Study Protocol Clinical Trial Medicine ®

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The effects of green cardamom supplementation

on blood pressure and endothelium function in
type 2 diabetic patients
A study protocol for a randomized controlled clinical trial
Shohreh Ghazi Zahedi, PhD student in Nutritiona, Fariba Koohdani, Professor, PhDb, Mostafa Qorbani, PhDc,
Fereydoun Siassi, Professor, PhDa, Ali Keshavarz, Professor, PhDd, Ensieh Nasli-Esfahanie,
Mohadeseh Aghasi, PhD student in Nutritiona, Hoorieh Khoshamal, MSc student in Nutritiona,
∗
Gity Sotoudeh, Professor, PhDa,

Abstract
Introduction: Cardamom possesses antioxidant, anti-inflammation, and blood pressure lowering properties, which might improve
endothelial function in type 2 diabetic patients. However, no study has examined the effect of cardamom on diabetic patients. The
present study aimed to examine the effects of 10-week green cardamom intake on blood pressure, concentrations of inflammatory
and endothelial function biomarkers in type 2 diabetes mellitus patients, and its potential mechanisms.
Methods and Analysis Design: Eighty overweight or obese patients with type 2 diabetes mellitus (aged 30–60 years) will be
recruited into the trial and will assign to receive either cardamom (3 g/day, 6 capsules) or placebo (rusk powder, 6 capsules) for a
period of 10 weeks. Systolic blood pressure and diastolic blood pressure, asymmetric dimethylarginine, and nitric oxide will be
measured. Serum inflammatory markers namely interleukin 6, tumor necrosis factor-a, high-sensitivity C-reactive protein, and factors
related to endothelial function including intercellular adhesion molecule-1, vascular cell adhesion molecule 1, CD62 antigen-like family
member E, and cluster of differentiation 163 will be measured at baseline and at the end of the trial. Sociodemographic, International
Physical Activity Questionnaire, and three 24-hour dietary recall questionnaires will be collected for each participant.
Ethics and dissemination: The study has been approved by The Ethics Committee of Tehran University of Medical Sciences (IR.
TUMS.REC.1395.2700). Each participant will sign a written informed consent at the beginning of the study. At the end of the study,
results will be published timely manner.
Trial registration number: (http://www.irct.ir, identifier: IRCT-2016042717254N5) Date of registration: 2016-11-23
Abbreviations: ADMA = asymmetric dimethylarginine, BMI = body mass index, CD163 = cluster of differentiation 163, CVD =
cardiovascular disease, E-selectin = CD62 antigen-like family member E, hsCRP = high-sensitivity C-reactive protein, ICAM =
intercellular adhesion molecule, IL-6 = interleukin 6, IPAQ = International Physical Activity Questionnaire, NF-kB = nuclear factor
kappa-light-chain-enhancer of activated B cells, NO = nitric oxide, SIRT1 = sirtuin 1, T2DM = type 2 diabetes mellitus, TNF-a = tumor
necrosis factor-a, VCAM = vascular cell adhesion molecule.
Keywords: blood pressure, diabetes, endothelial dysfunction, green cardamom, trial protocol

Ethics approval and consent to participate: The Ethics Committee of Tehran University of Medical Sciences has approved study protocol (IR.TUMS.REC.1395.2700). A
written informed consent form will be signed and dated by subjects and investigators at the beginning of the study. Participation is free, and a patient can withdraw at
whatever point the person feels he/she is unable to continue. Side effects of the supplements have not been reported in previous studies. The personal information of
participants will be kept secret before, during, and after the trial.
This research has been supported by Tehran University of Medical Sciences and Health services (grant number 94-04-161-31132).
GS and FK contributed equally as corresponding authors to this paper.
The authors report no conflicts of interest.
a
Department of Community Nutrition, b Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical
Sciences, Tehran, c Noncommunicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences,
School of Medicine, Alborz University of Medical Sciences, Baghestan Boulevard, Karaj, d Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics,
e
Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
∗
Correspondence: Gity Sotoudeh, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Tehran Iran, Islamic Republic of
(e-mail: gsotodeh@tums.ac.ir).
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Zahedi SG, koohdani F, Qorbani M, Siassi F, Keshavarz A, Nasli-Esfahani E, Aghasi M, Khoshamal H, Sotoudeh G. The effects of green
cardamom supplementation on blood pressure and endothelium function in type 2 diabetic patients: A study protocol for a randomized controlled clinical trial. Medicine
2020;99:18(e11005).
Received: 28 February 2018 / Received in final form: 4 May 2018 / Accepted: 17 May 2018
http://dx.doi.org/10.1097/MD.0000000000011005

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Zahedi et al. Medicine (2020) 99:18 Medicine

Cluster of differentiation 163 (CD163) is a macrophage-

specific receptor involved in the clearance and endocytosis of
Limitations
hemoglobin-haptoglobin complexes.[9] A high CD163 expres-
sion in macrophages is a characteristic of tissues responding to

Some patients might not cooperate till the end of the
inflammation and indirectly contributes to the anti-inflammatory
study, which will be replaced with other patients.
response. sCD163 is a biomarker for inflammation in adipose

Because of the strong aroma of cardamom the placebo
tissues and also a biomarker for the development of T2DM.[10] It
group might find out that they are not taking cardamom
has been indirectly associated with anti-inflammatory and
and vice versa and this limits the study to be double blinded.
atheroprotective activity[11] and is a therapeutic target.[10]

Small sample size which might affect generalizability of
The exact mechanisms of endothelial dysfunction in T2DM is
the results.
not known but it might be related to decreased synthesis of nitric

Short follow-up period (10 weeks) and dose of the
oxide (NO) or increased inactivation of NO.[12] NO has
cardamom supplementation (3 g/day).
cardioprotective roles which include regulation of blood pressure
Strengths and vascular tone, inhibition of platelet aggregation and
leukocyte adhesion, and smooth muscle cell proliferation

According to our knowledge and searches we have done,
prevention.[13] NO impairment is regarded as an early step in
this is one of the first randomized controlled clinical trials
the development of insulin resistance, atherosclerosis, and
to assess the effects of Elettaria cardamomum supple-
T2DM.[14] Asymmetric dimethylarginine (ADMA) is a com-
mentation in patients with type 2 diabetes mellitus.
pound found in human plasma and is endogenous inhibitor of

The present study will provide the required base for future
NO synthase.[14] Elevated plasma ADMA levels have been
greater clinical trials.
observed in patients with insulin resistance and diabetes, and

This is a double-blind study with the least dropout.
have been reported to predict adverse cardiovascular events in

We will place placebo capsules next to cardamom
patients with T2DM.[15]
capsules so the placebo capsules will have the aroma of
It has been shown that many risk factors for CVD such as
cardamom and by this we try to lessen the limitation of
hypercholesterolaemia, obesity, and T2DM are conditions in
the study.
which the activation of the sirtuins had shown to have protective

We will exclude participants who are taking supplements,
effects in experimental models.[16] Sirtuins are the class III histone
as well as those participating in a weight loss program,
deacetylases, which are widely distributed in the body and
and thus will be able to exclude potential confounding by
regulate physiopathological processes, such as inflammation and
these factors.
have cardioprotective effects.[16,17] The best characterized and
well-studied among the human sirtuins is sirtuin 1 (SIRT1) which
has anti-inflammatory functions in macrophages and endothelial
cells. SIRT1 interferes with the transcription factor nuclear factor
kappa B (NF-kB) signaling pathway which leads to down-
1. Introduction
regulation of the expression of various proinflammatory
Type 2 diabetes mellitus (T2DM) is one of the most important cytokines.[18] The production of proinflammatory cytokines in
causes of mortality and morbidity around the world.[1] The human atherosclerotic plaques is NF-kB dependent[19] and NF-
International Diabetes Federation estimates that in 2010, 285 kB activation leads to the expression of many proinflammatory
million people of the world population suffered from diabetes cytokines (e.g., IL-1, IL-2, IL-6, and TNF-a), adhesion molecules
and by 2030 this number will increase to 439 million people of (e.g., VCAM, ICAM, E-selectin), and inducible proinflammatory
the world population.[2] The incidence of cardiovascular diseases enzymes (cyclooxygenase-2 and inducible NO synthase), which
(CVDs) is 2- to 4-fold in people with T2DM.[3] CVD is the major exacerbate the inflammatory process and make it perpetual.[20]
reason of morbidity in patients with T2DM, and a cause of death The results of a study demonstrate that SIRT1 plays a
in approximately 3 out of 4 diabetic patients.[4] Raised blood fundamental role in regulating endothelial NO by activating
pressure is more common in people with T2DM.[5] NO synthase eNOS, which increases endothelial NO.[21] SIRT1
CVD is generally attributed to the adverse effects of impairs synthesis and increases metabolism of ADMA.[22]
hyperglycemia and oxidative stress on vascular biology. Vascular There are developing evidence that shows, because of their
endothelial cells play an important role in maintaining biological properties, plant foods polyphenols, may be unique
cardiovascular homeostasis and endothelial dysfunction causes nutraceuticals and supplementary treatments for various aspects
the development of atherosclerosis. In diabetic patients, endo- of T2DM.[23] Polyphenols have been shown to activate SIRT1
thelial dysfunction is a consistent finding.[6] either directly or indirectly in vitro and in vivo. Hence, the
Inflammation is an integral part of the atherosclerotic process. activation of SIRT1 by polyphenols would be beneficial in
Plasma concentration of inflammatory mediators, such as tumor therapeutic intervention of a variety of chronic diseases.[17]
necrosis factor-a (TNF-a), interleukin-6 (IL-6), and C-reactive Seeds of cardamom (Elettaria cardamomum) are from the
protein (CRP) are higher in obesity and patients with T2DM in Zingiberaceae family and are used as the spice ingredient in food.
which insulin resistance occurs.[7] Inflammatory markers stimu- Cardamom contains flavonoids like quercetin, kaempferol,
late endothelial production of adhesion molecules such as luteolin, and pelargonidin.[24] Key components of essential oil
intercellular adhesion molecules (ICAMs), vascular cell adhesion in cardamom [i.e., 1,8-cineol (eucalyptol); beta-pinene; geraniol]
molecule (VCAM), and endothelial-leukocyte adhesion molecule by binding to NF-kB, provides anti-inflammatory activity.[25] The
(E-selectin). These proinflammatory cytokines have a direct effect effect of E cardamomum on some of the cardiovascular risk
on vascular walls, which promotes atherosclerosis and leads to factors in individuals with stage 1 hypertension was studied. The
impaired vascular reactivity.[8] result showed that E cardamom effectively reduces blood

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pressure, enhances fibrinolysis, and improves antioxidant 2.1. Objectives

status.[26]
Traditional remedies and as a part of that, herbal medicines are
Compare the mean SBP and DBP and serum NO and ADMA
a potential source for the development of new therapeutic between the 2 groups and within each group, before and after
medicines to be used in the treatment of various diseases.[27] To intervention.
the best of our knowledge, no study has yet evaluated the anti-
Compare the mean serum inflammatory factors [TNF-a, IL-6,
inflammatory and vascular protection effect of cardamom in hs-CRP, CD163] between the 2 groups and within each group,
patients with T2DM. The objective of this study is to investigate before and after intervention.
the effects of green cardamom supplementation on blood
Compare the mean of serum ICAM, VCAM, E-selectin, and
pressure and endothelial function. To show the mechanism of SIRT1, between the 2 groups and within each group, before
cardamom effect, inflammatory markers, CD163, SIRT1, NO, and after intervention.
and ADMA will be measured.
2.2. Methods and analysis design
2.2.1. Study design. The study consisted of a parallel, double-
2. Study design and objectives blind randomized, placebo controlled clinical trial with treatment
A double-blind randomized clinical trial design is to be used in and control groups. A flow chart of the study protocol is shown in
this study. Figure 1.

Figure 1. Participants flow diagram.

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Zahedi et al. Medicine (2020) 99:18 Medicine

2.2.2. Sample size. Eighty patients with T2DM diagnosed by allocation will be blinded as A and B packages for investigators
diabetes specialist physicians were recruited from Diabetes and patients.
Research Center, Endocrinology and Metabolism Clinical
Sciences Institute, Tehran University of Medical Sciences Tehran, 2.2.7. Intervention. The participants will be randomly assigned
Iran to detect a significant mean difference of hsCRP,[28] 95% into 2 groups (green cardamom powder or rusk powder) for 10
confidence level, and 80% power. Regarding a possible loss to weeks. Each patient will receive 2 capsules with each meal (3 g/
follow-up, a safety margin of 20% was determined The patients day) for 10 weeks. Every 5 weeks supplements taken will be
were divided equally in the placebo and cardamom supplement checked and empty packs will be received and new packages will
groups. We started recruiting participants from Diabetes be delivered to patients and the number of supplements will be
Research Center from November 20, 2016 to July 20, 2017 counted. The supplements will be given simultaneously with the
and by now we are collecting data from the questionnaires and usual diabetes care drugs that include maintenance of the oral
blood sample tests. antidiabetic drugs dosage. All patients receive medical nutrition
therapy and physical activity enforcement at this clinic. The 24

2
hour dietary recall will be taken from all patients at the beginning,
Z1a=2 þ Z1b S21 þ S22
n¼ middle and end of intervention to be confidant of constant dietary
ðm1  m2 Þ2 intake. Cardamom and placebo capsules will be prepared by
Traditional Medicine Research Center, Tehran, Iran. Each
2.2.3. Study population. Patients with T2DM attending the capsule contains 0.5 g of whole green cardamom or rusk powder.
outpatient of Endocrinology and Metabolism Clinical Sciences Placebo capsules will be completely similar to cardamom
Institute of Tehran University of Medical Sciences in Tehran will capsules by the means of shape, size, and color. All capsules
be invited to the study. The patients will be diagnosed by an containing placebo will be put on the same bag of the cardamom
endocrinologist and by their medical records, using the American capsules to take the smell of cardamom. Participants will be asked
Diabetic Association, fasting blood sugar ≥126 mg/dL or 2 hours to keep their usual lifestyle including medical nutrition therapy
postparandial ≥200 mg/dL, or HbA1C ≥6.5%.[29] Patients and physical activity level.
should meet the eligibility criteria. After their identification, Voucher number of green cardamom is E cardamomum (L)
the patients will be referred to the investigator to be enrolled in Maton, Family: Zingiberaceae, PMP-669 which was identified by
the study and to be explained about the goals, methods, and School of Pharmacy, Tehran University of Medical Sciences.
benefits of the intervention. Written informed consent will be Essential oil content, essential oil compounds including phenolic
obtained prior to the recruitment. The general questionnaire, and flavonoid content of whole green cardamom using GC-mass
24-hour dietary recall questionnaire, short-form International and HPLC will be measured in the institute of Medicinal Plants,
Physical Activity Questionnaire (IPAQ) and will be completed by Shahid Beheshti University of Medical Sciences. Some polyphe-
interviewers. nolic compounds of green cardamom such as caffeic acid, gallic
acid, quercetin, and luteolin, which was mentioned in the other
2.2.4. Inclusion criteria. Eighty patients within the age group article will be determined by HPLC.[30]
of 30 to 50 years of either sex, body mass index (BMI) between
25 and 34.9 kg/m2, patients with T2DM who have been 2.2.8. Adherence. To check patients’ compliance during the 10
diagnosed with at least 2 years history, according to American weeks, the researcher will interview with them weekly by
Diabetes Association criteria, namely fasting serum glucose >7.0 telephone. In both group (cardamom and placebo), patients will
mmol and last HbA1C value >7%, will be recruited from the be interviewed to discern whether they are consuming supple-
regional outpatient diabetes care center. The patients should ments.
be on the stable doses of oral antidiabetic drugs throughout the
study. 2.2.9. Patient safety. Patients will be monitored weekly during
the study period and all the occurrence of the adverse events will
2.2.5. Exclusion criteria. Having any acute illnesses and be assessed by patient interview.
presence of some chronic diseases including cardiovascular,
kidney, liver, and gastrointestinal diseases and taking related 2.2.10. Study outcomes
drugs and medications. Any-inflammatory and thyroid disease;
2.2.10.1. Primary outcome. Primary outcome of this trial
pregnancy and lactation; menopause; being on insulin regimen;
includes changes in SBP and DBP, NO, and ADMA. Changes
individuals taking drugs such as fibrates (which are PPAR-a
in serum inflammatory markers Il-6, TNF-a, hsCRP, and changes
ligand) and TZD (which are PPAR-gamma ligand); aspirin,
in factors related to endothelial function serum ICAM, VCAM,
warfarin, and antidepressant medication; history of smoking or
E-selectin, CD163, and SIRT1.
alcohol intake at least once a week in the past month; changing
diet during the past 3 months; consumption of (at least once a
week) ginger or other botanical supplements, antioxidant, and 2.2.10.2. Secondary outcomes. The secondary outcomes of this
multivitamin/mineral supplement in the past 3 months. clinical trial are changes in weight, BMI, and waist circum-
ferences (WCs).
2.2.6. Randomization. The participants will be randomly
assigned into 2 groups green cardamom powder (n = 40) or 2.2.11. Procedure. Patients will be asked to attend the diabetes
rusk powder (n = 40). The permuted block randomization will research center on 3 occasions. The first time sociodemographic
be used in this study. Stratified randomization will be used to questionnaire will be completed. Blood test will be taken at the
control BMI and gender distribution, those will be 25–29.9/ first time and week 10 of the study by trained nurses. Twenty
30–34.9 kg/m2 for BMI and for gender, respectively. Randomi- milliliter blood sample will be taken after an overnight fasting
zation will be performed by an assistant and the intervention from the antecubital vein with patients in seated position.

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Prechilled tubes will be used to collect bloods. Blood sample that 2.4. Ethical considerations
are collected will be centrifuged at 3000 rpm for 10 minutes at This clinical trial is conducted after approval of the Ethics
4°C to obtain the serum and plasma. Blood sample that are Committee of Tehran University of Medical Sciences and
collected will be stored at 80°C until further analysis. Serum completion the informed consent. Whenever a person is unable
inflammatory factors (IL-6, TNF-a, hsCRP, CD163); adhesive to continue supplementation he/she will be excluded from the study.
molecules (ICAM, VCAM, E-selectin); and ADMA, NO, and
SIRT1 will be measured by using the specific kits and methods.
Anthropometric measurements including weight, height, and WC 3. Discussion
will be performed by standard methods. Height will be measured Diabetes is a group of metabolic disorders in which over a
using SECA stadiometer without shoes to the nearest 0.1 cm. prolonged period there are high blood sugar levels which results
Body weight will be measured without shoes and light clothing by from cells failure to respond to insulin properly which is due to
using a SECA electronic scale (Seca, Hamburg, Germany) to the defects in insulin secretion, insulin action, or both.[32] Obesity
nearest 0.1 kg. WC in centimeter will be assessed midway and T2DM are linked with a low-grade inflammation state.
between the lowest rib and the iliac crest using a nonstretchable Inflammation markers are associated with an increased cardio-
tape measure. BMI will be calculated by dividing weight by the vascular risk.[33] In patients with diabetes, endothelial dysfunc-
square of height. Twenty-four hours dietary recall questionnaire tion appears to be a consistent finding.[34]
and IPAQ will also be completed. Seeds of cardamom (E cardamomum) from family Zingiber-
2.2.12. Dietary intake assessment. Dietary intake will be aceae are used as the spice ingredient in food. Cardamom
estimated by using three 24-hour dietary recall at the beginning, contains flavonoids such as quercetin, kaempferol, luteolin, and
middle, and at the end of the study. Patients will be asked to pelargonidin.[24] Epidemiological studies have shown an inverse
recall foods and drinks they consumed 24 hours before the correlation between polyphenols-enriched diet and reduced risks
interview by the investigator. Detailed descriptions such as time of CVD. Because of their chemical structures polyphenols may
of the day, food ingredients, and portion size will be obtained by interfere with different factors involved in the pathogenesis of
using Pictures of foods commonly consumed in Iran and CVD.[35] The present study is performed with the aim of assessing
common household measurement tools. Dietary intake will be the effects of cardamom powder on inflammation and endothelial
analyzed with Nutritionist software version 4 (First Data Bank, function in patients with T2DM.
San Bruno, CA). The strength of this trial is that this study is the first randomized
controlled trial to determine the effectiveness of cardamom on the
2.2.13. Physical activity levels assessment. IPAQ will be outcome measurements including inflammatory markers,
administered to assess the physical activity level of the subjects. CD163, SIRT1, NO, and ADMA in patients with T2DM.
The IPAQ-SF form records 3 types of activities and time spent
sitting. According to the IPAQ scoring protocol responses will be
Acknowledgments
converted to metabolic equivalent task minutes per week (MET-
min/wk): total minutes over the last 7 days spent on vigorous This research has been supported by Tehran University of
activity, moderate-intensity activity, and walking were multiplied Medical Sciences and Health services
by the energy cost of each activity: 8.0, 4.0, and 3.3 MET for
vigorous, moderate, and walking, respectively.[31] Author contributions
Figure 1 presents the overall contents of enrollment,
interventions, and assessments. Moreover, the SPIRIT checklist Data curation: Ensieh Nasli-Esfahani, Mohadeseh Aghasi.
is provided as an additional file. Formal analysis: Mostafa Qorbani, Ensieh Nasli-Esfahani.
The trial conduct is to be frequently audited by an assistant Investigation: Gity Sotoudeh, Hoorieh Khoshamal.
though an independent process. Project administration: Shohreh Ghazi Zahedi, Mohadeseh
Aghasi, Hoorieh Khoshamal.
2.2.14. Statistical analysis. The normality of the distribution of Supervision: Gity Sotoudeh, Fariba Koohdani, Fereydoun Siassi,
data will be assessed by using Shapiro-Wilk tests carried out on Ali Keshavarz, Mohadeseh Aghasi.
each parameter before analysis. By using “regression imputa- Writing – original draft: Shohreh Ghazi Zahedi.
tion” missing values will be replaced from a regression equation Writing – review and editing: Gity Sotoudeh, Shohreh Ghazi
from observed data. By using intention-to-treat all randomized Zahedi, Fariba Koohdani, Mohadeseh Aghasi.
participants will be analyzed in their group. Independent t test
will be used to evaluate the differences between the means of 2
independent groups with normal data and Mann-Whitney for References
non-normal data. In order to assess time-by-treatment inter- [1] Goyal BR, Mehta AA. Diabetic cardiomyopathy: pathophysiological
actions and time effects on all outcomes two way repeated- mechanisms and cardiac dysfunction. Hum Exp Toxicol 2013;32:571–90.
[2] Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of
measures regression analysis will be used. A P value of <.05 will diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4–14.
be considered as significant. All statistical analyses will be [3] Raza A, Movahed A. Current concepts of cardiovascular diseases in
performed using SPSS version 21 (SPSS Inc, Chicago, IL). diabetes mellitus. Int J Cardiol 2003;89:123–34.
[4] Esteghamati A, Gouya MM, Abbasi M, et al. Prevalence of diabetes and
impaired fasting glucose in the adult population of Iran: National Survey
2.3. Data accessibility of Risk Factors for Non-Communicable Diseases of Iran. Diabetes Care
2008;31:96–8.
The principal investigator will have access to the final trial [5] Amanda AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure
dataset, and such access for other investigators is limited. The with macrovascular and microvascular complications of type 2 diabetes
trial results will be presented only through the publication. (UKPDS 36): prospective observational study. BMJ 2000;321:412–9.

5
Zahedi et al. Medicine (2020) 99:18 Medicine

[6] Avogaro A, Albiero M, Menegazzo L, et al. Endothelial dysfunction in [21] Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotes endothelium-
diabetes. The role of reparatory mechanisms. Diabetes Care 2011;34: dependent vascular relaxation by activating endothelial nitric oxide
S285–90. synthase. Proc Natl Acad Sci U S A 2007;104:14855–60.
[7] Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest [22] Scalera F, Fulge B, Martens-Lobenhoffer J, et al. Red wine decreases
2000;106:473–81. asymmetric dimethylarginine via SIRT1 induction in human endothelial
[8] Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link cells. Biochem Biophys Res Commun 2009;390:703–9.
between insulin resistance, obesity and diabetes. Trends Immunol [23] Bahadoran Z, Mirmiran P, Azizi F. Dietary polyphenols as potential
2004;25:4–7. nutraceuticals in management of diabetes: a review. J Diabetes Metab
[9] Waheed S, Chaves PH, Gardin JM, et al. Cardiovascular and mortality Disord 2013;12:43.
outcomes in the elderly with impaired cardiac and pulmonary function: [24] Sultana S, Ripa FA, Hamid K. Comparative antioxidant activity study
the Cardiovascular Health Study (CHS). J Am Heart Assoc 2015;4: pii: of some commonly used spices in Bangladesh. Pak J Biol Sci
e002308. 2010;13:340–3.
[10] Etzerodt A, Moestrup SK. CD163 and inflammation: biological, [25] Bhattacharjee B, Chatterjee J. Identification of proapoptopic, anti-
diagnostic, and therapeutic aspects. Antioxid Redox Signal 2013;18: inflammatory, antiproliferative, anti-invasive and anti-angiogenic targets
2352–63. of essential oils in cardamom by dual reverse virtual screening and
[11] Philippidis P, Mason JC, Evans BJ, et al. Hemoglobin scavenger receptor binding pose analysis. Asian Pacific J Cancer Prev 2013;14:3735–42.
CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: [26] Verma SK, Jain V, Katewa SS. Blood pressure lowering, fibrinolysis
antiinflammatory monocyte-macrophage responses in vitro, in resolving enhancing and antioxidant activities of cardamom (Elettaria cardamo-
skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res mum). Indian J Biochem Biophys 2009;46:503–6.
2004;94:119–26. [27] Wang X, Kageyama-Yahara N, Hayashi S, et al. Sphingosine kinase-1-
[12] Heitzer T, Krohn K, Albers S, et al. Tetrahydrobiopterin improves dependent and -independent inhibitory effects of zanthoxyli fructus to
endothelium-dependent vasodilation by increasing nitric oxide activity in attenuate the activation of mucosal mast cells and ameliorate food
patients with type II diabetes mellitus. Diabetologia 2000;43:1435–8. allergies in mice. Evid Based Complement Alternat Med 2012;2012:
[13] De Luca C, Olefsky JM. Inflammation and Insulin resistance. FEBS Lett 862743.
2008;582:97–105. [28] Mahluji S, Ostadrahimi A, Mobasseri M, et al. Anti-inflammatory effects
[14] Monti LD, Barlassina C, Citterio L, et al. Endothelial nitric oxide of zingiber officinale in type 2 diabetic patients. Adv Pharm Bull
synthase polymorphisms are associated with type 2 diabetes and the 2013;3:273–6.
insulin resistance syndrome. Diabetes 2003;52:1270–5. [29] American Diabetes AssociationDiagnosis and classification of diabetes
[15] Hsu CP, Hsu PF, Chung MY, et al. Asymmetric dimethylarginine and mellitus. Diabetes Care 2012;35(suppl 1):S64–71.
long-term adverse cardiovascular events in patients with type 2 diabetes: [30] Evdokimova O, Tarrab V, Neneleva I E, et al. Testing phenol compounds
relation with the glycemic control. Cardiovasc Diabetol 2014;13:156. in spices. Eur J Appl Sci 2013;5:142–5.
[16] Winnik S, Auwerx J, Sinclair DA, et al. Protective effects of sirtuins in [31] Craig CL, Marshall AL, Sjöström M, et al. International Physical Activity
cardiovascular diseases: from bench to bedside. Eur Heart J Questionnaire: 12-country reliability and validity. Med Sci Sports Exerc
2015;36:3404–12. 2003;35:1381–95.
[17] Chung S, Yao H, Caito S, et al. Regulation of SIRT1 in cellular functions: [32] Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: a
role of polyphenols. Arch Biochem Biophys 2010;501:79–90. consensus on type 2 353 diabetes prevention. Diabet Med
[18] Stein S, Matter CM. Protective roles of SIRT1 in atherosclerosis. Cell 2007;24:451–63.
Cycle 2011;10:640–7. [33] Avogaro A, Albiero M, Menegazzo L, et al. Endothelial dysfunction in
[19] Prasad S, Aggarwal BB. Chronic diseases caused by chronic inflamma- diabetes: the role of reparatory mechanisms. Diabetes Care 2011;34
tion require chronic treatment: anti-inflammatory role of dietary spices. J (suppl 2):S285–90.
Clin Cell Immunol 2014;5:4. [34] Han X, Shen T, Lou H. Dietary polyphenols and their biological
[20] Karunaweera N, Raju R, Gyengesi E, et al. Plant polyphenols as significance. Int J Mol Sci 2007;8:950–88.
inhibitors of NF-kB induced cytokine production—a potential anti- [35] Kris-Etherton PM, Hecker KD, Bonanome A, et al. Bioactive compounds
inflammatory treatment for Alzheimer’s disease? Front Mol Neurosci in foods: their role in the prevention of cardiovascular disease and cancer.
2015;8:24. Am J Med 2002;113:71S–88S.