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JNFS 2025, 10(2): 194-203 |
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Faghfouri A H, Seyyed Shoura S M, shahhosseini G, Khodabandehloo A A, Fathollahia P, Khabbazi A, et al . Effect of Zinc Gluconate Supplementation on C-Reactive Protein and Malondialdehyde in Patients with Behcet's Disease: A Double-Blind Randomized Controlled Clinical Trial. JNFS 2025; 10 (2) :194-203
URL: http://jnfs.ssu.ac.ir/article-1-1063-en.html
URL: http://jnfs.ssu.ac.ir/article-1-1063-en.html
Amir Hossein Faghfouri 
, Seyyed Morteza Seyyed Shoura , Ghazaleh Shahhosseini , Amir Arshia Khodabandehloo , Pourya Fathollahia , Alireza Khabbazi , Vali Musazadeh , Beitullah Alipour *
, Seyyed Morteza Seyyed Shoura , Ghazaleh Shahhosseini , Amir Arshia Khodabandehloo , Pourya Fathollahia , Alireza Khabbazi , Vali Musazadeh , Beitullah Alipour *
Department of Community Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Effect of Zinc Gluconate Supplementation on C-Reactive Protein and Malondialdehyde in Patients with Behcet's Disease: A Double-Blind Randomized Controlled Clinical Trial
Amir Hossein Faghfouri; PhD1, Seyyed Morteza Seyyed Shoura; MSc2, Ghazaleh shahhosseini; MSc3, Amir Arshia Khodabandehloo; MSc4, Pourya Fathollahia; MSc2, Alireza Khabbazi; PhD5, Vali Musazadeh; PhD6,7 & Beitullah Alipour; PhD*8
1 Maternal and Childhood Obesity Research Center, Urmia University of Medical Sciences, Urmia, Iran; 2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; 3Department of Dentistry, Islamic Azad university, Tehran, Iran; 4Department of Converging Sciences and Technologies, Islamic Azad University Science and Research Branch ,Tehran, Iran; 5 Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 6 Student research committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran; 7 Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran;
8 Department of Community Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
1 Maternal and Childhood Obesity Research Center, Urmia University of Medical Sciences, Urmia, Iran; 2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; 3Department of Dentistry, Islamic Azad university, Tehran, Iran; 4Department of Converging Sciences and Technologies, Islamic Azad University Science and Research Branch ,Tehran, Iran; 5 Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 6 Student research committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran; 7 Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran;
8 Department of Community Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Behçet's disease (BD) with autoimmune and auto-inflammatory nature is more prevalent in Silk Road countries. The current study aimed to investigate the effect of zinc gluconate supplementation on C-reactive protein (CRP) and malondialdehyde (MDA) levels in BD patients. Methods: This randomized controlled clinical trial was conducted on 50 Iranian BD patients. Participants were randomly assigned into either placebo or zinc gluconate (30 mg/day) groups for 12 weeks. Before and after the intervention, serum MDA and CRP levels were measured. Results: Zinc supplementation led to a significant increase in serum zinc levels compared to the placebo group (P<0.05). There was no significant difference in MDA serum levels between the groups after adjusting for the baseline values and confounding factors (P>0.05). Zinc supplementation led to a significant improvement in CRP serum levels compared to the placebo group following adjustment for the effect of baseline values and confounding factors (P=0.012 and 0.04, respectively). Conclusion: Zinc supplementation in an elemental dose of 30 mg per day has an anti-inflammatory effect in BD patients by reducing CRP levels. The beneficial effect of zinc on lipid peroxidation in BD patients was not shown in the study. Clinical trial registration: IRCT20100606004105N30 |
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| Article history: Received: 17 May 2024 Revised: 8 Sep 2024 Accepted: 21 Sep 2024 |
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| *Corresponding author alipourb@tbzmed.ac.ir School of Nutrition and Food Sciences, Attar-Neishaburi St., Golgasht Alley, Azadi Blvd., Tabriz, Iran. Postal code: 5165665931 Tel: +98 9144157042 |
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| Keywords Malondialdehyde; Zinc; CRP; Behcet disease. |
Introduction
Behçet's disease (BD) is a rare debilitating autoimmune vasculitis that can be associated with mucocutaneous lesions and can lead to serious complications and even death if not properly managed (Nair and Moots, 2017). Due to inflammation in the arteries and veins, BD causes inflammation in various body systems, including the respiratory system, digestive system, reproductive system, visual system, central nervous system, and eyes (Alibaz-Oner and Direskeneli, 2022). This disease is characterized by frequent recurrence of oral ulcers (appeared in 97.5% and 65.7% of patients, respectively), genital ulcers, skin lesions (appeared in 64.6% of patients), joint pain, and uveitis (Davatchi et al., 2016, Khan et al., 2020, Sakane et al., 1999). The exact cause of BD is not known, but research has shown that genetic factors (HLA-B51) (Fei et al., 2009, Kirino et al., 2013, Lee et al., 2013, Remmers et al., 2010), viral and bacterial infections (Cho et al., 2012), immune system imbalance (Ekinci et al., 2010), environmental factors such as poor diet (Tanaka et al., 1985), and using tobacco and cigarettes may play a role in the pathogenesis of this disease (Alpsoy, 2016, Aramaki et al., 2007).
BD is considered a rare disease with an estimated prevalence of 13.5–500 per 100,000 people along the Silk Road (Shahram et al., 2013). The prevalence of BD is not the same in different regions of the world and it is higher in certain regions such as the Silk Road, which includes the Middle East, the Mediterranean, and the Far East (Alpsoy et al., 2007), where Turkey has the highest prevalence in the world with 1 in 250 people (Azizlerli et al., 2003). In Western countries, this statistic is much lower, for example, in the United States and England, 0.3 and 1 out of every 100,000 people are affected by this disease, respectively (Woźniacka et al., 2014). BD can occur at any age, but it mostly affects people in their 20s and 30s (Alpsoy, 2016). Epidemiological studies usually consider its prevalence to be the same in men and women. However, in some populations, such as the Far East, the disease is more common in women than in men, while in the Middle East, men predominate (Cho et al., 2012).
Zinc is a mineral that is essential for the proper functioning of the epidermal, skeletal, digestive, reproductive, central nervous system, and immune system, and plays a role in the production of antibodies (Roohani et al., 2013).It also plays a fundamental role in the activity of the innate and adaptive immune system (Wessels et al., 2017). In BD, due to the presence of inflammation in the body, activated neutrophils can produce reactive oxygen species (ROS) in response to the inflammatory process, which causes damage to surrounding cells and tissues (Chambers et al., 2001, Kökçam and Nazıroǧlu, 2002, Köse et al., 2001). Antioxidants can convert the generated ROS into safe derivatives. Zinc plays an important role in the body's antioxidant system, which is significantly reduced in serum in BD (Powell, 2000, Saglam et al., 2002).
Limited studies have shown an inverse correlation between serum zinc levels and BD (Sharquie et al., 2006). However, the number of studies conducted on the effect of oral zinc supplementation in BD was very limited (Faghfouri et al., 2022a, Faghfouri et al., 2022b, Sharquie et al., 2006). Although, these studies demonstrated some aspects of the antioxidant and anti-inflammatory effects of zinc in BD, they recommended that more studies should be conducted to elucidate other aspects of zinc in BD to have a more comprehensive insight into the beneficial effects of zinc in BD. Since BD has an inflammatory nature and zinc has antioxidant and anti-inflammatory functions, and on the other hand, due to limited studies on the effect of oral zinc supplements on BD, this study aimed to investigate the relationship between zinc supplementation and BD with emphasis on the level of C-reactive protein (CRP) as a main biomarker of systemic inflammation and malondialdehyde (MDA) as one of the main biomarker of oxidative stress in the body.
Materials and Methods
Study design and participants
Fifty active BD patients (non-ocular IBDDAM > 0.45) enrolled from the BD clinic of Tabriz University of Medical Sciences between August 2020 to February 2021 were subjected to a double-blind, placebo-controlled, randomized, parallel clinical trial. A rheumatologist used the International Criteria for BD (ICBD) to diagnose BD (Davatchi, 2012). Adult active BD patients aged 20 to 50 (women in the pre-menopause age) (S. Lashkari and Anumba, 2017) were enrolled in the current study after providing written informed consent. Pregnant or lactating mothers, patients with a history of liver disease, diabetes, or kidney disease, smokers, and those who had taken nutritional supplements more than two months prior to the study were excluded. Demographics and BD history of each patient were also documented.
Sample size
The sample size was estimated using the effect of zinc gluconate supplementation on CRP (mean change and its related standard deviation (SD)) from Kim et al.'s study (Kim and Ahn, 2014). A total of 21 BD patients were chosen to be in each group using a power of 80% and a 95% confidence interval (CI) for two-sided tests. With a 20% dropout rate, 25 patients per cohort were considered.
Randomization and intervention
Using the blocking method, patients were randomly assigned to the zinc (ZG) or placebo group (PG) in a 1:1 ratio. Using STATA 16.0 software (StataCorp, College Station, TX), quadruple blocks (A, B, C, and D) were determined based on gender and age (20–35 and 35–50 years). Throughout the trial, both researchers and participants were blinded to the assignment group.
Zinc gluconate tablet containing 30 mg elemental zinc was the intervention and placebo tablet containing microcrystalline cellulose was the control (Dina Iran Company, Tehran, Iran). To prevent digestive problems, it is recommended that all tablets be taken with food. The ZG received one daily zinc gluconate tablet and the PG received the same amount of placebo for 12 weeks. Tablets were labeled and placed in containers by a third party based on random blocks. Each registered patient was assigned an order letter and pill container. In order to determine whether the 90% compliance threshold was met, we asked all patients to return the bottles at the end of the study.
Assessment of clinical manifestations
Before and after the intervention, a rheumatologist examined the clinical symptoms of BD. The Iranian Behcet's disease dynamic activity measure (IBDDAM) was scored based on a variety of BD-related clinical symptoms (Davatchi et al., 1991).
Biochemical measures
Five milliliters of venous blood samples were collected in gel separator vacuumed tubes by venipuncture, both at the beginning of the study and at the end of the trial. Then, blood was freshly centrifuged at 4000 rpm for 15 minutes to extract serum, which was then stored at -80 °C until measurement. Serum CRP concentration was measured by CRP-latex immunoturbidimetric assay (Biorex Fars; Iran), and MDA level was measured by a spectrophotometric assay utilizing thiobarbituric acid reactive substances (TBARS) (Janero, 1990) .
Ethical considerations
The Ethics Committee of Tabriz University of Medical Sciences approved the study protocol (IR. TBZMED. REC.1401.284). This study adheres to the standards of the Helsinki Declaration and current ethical guidelines. IRCT.ir (number IRCT20100606004105N30) was notified of and approved the study protocol. Consolidated Standards of Reporting Trials (CONSORT) was used to report the current study.
Data analysis
All statistical analyses were performed employing intention-to-treat (ITT) approach in STATA version 16.0 (Stata Corporation, College Station, TX, USA). Multiple imputation method was used to replace missing data (Sterne et al., 2009). As described previously, descriptive statistics such as skewness, kurtosis, z value of skewness and kurtosis, and SD relative to the mean were evaluated to determine the normality of the data (Mishra et al., 2019). The numerical and categorical data were reported as mean SD and frequency (%), respectively. The mean changes within each cohort were calculated using standard errors (SE). The differences within each group as well as those between groups were examined using independent and paired sample t-tests. Using analysis of covariance (ANCOVA), the effect of confounders and baseline values on the effect size of zinc on various dependent variables was adjusted. In all analyses, P-values of 0.05 or less were regarded as significant.
Results
Participants' characteristics
Five of the 50 patients who were recruited for the trial withdrew for reasons unrelated to the therapy. Figure 1 shows the CONSORT flowchart for the investigation which was also presented in our previous studies (Faghfouri et al., 2022a, Faghfouri et al., 2022b). Table 1 illustrates that there was no significant difference in demographic characteristics (age, gender, and BMI), BD history (disease duration, IBDDAM, and medication history), and blood zinc level between ZG and PG. Zinc supplementation led to a significant increase in serum zinc levels compared to the PG (P<0.05) as reported in our previous study (Faghfouri et al., 2022b). This indicated the high patient compliance in the present study.
BD is considered a rare disease with an estimated prevalence of 13.5–500 per 100,000 people along the Silk Road (Shahram et al., 2013). The prevalence of BD is not the same in different regions of the world and it is higher in certain regions such as the Silk Road, which includes the Middle East, the Mediterranean, and the Far East (Alpsoy et al., 2007), where Turkey has the highest prevalence in the world with 1 in 250 people (Azizlerli et al., 2003). In Western countries, this statistic is much lower, for example, in the United States and England, 0.3 and 1 out of every 100,000 people are affected by this disease, respectively (Woźniacka et al., 2014). BD can occur at any age, but it mostly affects people in their 20s and 30s (Alpsoy, 2016). Epidemiological studies usually consider its prevalence to be the same in men and women. However, in some populations, such as the Far East, the disease is more common in women than in men, while in the Middle East, men predominate (Cho et al., 2012).
Zinc is a mineral that is essential for the proper functioning of the epidermal, skeletal, digestive, reproductive, central nervous system, and immune system, and plays a role in the production of antibodies (Roohani et al., 2013).It also plays a fundamental role in the activity of the innate and adaptive immune system (Wessels et al., 2017). In BD, due to the presence of inflammation in the body, activated neutrophils can produce reactive oxygen species (ROS) in response to the inflammatory process, which causes damage to surrounding cells and tissues (Chambers et al., 2001, Kökçam and Nazıroǧlu, 2002, Köse et al., 2001). Antioxidants can convert the generated ROS into safe derivatives. Zinc plays an important role in the body's antioxidant system, which is significantly reduced in serum in BD (Powell, 2000, Saglam et al., 2002).
Limited studies have shown an inverse correlation between serum zinc levels and BD (Sharquie et al., 2006). However, the number of studies conducted on the effect of oral zinc supplementation in BD was very limited (Faghfouri et al., 2022a, Faghfouri et al., 2022b, Sharquie et al., 2006). Although, these studies demonstrated some aspects of the antioxidant and anti-inflammatory effects of zinc in BD, they recommended that more studies should be conducted to elucidate other aspects of zinc in BD to have a more comprehensive insight into the beneficial effects of zinc in BD. Since BD has an inflammatory nature and zinc has antioxidant and anti-inflammatory functions, and on the other hand, due to limited studies on the effect of oral zinc supplements on BD, this study aimed to investigate the relationship between zinc supplementation and BD with emphasis on the level of C-reactive protein (CRP) as a main biomarker of systemic inflammation and malondialdehyde (MDA) as one of the main biomarker of oxidative stress in the body.
Materials and Methods
Study design and participants
Fifty active BD patients (non-ocular IBDDAM > 0.45) enrolled from the BD clinic of Tabriz University of Medical Sciences between August 2020 to February 2021 were subjected to a double-blind, placebo-controlled, randomized, parallel clinical trial. A rheumatologist used the International Criteria for BD (ICBD) to diagnose BD (Davatchi, 2012). Adult active BD patients aged 20 to 50 (women in the pre-menopause age) (S. Lashkari and Anumba, 2017) were enrolled in the current study after providing written informed consent. Pregnant or lactating mothers, patients with a history of liver disease, diabetes, or kidney disease, smokers, and those who had taken nutritional supplements more than two months prior to the study were excluded. Demographics and BD history of each patient were also documented.
Sample size
The sample size was estimated using the effect of zinc gluconate supplementation on CRP (mean change and its related standard deviation (SD)) from Kim et al.'s study (Kim and Ahn, 2014). A total of 21 BD patients were chosen to be in each group using a power of 80% and a 95% confidence interval (CI) for two-sided tests. With a 20% dropout rate, 25 patients per cohort were considered.
Randomization and intervention
Using the blocking method, patients were randomly assigned to the zinc (ZG) or placebo group (PG) in a 1:1 ratio. Using STATA 16.0 software (StataCorp, College Station, TX), quadruple blocks (A, B, C, and D) were determined based on gender and age (20–35 and 35–50 years). Throughout the trial, both researchers and participants were blinded to the assignment group.
Zinc gluconate tablet containing 30 mg elemental zinc was the intervention and placebo tablet containing microcrystalline cellulose was the control (Dina Iran Company, Tehran, Iran). To prevent digestive problems, it is recommended that all tablets be taken with food. The ZG received one daily zinc gluconate tablet and the PG received the same amount of placebo for 12 weeks. Tablets were labeled and placed in containers by a third party based on random blocks. Each registered patient was assigned an order letter and pill container. In order to determine whether the 90% compliance threshold was met, we asked all patients to return the bottles at the end of the study.
Assessment of clinical manifestations
Before and after the intervention, a rheumatologist examined the clinical symptoms of BD. The Iranian Behcet's disease dynamic activity measure (IBDDAM) was scored based on a variety of BD-related clinical symptoms (Davatchi et al., 1991).
Biochemical measures
Five milliliters of venous blood samples were collected in gel separator vacuumed tubes by venipuncture, both at the beginning of the study and at the end of the trial. Then, blood was freshly centrifuged at 4000 rpm for 15 minutes to extract serum, which was then stored at -80 °C until measurement. Serum CRP concentration was measured by CRP-latex immunoturbidimetric assay (Biorex Fars; Iran), and MDA level was measured by a spectrophotometric assay utilizing thiobarbituric acid reactive substances (TBARS) (Janero, 1990) .
Ethical considerations
The Ethics Committee of Tabriz University of Medical Sciences approved the study protocol (IR. TBZMED. REC.1401.284). This study adheres to the standards of the Helsinki Declaration and current ethical guidelines. IRCT.ir (number IRCT20100606004105N30) was notified of and approved the study protocol. Consolidated Standards of Reporting Trials (CONSORT) was used to report the current study.
Data analysis
All statistical analyses were performed employing intention-to-treat (ITT) approach in STATA version 16.0 (Stata Corporation, College Station, TX, USA). Multiple imputation method was used to replace missing data (Sterne et al., 2009). As described previously, descriptive statistics such as skewness, kurtosis, z value of skewness and kurtosis, and SD relative to the mean were evaluated to determine the normality of the data (Mishra et al., 2019). The numerical and categorical data were reported as mean SD and frequency (%), respectively. The mean changes within each cohort were calculated using standard errors (SE). The differences within each group as well as those between groups were examined using independent and paired sample t-tests. Using analysis of covariance (ANCOVA), the effect of confounders and baseline values on the effect size of zinc on various dependent variables was adjusted. In all analyses, P-values of 0.05 or less were regarded as significant.
Results
Participants' characteristics
Five of the 50 patients who were recruited for the trial withdrew for reasons unrelated to the therapy. Figure 1 shows the CONSORT flowchart for the investigation which was also presented in our previous studies (Faghfouri et al., 2022a, Faghfouri et al., 2022b). Table 1 illustrates that there was no significant difference in demographic characteristics (age, gender, and BMI), BD history (disease duration, IBDDAM, and medication history), and blood zinc level between ZG and PG. Zinc supplementation led to a significant increase in serum zinc levels compared to the PG (P<0.05) as reported in our previous study (Faghfouri et al., 2022b). This indicated the high patient compliance in the present study.
| Table 1. Baseline characteristics of participants in zinc and placebo groups. | |||
| Variable | Zinc group (n=25) | Placebo group (n=25) | P-valuea |
| Age (y) | 43.00 ± 11.18b | 40.56 ± 9.33 | 0.406 |
| Body mass index (kg/m2) | 27.02 ± 6.64 | 26.81 ± 5.95 | 0.907 |
| Serum Zinc (μg/dl) | 68.18 ± 5.71 | 65.35 ± 6.78 | 0.117 |
| IBDDAM | 1.62 ± 0.88 | 1.37 ± 0.74 | 0.297 |
| Sex Male Female |
18 (72.0)c 7 (28.0) |
18 (72.0) 7 (28.0) |
1.000 |
| Duration of Behcet's disease (y) <1 >1 |
3 (12.0) 22 (88) |
0 (0.0) 25 (100) |
0.235 |
| Medications None Prednisolone Colchicine Azathioprine Interferon ɑ Methotrexate Cyclosporine Sulfasalazine NSAIDs Mycophenolate Mofetil |
0 (0.0) 14 (56.0) 11 (44.0) 9 (36.0) 0 (0.0) 4 (16.0) 0 (0.0) 0 (0.0) 1 (4.0) 2 (8.0) |
2 (8.0) 16 (64.0) 11 (44.0) 3 (12.0) 2 (8.0) 2 (8.0) 1 (4.0) 2 (8.0) 3 (12.0) 2 (8.0) |
0.264 |
| a: P-values are for comparison of variable between zinc and placebo groups (qualitative variables were analyzed by Chi-squared test and quantitative variables were analyzed by t-independent test); b: Mean±SD; c: n (%); NSAIDs, Non-steroidal anti-inflammatory drugs; IBDDAM: Iranian Behcet's disease dynamic activity measure. | |||
Clinical assessments of BD
Zinc supplementation had a significant improvement in nonocular IBDDAM score compared to the placebo treatment after baseline adjustment (mean change: -0.43±0.15 in the ZG; mean change: -0.04±0.07 in the PG, P=0.046) and adjusting based on the confounding factors, i.e., age, BMI, and BD duration (P=0.026) (Faghfouri et al., 2022b). Zinc led to a significant improvement in genital ulcers (P=0.19). Other clinical manifestations did not change significantly in ZG compared to PG (P>0.05) (Faghfouri et al., 2022a).
The serum levels of MDA
The baseline MDA levels did not differ significantly between groups (P>0.05). A paired t-test revealed that MDA level in ZG decreased significantly after 12 weeks (P=0.044), which is shown in Table 2. There was no significant difference in MDA serum levels between the groups after adjusting for baseline values (P>0.05).
The serum levels of CRP
The baseline CRP levels did not differ across the groups (P>0.05, Table 2). CRP decreased significantly in ZG (P=0.006), according to a paired t-test. After adjusting for baseline values, ANCOVA test showed that zinc supplementation led to a significant improvement in CRP serum levels compared to the placebo group (P= 0.012).
Zinc supplementation had a significant improvement in nonocular IBDDAM score compared to the placebo treatment after baseline adjustment (mean change: -0.43±0.15 in the ZG; mean change: -0.04±0.07 in the PG, P=0.046) and adjusting based on the confounding factors, i.e., age, BMI, and BD duration (P=0.026) (Faghfouri et al., 2022b). Zinc led to a significant improvement in genital ulcers (P=0.19). Other clinical manifestations did not change significantly in ZG compared to PG (P>0.05) (Faghfouri et al., 2022a).
The serum levels of MDA
The baseline MDA levels did not differ significantly between groups (P>0.05). A paired t-test revealed that MDA level in ZG decreased significantly after 12 weeks (P=0.044), which is shown in Table 2. There was no significant difference in MDA serum levels between the groups after adjusting for baseline values (P>0.05).
The serum levels of CRP
The baseline CRP levels did not differ across the groups (P>0.05, Table 2). CRP decreased significantly in ZG (P=0.006), according to a paired t-test. After adjusting for baseline values, ANCOVA test showed that zinc supplementation led to a significant improvement in CRP serum levels compared to the placebo group (P= 0.012).
| Table 2. Comparison serum levels of Malondialdehyde and C-reactive protein in zinc and placebo groups. | |||
| Variable | Group Zinc (n=25) | Placebo group (n=25) | P-valuea |
| Malondialdehyde (μmol/l) Baseline |
9.19 ± 2.15c |
9.08 ± 2.20 |
0.85 |
| After 12 weeks | 8.77 ± 2.30 | 9.1 ± 2.34 | |
| P-valueb | 0.044 | 0.830 | |
| Change | -0.42 ± 1.97 | 0.02 ± 0.11 | |
| C-reactive protein (mg/l) Baseline |
23.71 ± 4.63 |
22.96 ± 5.09 |
0.591 |
| After 12 weeks | 22.25 ± 4.83 | 23.23 ± 5.53 | |
| P-value | 0.006 | 0.529 | |
| Change | -1.46 ± 0.48 | 0.27 ± 0.42 | |
| a: Independent samples t-test; b: Paired samples t-test; c: Mean±SE. | |||
Discussion
The current double-blind clinical trial study showed that zinc gluconate supplementation at an elemental dose of 30 mg per day led to a significant decrease in the CRP level of BD patients compared to the placebo group. However, it had no significant effect on MDA. The result of CRP was consistent with a previous recent meta-analysis that pooled all clinical trial studies in this regard (Ghaedi et al.).
Three studies were conducted on the effect of zinc supplementation on BD patients. In two studies conducted in Iran, a dose of 30 mg of elemental zinc in gluconate form for 12 weeks led to significant improvement in immune system markers (TLR-2 gene and surface expression), genital ulcer, NLRP-3 inflammasome complex, and BD activity. Regarding inflammatory markers, these studies showed that zinc led to a significant reduction in IL-1β, although it had no significant effect on TNF-α levels. However, as many symptoms of BD, including digestive symptoms, neurological symptoms and joint disorders, require longer treatment to recover, these two studies suggested that zinc supplementation may have more improving effect on BD for periods longer than 12 weeks (Faghfouri et al., 2022a, Faghfouri et al., 2022b). However, it must be noted that zinc in a long-term administration and higher doses can have pro-oxidant effect through disrupting of mitochondria homeostasis and excessive ROS production (Lee, 2018). Moreover, zinc overload can be related to increase in pro-inflammatory cytokine production (Plum et al., 2010) . Therefore, high doses and long-term administration of zinc should be used with precaution. In another study, a dose of 300 mg of zinc sulfate per day for 3 months without side effects led to an improvement in clinical manifestations index (Sharquie et al., 2006). CRP and TNF-α respond differently to inflammation. CRP increases slightly with mild inflammation and higher levels are observed in severe inflammation. In contrast to CRP, TNF-α is an early indicator of inflammation and increases in the first times of exposure to the inflammatory stimulus and then has a decreasing trend (Kumolosasi et al., 2014, Yousef et al., 2010). Most of the participants were not new cases. As a result, this difference in kinetics of CRP and TNF-α production can be the cause of difference in the effect of zinc on these two markers in BD patients. Future studies should investigate the effect of zinc on TNF-α in new case BD patients to get a complete picture of anti-inflammatory effects of zinc in BD.
Zinc exerts its anti-inflammatory action through down-regulating Nuclear Factor-Kappa-B (NF-ĸB). Some zinc finger proteins like A20 and growth factor independence-1 (Gfi-1) are involved in the inhibition of NF-ĸB dimerization (Faghfouri et al., 2020). It has been reported that zinc supplementation can lead to induction of A20 binding to mRNA and DNA through the upregulation of mRNA and DNA-specific sites (Prasad et al., 2004). Moreover, zinc status can contribute to the expression of a cytokines via binding to metal response elements (MREs) on the promoter of target genes (Bao et al., 2003, Cousins, 1998). Moreover, immunomodulatory effects of zinc can balance inflammatory responses (Faghfouri et al., 2022b). It should also be mentioned that inflammation and oxidative stress have a two-way relationship and an increase in one leads to the stimulation of the other. The antioxidant effects of zinc can also lead to anti-inflammatory consequences. Zinc is effective as a cofactor in the action of superoxide dismutase (SOD) as an anti-oxidant enzyme (Mariani et al., 2008). Zinc also leads to membrane strength through competition with toxic metals and prevents the oxidation of sulfhydryl groups of proteins (O'Dell, 2000). Zinc leads to the maintenance of mitochondrial homeostasis, thereby reducing ROS production (Lee, 2018) .
It was reported that superoxide radical anion generation can lead to lipid peroxidation in BD patients. Lipid peroxidation is the main cause of atherosclerosis pathogenesis in BD (Orem et al., 1997). MDA level is considered as the main marker of lipid peroxidation. MDA level has been reported to be higher in BD patients compared to healthy subjects (Mungan et al., 2006, Sandikci et al., 2003). The results of previous studies on the effect of zinc on MDA levels are contradictory. Some studies showed a positive effect of zinc (Momen-Heravi et al., 2017, Velázquez-Pérez et al., 2011), while some other studies failed to show an improvement effect (Aboomardani et al., 2012, Ribeiro et al., 2016). A meta-analysis study combining studies in this field showed that doses less than 40 mg per day do not have a significant effect on MDA. However, doses higher than 40 mg per day lead to a significant decrease in MDA. Dose-response analysis also showed that the relationship between zinc and MDA level was dose-dependent (Mousavi et al., 2020). As a result, the lack of significant effect of zinc on MDA in the present study may be related to the prescribed dose. However, as mentioned above, zinc overload has pro-oxidant effects. Therefore, future studies should compare effects of different doses of zinc on MDA levels in order to obtain the optimal dose using dose-response analysis.
The present study had some limitations. First, CRP was measured as the only inflammatory factor. Although in our previous studies we examined TNF-α and IL-1β in these patients in response to zinc gluconate supplementation (Faghfouri et al., 2022a, Faghfouri et al., 2022b), other inflammatory indicators should also be performed in future studies to fully determine the anti-inflammatory effects of zinc supplementation in BD patients. Second, we could not administer doses higher than the upper safety level (40 mg/day), due to ethical constraints. The observed lack of significant effect on MDA may be due to the administered dose. However, the study has some strengths. First, it is registered in IRCT and is reported based on the CONSORT checklist. Second, this is the first study that examines the effect of zinc on CRP and MDA in BD patients.
Conclusion
Zinc supplementation in an elemental dose of 30 mg per day has an anti-inflammatory effect in BD patients by reducing CRP levels. The beneficial effect of zinc on lipid peroxidation in BD patients was not shown in the present study.
Acknowledgement
The research protocol was approved and supported by Student Research Committee, Tabriz University of Medical Sciences (grant number: 68974).
Authors’ contributions
AH Faghfouri and B Alipour designed the study, collected the data, analyzed the data, drafted, and prepared the manuscript. AA Khodabandehloo, G shahhosseini and SM Seyyed Shoura. collected the data, drafted, and prepared the manuscript. V Musazadeh and A Khabbazi designed the study, collected the data, and critically revised the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Funding
The research protocol was approved and supported by Student Research Committee, Tabriz University of Medical Sciences (Grant number: 68974).
References
Aboomardani M, Rafraf M, Arefhosseini R & Rashidi M 2012. Effect of zinc supplementation on serum mlondealdehyde and lipid profiles on beta thalassemia major patients. Pharmaceutical sciences. 18 (1): 25-32.
Alibaz-Oner F & Direskeneli H 2022. Update on the diagnosis of Behçet's disease. Diagnostics (Basel). 13 (1): 41.
Alpsoy E 2016. Behcet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. Journal of dermatology. 43 (6): 620-632.
Alpsoy E, Zouboulis CC & Ehrlich GE 2007. Mucocutaneous lesions of Behcet's disease. Yonsei medical journal. 48 (4): 573-585.
Aramaki K, Kikuchi H & Hirohata S 2007. HLA-B51 and cigarette smoking as risk factors for chronic progressive neurological manifestations in Behçet's disease. Modern rheumatology. 17 (1): 81-82.
Azizlerli G, et al. 2003. Prevalence of Behçet's disease in Istanbul, Turkey. International journal of dermatology. 42 (10): 803-806.
Bao B, Prasad A, Beck F & Godmere M 2003. Zinc modulates mRNA levels of cytokines. American journal of physiology-endocrinology and metabolism. 285 (5): E1095-E1102.
Chambers JC, Haskard DO & Kooner JS 2001. Vascular endothelial function and oxidative stress mechanisms in patients with Behçet’s syndrome. Journal of the American College of Cardiology. 37 (2): 517-520.
Cho SB, Cho S & Bang D 2012. New insights in the clinical understanding of Behçet's disease. Yonsei medical journal. 53 (1): 35-42.
Cousins RJ 1998. A role of zinc in the regulation of gene expression. Proceedings of the nutrition society. 57 (2): 307-311.
Davatchi F 2012. Diagnosis/classification criteria for Behcet's disease. Pathology research international. 2012.
Davatchi F, Akbarian M & Shahram F 1991. Iran Behcet’s disease dynamic activity measure. Journal: Hungarian rheumatology. 32 (Suppl): 1340.
Davatchi F, et al. 2016. Adult Behcet's disease in Iran: analysis of 6075 patients. International journal of rheumatic diseases. 19 (1): 95-103.
Ekinci NS, Alpsoy E, Karakas AA, Yilmaz SB & Yegin O 2010. IL-17A has an important role in the acute attacks of Behcet's disease. Journal of investigative dermatology. 130 (8): 2136-2138.
Faghfouri AH, et al. 2022a. Regulation of NLRP3 inflammasome by zinc supplementation in Behçet's disease patients: A double-blind, randomized placebo-controlled clinical trial. International immunopharmacology. 109: 108825.
Faghfouri AH, et al. 2022b. Immunomodulatory and clinical responses to zinc gluconate supplementation in patients with Behçet's disease: A double-blind, randomized placebo-controlled clinical trial. Clinical nutrition. 41 (5): 1083-1092.
Faghfouri AH, Zarrin R, Maleki V, Payahoo L & Khajebishak Y 2020. A comprehensive mechanistic review insight into the effects of micronutrients on toll-like receptors functions. Pharmacological research. 152: 104619.
Fei Y, et al. 2009. Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study. Arthritis research & therapy. 11: 1-7.
Ghaedi K, et al. Effect of zinc supplementation in the management of type 2 diabetes: A grading of recommendations assessment, development, and evaluation-assessed, dose-response meta-analysis of randomized controlled trials. Critical reviews in food science and nutrition. 64 (25): 9228-9239.
Janero DR 1990. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free radical biology and medicine. 9 (6): 515-540.
Khan A, Haroon M, Bashir F & ud Din Z 2020. Behcet's disease: Pakistani experience. Pakistan journal of medical sciences. 36 (5): 1005.
Kim J & Ahn J 2014. Effect of zinc supplementation on inflammatory markers and adipokines in young obese women. Biological trace element research. 157 (2): 101-106.
Kirino Y, et al. 2013. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B* 51 and ERAP1. Nature genetics. 45 (2): 202-207.
Kökçam I & Nazıroǧlu M 2002. Effects of vitamin E supplementation on blood antioxidants levels in patients with Behçet’s disease. Clinical biochemistry. 35 (8): 633-639.
Köse K, Yazici C & Aşçioğlu Ö 2001. The evaluation of lipid peroxidation and adenosine deaminase activity in patients with Behcet’s disease. Clinical biochemistry. 34 (2): 125-129.
Kumolosasi E, Salim E, Jantan I & Ahmad W 2014. Kinetics of intracellular, extracellular and production of pro-inflammatory cytokines in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Tropical journal of pharmaceutical research. 13 (4): 536-543.
Lee SR 2018. Critical role of zinc as either an antioxidant or a prooxidant in cellular systems. Oxidative medicine and cellular longevity. 2018: 9156285.
Lee YJ, et al. 2013. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease. Annals of the rheumatic diseases. 72 (9): 1510-1516.
Mariani E, et al. 2008. Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects. Experimental gerontology. 43 (5): 445-451.
Mishra P, et al. 2019. Descriptive statistics and normality tests for statistical data. Annals of cardiac anaesthesia. 22 (1): 67.
Momen-Heravi M, et al. 2017. The effects of zinc supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial. Wound repair regen. 25 (3): 512-520.
Mousavi S, et al. 2020. Clinical effectiveness of zinc supplementation on the biomarkers of oxidative stress: A systematic review and meta-analysis of randomized controlled trials. Pharmacological research. 161: 105166.
Mungan A, Can M, Açikgöz S, Eştürk E & Altinyazar C 2006. Lipid peroxidation and homocysteine levels in Behçet's disease. Clinical chemistry and laboratory medicine. 44 (9): 1115-1118.
Nair JR & Moots RJ 2017. Behcet's disease. Clinical medicine. 17 (1): 71.
O'Dell BL 2000. Role of zinc in plasma membrane function. Journal of nutrition. 130 (5S Suppl): 1432s-1436s.
Orem A, et al. 1997. Relationship between lipid peroxidation and disease activity in patients with Behçet's disease. Journal of dermatological science. 16 (1): 11-16.
Plum LM, Rink L & Haase H 2010. The essential toxin: impact of zinc on human health. International journal of environmental research and public health. 7 (4): 1342-1365.
Powell SR 2000. The antioxidant properties of zinc. Journal of nutrition. 130 (5): 1447S-1454S.
Prasad A, Bao B, Beck F, Kucuk O & Sarkar F 2004. Antioxidant effect of zinc in humans. Free radical biology and medicine. 37 (8): 1182-1190.
Remmers EF, et al. 2010. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nature genetics. 42 (8): 698-702.
Ribeiro S, et al. 2016. Effect of zinc supplementation on antioxidant defenses and oxidative stress markers in patients undergoing chemotherapy for colorectal cancer: A placebo-controlled, prospective randomized trial. Biological trace element research. 169 (1): 8-16.
Roohani N, Hurrell R, Kelishadi R & Schulin R 2013. Zinc and its importance for human health: An integrative review. Journal of research in medical sciences. 18 (2): 144.
S. Lashkari B & Anumba DO 2017. Estradiol alters the immune-responsiveness of cervical epithelial cells stimulated with ligands of Toll-like receptors 2 and 4. Plos one. 12 (3): e0173646.
Saglam K, et al. 2002. Trace elements and antioxidant enzymes in Behçet's disease. Rheumatology international. 22: 93-96.
Sakane T, Takeno M, Suzuki N & Inaba G 1999. Behçet's disease. New England journal of medicine. 341 (17): 1284-1291.
Sandikci R, et al. 2003. Lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet's disease. Acta dermato-venereologica. 83 (5): 342-346.
Shahram F, et al. 2013. Scientometric analysis and mapping of scientific articles on B ehcet's disease. International journal of rheumatic diseases. 16 (2): 185-192.
Sharquie KE, Najim RA, AL‐Dori WS & AL‐Hayani RK 2006. Oral zinc sulfate in the treatment of Behcet's disease: a double blind cross‐over study. Journal of dermatology. 33 (8): 541-546.
Sterne JA, et al. 2009. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. British medical journal 339 (7713): 157-160.
Tanaka K, et al. 1985. Genetic and environmental factors in the development of Behcet's disease. Tohoku journal of experimental medicine. 145 (2): 205-213.
Velázquez-Pérez L, et al. 2011. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochemical research. 36 (10): 1793-1800.
Wessels I, Maywald M & Rink L 2017. Zinc as a gatekeeper of immune function. Nutrients. 9 (12): 1286.
Woźniacka A, Jurowski P, Omulecki A, Kot M & Dziankowska-Bartkowiak B 2014. Behçet’s disease leaves the silk road. Advances in dermatology and allergology/postępy dermatologii i alergologii. 31 (6): 417-420.
Yousef A, Amr Y & Suliman G 2010. The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Critical care. 14 (2): 1-9.
The current double-blind clinical trial study showed that zinc gluconate supplementation at an elemental dose of 30 mg per day led to a significant decrease in the CRP level of BD patients compared to the placebo group. However, it had no significant effect on MDA. The result of CRP was consistent with a previous recent meta-analysis that pooled all clinical trial studies in this regard (Ghaedi et al.).
Three studies were conducted on the effect of zinc supplementation on BD patients. In two studies conducted in Iran, a dose of 30 mg of elemental zinc in gluconate form for 12 weeks led to significant improvement in immune system markers (TLR-2 gene and surface expression), genital ulcer, NLRP-3 inflammasome complex, and BD activity. Regarding inflammatory markers, these studies showed that zinc led to a significant reduction in IL-1β, although it had no significant effect on TNF-α levels. However, as many symptoms of BD, including digestive symptoms, neurological symptoms and joint disorders, require longer treatment to recover, these two studies suggested that zinc supplementation may have more improving effect on BD for periods longer than 12 weeks (Faghfouri et al., 2022a, Faghfouri et al., 2022b). However, it must be noted that zinc in a long-term administration and higher doses can have pro-oxidant effect through disrupting of mitochondria homeostasis and excessive ROS production (Lee, 2018). Moreover, zinc overload can be related to increase in pro-inflammatory cytokine production (Plum et al., 2010) . Therefore, high doses and long-term administration of zinc should be used with precaution. In another study, a dose of 300 mg of zinc sulfate per day for 3 months without side effects led to an improvement in clinical manifestations index (Sharquie et al., 2006). CRP and TNF-α respond differently to inflammation. CRP increases slightly with mild inflammation and higher levels are observed in severe inflammation. In contrast to CRP, TNF-α is an early indicator of inflammation and increases in the first times of exposure to the inflammatory stimulus and then has a decreasing trend (Kumolosasi et al., 2014, Yousef et al., 2010). Most of the participants were not new cases. As a result, this difference in kinetics of CRP and TNF-α production can be the cause of difference in the effect of zinc on these two markers in BD patients. Future studies should investigate the effect of zinc on TNF-α in new case BD patients to get a complete picture of anti-inflammatory effects of zinc in BD.
Zinc exerts its anti-inflammatory action through down-regulating Nuclear Factor-Kappa-B (NF-ĸB). Some zinc finger proteins like A20 and growth factor independence-1 (Gfi-1) are involved in the inhibition of NF-ĸB dimerization (Faghfouri et al., 2020). It has been reported that zinc supplementation can lead to induction of A20 binding to mRNA and DNA through the upregulation of mRNA and DNA-specific sites (Prasad et al., 2004). Moreover, zinc status can contribute to the expression of a cytokines via binding to metal response elements (MREs) on the promoter of target genes (Bao et al., 2003, Cousins, 1998). Moreover, immunomodulatory effects of zinc can balance inflammatory responses (Faghfouri et al., 2022b). It should also be mentioned that inflammation and oxidative stress have a two-way relationship and an increase in one leads to the stimulation of the other. The antioxidant effects of zinc can also lead to anti-inflammatory consequences. Zinc is effective as a cofactor in the action of superoxide dismutase (SOD) as an anti-oxidant enzyme (Mariani et al., 2008). Zinc also leads to membrane strength through competition with toxic metals and prevents the oxidation of sulfhydryl groups of proteins (O'Dell, 2000). Zinc leads to the maintenance of mitochondrial homeostasis, thereby reducing ROS production (Lee, 2018) .
It was reported that superoxide radical anion generation can lead to lipid peroxidation in BD patients. Lipid peroxidation is the main cause of atherosclerosis pathogenesis in BD (Orem et al., 1997). MDA level is considered as the main marker of lipid peroxidation. MDA level has been reported to be higher in BD patients compared to healthy subjects (Mungan et al., 2006, Sandikci et al., 2003). The results of previous studies on the effect of zinc on MDA levels are contradictory. Some studies showed a positive effect of zinc (Momen-Heravi et al., 2017, Velázquez-Pérez et al., 2011), while some other studies failed to show an improvement effect (Aboomardani et al., 2012, Ribeiro et al., 2016). A meta-analysis study combining studies in this field showed that doses less than 40 mg per day do not have a significant effect on MDA. However, doses higher than 40 mg per day lead to a significant decrease in MDA. Dose-response analysis also showed that the relationship between zinc and MDA level was dose-dependent (Mousavi et al., 2020). As a result, the lack of significant effect of zinc on MDA in the present study may be related to the prescribed dose. However, as mentioned above, zinc overload has pro-oxidant effects. Therefore, future studies should compare effects of different doses of zinc on MDA levels in order to obtain the optimal dose using dose-response analysis.
The present study had some limitations. First, CRP was measured as the only inflammatory factor. Although in our previous studies we examined TNF-α and IL-1β in these patients in response to zinc gluconate supplementation (Faghfouri et al., 2022a, Faghfouri et al., 2022b), other inflammatory indicators should also be performed in future studies to fully determine the anti-inflammatory effects of zinc supplementation in BD patients. Second, we could not administer doses higher than the upper safety level (40 mg/day), due to ethical constraints. The observed lack of significant effect on MDA may be due to the administered dose. However, the study has some strengths. First, it is registered in IRCT and is reported based on the CONSORT checklist. Second, this is the first study that examines the effect of zinc on CRP and MDA in BD patients.
Conclusion
Zinc supplementation in an elemental dose of 30 mg per day has an anti-inflammatory effect in BD patients by reducing CRP levels. The beneficial effect of zinc on lipid peroxidation in BD patients was not shown in the present study.
Acknowledgement
The research protocol was approved and supported by Student Research Committee, Tabriz University of Medical Sciences (grant number: 68974).
Authors’ contributions
AH Faghfouri and B Alipour designed the study, collected the data, analyzed the data, drafted, and prepared the manuscript. AA Khodabandehloo, G shahhosseini and SM Seyyed Shoura. collected the data, drafted, and prepared the manuscript. V Musazadeh and A Khabbazi designed the study, collected the data, and critically revised the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Funding
The research protocol was approved and supported by Student Research Committee, Tabriz University of Medical Sciences (Grant number: 68974).
References
Aboomardani M, Rafraf M, Arefhosseini R & Rashidi M 2012. Effect of zinc supplementation on serum mlondealdehyde and lipid profiles on beta thalassemia major patients. Pharmaceutical sciences. 18 (1): 25-32.
Alibaz-Oner F & Direskeneli H 2022. Update on the diagnosis of Behçet's disease. Diagnostics (Basel). 13 (1): 41.
Alpsoy E 2016. Behcet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. Journal of dermatology. 43 (6): 620-632.
Alpsoy E, Zouboulis CC & Ehrlich GE 2007. Mucocutaneous lesions of Behcet's disease. Yonsei medical journal. 48 (4): 573-585.
Aramaki K, Kikuchi H & Hirohata S 2007. HLA-B51 and cigarette smoking as risk factors for chronic progressive neurological manifestations in Behçet's disease. Modern rheumatology. 17 (1): 81-82.
Azizlerli G, et al. 2003. Prevalence of Behçet's disease in Istanbul, Turkey. International journal of dermatology. 42 (10): 803-806.
Bao B, Prasad A, Beck F & Godmere M 2003. Zinc modulates mRNA levels of cytokines. American journal of physiology-endocrinology and metabolism. 285 (5): E1095-E1102.
Chambers JC, Haskard DO & Kooner JS 2001. Vascular endothelial function and oxidative stress mechanisms in patients with Behçet’s syndrome. Journal of the American College of Cardiology. 37 (2): 517-520.
Cho SB, Cho S & Bang D 2012. New insights in the clinical understanding of Behçet's disease. Yonsei medical journal. 53 (1): 35-42.
Cousins RJ 1998. A role of zinc in the regulation of gene expression. Proceedings of the nutrition society. 57 (2): 307-311.
Davatchi F 2012. Diagnosis/classification criteria for Behcet's disease. Pathology research international. 2012.
Davatchi F, Akbarian M & Shahram F 1991. Iran Behcet’s disease dynamic activity measure. Journal: Hungarian rheumatology. 32 (Suppl): 1340.
Davatchi F, et al. 2016. Adult Behcet's disease in Iran: analysis of 6075 patients. International journal of rheumatic diseases. 19 (1): 95-103.
Ekinci NS, Alpsoy E, Karakas AA, Yilmaz SB & Yegin O 2010. IL-17A has an important role in the acute attacks of Behcet's disease. Journal of investigative dermatology. 130 (8): 2136-2138.
Faghfouri AH, et al. 2022a. Regulation of NLRP3 inflammasome by zinc supplementation in Behçet's disease patients: A double-blind, randomized placebo-controlled clinical trial. International immunopharmacology. 109: 108825.
Faghfouri AH, et al. 2022b. Immunomodulatory and clinical responses to zinc gluconate supplementation in patients with Behçet's disease: A double-blind, randomized placebo-controlled clinical trial. Clinical nutrition. 41 (5): 1083-1092.
Faghfouri AH, Zarrin R, Maleki V, Payahoo L & Khajebishak Y 2020. A comprehensive mechanistic review insight into the effects of micronutrients on toll-like receptors functions. Pharmacological research. 152: 104619.
Fei Y, et al. 2009. Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study. Arthritis research & therapy. 11: 1-7.
Ghaedi K, et al. Effect of zinc supplementation in the management of type 2 diabetes: A grading of recommendations assessment, development, and evaluation-assessed, dose-response meta-analysis of randomized controlled trials. Critical reviews in food science and nutrition. 64 (25): 9228-9239.
Janero DR 1990. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free radical biology and medicine. 9 (6): 515-540.
Khan A, Haroon M, Bashir F & ud Din Z 2020. Behcet's disease: Pakistani experience. Pakistan journal of medical sciences. 36 (5): 1005.
Kim J & Ahn J 2014. Effect of zinc supplementation on inflammatory markers and adipokines in young obese women. Biological trace element research. 157 (2): 101-106.
Kirino Y, et al. 2013. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B* 51 and ERAP1. Nature genetics. 45 (2): 202-207.
Kökçam I & Nazıroǧlu M 2002. Effects of vitamin E supplementation on blood antioxidants levels in patients with Behçet’s disease. Clinical biochemistry. 35 (8): 633-639.
Köse K, Yazici C & Aşçioğlu Ö 2001. The evaluation of lipid peroxidation and adenosine deaminase activity in patients with Behcet’s disease. Clinical biochemistry. 34 (2): 125-129.
Kumolosasi E, Salim E, Jantan I & Ahmad W 2014. Kinetics of intracellular, extracellular and production of pro-inflammatory cytokines in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Tropical journal of pharmaceutical research. 13 (4): 536-543.
Lee SR 2018. Critical role of zinc as either an antioxidant or a prooxidant in cellular systems. Oxidative medicine and cellular longevity. 2018: 9156285.
Lee YJ, et al. 2013. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease. Annals of the rheumatic diseases. 72 (9): 1510-1516.
Mariani E, et al. 2008. Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects. Experimental gerontology. 43 (5): 445-451.
Mishra P, et al. 2019. Descriptive statistics and normality tests for statistical data. Annals of cardiac anaesthesia. 22 (1): 67.
Momen-Heravi M, et al. 2017. The effects of zinc supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial. Wound repair regen. 25 (3): 512-520.
Mousavi S, et al. 2020. Clinical effectiveness of zinc supplementation on the biomarkers of oxidative stress: A systematic review and meta-analysis of randomized controlled trials. Pharmacological research. 161: 105166.
Mungan A, Can M, Açikgöz S, Eştürk E & Altinyazar C 2006. Lipid peroxidation and homocysteine levels in Behçet's disease. Clinical chemistry and laboratory medicine. 44 (9): 1115-1118.
Nair JR & Moots RJ 2017. Behcet's disease. Clinical medicine. 17 (1): 71.
O'Dell BL 2000. Role of zinc in plasma membrane function. Journal of nutrition. 130 (5S Suppl): 1432s-1436s.
Orem A, et al. 1997. Relationship between lipid peroxidation and disease activity in patients with Behçet's disease. Journal of dermatological science. 16 (1): 11-16.
Plum LM, Rink L & Haase H 2010. The essential toxin: impact of zinc on human health. International journal of environmental research and public health. 7 (4): 1342-1365.
Powell SR 2000. The antioxidant properties of zinc. Journal of nutrition. 130 (5): 1447S-1454S.
Prasad A, Bao B, Beck F, Kucuk O & Sarkar F 2004. Antioxidant effect of zinc in humans. Free radical biology and medicine. 37 (8): 1182-1190.
Remmers EF, et al. 2010. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nature genetics. 42 (8): 698-702.
Ribeiro S, et al. 2016. Effect of zinc supplementation on antioxidant defenses and oxidative stress markers in patients undergoing chemotherapy for colorectal cancer: A placebo-controlled, prospective randomized trial. Biological trace element research. 169 (1): 8-16.
Roohani N, Hurrell R, Kelishadi R & Schulin R 2013. Zinc and its importance for human health: An integrative review. Journal of research in medical sciences. 18 (2): 144.
S. Lashkari B & Anumba DO 2017. Estradiol alters the immune-responsiveness of cervical epithelial cells stimulated with ligands of Toll-like receptors 2 and 4. Plos one. 12 (3): e0173646.
Saglam K, et al. 2002. Trace elements and antioxidant enzymes in Behçet's disease. Rheumatology international. 22: 93-96.
Sakane T, Takeno M, Suzuki N & Inaba G 1999. Behçet's disease. New England journal of medicine. 341 (17): 1284-1291.
Sandikci R, et al. 2003. Lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet's disease. Acta dermato-venereologica. 83 (5): 342-346.
Shahram F, et al. 2013. Scientometric analysis and mapping of scientific articles on B ehcet's disease. International journal of rheumatic diseases. 16 (2): 185-192.
Sharquie KE, Najim RA, AL‐Dori WS & AL‐Hayani RK 2006. Oral zinc sulfate in the treatment of Behcet's disease: a double blind cross‐over study. Journal of dermatology. 33 (8): 541-546.
Sterne JA, et al. 2009. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. British medical journal 339 (7713): 157-160.
Tanaka K, et al. 1985. Genetic and environmental factors in the development of Behcet's disease. Tohoku journal of experimental medicine. 145 (2): 205-213.
Velázquez-Pérez L, et al. 2011. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochemical research. 36 (10): 1793-1800.
Wessels I, Maywald M & Rink L 2017. Zinc as a gatekeeper of immune function. Nutrients. 9 (12): 1286.
Woźniacka A, Jurowski P, Omulecki A, Kot M & Dziankowska-Bartkowiak B 2014. Behçet’s disease leaves the silk road. Advances in dermatology and allergology/postępy dermatologii i alergologii. 31 (6): 417-420.
Yousef A, Amr Y & Suliman G 2010. The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Critical care. 14 (2): 1-9.
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Received: 2024/05/17 | Published: 2025/05/30 | ePublished: 2025/05/30
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