biochemical parameters at the baseline and after 12 weeks. | ||||
| Variable | Baseline | 12 weeks | P-valueb | Change |
| Total antioxidant capacity (mmol/l) Placebo Cranberry P-valuea |
1.42±0.50c 1.21±0.47 0.197 |
1.20±0.67 1.73±0.72 0.004 |
0.325 0.006 |
-0.21±0.99 0.52±0.75 0.011 |
| Malondialdehyde (nmol/ml) Placebo Cranberry P-value |
13.14±7.11 12.28±6.33 0.686 |
15.52±14.59 9.95±3.67 0.106 |
0.512 0.208 |
2.38±16.34 -2.33±8.00 0.252 |
| CK-18 M30 (ngl/ml) Placebo Cranberry P-value |
16.01±7.88 18.76±7.06 0.248 |
16.27±6.84 18.12±7.18 0.403 |
0.914 0.736 |
0.26±10.94 -0.63±8.29 0.316 |
| CCL2 (ng/l) Placebo Cranberry P-value |
851.05±875.96 916.94±374.78 0.669 |
960.16±591.13 890.02±410.38 0.663 |
0.585 0.752 |
109.10±900.31 -26.91±375.66 0.535 |
| TNF-α (ng/l) Placebo Cranberry P-value |
433.98±300.22 547.13±242.38 0.193 |
512.57±305.90 502.12±252.72 0.906 |
0.443 0.505 |
78.59±460.21 -45.01±296.46 0.316 |
| CK-18 M30: Cytokeratin 18-M30, CCL2: Chemokine C-C motif ligand 2 (CCL2), TNF-α: Tumor necrosis factor alpha; a: Student t-test; b: Paired t-test; c: Means±SD. | ||||
The results showed that cranberry could alleviate markers of oxidative stress (MDA, glutathione, catalase and superoxide dismutase), inflammation (TNF-α, IL-6 and NFκB) and improved markers of insulin resistance (Faheem et al., 2020). Apoptosis is a key mechanism in the progression of steatosis to NASH, and apoptosis markers are related to histologic severity of NAFLD (He et al., 2023). CK-18 M30 is a well-known substrate of caspase activity during apoptotic hepatocyte death (Yip et al., 2023) and has been shown to have a high accuracy in differentiating NAFLD from control subjects (Zhang et al., 2015). Accordingly, in the current study, CK-18 M30 was assessed as a marker of apoptosis which did not significantly change during intervention. There are few studies regarding anti-apoptotic effects of cranberries. However, some studies have been conducted on other polyphenol-rich compounds in this area. In a randomized clinical trial, 44 participants were given either 250 ml of bayberry juice or placebo twice a day for 4 weeks. Bayberry consumption could significantly improve markers of inflammation and apoptosis including polypeptide specific antigen and CK-18 M30 (Zhang et al., 2015). In another study, 14 days of dark chocolate consumption, as a source of polyphenols, led to a significant reduction in CK-18 M30 in NAFLD patients (Loffredo et al., 2016). According to the findings, multistage processing of fruit extraction leads to a considerable loss in phytochemical content through thermal degradation and polyphenol oxidation which could have been considered as a reason for null findings. Therefore, future research should focus on comparisons between different forms of cranberry supplements.
On the other hand, a significant improvement in TAC was observed in intervention group which indicated possible anti-oxidative effects of cranberry supplements in NAFLD patients. Oxidative stress is the result of an imbalance between pro-oxidants and anti-oxidants and plays a crucial role in pathogenesis of NAFLD (Su et al., 2016). A considerable amount of research has been conducted regarding anti-oxidative effects of berries. In one study, mulberry treatment in HFD rats significantly suppressed hepatic reactive oxygen species (ROS) overproduction and mitochondrial oxidative stress (Yang and Jo, 2018). Another research team investigated the effects of raspberry on obese diabetic (db/db) mice for 8 weeks. The findings showed that raspberry intake could improve antioxidant status and lessen IL-6 in treatment group (Noratto et al., 2017). Results of a double-blind randomized trial showed that 4 weeks supplementation with maqui berry (delphinol) significantly reduced markers of oxidative stress (ox-LDL and urinary F2-isoprostane) in intervention group (Davinelli et al., 2015). Wild blueberry consumption significantly improved postprandial oxidative stress in male subjects. Oxygen radical absorbance capacity (ORAC) assay and the total antioxidant status (TAS) were evaluated as markers of oxidative stress in the study (Kay and Holub, 2002). On the other hand, in a randomized controlled trial, 40 post-menopausal women consumed either 22 grams of blueberry or placebo for 8 weeks. As a result, blood markers of oxidative stress, inflammation, and antioxidant defense did not change in blueberry group after 8 weeks (Johnson et al., 2017).
have immunomodulatory and anti-inflammatory
effects by interacting with gut microbiota (Alves-Santos et al., 2020). In one study, dietary cranberry supplementation in a mouse model of IBD, not only suppressed colonic levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) but also increased the abundance of beneficial gut bacteria including lactobacillus and bifidobacterium (Cai et al., 2019). It has also been shown that phenolic compounds can suppress IL-1β secretion and exert anti-inflammatory effects through inhibition of cyclo-oxygenase and lipoxygenase activity (Lopez-Corona et al., 2022). Antioxidant properties of cranberry are attributed to free radical scavenging properties of polyphenols against ROSs as well as inhibition of lipid and protein oxidation (Côté et al., 2010). According to the studies, cranberry supplementation has also the potential to decrease NO synthase activity, improve homocysteine levels and endothelial function, thus suppressing oxidative stress (Lozovoy et al., 2013).
Certain limitations of the present study include a small sample size and the short study duration. Another limitation might be the lack of polyphenol measurements in cranberry tablet via high performance liquid chromatography (HPLC) method.
Conclusion
In conclusion, this randomized, double-blind, placebo-controlled trial indicates that 288 mg/d of cranberry supplementation in addition to weight loss diet may not change MDA, CK-18 M30, CCL2, and TNF-α, but it will be beneficial in improving serum levels of TAC in NAFLD patients. Further studies are needed to investigate the effects of anti-inflammatory and antioxidant properties of cranberry on NAFLD.
Acknowledgements
This study was part of a PhD thesis by MS Hormoznejad. The authors would like to thank Golestan Hospital of Ahvaz Jundishapur University of Medical Sciences for their support.
Conflict of interests
The authors declared no conflict of interests.
Funding
The present study was financially supported by a grant (NRC-9718) from Vice-Chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences.
Authors’ contributions
Mohammad Shahi M, Rahimi F, and Hormoznejad R were involved in the conception and design of the study. Sharhani A, Helli B, and Alavinejad P contributed to the methodology. Sharhani A performed data analysis and interpretation. Hormoznejad R, Sadeghi N, Dehghanseresht N, and Mahboobi S participated in conducting the study and drafting the manuscript. All the authors read and approved the final manuscript.
References
Abenavoli L, et al. 2017. Effect of Mediterranean diet and antioxidant formulation in non-alcoholic fatty liver disease: a randomized study. Nutrients. 9 (8): 870.
Abenavoli L, et al. 2016. Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World journal of gastroenterology. 22 (31): 7006.
Ainsworth BE, et al. 2000. Compendium of physical activities: an update of activity codes and MET intensities. Medicine and science in sports and exercise. 32 (9; SUPP/1): S498-S504.
Alves-Santos AM, Sugizaki CSA, Lima GC & Naves MMV 2020. Prebiotic effect of dietary polyphenols: A systematic review. Journal of functional foods. 74: 104169.
Anhê FF, et al. 2013. Polyphenols and type 2 diabetes: A prospective review. Pharma nutrition. 1 (4): 105-114.
Asrih M & Jornayvaz FR 2015. Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link? Molecular and cellular endocrinology. 418: 55-65.
Benedict M & Zhang X 2017. Non-alcoholic fatty liver disease: An expanded review. World journal of hepatology. 9 (16): 715.
Cai X, et al. 2019. Dietary cranberry suppressed colonic inflammation and alleviated gut microbiota dysbiosis in dextran sodium sulfate-treated mice. Food & function. 10 (10): 6331-6341.
Côté J, Caillet S, Doyon G, Sylvain J-F & Lacroix M 2010. Bioactive compounds in cranberries and their biological properties. Critical reviews in food science and nutrition. 50 (7): 666-679.
Davinelli S, Bertoglio JC, Zarrelli A, Pina R & Scapagnini G 2015. A randomized clinical trial evaluating the efficacy of an anthocyanin–maqui berry extract (Delphinol®) on oxidative stress biomarkers. Journal of the American College of Nutrition. 34 (sup1): 28-33.
Faheem SA, Saeed NM, El-Naga RN, Ayoub IM & Azab SS 2020. Hepatoprotective effect of cranberry nutraceutical extract in non-alcoholic fatty liver model in rats: Impact on insulin resistance and Nrf-2 expression. Frontiers in pharmacology. 11: 218.
Flammer AJ, et al. 2013. Polyphenol-rich cranberry juice has a neutral effect on endothelial function but decreases the fraction of osteocalcin-expressing endothelial progenitor cells. European journal of nutrition. 52: 289-296.
Friedman SL, Neuschwander-Tetri BA, Rinella M & Sanyal AJ 2018. Mechanisms of NAFLD development and therapeutic strategies. Nature medicine. 24 (7): 908-922.
Glisan SL, Ryan C, Neilson AP & Lambert JD 2016. Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice. Journal of nutritional biochemistry. 37: 60-66.
He L, et al. 2023. Deleting Gata4 in hepatocytes promoted the progression of NAFLD via increasing steatosis and apoptosis, and desensitizing insulin signaling. Journal of nutritional biochemistry. 111: 109157.
Henig YS & Leahy MM 2000. Cranberry juice and urinary-tract health: science supports folklore. Nutrition. 16 (7-8): 684-687.
Hormoznejad R, et al. 2021. Effects of cranberry consumption on features of the metabolic syndrome: a systematic review and meta-analysis of randomized control trials. Nutrition & food science. 51 (6): 1006-1016.
Johnson SA, et al. 2017. Effects of daily blueberry consumption on circulating biomarkers of oxidative stress, inflammation, and antioxidant defense in postmenopausal women with pre-and stage 1-hypertension: a randomized controlled trial. Food & function. 8 (1): 372-380.
Kay CD & Holub BJ 2002. The effect of wild blueberry (Vaccinium angustifolium) consumption on postprandial serum antioxidant status in human subjects. British journal of nutrition. 88 (4): 389-397.
Kwon OY, Choi J-y & Jang Y 2023. The Effectiveness of EHealth Interventions on Lifestyle Modification in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Journal of medical internet research. 25: e37487.
Le MH, et al. 2022. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clinical and molecular hepatology. 28 (4): 841-850.
Loffredo L, et al. 2016. Effects of dark chocolate on NOX‐2‐generated oxidative stress in patients with non‐alcoholic steatohepatitis. Alimentary pharmacology & therapeutics. 44 (3): 279-286.
Lopez-Corona AV, et al. 2022. Antioxidant, Anti-Inflammatory and Cytotoxic Activity of Phenolic Compound Family Extracted from Raspberries (Rubus idaeus): A General Review. Antioxidants. 11 (6): 1192.
Lozovoy MAB, et al. 2013. Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome. British journal of nutrition. 110 (10): 1885-1894.
Mansoori A, et al. 2020. The effect of melatonin supplementation on liver indices in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized clinical trials. Complementary therapies in medicine. 52: 102398.
Nisar A 2022. Medicinal plants and phenolic compounds. In Phenolic Compounds: Chemistry, Synthesis, Diversity, Non-Conventional Industrial, Pharmaceutical and Therapeutic Applications.
Noratto GD, Chew BP & Atienza LM 2017. Red raspberry (Rubus idaeus L.) intake decreases oxidative stress in obese diabetic (db/db) mice. Food chemistry. 227: 305-314.
Novotny JA, Baer DJ, Khoo C, Gebauer SK & Charron CS 2015. Cranberry juice consumption lowers markers of cardiometabolic risk, including blood pressure and circulating C-reactive protein, triglyceride, and glucose concentrations in adults. Journal of nutrition. 145 (6): 1185-1193.
Pappas E & Schaich K 2009. Phytochemicals of cranberries and cranberry products: characterization, potential health effects, and processing stability. Critical reviews in food science and nutrition. 49 (9): 741-781.
Shidfar F, et al. 2012. The effects of cranberry juice on serum glucose, apoB, apoA-I, Lp (a), and Paraoxonase-1 activity in type 2 diabetic male patients. Journal of research in medical sciences. 17 (4): 355.
Shimizu K, et al. 2019. Cranberry attenuates progression of non-alcoholic fatty liver disease induced by high-fat diet in mice. Biological and pharmaceutical bulletin. 42 (8): 1295-1302.
Slavin JL & Lloyd B 2012. Health benefits of fruits and vegetables. Advances in nutrition. 3 (4): 506-516.
Speliotes EK & George J 2022. Metabolic and genetic contributions to NAFLD: Really distinct and homogeneous? Journal of hepatology. 76 (3): 498-500.
Su H-m, Feng L-n, Zheng X-d & Chen W 2016. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice. Journal of Zhejiang University. Science. B. 17 (6): 437.
Wieland A, Frank D, Harnke B & Bambha K 2015. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Alimentary pharmacology & therapeutics. 42 (9): 1051-1063.
Yang DK & Jo D-G 2018. Mulberry fruit extract ameliorates nonalcoholic fatty liver disease (NAFLD) through inhibition of mitochondrial oxidative stress in rats. Evidence-Based Complementary and Alternative Medicine. 2018 (1): 8165716.
Yip TC-F, et al. 2023. Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future. Clinical and molecular hepatology. 29 (Suppl): S171.
Zhang P-W, Chen F-X, Li D, Ling W-H & Guo H-H 2015. A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease. Medicine. 94 (20): e758.
On the other hand, a significant improvement in TAC was observed in intervention group which indicated possible anti-oxidative effects of cranberry supplements in NAFLD patients. Oxidative stress is the result of an imbalance between pro-oxidants and anti-oxidants and plays a crucial role in pathogenesis of NAFLD (Su et al., 2016). A considerable amount of research has been conducted regarding anti-oxidative effects of berries. In one study, mulberry treatment in HFD rats significantly suppressed hepatic reactive oxygen species (ROS) overproduction and mitochondrial oxidative stress (Yang and Jo, 2018). Another research team investigated the effects of raspberry on obese diabetic (db/db) mice for 8 weeks. The findings showed that raspberry intake could improve antioxidant status and lessen IL-6 in treatment group (Noratto et al., 2017). Results of a double-blind randomized trial showed that 4 weeks supplementation with maqui berry (delphinol) significantly reduced markers of oxidative stress (ox-LDL and urinary F2-isoprostane) in intervention group (Davinelli et al., 2015). Wild blueberry consumption significantly improved postprandial oxidative stress in male subjects. Oxygen radical absorbance capacity (ORAC) assay and the total antioxidant status (TAS) were evaluated as markers of oxidative stress in the study (Kay and Holub, 2002). On the other hand, in a randomized controlled trial, 40 post-menopausal women consumed either 22 grams of blueberry or placebo for 8 weeks. As a result, blood markers of oxidative stress, inflammation, and antioxidant defense did not change in blueberry group after 8 weeks (Johnson et al., 2017).
have immunomodulatory and anti-inflammatory
effects by interacting with gut microbiota (Alves-Santos et al., 2020). In one study, dietary cranberry supplementation in a mouse model of IBD, not only suppressed colonic levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) but also increased the abundance of beneficial gut bacteria including lactobacillus and bifidobacterium (Cai et al., 2019). It has also been shown that phenolic compounds can suppress IL-1β secretion and exert anti-inflammatory effects through inhibition of cyclo-oxygenase and lipoxygenase activity (Lopez-Corona et al., 2022). Antioxidant properties of cranberry are attributed to free radical scavenging properties of polyphenols against ROSs as well as inhibition of lipid and protein oxidation (Côté et al., 2010). According to the studies, cranberry supplementation has also the potential to decrease NO synthase activity, improve homocysteine levels and endothelial function, thus suppressing oxidative stress (Lozovoy et al., 2013).
Certain limitations of the present study include a small sample size and the short study duration. Another limitation might be the lack of polyphenol measurements in cranberry tablet via high performance liquid chromatography (HPLC) method.
Conclusion
In conclusion, this randomized, double-blind, placebo-controlled trial indicates that 288 mg/d of cranberry supplementation in addition to weight loss diet may not change MDA, CK-18 M30, CCL2, and TNF-α, but it will be beneficial in improving serum levels of TAC in NAFLD patients. Further studies are needed to investigate the effects of anti-inflammatory and antioxidant properties of cranberry on NAFLD.
Acknowledgements
This study was part of a PhD thesis by MS Hormoznejad. The authors would like to thank Golestan Hospital of Ahvaz Jundishapur University of Medical Sciences for their support.
Conflict of interests
The authors declared no conflict of interests.
Funding
The present study was financially supported by a grant (NRC-9718) from Vice-Chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences.
Authors’ contributions
Mohammad Shahi M, Rahimi F, and Hormoznejad R were involved in the conception and design of the study. Sharhani A, Helli B, and Alavinejad P contributed to the methodology. Sharhani A performed data analysis and interpretation. Hormoznejad R, Sadeghi N, Dehghanseresht N, and Mahboobi S participated in conducting the study and drafting the manuscript. All the authors read and approved the final manuscript.
References
Abenavoli L, et al. 2017. Effect of Mediterranean diet and antioxidant formulation in non-alcoholic fatty liver disease: a randomized study. Nutrients. 9 (8): 870.
Abenavoli L, et al. 2016. Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World journal of gastroenterology. 22 (31): 7006.
Ainsworth BE, et al. 2000. Compendium of physical activities: an update of activity codes and MET intensities. Medicine and science in sports and exercise. 32 (9; SUPP/1): S498-S504.
Alves-Santos AM, Sugizaki CSA, Lima GC & Naves MMV 2020. Prebiotic effect of dietary polyphenols: A systematic review. Journal of functional foods. 74: 104169.
Anhê FF, et al. 2013. Polyphenols and type 2 diabetes: A prospective review. Pharma nutrition. 1 (4): 105-114.
Asrih M & Jornayvaz FR 2015. Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link? Molecular and cellular endocrinology. 418: 55-65.
Benedict M & Zhang X 2017. Non-alcoholic fatty liver disease: An expanded review. World journal of hepatology. 9 (16): 715.
Cai X, et al. 2019. Dietary cranberry suppressed colonic inflammation and alleviated gut microbiota dysbiosis in dextran sodium sulfate-treated mice. Food & function. 10 (10): 6331-6341.
Côté J, Caillet S, Doyon G, Sylvain J-F & Lacroix M 2010. Bioactive compounds in cranberries and their biological properties. Critical reviews in food science and nutrition. 50 (7): 666-679.
Davinelli S, Bertoglio JC, Zarrelli A, Pina R & Scapagnini G 2015. A randomized clinical trial evaluating the efficacy of an anthocyanin–maqui berry extract (Delphinol®) on oxidative stress biomarkers. Journal of the American College of Nutrition. 34 (sup1): 28-33.
Faheem SA, Saeed NM, El-Naga RN, Ayoub IM & Azab SS 2020. Hepatoprotective effect of cranberry nutraceutical extract in non-alcoholic fatty liver model in rats: Impact on insulin resistance and Nrf-2 expression. Frontiers in pharmacology. 11: 218.
Flammer AJ, et al. 2013. Polyphenol-rich cranberry juice has a neutral effect on endothelial function but decreases the fraction of osteocalcin-expressing endothelial progenitor cells. European journal of nutrition. 52: 289-296.
Friedman SL, Neuschwander-Tetri BA, Rinella M & Sanyal AJ 2018. Mechanisms of NAFLD development and therapeutic strategies. Nature medicine. 24 (7): 908-922.
Glisan SL, Ryan C, Neilson AP & Lambert JD 2016. Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice. Journal of nutritional biochemistry. 37: 60-66.
He L, et al. 2023. Deleting Gata4 in hepatocytes promoted the progression of NAFLD via increasing steatosis and apoptosis, and desensitizing insulin signaling. Journal of nutritional biochemistry. 111: 109157.
Henig YS & Leahy MM 2000. Cranberry juice and urinary-tract health: science supports folklore. Nutrition. 16 (7-8): 684-687.
Hormoznejad R, et al. 2021. Effects of cranberry consumption on features of the metabolic syndrome: a systematic review and meta-analysis of randomized control trials. Nutrition & food science. 51 (6): 1006-1016.
Johnson SA, et al. 2017. Effects of daily blueberry consumption on circulating biomarkers of oxidative stress, inflammation, and antioxidant defense in postmenopausal women with pre-and stage 1-hypertension: a randomized controlled trial. Food & function. 8 (1): 372-380.
Kay CD & Holub BJ 2002. The effect of wild blueberry (Vaccinium angustifolium) consumption on postprandial serum antioxidant status in human subjects. British journal of nutrition. 88 (4): 389-397.
Kwon OY, Choi J-y & Jang Y 2023. The Effectiveness of EHealth Interventions on Lifestyle Modification in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Journal of medical internet research. 25: e37487.
Le MH, et al. 2022. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clinical and molecular hepatology. 28 (4): 841-850.
Loffredo L, et al. 2016. Effects of dark chocolate on NOX‐2‐generated oxidative stress in patients with non‐alcoholic steatohepatitis. Alimentary pharmacology & therapeutics. 44 (3): 279-286.
Lopez-Corona AV, et al. 2022. Antioxidant, Anti-Inflammatory and Cytotoxic Activity of Phenolic Compound Family Extracted from Raspberries (Rubus idaeus): A General Review. Antioxidants. 11 (6): 1192.
Lozovoy MAB, et al. 2013. Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome. British journal of nutrition. 110 (10): 1885-1894.
Mansoori A, et al. 2020. The effect of melatonin supplementation on liver indices in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized clinical trials. Complementary therapies in medicine. 52: 102398.
Nisar A 2022. Medicinal plants and phenolic compounds. In Phenolic Compounds: Chemistry, Synthesis, Diversity, Non-Conventional Industrial, Pharmaceutical and Therapeutic Applications.
Noratto GD, Chew BP & Atienza LM 2017. Red raspberry (Rubus idaeus L.) intake decreases oxidative stress in obese diabetic (db/db) mice. Food chemistry. 227: 305-314.
Novotny JA, Baer DJ, Khoo C, Gebauer SK & Charron CS 2015. Cranberry juice consumption lowers markers of cardiometabolic risk, including blood pressure and circulating C-reactive protein, triglyceride, and glucose concentrations in adults. Journal of nutrition. 145 (6): 1185-1193.
Pappas E & Schaich K 2009. Phytochemicals of cranberries and cranberry products: characterization, potential health effects, and processing stability. Critical reviews in food science and nutrition. 49 (9): 741-781.
Shidfar F, et al. 2012. The effects of cranberry juice on serum glucose, apoB, apoA-I, Lp (a), and Paraoxonase-1 activity in type 2 diabetic male patients. Journal of research in medical sciences. 17 (4): 355.
Shimizu K, et al. 2019. Cranberry attenuates progression of non-alcoholic fatty liver disease induced by high-fat diet in mice. Biological and pharmaceutical bulletin. 42 (8): 1295-1302.
Slavin JL & Lloyd B 2012. Health benefits of fruits and vegetables. Advances in nutrition. 3 (4): 506-516.
Speliotes EK & George J 2022. Metabolic and genetic contributions to NAFLD: Really distinct and homogeneous? Journal of hepatology. 76 (3): 498-500.
Su H-m, Feng L-n, Zheng X-d & Chen W 2016. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice. Journal of Zhejiang University. Science. B. 17 (6): 437.
Wieland A, Frank D, Harnke B & Bambha K 2015. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Alimentary pharmacology & therapeutics. 42 (9): 1051-1063.
Yang DK & Jo D-G 2018. Mulberry fruit extract ameliorates nonalcoholic fatty liver disease (NAFLD) through inhibition of mitochondrial oxidative stress in rats. Evidence-Based Complementary and Alternative Medicine. 2018 (1): 8165716.
Yip TC-F, et al. 2023. Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future. Clinical and molecular hepatology. 29 (Suppl): S171.
Zhang P-W, Chen F-X, Li D, Ling W-H & Guo H-H 2015. A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease. Medicine. 94 (20): e758.
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Received: 2023/03/5 | Published: 2024/11/20 | ePublished: 2024/11/20
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