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Open Access
AbstrAct
Objectives Different studies have been conducted on the
role of curcumin in health since having multiple properties,
including antioxidant and anti-inammatory effects. Due
to the lack of studies regarding curcumin effects on obese
patients with non-alcoholic fatty liver disease (NAFLD), our
protocol was designed to assess nanocurcumin impacts on
blood sugar, lipids, inammatory indices, insulin resistance
and liver function, especially by nesfatin.
Setting This trial will be conducted in the Oil Company
central hospital of Tehran, Iran with a primary level of care.
Participants 84 obese patients with NAFLD diagnosed
using ultrasonography will be employed according to the
eligibility criteria.
Interventions The patients will be randomly divided
into two equal groups (nanocurcumin and placebo, two
40 mg capsules per day with meals for 3 months, follow-
up monthly). Also, lifestyle changes (low-calorie diet and
physical activity) will be advised.
Measures of the primary and secondary outcomes A
general questionnaire, 24 hours food recall (at the
beginning, middle and end) and short-form International
Physical Activity Questionnaire will be completed. Blood
pressure, anthropometrics, serum sugar indices (fasting
blood sugar and insulin, insulin resistance and sensitivity
and glycosylated haemoglobin), lipids (triglyceride, total
cholesterol and low-density and high-density lipoprotein-
cholesterol, inammatory proles (interleukin-6, high-
sensitivity C-reactive protein, and tumour necrosis factor-
alpha), liver function (alanine and aspartate transaminase)
and nesfatin will be measured at the beginning and end of
the study.
Conclusion This trial would be the rst experiment
to determine nanocurcumin efcacy on certain blood
factors among obese patients with NAFLD. Nevertheless,
studying the potential consequences of curcumin in
various diseases, especially NAFLD, is required for
clinical use.
Trial registration number IRCT2016071915536N3; pre-
results.
INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD)
occurs when triglyceride (TG) is depos-
ited in liver cells. Intrahepatic TG (IHTG)
content of more than 5% of liver weight or
volume or visible intracellular TG content of
5% of hepatocytes or more are chemically or
histologically defined as excessive IHTG or
steatosis, respectively.1 The three degrees of
NAFLD are mild (<33% of fat accumulation),
moderate (33%–66% of fat accumulation)
and severe (>66% of fat accumulation).2
The standard method of diagnosis is liver
biopsy. Since biopsy is an invasive method,
non-invasive diagnostic approaches, such as
ultrasound examination, CT scan and MRI,
are mostly employed. However, it is difficult
to exactly differentiate between the disease
stages by these techniques. Most patients
with NAFLD are implicitly identified via
elevated liver enzymes (aminotransferases:
alanine transaminase (ALT) and aspar-
tate transaminase (AST) contents of about
1.5–2 times higher than normal levels) in
Efcacy of nanocurcumin
supplementation on insulin resistance,
lipids, inammatory factors and
nesfatin among obese patients with
non-alcoholic fatty liver disease
(NAFLD): a trial protocol
Seyed Ali Jazayeri-Tehrani,1 Seyed Mahdi Rezayat,2,3,4 Siavash Mansouri,5
Mostafa Qorbani,6 Seyed Moayed Alavian,7 Milad Daneshi-Maskooni,8
Mohammad-Javad Hosseinzadeh-Attar1
To cite: Jazayeri-TehraniSA,
RezayatSM, MansouriS, etal.
Efcacy of nanocurcumin
supplementation on
insulin resistance, lipids,
inammatory factors and
nesfatin among obese
patients with non-alcoholic
fatty liver disease (NAFLD):
a trial protocol. BMJ Open
2017;7:e016914. doi:10.1136/
bmjopen-2017-016914
►Prepublication history for
this paper is available online.
To view these les please visit
the journal online (http:// dx. doi.
org/ 10. 1136/ bmjopen- 2017-
016914).
Received 9 April 2017
Revised 24 May 2017
Accepted 26 May 2017
For numbered afliations see
end of article.
Correspondence to
Professor Mohammad-
Javad Hosseinzadeh-Attar;
mhosseinzadeh@ tums. ac. ir
Protocol
Strengths and limitations of this study
►Providing a randomised double-blinded design and
protocol publication.
►Determining dietary intake and physical activity
statuses and registering any possible patient-
reported problems.
►Selecting a single and slow polyclinic recruitment of
the patients to satisfy the eligibility criteria.
►Self-reporting of the dietary intake and physical
activity statuses and lack of cooperation of some
participants to complete the intervention.
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Open Access
medical examinations. According to the recent studies,
many patients with advanced non-alcoholic steato-
hepatitis (NASH) and even cirrhosis can have normal
levels of liver enzymes.3–6 Thus, NAFLD prevalence is
probably more than what has been reported. Its symp-
toms often include fatigue and discomfort in the right
upper quarter of the abdomen. Its average prevalence
in adults is about 30% (nearly 65%–85% and 15%–20%
in obese (body mass index (BMI) ≥25) and non-obese
(BMI <25) patients, respectively).7–11 NAFLD is more
common in men. The disease pathology is a two-phase
event, including fat reposition in hepatocytes following
hepatic steatosis and NASH. Insulin resistance has
a key role in both phases, while oxidative stress and
pro-inflammatory cytokines are the major irritants.12
The common causes of macrovascular steatosis include
insulin resistance, increasing blood insulin levels,
central obesity, diabetes type 2, medications (eg, gluco-
corticoid, oestrogen, tamoxifen and amiodarone),
nutrition status (starvation, protein deficiency and
choline deficiency), liver diseases (Wilson's disease
and chronic hepatitis C-III), Hindi child cirrhosis and
jejunum bypass.6 Liver fat content is directly related to
insulin resistance. Activation of nuclear factor kappa-
light-chain-enhancer of activated B cells upregulates
the production of pro-inflammatory cytokines that
influence the insulin activity. Thus, inflammation,
adipokines, oxidative stress or lipid metabolites can
change insulin sensitivity, but intrahepatic fat content
is not necessarily directly related to any of them.1 Age,
family history, malnutrition, severe weight loss, gastro-
intestinal tract infection, certain medication and some
diseases, such as inflammatory bowel disease are the
other risk factors of NAFLD.13–15 In some studies, the
disease incidence has been related to the high intakes
of saturated fats or carbohydrates.16 17 Some patients
have normal weights although they may have abdom-
inal obesity and insulin resistance.18 19
Nesfatin as a neuropeptide secreted by the hypo-
thalamus in mammals is involved in the regulation of
appetite and body fat stores. Nesfatin gene is expressed
in other locations, such as brain, pancreas, endocrine
cells of stomach and adipocytes. Nesfatin gene expres-
sion is activated by peroxisome proliferator-activated
receptors (PPARs), especially PPARγ. Nesfatin plays an
important role in glucose metabolism, phosphorylation
of certain signalling proteins and increasing insulin
sensitivity in the liver, particularly through AMP-acti-
vated protein kinase.20 21 In a recent study, the serum
levels of nesfatin in overweight/obese patients with
NAFLD with an age of 30–60 years were found to be
significantly lower than those of the healthy group.21
A common treatment for NAFLD is changing the life-
style (gradual weight loss and increasing physical activity)
that can improve liver enzymes, fat reposition, inflamma-
tion and fibrosis.22–27 It seems that changes in the dietary
ingredients can be presented as a therapy method for
these patients28 29 since losing weight and its maintenance
for a long period of time is a hard task.30 Accordingly,
assessment of the relationship between NAFLD and
certain nutrients or dietary ingredients is very important.
Different studies have been conducted on the roles
of curcumin in health. Curcumin as a turmeric spice
of the ginger family has multiple properties, including
antioxidant, anti-inflammatory, antimicrobial and anti-
carcinogenic effects.31–38 Due to the importance of
PPARs in the metabolic pathways, numerous studies
have been carried out to investigate curcumin effects
on PPARs, especially on PPARγ gene expression. It
increases both the activity and expression of PPARγ,
which is important for inhibiting inflammation and
oxidative stress as the main factors of insulin resistance
and NAFLD.39–42
NAFLD prevalence and implications are increasing.
Due to the lack of any drugs for it and the role of
nutrition (weight loss and changing food components
associated with increased physical activity) as the key
factor of treatment, assessment of the effects of some
food components like curcumin as a polyphenol on
NAFLD improvement can further help to find new
ways of treatment. Curcumin plays numerous metabolic
roles in the improvement of insulin resistance through
its antioxidant, anti-inflammatory, hypolipidaemic and
antimicrobial effects. Despite the multiple benefits
of curcumin for health, it has a very low stability and
bioavailability that affect its efficacy in therapy. Recently,
many approaches have been assessed to improve
its stability and bioavailability by using polymeric
nanoparticles named nanocurcumin. For example,
poly(lactic-co-glycolic acid (PLGA) nanoparticles can
increase curcumin bioavailability up to 22 times.43
Hence, in this study, nanocurcumin was applied. Fat
accumulation in the liver, inflammation and oxidative
stress result in NAFLD onset and progression, which
may be improved by curcumin. NAFLD exacerbates
with overweight or obesity; yet, no human studies have
been conducted on curcumin effects on them. Thus,
this study aimed to assess the effects of curcumin on
blood glucose, lipid, inflammatory profiles, liver func-
tion (fatty liver degree, ALT and AST) and insulin
resistance (homeostasis model assessment-insulin resis-
tance (HOMA-IR) and quantitative insulin sensitivity
check index [QUICKI]), especially through nesfatin in
obese patients with NAFLD.
METHODS
Study design
In this research, a double-blind randomised clinical trial
will be performed.
Objectives
1. Comparing the subjects’ economic, occupational
and marital statuses, as well as education levels with
nanocurcumin and placebo supplementations before
the intervention
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2. Comparing the means of serum TG, low-density
lipoprotein cholesterol, total cholesterol (TC), high-
density lipoprotein (HDL) cholesterol, fasting blood
sugar (FBS), insulin, haemoglobin A1c (HbA1c),
insulin resistance, sensitivity indices (HOMA-IR,
QUICKI), tumour necrosis factor-alpha (TNF-α),
interleukin-6 (IL-6), high-sensitivity C-reactive protein
(hs-CRP) and nesfatin within each group and between
the two groups before and after the intervention
3. Comparing the means of weight, waist circumference,
BMI, body composition percentage and systolic
and diastolic blood pressures within each group
and between the two groups before and after the
intervention
4. Comparing the means of physical activity score and
energy intakes, micronutrients and macronutrients
within each group and between the two groups before
and after the intervention
5. Comparing the means of age and height between the
two groups before the intervention
Inclusion criteria
1. Age: 25–50 years.
2. Overweight/obesity (25 ≤BMI<35).
3. NAFLD diagnosis by a radiologist based on the
ultrasound test.
4. An informed consent.
Exclusion criteria
1. A history of alcohol consumption during the last 12
months based on personal admission.
2. Regular intakes of non-steroidal anti-inflammatory
drugs, antibiotics and corticosteroids during the last
6 months.
3. Misuses of narcotics, psychotropic medication and
cigarettes over the last 6 months.
4. Intakes of antisecretory drugs causing achlorhydria,
amiodarone, valproate, prednisone, tamoxifen,
perhexiline and methotrexate, liver fat-inducing
drugs, hormone drugs, statins, antihypertensives
and ursodeoxycholic acid during the last 6 months.
5. Intakes of supplements, such as probiotics,
multivitamins/minerals, antioxidants and omega-3
at least twice a week during the study or the last 3
months.
6. Diagnosis of pathological conditions affecting the
liver, such as viral hepatitis, acute or chronic liver
failure, cholestasis, liver transplantation, acute
systemic disease, cystic fibrosis disease, muscular
dystrophy, previous gastrointestinal surgery,
neurological disorders, structural abnormalities of
the gastrointestinal tract, diabetes, heart failure,
thyroid disorders, kidney diseases, respiratory
failure, psychological disorders, hereditary
haemochromatosis, Wilson's disease, alpha-1
antitrypsin deficiency, autoimmune diseases, coeliac
disease and any types of malignancy.
7. Rapid weight loss, total parenteral nutrition and
protein malnutrition over the last 6 months.
8. NAFLD secondary causes, such as drugs, surgical
procedures and environmental toxins.
9. Conditions leading to physical disability.
10. Uncontrolled hypertension (>140/90 mm Hg).
11. Breast feeding, pregnancy or a plan for pregnancy
in the next 3 months.
12. Being a professional athlete or doing regular
exercise.
13. Taking no more than 10% of the prescription
supplements.
Subjects
The patients will be referred to a major executor after
being diagnosed by a radiologist if meeting the eligi-
bility criteria at the central hospital of the polyclinic
of the National Iranian Oil Company (NIOC), Tehran,
Iran. At the beginning, all the study details will be clar-
ified and an informed consent form will be provided.
Then, a general questionnaire, the short form of Inter-
national Physical Activity Questionnaire (IPAQ), and
24 hours food recall questionnaire will be filled out
by the interviewer. The necessary lifestyle changes,
including a low-calorie diet (weight loss of 0.5–1 kg
per week based on BMI during the trial) and increased
physical activity (aerobic exercise of moderate inten-
sity about 30–45 min at least three times a week) will
be prescribed. Anthropometrics, including weight,
height and waist circumference will be measured using
a digital scale, stadiometer and non-elastic tape, respec-
tively. Weight without shoes and minimum clothing
with an accuracy of 100 g, height in a standing posi-
tion without shoes with heels stuck to the wall and head
looking frontwards with an accuracy of 0.5 cm and waist
circumference in the middle of the last rib and the iliac
crest with minimal clothing with an accuracy of 0.5 cm
will be measured.
The questionnaire of 24 hours food recall will be
completed at the beginning, middle and end of the
study. Blood pressure will be measured with a manom-
eter (cuff in two-thirds of the upper right arm) after
10 min of resting in a sitting position at the beginning
and end of the study. At both the beginning and end of
the intervention, 10 mL of blood will be taken from the
brachial vein to measure the mentioned factors. Finally,
these measurements will be privately presented to the
patients.
Sample size
According to Chuengsamarn et al44, the mean±SD of
HOMA-IR index in the curcumin and placebo groups
were 3.22±1.30 and 4.08±1.35, respectively. The sample
size was 42 patients in each group with a CI of 95%,
power of 80% and loss of 15%. A total of 84 patients will
be invited and divided into two equal groups by using
the block randomisation method as follows:
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1. 42 overweight/obese patients with NAFLD with
nanocurcumin supplement and advice on lifestyle
changes (a weight loss diet and increase of physical
activity) for 3 months of intervention.
2. 42 overweight/obese patients with NAFLD with the
placebo supplement and advice on lifestyle changes
(a weight loss diet and increase of physical activity) for
3 months of intervention.
Intervention and randomisation
The block randomisation method was used to divide the
patients into two equal groups. Age and gender distribu-
tions will be controlled using a stratified randomisation.
The supplementation ratio is 1:1 for the groups in this
study. An assistant performed the block randomisation
and the intervention allotment will be blinded to the
investigator and patients. The subjects will be randomly
allocated into the two groups of taking nanocurcumin
and placebo supplements. The supplements offered in
A and B packages will be blinded to the investigators
and participants.
No side effects and toxicity caused by taking 210 mg
of nanocurcumin have been reported.34 The supple-
mentation dose of Sinacurcumin is 80 mg/day (two
40 mg capsules per day according to company's order:
one capsule with breakfast and one with dinner). Sina-
curcumin and placebo supplements will be prepared by
Exir-nanosina Pharmaceutical Company. The placebo
supplement contained polysorbate 80, soy oil, purified
water, sorbitol 70, methyl paraben and propyl paraben
associated with nanocurcumin particles.
Curcumin is of a very low stability and bioavailability.
It is hardly dissolved in water, rapidly metabolised and
very weakly absorbed in the intestine so that it remains
at a very low level in plasma. Human studies have shown
that a daily consumption of 12 g of curcumin is safe. Less
than 1% of curcumin taken enters the bloodstream to
be mostly metabolised in the liver. Today, new ways are
being investigated to enhance curcumin bioavailability,
especially through polymeric nanoparticles called
nanocurcumin. PLGA as a nanoparticle can augment
curcumin bioavailability in mice up to 22 times.43
The supplements will be distributed on a monthly
basis, while any possible complications regarding the
numbers of ingested capsules and packets given back will
be recorded. Also, the study progress will be pursued by
calling the subjects once a week.
Lifestyle changes
A low-calorie diet for a weight loss of 0.5–1 kg/week
based on the BMI and increased physical activity will be
presented as the lifestyle changes by a qualified dietitian
present in the central hospital of the polyclinic of NIOC,
Tehran, Iran.
Assessments and measurements
The ultrasound test will be done by a radiologist after
12 hours of fasting. The measurements of blood lipids
(TC, HDL, LDL and TG) and liver enzymes (ALT
and AST) will be determined using special kits and
Hitachi analyser (or BT-3500) device after 12 hours
of fasting. Blood sugar (FBS) is determined using the
glucose oxidase method. Fasting blood insulin (FBI)
and HbA1c will be measured via electrochemilumines-
cence application using cobas e411 analyser device and
immunoturbidimetric method. Insulin resistance and
sensitivity indices (HOMA and QUICKI) are calculated
according to the following formula:
QUICKI = 1/(log (FBI µU/mL) + log (FBS mg/dL))
HOMA1 −IR = (FBI (mU/l) x FBS (mmol/l))/22.5
The serum inflammatory markers (IL-6, TNF-α and
hs-CRP) and nesfatin will be determined using the
ELISA method (sandwich ELISA format) and specific
kits. The ELISA test will be done using Elisa washer
(Combiwash Human) and bioElisa reader devices
(biokit EL x 800).
Food intake status at the beginning, middle and end of
the study and physical activity at the beginning and end
of the study will be investigated using the questionnaire
of 24 hours food recall and the short form of IPAQ. The
dietary intakes will thus be examined and controlled. The
body composition percentage, including body fat and
lean body mass will be determined using Bioimpedance
Analyzer device (Tanita).
At the beginning and end of the study, the systolic
and diastolic blood pressures will be determined using
a mercury manometer. The values are reported in mm
Hg. Waist circumference, weight and height will be
measured using a non-elastic tape, digital scale and
stadiometer, respectively. Weight with minimal clothing
without shoes (100 g accuracy), height in a standing
position without shoes with heels sticking to the wall
and head keeping flat and looking forward (0.5 cm
accuracy) and waist circumference at the middle of the
last rib and the iliac crest with minimal clothing were
measured at the beginning and end of the study. Blood
taking, storage of blood samples and performance of
the laboratory tests will be conducted at the central
hospital of the NIOC, Tehran, Iran.
The details of enrolments, interventions and assess-
ments are presented in table 1. Furthermore, the Standard
Protocol Items: Recommendations for Interventional
Trials (SPIRIT) checklist was completed in an additional
file. The trial progress will be regularly and independently
checked by an assistant.
Data analysis
The data entry, coding, security and saving will be checked.
The data normality will be examined using a Kolmogor-
ov-Smirnov test. Non-parametric/χ2, Wilcoxon, analysis
of covariance and Pearson's correlation coefficient statis-
tical tests as well as t-test will be applied. A CI of 95% will
be considered in all the tests. The significance value is
considered to be less than 0.05. Finally, SPSS16 statistical
software will be applied to analyse the data.
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Table 1 Contents of enrolments, interventions and assessments.
Trial contents
Study period
Enrolment Allocation Postallocation Close-out
Timepoint -t10+1 Month +1.5 Months +2 Months +3 Months
Enrolments
Eligibility screen X
Informed consent X X
General questionnaire X
24 hours food recall X X X
SF-IPAQ questionnaire X X
Anthropometrics X X
Other questionnaires X X
Blood taking X X
Allocation X
Interventions
(Intervention A) X X X
(Intervention B) X X X
Assessments
Dietary status XXX
Blood pressure X X
Inammatory factors X X
Lipid prole X X
Blood sugar indices X X
Nesfatin X X
Physical activity status X X
Anthropometrics X X
Socioeconomic status X
SF-IPAQ, Short-Form International Physical Activity Questionnaire.
Data accessibility
Accessibility to the ultimate data set is only limited to the
major investigator. The results will be presented only via
publication.
DISCUSSION
This is a novel study proposed for the first time with
regard to the evaluation of nanocurcumin efficacy on
various parameters, such as blood sugar, lipids, inflam-
matory markers, insulin resistance and nesfatin among
overweight/obese patients with NAFLD. It is of high
relevance due to the various clinical uses of curcumin
and lack of any studies related to its advantages or
disadvantages in patients with NAFLD. However,
curcumin clinical practice for the treatment of some
disorders needs to be investigated, while taking into
account its possible prospective applications for several
diseases, especially NAFLD. Due to the increasing
values of obesity and NAFLD associated with significant
alterations of some blood factors and the presence of
few studies on nanocurcumin efficacy, the proposed
research aimed to select these groups of patients as the
most pertinent participants for intervention.
The strengths of the trial are using a randomised double-
blind design and protocol publication, determining
dietary and physical activity statuses and registering any
possible patient-reported problems.
The trial limitations are patients’ slow recruitments
and increase of the study period due to the multiple
eligibility criteria, selection of a single polyclinic
centre, participants’ self-reporting on the drugs and
supplement consumptions, dietary intakes and physical
activities and lack of cooperation of some participants
to complete the intervention, which would lead to a
replacement with other patients if the loss percentage
will be more than expected.
Trial status
The patients’ employments were continued at the time of
the protocol submission.
Author afliations
1Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics,
International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran
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2Department of Pharmacology, School of Medicine, Tehran University of Medical
Sciences, Tehran, Iran
3Department of Medical Nanotechnology, School of Advanced Technologies in
Medicine, Tehran University of Medical Sciences, Tehran, Iran
4Department of Toxicology–Pharmacology, Faculty of Pharmacy, Pharmaceutical
Science Branch, Islamic Azad University (IAUPS), Tehran, Iran
5National Iranian Oil Company (NIOC) Central Hospital, Tehran, Iran
6Non-Communicable Diseases Research Center, Alborz University of Medical
Sciences, Karaj, Iran
7Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL),
Baqiyatollah University of Medical Sciences, Tehran, Iran
8Department of Community Nutrition, Tehran University of Medical Sciences, Tehran,
Iran
Acknowledgements The support of Tehran University of Medical Sciences and
cooperation of the central hospital of the NIOC, Tehran, Iran, are acknowledged.
Contributors SAJT, MJHA and SMR conceived and developed the idea for
the study and revised the manuscript. SM, SMA and MDM contributed to data
collection. MDM wrote numerous drafts of the study. MQ contributed to statistical
interpretations. All authors read and approved the nal manuscript.
Funding The trial funding was supported by Tehran University of Medical Sciences.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case
descriptions to ensure anonymity. The editors and reviewers have seen the detailed
information available and are satised that the information backs up the case the
authors are making.
Ethics approval The ethical approval of this trial was conducted by the ethics
committee of Tehran University of Medical Sciences (Ethical Code: IR.TUMS.
REC.1395.2612). All the participants will complete an informed consent form
(in Persian). Participation in and continuation of the supplementation is free and
voluntary for the patients. In the trial, advice on the lifestyle modication will be
presented to the patients free of charge. The health care services of the hospital will
be provided without inconsistency. The side effects of the supplements had not been
previously published. The patients' personal information will be kept condential.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional data to share.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http:// creativecommons. org/
licenses/ by- nc/ 4. 0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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(NAFLD): a trial protocol
with non-alcoholic fatty liver disease
factors and nesfatin among obese patients
on insulin resistance, lipids, inflammatory
Efficacy of nanocurcumin supplementation
Mohammad-Javad Hosseinzadeh-Attar
Mostafa Qorbani, Seyed Moayed Alavian, Milad Daneshi-Maskooni and
Seyed Ali Jazayeri-Tehrani, Seyed Mahdi Rezayat, Siavash Mansouri,
doi: 10.1136/bmjopen-2017-016914
2017 7: BMJ Open
http://bmjopen.bmj.com/content/7/7/e016914
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