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Effects of Hydroalcoholic extract of Berberis Integerrima on theanthropometric indices and metabolic profile in active RheumatoidArthritis patients
Please cite this article as: Aryaeian N, Sedehi SK, Khorshidi M, Zarezadeh M, Hosseini A,Shahram F, Effects of Hydroalcoholic extract of Berberis Integerrima on the anthropometricindices and metabolic profile in active Rheumatoid Arthritis patients, ComplementaryTherapies in Medicine (2020), doi: https://doi.org/10.1016/j.ctim.2020.102331
This is a PDF file of an article that has undergone enhancements after acceptance, such asthe addition of a cover page and metadata, and formatting for readability, but it is not yet thedefinitive version of record. This version will undergo additional copyediting, typesetting andreview before it is published in its final form, but we are providing this version to give earlyvisibility of the article. Please note that, during the production process, errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journalpertain.
protein kinase in the cell and reducing the activity of sucrose and α-glucosidase in the
intestine (38). The average levels fasting blood glucose in RA patients are higher than the
normal population due to the intake of glucocorticoids. In this study, we observed a
decrease in blood glucose in the intervention group.
Following supplementation, the systolic blood pressure was significantly
decreased in the intervention group and diastolic blood pressure remained unchanged. It
should be noted that the values of blood pressure in this study were in the normal ranges.
The findings of Perez-Rubio et al., study indicated a positive effect of 3 months berberine
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supplementation (1500 mg daily) on blood pressure (39). In the study of Golzarand et al.,
black barberry had no effect on systolic and diastolic blood pressure that is probably due
to the low amount of barberry consumption (40). The results of animal studies showed
that berberine decreases blood pressure by inhibiting ACE (41). Moreover, the results of
the studies have shown that berberine increases the production of NO and cyclic
guanosine monophosphate (cGMP) as a major causes of vasodilatation. Therefore, it
appears that the blood pressure lowering effect of berberine is mediated by the ACE and
NO / cGMP pathways (41).
Following intervention serum LDL-C levels were significantly decreased. TC
decreased in both groups, but it wasn’t statistically significant. TG was decreased in the
intervention group and increased in the placebo group, however, the changes were not
significant. The difference in HDL-C levels between the two groups was significant at
the end of the intervention. It should be noted that RA patients have normal lipid profile.
Many studies showed the positive effect of berberine on lipid profile (35, 42, 43). In the
study by Shidfar et al., barberry extract consumption significantly decreased the serum
TG and TC levels, at the end of the study in the intervention group. However, there was
no significant change in HDL-C levels, which is probably due to low amounts of barberry
or low levels of effective compounds in the extract (25). Studies have shown that
berberine improves hyperlipidemia by stimulating the oxidation of fatty acids and
restoring metabolic programs through the activity of liver and muscle AMPK (44).
Berberine also seems to carry out its effect to lower cholesterol by increasing the
expression of the LDL-C receptor (35).
We suggest assessing the effect of Berberine on RMR (Resting Metabolic Rate) by
colorimetric assay, and using a high accuracy method such as DXA (Dual x-ray
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absorptiometry) for body composition analysis in the further study. As limitations, we
were unable to conduct study with larger sample size due to the financial constraints.
Lack of measurement of the bioactive factors of berberine in the blood which could
determine its bioavailability also was one the limitations. besides, since the participants
in the study were overweight on average, having a normal weight group would allow the
interpretation of the results.
In conclusion, daily consumption of 3000 mg barberry extract for 3 months in active RA
patients, significantly decreased body fat, FBS, and increased HDL levels. Following
supplementation, barberry prevented weight gain and decreased body mass in comparison
with placebo. The current findings demonstrated that barberry might have beneficial
effects in modulating some major comorbidities in patients with RA. The efficacy of this
compound, with especial focus on inflammation, should be further investigated as an
adjuvant therapy in RA.
Author contributions:
Naheed Aryaeian: designed and supervised the study, participated in the presentation of
the results, drafting and review of the manuscript.
Sara Khorshidi Sedehi: Participated in writing proposal, sampling, and filling the
questionnaires and data collection.
Farhad Shahram: Clinical assessment of RA patients, determined the disease activity
and participated in review of the manuscript.
Masoud Khorshidi: participated in writing and review of the manuscript.
Meysam Zarezadeh: participated in writing and review of the manuscript.
AghaFatemeh Hosseini: participating in statistical Analysis.
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Declaration of interest
All authors declare no conflict of interest.
Acknowledgment
This study was supported by the Iran University of Medical Sciences Grant 25092. We
are thankful for the cooperation of the staff of green plants of life factory for preparation
of supplements and placebos for this research. We also would like to show our gratitude
to the participants of the study and Rheumatology Research Center Tehran University of
Medical Sciences for participating in the patinet selection phase.
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expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyte. Experimental & molecular medicine. 2006;38(6):599. 34. Berthon BS, MacDonald-Wicks LK, Wood LG. A systematic review of the effect of oral
glucocorticoids on energy intake, appetite, and body weight in humans. Nutrition research (New York, NY). 2014;34(3):179-90.
35. Wei J, Wu J, Jiag J. Clinical study on improvement of typeⅡdiabetes mellitus complicated with fatty liver treated by berberine. Chinese J Integ Tradition West Med Liver Dis. 2004;6:334-6. 36. Moazezi Z, Qujeq D. Berberis fruit extract and biochemical parameters in patients with
type II diabetes. Jundishapur journal of natural pharmaceutical products. 2014;9 (2.) 37. Zhang W, Xu Y-c, Guo F-j, Ye M, Li M-l. Anti-diabetic effects of cinnamaldehyde and
berberine and their impacts on retinol-binding protein 4 expression in rats with type 2 diabetes mellitus. Chinese Medical Journal. 2008;121(21):2124-8. 38. Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, et al. Treatment of type 2 diabetes and
dyslipidemia with the natural plant alkaloid berberine. The Journal of Clinical Endocrinology & Metabolism. 2008;93(7):2559-65. 39. Perez-Rubio KG, Gonzalez-Ortiz M, Martinez-Abundis E, Robles-Cervantes JA, Espinel-
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processed Berberis vulgaris in apple vinegar on blood pressure and inflammatory markers in type 2 diabetic patients. Journal of Diabetes and Metabolic Disorders. 2008;7:3. 41. Kang DG, Sohn EJ, Kwon EK, Han JH, Oh H, Lee HS. Effects of berberine on angiotensin-
converting enzyme and NO/cGMP system in vessels. Vascul Pharmacol. 2002;39(6):281-6. 42. Derosa G, Bonaventura A, Bianchi L, Romano D, Fogari E, Maffioli P. Effects of Berberis
aristata/Silybum marianum association on metabolic parameters and adipocytokines in overweight dyslipidemic patients .Journal of biological regulators and homeostatic agents. 2013;27(3):717-28. 43. Farhadi A, Gavadifar K. Effects of Berberise Vulgaris fruit extract on blood cholesterol
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Figure 1. Flow diagram of the study
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Table 1: Participant characteristics in the extract of Berberis Integrima and placebo groups
before supplementation (Mean±SD)
p-
value¶,
£
HPMC
(n=31)
Berberis Integrima extract
(n=31)
0.59 47.1±10.75 48.61±11.69 Age (years)
0.24 74.68±15.05 70.44±13.19 Body weight
(kg)
0.98 1.59±0.07 1.59±0.08 Height(m)
0.30 29.46±5.70 27.90±6.06 BMI (kg/m2)
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0.36 13.84±17.98 10.61±8.40 Duration of
RA(years)
1.00
28(90.3)
3(9.7)
28(90.3)
3(9.7)
Sex
Female (%)
Male (%)
0.39
21(67.7)
8(25.8)
2(6.5)
20(64.5)
6(19.3)
5 (16.1)
Physical
activity
Light (%)
Moderate (%)
Severe (%)
0.37 7.42±4.35 8.36±4.21 Glucocorticoid
s (mg per day)
0.87 Sever
e
Moderat
e
Mild Non
activ
e
Severe Moderat
e
Mild Non
activ
e
GPA n(%)
3(9.7) 18(58) 10(32.3
)
0(0) 5(16.2
)
17(54.8) 9(29
)
0(0)
¶ P-value (age, body weight, height, BMI and duration of RA) calculated by Independent sample t-test. £ P-value (sex and physical activity) calculated by fisher-test. SD, Standard Deviation; HPMC,
Hydroxypropyl Methylcellulose; n, number of patients; BMI, Body Mass Index; RA, rheumatoid arthritis;
GPA, Global Physician Assessment
Table2. Glucocorticoids, energy, macronutrients and some micronutrients intake in
the extract of Berberis Integrima and placebo groups before and after intervention
(Mean±SD)
p-value¶,$ HPMC
(n=31)
Berberis Integrima extract
(n=31)
0.21
0.13
1395.90±447.90
1313.8±555.46
0.36
1508.87±226.24
1490.81±325.35
0.52
Energy(Kcal)
Before
After
p‡
0.23
0.13
69.18±7.60
68.17±11.80
0.67
67.02±9.54
64.10±9.49
0.20
Carbohydrate (%)
Before
After
p‡
0.84
0.14
14.23±3.82
13.5±5.10
0.51
14.42±3.49
15.24±4.16
0.40
Protein (%)
Before
After
p‡
0.12
0.16
16.49±5.64
18.13±10.83
0.42
19.67±9.90
21.80±9.62
0.38
Fat (%)
Before
After
p‡
0.94
0.08
102.84±129.70
70.65±74.36
68.28±34.64
68.48±26.65
Vitamin C(mg)
Before
After
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0.20 0.89 p†
0.07
0.83
0.55±0.75
0.36±0.63
0.10
0.61±1.23
0.83±1.06
0.40
Vitamin D(μg)
Before
After
p†
0.61
0.42
6.27±3.24
5.79±2.76
0.46
5.90±2.42
6.26±1.67
0.32
Zinc(mg)
Before
After
p‡
0.41
0.07
0.03±0.04
0.04±0.05
0.93
0.03±0.03
0.04±0.05
0.22
Selenium(mg)
Before
After
p†
SD, standard deviation; HPMC, Hydroxypropyl methylcellulose; n, number of patients. ¶ P-value (energy,
carbohydrate, protein, fat, and zinc) calculated by Independent sample t-test between two groups. $ P-value
(vitamin C, vitamin D, and selenium) calculated by Mann-Whitney between two groups.
† P-value (vitamin C, vitamin D, and selenium) calculated by Wilcoxon test for before and after the
intervention within each group. ‡ P-value (energy, carbohydrate, protein, fat, and zinc) calculated by the
paired-t test for before and after the intervention within each group.
Table3. Weight, BMI, body fat percent, waist circumference, hip circumference, waist-to-
hip ratio, and Conicity index in the extract of Berberis Integrima and placebo groups before
and after intervention )Mean±SD)
p¶ HPMC
(n=31)
Berberis Integrima extract
(n=31)
0.24
0.15
0.23
74.68±15.05
76.57±15.53
1.92±2.29 < 0.001***
70.44±13.19
71.27±13.40
0.90±4.04 0.27
Weight (Kg)
Before
After
Difference p‡
0.30
0.24
0.49
29.46±5.70
30.23±5.90
0.76±0.95
< 0.001***
27.90±6.06
28.42±6.26
0.51±1.77
0.11
BMI
Before
After
Difference
p‡
0.97
0.45
0.05*
35.08±7.52
35.45±7.43
0.37±2.89
0.48
35.02±7.40
33.98±7.81
-1.03±2.77
0.04*
Body fat percent
Before
After
Difference
p‡
0.71
0.37 0.17
89.87±11.81
91.52±11.12 1.64±2.78
< 0.001***
88.64±13.96
88.58±14.44 -0.06±6.27
0.95
Waist circumference
Before
After Difference
p‡
0.14
0.59
< 0.001***
107.55±10.75
109.55±10.75
2.00±2.50
< 0.001***
105.90±13.56
105.12±12.84
-0.77±4.70
0.36
Hip circumference
Before
After
Difference
p‡
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0.99
0.76
0.69
0.83±0.06
0.83±0.05
-0.00±0.02
0.99
0.83±0.04
0.83±0.05
0.00±0.05
0.67
Waist-to-hip ratio
Before
After
Difference
p‡
0.50
0.28
0.13
56.77±12.50
58.52±12.37
1.74±2.22
< 0.001***
54.57±13.30
54.93±13.83
0.35±4.51
0.66
Conicity index Before
After
Difference
p‡ *p< 0.05, ***p<0.001. SD, standard deviation; HPMC, Hydroxypropyl methylcellulose; n, number of
patients. ¶ P-value calculated by Independent sample t-test between two groups. ‡ P-value calculated by the
paired-t test for before and after the intervention within each group.
Table4. Systolic and diastolic blood pressure and FBS level in the extract of Berberis Integrima and
placebo groups before and after the intervention (Mean ± SD)
$ p HPMC
(n=31)
Berberis Integrima extract
(n=31)
0.36
0.04*
0.76
12.16±1.38
11.74±1.50
- 0.48±1.31
0.06
12.56±1.29
12.05±0.48
- 0.51±1.15
0.02*
Systolic blood pressure
(mmHg)
Before
After
Difference
p†
0.76
0.98
0.50
7.79±1.13
7.81±1.22
0.00±1.31
0.97
7.77±1.08
7.94±0.44
0.16±0.93
0.33
Diastolic blood pressure
(mmHg)
Before
After
Difference
p†
0.21
<0.001***
0.03*
104.56±21.62
115.12±40.93
10.54±36.52
0.41
101.76±24.61
86.86±17.35
-14.89±30.02
0.02*
Fasting blood sugar (mg/dl)
Before
After
Difference
p† *p< 0.05, ***p<0.001. SD, standard deviation; HPMC, Hydroxypropyl methylcellulose; n, number of
patients. $ P-value calculated by Mann-Whitney between two groups. † P-value calculated by Wilcoxon
test for before and after the intervention within each group.
Table 5. TC, TG, LDL- cholesterol and HDL- cholesterol levels in the extract of Berberis Integrima,
and placebo groups before and after the intervention (Mean±SD)
p¶ HPMC
(n=31)
Berberis Integrima extract
(n=31)
0.21
0.20
0.93
200.66±35.69
195.03±35.44
- 5.62±20.54
0.15
188.61±37.85
182.32±41.51
- 6.29±40.56
0.39
Total cholesterol (mg/dl)
Before
After
Difference
p‡
0.31
134.68±58.32
119.52±56.71 Triglyceride (mg/dl)
Before
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0.27
0.79
134.93±65.11
0.25±35.36
0.97
116.77±62.00
- 2.74±48.68
0.75
After
Difference
p‡
0.48
0.90
0.32
113.43±28.01
109.73±37.22
-3.70±24.46
0.41
119.16±34.62
108.71±27.78
-10.45±28.56
0.05*
LDL cholesterol(mg/dl)
Before
After
Difference
p‡
0.46
0.01**
0.03*
59.23±13.69
57.55±13.88
-1.67±6.20 0.14
61.87±14.24
65.97±11.43
4.10±13.54 0.10
HDL cholesterol(mg/dl)
Before
After
Difference
p‡ p<0.01. SD, standard deviation; HPMC, Hydroxypropyl methylcellulose; n, number of patients. **p< 0.05, *
t -value calculated by the paired-P ‡test between two groups. -value calculated by Independent sample t-P ¶
test for before and after the intervention within each group.