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Activity of liver enzymes in multiple sclerosis patients with Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention
Complementary Therapies in Medicine, 6, 22, pages 986 - 993
- Co-supplemented oils with Hot-natures Diet are useful for MS patients.
- Selecting foods with a high dietary TAC markedly can have beneficial effects in improving activity of liver enzymes in MS patients.
- Decrease of liver enzymes ratio in serum agrees with decrease of EDSS in RRMS patients.
- Diets with a high dietary TAC can decrease the risk of developing MS.
- Decrease of liver enzymes ratio in serum may be result of removing saturated andtransfatty acids from diet.
It is unknown whether diets with a high dietary total antioxidant capacity (TAC) can modify oxidative stress, low-grade inflammation, or liver dysfunction, all of which are risk factors for multiple sclerosis disease. This study assesses alanine amino-transferase (ALT), aspartate-aminotransferase (AST) and gamma-glutamyl transferase (GGT) activities in MS patients treated with co-supplemented hemp seed and evening primrose oils as well as Hot-nature diet and the therapeutic potential this intervention.
Methods and materials
In this double blind, randomized trial, 100 MS patients with EDSS < 6 were allocated into 3 groups: “group A”, who received co-supplementedhemp seedandevening primroseoils with advised Hot-nature diet; “group B”,who received olive oil; and “group C”, who received the co-supplemented oils. Clinically, EDSS as well as serum level of liver enzymes (GGT, AST, and ALT) were assessed at baseline and after 6 months.
Mean follow-up was 180 ± 2.9 SD days (N = 65, 23 M and 42 F aged 34.25 ± 8.07 years with disease duration of 6.80 ± 4.33 years). There was no significant difference in the study parameters at baseline. Serum levels of liver enzymes (GGT, AST, and ALT) were serially monitored. Intervention was associated with liver function alteration in three groups. Significance decreased in EDSS score and the levels of liver enzymes were found in groups A and C, whereas elevated serum liver enzymes and EDSS score were observed in group B after the intervention.
Selecting foods according to their Total antioxidant capacity such as co-supplementedhemp seedandevening primroseoils with Hot-nature diet affects antioxidant intake and can have beneficial effects on improving EDSS score and activity of liver enzymes in RRMS patients.
Keywords: Side effects, Oenothera biennis L., Cannabis sativa L., Inflammation, PUFA, Autoimmune liver dysfunction, Total antioxidant capacity.
Abbreviations: AA - arachidonic acid, ALA - alpha-linolenic acid, ALT - (SGPT)alanine-aminotransferase, AST - (SGOT)aspartate-aminotransferase, BBB - blood–brain barrier, CNS - central nervous system, DGLA - dihomo-gammalinolenic acid, EDSS - extended disability status score, EP - evening primrose, EPO - evening primrose oil, FA - fatty acid, FDA - food and drug administration, FR - food records, FSS - functional system scores, GGT - gamma-glutamyl transferase, GLA - gamma linoleic acid, HS - hemp seed, H-TAC - high-total antioxidant capacity, HSO - hemp seed oil, IFN - interferon (β1b-β1a-β), IFN- - γinterferon-γ, IL - interleukin (IL-2-IL-4, IL-5, IL-10, IL-12, IL-13), LA - linoleic acid (omega-6 Family), LC-PUFA - long chain-polyunsaturated fatty acid, L-TAC - low-total antioxidant capacity, MS - multiple sclerosis, nqFFQ - non-quantitative food frequency questionnaires, PGE - prostaglandin (E1, E2, E3), PPMS - primary progressive multiple sclerosis, PRMS - progressive relapsing multiple sclerosis, PUFA - polyunsaturated fatty acid, RBCs - red blood cells, ROS - reactive oxygen species, RRMS - relapsing remitting multiple sclerosis, SDA(STA) - stearidonic acid, SPMS - secondary progressive multiple sclerosis, TAC - total antioxidant capacity, Th - T helper (1-2-10-13), TIM - traditional Iranian medicine, TNF-α - tumor necrosis factor-alpha, USFA - unsaturated fatty acid, W/C - warmth/coldness.
Multiple sclerosis (MS) is a relatively common disease with an unknown etiology and with no cure which results in neurological disability in young adults. This condition affects over two million people worldwide. 1 Many of the current treatments are costly and limited in efficacy, and cause unpleasant side effects. 2 Although the exact etiology of developing MS is dependent on both genetic and environmental factors, 3 pathological events such as impairment of T helpers (Th) are involved. 4 The major types of Th cells are Th1 cells that produce interferon-γ (IFN-γ), Th2 cells that produce interleukin-4 (IL-4) and Th1/Th2 balance is considered as one of the risk factors in MS etiology.4, 5, and 6Interferon-β (IFN-β) treatment shifts the immune response from the Th1 to Th2 pattern by enhancing the production of anti-inflammatory Th2 cytokines (ex. IL-4) and decreasing the production of pro-inflammatory Th1 cytokines (ex. IFN-γ). Liver enzymes by treatment of interferon-β1b cause elevation, 7 because the liver is the organ responsible for plasma synthesis, drug detoxification and digestion.
Traditional Iranian Medicine (TIM) practiced in Iran and cold and hot natures have been believed to exist in TIM and in many other traditional medical theories. 8 The study of Shahabi et al., on IL-4/IFN-γ ratio showed that the tendency of the Hot nature people was to deviate toward Th2-like immune responses to a greater extent than of the cold nature people. 8 In this way, the consumption of Hot-nature foods in a person suffering from an autoimmune disease with a deviation toward Th1 immune responses (such as MS) may be useful because they can accelerate the warmth of nature and deviation toward Th2 immune responses. Evidence was found that ω3-polyunsaturated fatty acids (ω3-PUFAs) can suppress IFN-γ production in MS patients. 9 It seems that the combinationof virgin hemp seed oil (HSO)andvirgin evening primrose oil (EPO) [as co-supplemented oils] with Hot-natured diet causes effective reduction on pro-inflammatory cytokines and targets this key mechanism of disease and works like approved treatments. HSO has been used as a food/medicine in China for at least 3000 years. It contains over 80% in PUFAs, with omega 3/omega 6 (ω3/ω6) ratio between 1:2 and 1:3, which is considered to be optimal for human health. 10 HSO contains phytosterols, terpenes and kinds of tocopherol that not only exhibit potent antioxidative properties for scavenging free radicals but also may act on specific signaling pathways for regulating inflammatory responses.11, 12, and 13EPO is being used in increasing amounts in nutritional and pharmaceutical preparations, and may alleviate various chronic disease states. 14 Therefore, the co-supplemented oils with Hot-nature diet may appear to possess anti-inflammatory roles; and related to this treatment, liver enzymes assay is extremely helpful to understand the pathologic mechanisms in a disease like MS.
Material and methods
To test the above hypotheses, we conducted a double-blind, randomized clinical trial study on 100 relapsing–remitting multiple sclerosis (RRMS) patients to investigate the effects of Hot-nature diet and the co-supplemented oils compared with olive oil on liver dysfunction. Patients consumed a diet with high TAC (H-TAC) with or without Hot-nature diet compared with a diet with low TAC (L-TAC) such as olive oil. The study was approved by the Neurosciences Research Center (NSRC) and local ethics committee of Tabriz University of Medical Sciences. MS patients were contacted and recruited through the MS Society of Tabriz. Patients with a definite diagnosis of MS using the Kurtzke Extended disability status score (EDSS) <6 criteria, 15 with type of RRMS, aged 14–55 were enrolled. Patients with secondary or primary progressive MS, pregnancy, corticosteroid treatment as well as patients suffering concomitantly from another chronic disease such as rheumatic diseases, serious heart diseases, malignant tumors, and other neurological and inflammatory illnesses were excluded. Patients were allowed to continue their routine medications (avonex: interferon β_1a, one time/week). A written informed consent was completed prior to the study for all patients. The patients completed a 3-d food record in the first week, a non-quantitative Food Frequency Questionnaire (nqFFQ) to assess food and drinks consumed and dietary habits. They were asked to maintain their usual level of physical activity and not to consume any supplements during the study. We must notice that the co-supplemented oils (combination ofhemp seed oilandevening primrose oilwith 9/1 ratio)are foodstuffs without side effects. To reduce or eliminate a number of factors possibly affecting the measured results, random block design was used by a statistician who was not involved directly in the trial. Then, the patients were randomly assigned into three groups to receive one of the three dietary interventions:
Group A: Those who received the co-supplemented oils (consumption of the co-supplemented oils as syrup), 18–21 g/day (6–7 g, three times daily) with advisedHot-nature diet.
Group B: Those who consumed olive oil 18–21 g/day (6–7 g, three times daily).
Group C: Those who received the co-supplemented oils, 18–21 g/day (6–7 g, three times daily) for 6 months.
To achieve this objective, group A was asked to consume “Hot nature diet” with a wide choice of food and drink items permitted during each dietary period and delivered at home for 6 months ( Fig. 1 ). Groups B and C were asked to consume their usual diet during the intervention.“Hot-nature diet” includes foods with Hot-nature, low intake of cholesterol, hydrogenated or trans fatty acids and saturated fats (fried foods), the consumption of olive or grape seed oils as main oils in diet, eating plenty of fresh fruits and vegetables with Hot nature, nuts and seeds without additives, fish and seafood, unrefined carbohydrates, drinking plenty of water (avoiding too much drink containing artificial additives, sweeteners or other stimulants), cutting down sugar and refined starch (i.e. non-whole meal bread, cakes, pastries, biscuits, sweets and soft drinks), consumption of dairy products with honey or date and removing foods withCold-nature( Fig. 2 ), avoidance of alcohol and smoking.
To prevent bias at several stages of the trial, the patients, the investigators and assessors (particularly neurologist who assess EDSS score were unaware and blinded of the assigned intervention. The patients were contacted monthly by telephone to assess compliance. After baseline assessments, 100 patients were randomized to three groups according to the following diagram) ( Fig. 3 ).
All measures were repeated similarly with the same approach and assessors at the end of intervention period. Researcher, patients and those involved in the data collection and assessment (neurologists and nutritionists) as well as data analysis were blind regarding the type of interventions.
Measurement of the disability status of the patients
A medical history to check clinical status (EDSS) and medications used was taken. The functional disability status (disease severity) of each patient was measured by a trained clinician using the Kurtzke EDSS. 15 Scales for the total Kurtzke EDSS are from 0 to 10, in which 0 score indicates no disability at all and 10 indicates death due to MS.
Blood sample processing and analysis
Venous blood samples were collected from the patients before and 6 months after treatment. Serum was separated and aliquots were stored at −80 °C. Catalytic activities of hepatic cytolytic [aspartate (AST) and alanine (ALT) aminotransferases] and cholestatic [gamma glutamyl transpeptidase (GGT) were determined by commercial tests (Alcoyon abbot-300, USA) in all serum samples. Liver enzymes values were expressed as IU/ml.
The statistical analysis was performed using SPSS software (ver 14.0; SPSS Inc, Chicago, IL). The data were expressed as mean ± standard deviation (SD). Differences in clinical and biochemical variables between pre- and post within each intervention group were analyzed using pairedt-test. Statistical significance was defined asp < .05.
Characteristic and demographic results in RRMS patients
One hundred patients (34 men and 66 women) with clinically definite RRMS were enrolled in this study. Fig. 3 summarizes the patient attrition patterns in the study. The dropout rate was 35 from 100 patients (11 in “group A”, 11 in “group B”, and 13 in “group C”). This study was performed between October 2010 and October 2011. The patients’ characteristics and demographics are shown in ( Table 1 ). The sample consisted of 23 males and 42 females with a mean age of 34.25 ± 8.07 years and mean disease duration of 6.80 ± 4.33 years. There was statistically no significant difference in the mean gender, disease duration, interferon intake, age, and average age at the onset between the treatment groups.
|Variable||Group A (N = 23)||Group B (N = 22)||Group C (N = 20)|
|Mean ± SD||Mean ± SD||Mean ± SD|
|Age (years)||34.2 ± 7.5||35.9 ± 7.8||33.7 ± 7.8|
|Average age at onset (years)||25.0 ± 7.5||30.3 ± 8.1||27.6 ± 6.4|
|Disease duration (years)||6.26 ± 3.9||7.55 ± 5.08||6.60 ± 4.0|
|N (%)||N (%)||N (%)|
|Interferon intake (avonex: interferon β_1a, One time/week)||22 (95.7)||22)100)||19 (95)|
Group A: co-supplemented hemp seed and evening primrose oils and advised Hot-nature diet. Group B: olive oil. Group C: co-supplemented hemp seed and evening primrose oils.
Clinical and biochemical results
Baseline serum hepatic enzymes were abnormal in all patients. The results of this study revealed the beneficial effects produced by co-supplemented oils and combined therapy of both co-supplemented oils and Hot-nature diet. The clinical results of the trial are summarized in ( Table 2 ). There were significantly better changes in EDSS in groups A and C at the end of the intervention, while olive oil consumption resulted in a significant increase in EDSS for group B.
|Variable||Group A)N = 23)||Group B (N = 22)||Group C (N = 20)|
|Base line||6 months||P||Base line||6 months||P||Base line||6 months||P *|
|SGOT **||42.0 ± 11.4||30.70 ± 8.98||.001||31.04 ± 8.76||40.41 ± 12.09||.001||36.65 ± 12.90||27.85 ± 8.66||.001|
|SGPT **||33.78 ± 12.56||24.56 ± 9.24||.001||29.18 ± 11.91||35.95 ± 13.56||.001||25.95 ± 7.87||23.35 ± 8.58||.060|
|GGT **||35.56 ± 12.78||27.35 ± 11.58||.001||30.95 ± 11.86||36.64 ± 11.33||.001||30.65 ± 13.54||30.10 ± 12.95||.693|
|EDSS||2.76 ± 1.39||1.77 ± 1.7||.001||3.45 ± 1.41||1.41 ± 3.86||.005||3.25 ± 1.94||1.83 ± 2.95||.002|
* P for paired-t test.
** Liver enzymes values were expressed as IU/ml.
Group A: co-supplemented hemp seed and evening primrose oils and advised Hot-nature diet. Group B: olive oil. Group C: co-supplemented hemp seed and evening primrose oils.
Table 2 indicates significant reductions in serum levels of liver enzymes including AST, ALT and GGT in group A and only AST level was significantly decreased in group C after the consumption of the co-supplemented oil. The intervention in groups A and C, with or without Hot-nature diet, respectively, indicated improvement in liver function after 6 months, whereas a significant increase was shown in the activity of enzymes in group B.
In addition, it was reported that GGT rate is the best parameter (better than C-reactive protein) was followed for evaluating the efficacy of new anti-inflammatory agents in MS patients. There were no serious adverse effects in any of the 65 MS patients. These results ( Table 2 ) mean that the co-supplemented oils with or without Hot-nature diet used in our study might have a therapeutic effect on MS.
The theory of “Hot and Cold natures” had its origin in ancient Greek medicine by Hippocrates (Greek physician, 460–375 BC) and Galen (199–129 BC). 8 The most important role of all the ancient theories was the maintenance of the balance between the fundamental body elements, among which Warmth and Coldness played a completely essential role. 8
Immunological assay confirmed that a hallmark in the pathogenesis of MS is a shift in the ratio of Th cells toward Th1 cells.4, 5, and 6After activation of CD4, T helper cells differentiate into either Th1-type cells, secreting IL-2, IL-12, IFN-γ and TNF-α, or Th2-type cells secreting IL-4, IL-5, IL-10, and IL-13. Indeed, the balance between Th1 and Th2 cytokines is critical for the orientation of the inflammatory response toward cell-mediated or humoral-mediated responses. Thus, any factors that can interfere with Th1/Th2 axis might affect the outcome of the response. 8
Shahabi et al. showed the persons of a hot nature had more deviation of the immune system toward Th2 responses than the persons of a cold nature, which is in agreement with TIM practitioners’ view that MS (Th1-mediated autoimmune disease), is more prevalent in cold nature persons than in hot nature once. 8 Based on TIM practitioners’ view Hot-nature foods are useful for MS patients, Cold-nature foods aggravate their disease. Also, women are dominated twice more than men by cold nature and this confirms that autoimmune diseases such as MS are mostly common in women more than men and that parameters like weather coldness, lack of exposure to sun light and stressful life enhances Coldness in subjects. 16
Hepatic cytolytic enzymes (ALT, AST) increased up to 3-fold of level in MS subjects. Increases in the catalytic activity of liver enzymes (GGT, AST and ALT) were produced by the interferon-β treatment, either alone or in combination with other MS drugs. Liver injury during IFN treatment may also be ascribed to direct IFN toxicity on liver tissue, where IFNs decrease cytochrome P450 or drug metabolizing enzyme activity. 7
We reported that plasma activities of AST decreased significantly in group C and that both parameters (AST and ALT) decreased significantly in group A ( Table 2 ). However, in group B a significant increase in plasma GGT, AST and ALT was shown. In group B, GGT levels continued increasing, up to 36.64 IU/ml, and there was a concomitant increase in AST and ALT levels. Disturbed liver function was observed in the follow-up of MS patients in group B ( Table 2 ).
In this study, the decrease in EDSS agreeing with the decrease in the activity of liver enzyme parameters were significantly better in groups A and C compared to group B, and groups A and C felt physically and emotionally healthier ( Table 2 ). A favorable trend in group A was maintained on EDSS until the end of the study for all measurements, while no therapy exists that can confirm prolonged remission in MS and therapeutic agents are only partly effective. Their long-term beneficial effects are uncertain with side effects. 17
Investigating the health benefits of phenolic compounds is an enormous challenge to modern medicine. 21 Phytosterols are phenolic compounds that not only exhibit potent antioxidative properties for scavenging free radicals but may also act on specific signaling pathways for regulating inflammatory responses. Investigations revealed that HSO contains 3.6–6.7 g phytosterols/kg oil (Total phytosterols, 3922–6719 mg/kg oil), with β-sitosterol as the main component (70% of the total phytosterol content). 12 Several findings suggest that β-sitosterol is responsible for radical scavenging and antioxidant activities for preventive effects on the development of diseases due to reactive oxygen species (ROS) such as MS. 22 ROS are implicated as mediators of demyelination and axonal damage in MS. 23 Moreover, study of Yoshida and Niki showed the antioxidant effects of the phytosterols β-sitosterol, stigmasterol, and campesterol, against lipid peroxidation. The efficacy of β-sitosterol in reducing hypercholesterolemia, additional antiviral, antifungal, and anti-inflammatory properties has been studied and observed. 24 The presence of several terpenes was confirmed in HSO, Such as β-caryophyllene and myrcene that were found at 740 mg/l and 160 mg/l, respectively. β-caryophyllene can include anti-inflammatory and cytoprotective activities, and it has been reported that myrcene exhibits antioxidant properties.11 and 13
Oenothera biennisL. or evening primroses (EP) contain oil rich in ω6-GLA, which are precursors of eicosanoids, which are constituents of cell membranes. The biochemical pathway for metabolism of dietary gamma linoleic acid (GLA) eventually leads to prostaglandin E1 (PGE1), which has potent anti-inflammatory activity and is often recommended for inflammatory and autoimmune conditions. 25 Horrobin showed that the preliminary results of the use of EPO and colchicine combined therapy in MS patients may be of considerable value. 26
The co-supplemented oil constituents possess potential immunomodulatory effects, which as a consequence might impact on the liver enzymes (GGT, AST and ALT) and EDSS inter relationship ( Table 2 ). Consistent with this notion, active ingredients of co-supplemented oils have been reported to exert anti-inflammatory activities and effects. Some of these anti-inflammatory effects have been attributed to the immune-modulatory properties of co-supplemented oils components. Agreeing with the above changes, dietary PUFA (co-supplemented oils) and their metabolites affect inflammatory functions and cytokines production during the 6 months, because ω3-PUFAs, can suppress IFN-γ production in MS patients; 6 Prior studies have demonstrated a relation between MS mortality and dietary fat. 27 Lipids can be found in two structural components: the neuronal membrane (about 50%) and the myelin sheath (about 70%). A high proportion of lipid 70–85%, and the blood–brain barrier (BBB) is a key to the bioavailability of brain essential fatty acid (EFA).28 and 29
The findings discussed above regarding the improvement in serum levels of liver enzymes (GGT, AST and ALT) were correlated with the EDSS benefits at the last visit ( Table 2 ). These results are likely due to remyelination that occurs during the early phases of the disease, though this is rare at more progressed stages. 30 Current estimates of the ω3/ω6 PUFAs ratio in developed countries is as low as 1:25 with recommendations to the public that it should be much higher (ideally 1:4). 31 A larger number of medicinal plants and their purified constituents have shown beneficial therapeutic potentials. The virgin HSO/virgin EPO ratio in this study is 9:1, so ω3/ω6 PUFAs ratio reached to 1:4 or higher, which is the competitive inhibition of the conversion of dihomo-gamma-linolenic acid (DGLA) to arachidonic acid (AA) resulting in more anti-inflammatory PGE1. 32 AA is a precursor of pro-inflammatory and pro-aggregator prostaglandinE2 (PGE2), while GLA and DGLA are precursors of anti-inflammatory PGE1 ( Fig. 4 ).
The above findings imply that compared to olive oil, the co-supplemented oils with Hot-nature diet produced a significant reduction in clinical symptoms, and the patients,general health improved, which may be due to higher PUFA in peripheral tissue (red blood cells) and maybe in brain tissue and mitochondrial [as an organelle with wide variety of enzymes’ activities in inner membrane and phospholipids 90% of total lipid, which is necessary for defense against lipid per oxidation with scavenging and antioxidant activities for preventive effects on the development of diseases due to ROS such as MS], 33 etc.
These results support the hypothesis of essential fatty acid (EFA) abnormalities in MS patients and indicate that the problem could well be one of conversion of EFA to long chain-polyunsaturated fatty acid (LC-PUFA) ( Fig. 4 ), as originally suggested before. It is important to note that supplementation with PUFAs may require additional vitamin E intake to prevent increased peroxidation of membrane lipids, while the total amount of tocopherols of (α-, β-, γ-tocopherol, δ-tocopherol) HSO is high between 80 and 110 mg/100 g, with γ-tocopherol as the main tocopherol (85%) that exhibits potent antioxidative properties for scavenging free radicals.12 and 14In recent years the protecting role of antioxidant system of the organism in pathogenesis of different diseases has actively been discussed. At the same time the deficiency of antioxidant defense can be not only of acquired, but also of hereditary nature. A lot of researches are dedicated to the study of the antioxidant groups role in producing the immune responses of the organism. 34
Recently, the total antioxidant capacity (TAC) of foods, which describes the ability of food antioxidants to scavenge preformed free radicals, has been suggested as a tool for investigating the health effects of antioxidants present in mixed diets.35 and 36
Actually, reactive oxygen species increasingly produced in the liver after saturated fatty acids or drug accumulation and interferon's toxicity are known to impair mitochondrial oxidation and function. 34 Because antioxidant compounds can neutralize reactive oxygen species, an increased influx of antioxidants to the liver could be likely to induce a decrease in markers of liver damage, as in our study.35 and 36
Further investigations of relevant enzyme activities in patients on short and long duration co-supplemented therapy are needed. Ultimately, diets with a high dietary total antioxidant capacity (TAC) can modify oxidative stress, low-grade inflammation, or liver dysfunction, all of which are risk factors for MS patients.35 and 36
Of course, the co-supplemented oils are foodstuffs that do not act as rapidly as most medications, so any effects will take time to appear. It means that most patients who respond to supplementation usually report noticeable benefits within one or two months.
Results emerging from such studies will substantially improve the immunotherapeutic application of co-supplemented oils and Hot-nature diet in clinical settings. The limitation of the intervention was caused by the consumption of the co-supplemented oils as syrup. We were not able to encapsulate the supplement for patients’ consumption by a protective coating or membrane, so the high prevalence of dropout in this study was caused by the mentioned parameters. Uncontrolled diet is the other important confounding factor.
We have demonstrated by our analysis of the enzyme activation profiles that supplementing with virgin hemp seed and virgin evening primrose oils accompanied by Hot-natured diet reduces the enzyme activation in 6 months and will lead to the identification of new therapeutic targets.
In conclusion, qualitatively selection of food items on the basis of their TAC was a useful and effective approach to demonstrate that the quality of certain food groups may be crucial to the improved functioning of the liver in MS patients, which is the independent risk factor for chronic disease. That such a result was achieved without modifying biomarkers of antioxidant status opens new perspectives to investigate the mechanisms of the action of antioxidant-rich foods. In the meantime, giving preference to foods naturally high in TAC could be a simple approach to further improving dietary habits.
Conflicts of interest statement
The authors declare that there are no conflicts of interest.
This work was supported by deputy of Tabriz University of Medical Sciences for a part of the budget (25% of grants) to run the project and authors (75% of grants) for the preparation of the herbal oils. This research was registered with main IRCT ID under IRCT138804252195N1 code on 2010/12/04. All authors read and approved the final manuscript.
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a Neurosciences Research Center, University of Medical Sciences, Tabriz, Iran
b School of Nutrition and Health, University of Medical Sciences, Tabriz, Iran
c Immunology Research Center, University of Medical Sciences, Tabriz, Iran
d Food &drug organization, University of Medical Sciences, Tabriz, Iran
e Islamic Azad University, Tabriz, Iran
1 Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz 5166614711, Iran. Tel.:+98 411 3357582.
2 School of Health & Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
4 Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
5 Food &drug organization, Tabriz University of Medical Sciences, Tabriz, Iran.
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