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Efficacy of nanocurcumin supplementation on insulin resistance, lipids, inflammatory factors and nesfatin among obese patients with non-alcoholic fatty liver disease (NAFLD): A trial protocol

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Abstract

Objectives Different studies have been conducted on the role of curcumin in health since having multiple properties, including antioxidant and anti-inflammatory 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, inflammatory 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, inflammatory profiles (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 first experiment to determine nanocurcumin efficacy 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.
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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-inammatory 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, inammatory 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, inammatory proles (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 efcacy 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
Efcacy of nanocurcumin
supplementation on insulin resistance,
lipids, inammatory 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-TehraniSA,
RezayatSM, MansouriS, etal.
Efcacy of nanocurcumin
supplementation on
insulin resistance, lipids,
inammatory 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 afliations 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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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
Inammatory factors X X
Lipid prole 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 afliations
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 satised 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 modication 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 condential.
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
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... As an anti-inflammatory modulator, curcumin might improve health parameters related to NAFLD (94). Some RCT reported the effectiveness of curcumin and curcuminoids in improving various health parameters in NAFLD patients, i.e., serum levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, monocyte chemoattractant protein-1, interferon γ, vascular endothelial growth factor, and epidermal growth factor, fasting plasma insulin (FPI), HOMA-IR, liver transaminases, fatty liver index, serum cortisol, ultrasound morphological of the liver, and other parameters included in MS (p < 0.05) (94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112). The findings were consistent regarding the beneficial effects on improving NAFLD risk factors (113), with only one study having conflicting results, whereby curcumin was reported to have no impact on liver transaminases, metabolic and inflammatory parameters. ...
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The metabolic syndrome (MS) is a multifactorial syndrome associated with a significant economic burden and healthcare costs. MS management often requires multiple treatments (polydrug) to ameliorate conditions such as diabetes mellitus, insulin resistance, obesity, cardiovascular diseases, hypertension, and non-alcoholic fatty liver disease (NAFLD). However, various therapeutics and possible drug-drug interactions may also increase the risk of MS by altering lipid and glucose metabolism and promoting weight gain. In addition, the medications cause side effects such as nausea, flatulence, bloating, insomnia, restlessness, asthenia, palpitations, cardiac arrhythmias, dizziness, and blurred vision. Therefore, is important to identify and develop new safe and effective agents based on a multi-target approach to treat and manage MS. Natural products, such as curcumin, have multi-modalities to simultaneously target several factors involved in the development of MS. This review discusses the recent preclinical and clinical findings, and up-to-date meta-analysis from Randomized Controlled Trials regarding the effects of curcumin on MS, as well as the metabonomics and a pharma-metabolomics outlook considering curcumin metabolites, the gut microbiome, and environment for a complementary personalized prevention and treatment for MS management.
... High bioavailability is a prerequisite for curcumin's biological activities in the human body (Dei Cas & Ghidoni, 2019). One of the recently proposed methods for promoting the bioavailability of curcumin is the synthesis of its nano-range formulations (Jazayeri-Tehrani et al., 2017. ...
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Sepsis is the final common pathway to death for severe infectious diseases worldwide. The present trial aimed to investigate the effects of nano‐curcumin supplementation on hematological indices in critically ill patients with sepsis. Fourteen ICU‐admitted patients were randomly allocated into either nano‐curcumin or placebo group for 10 days. The blood indices, serum levels of inflammatory biomarker and presepsin as well as nutrition status, and clinical outcomes were assessed before the intervention and on days 5 and 10. White blood cells, neutrophils, platelets, erythrocyte sedimentation rate (ESR), and the levels of interleukin‐8 significantly decreased in the nano‐curcumin group compared to the placebo after 10 days of intervention (p = .024, p = .045, p = .017, p = .041, and p = .004, respectively). There was also a marginal meaningful decrease in serum presepsin levels in the intervention group compared to the placebo at the end of the study (p = .054). However, total lymphocyte count showed a significant increase in the nano‐curcumin group compared to the placebo at the end‐point (p = .04). No significant differences were found in the level of lymphocyte and the ratios of neutrophil/lymphocyte and platelet/lymphocyte between the study groups. Moreover, no significant between‐group differences were observed for other study outcomes, post‐intervention. Collectively, nano‐curcumin may be a useful adjuvant therapy in critically ill patients with sepsis. However, further trials are suggested to examine the effects of nano‐curcumin in the management of sepsis and its complications. Practical applications Curcumin (1,7‐bis[4‐hydroxy‐3‐methoxyphenyl]‐1,6‐heptadiene‐3,5‐ dione) or diferuloylmethane is widely used in medicine due to its several biological properties. Recent evidence has shown that curcumin possesses multiple pharmacological activities including immune‐modulatory, antioxidant, anti‐inflammatory, anti‐cancer, and anti‐microbial effects. In this study, it was observed that nano‐curcumin at a dose of 160 mg for 10 days, without side effects, reduced some inflammatory factors and regulated the immune responses in sepsis patients. For the first time, this trial was conducted to determine the effect of nano‐curcumin on hematological indices and the serum levels of presepsin and IL‐8.
... Hyperandrogenism and insulin resistance are two main pathological characteristics of PCOS, and recent studies have shown that these two factors are associated with NALFD [5]. Several clinical studies found that hyperandrogenism alone can lead to NAFLD [5][6][7], and there is evidence that women with PCOS along with insulin resistance or obesity are more likely to be diagnosed with NAFLD [8][9][10]. However, the mechanisms through which PCOS and NAFLD are connected remain unclear. ...
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Objective: Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51 % of women with PCOS suffer from non-alcoholic fatty liver disease (NAFLD). Investigation into the pathological mechanism behind this association will provide insights for the prevention and treatment of this complication. Methods: Dihydrotestosterone (DHT), a nonaromatic androgen, was used to mimic the pathological conditions of hyperandrogenism and insulin resistance. Hematoxylin and eosin staining, Oil Red O staining, immunofluores-cent staining, Western blots, and qRT-PCR were used to verify the hepatic steatosis and inflammation, and the latter two methods were also used for energy and mitochondrion-related assays. ELISA was used to measure the level of reactive oxygen species. Results: Twelve weeks of DHT exposure led to obesity and insulin resistance as well as hepatic steatosis, lipid deposition, and different degrees of inflammation. The expression of molecules involved in respiratory chain and aerobic respiration processes, such as electron transfer complex II, pyruvate dehydrogenase, and succinate de-hydrogenase complex subunit A, was inhibited. In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver. Conclusions: Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS. Abbreviations: PCOS, polycystic ovary syndrome; NAFLD, non-alcoholic fatty liver disease; DHT, dihydrotestosterone; Tfam, transcription factor A, mitochondrial; Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1α; Nrf1, nuclear respiratory factor 1; Mfn1, mitofusin-1; Opa1, optic atrophy 1; Drp1, dynamin-related protein; OXPHOS, oxidative phosphorylation complex; HSP60, heat shock protein 60; SDHA, succinate dehydrogenase; VDAC, voltage-dependent anion channel; PHB1, prohibitin 1; SOD1, superoxide dismutase 1; Atg, autophagy-related protein; LC3, microtubule-associated protein 1A/1B-light chain 3 (acy-tosolic LC3-I is conjugated to phosphatidylethanolamine to form LC3-II, which is recruited to autophagosomal membranes); AR, androgen receptor; p-MEK1/2, phospho-mitogen-activated protein kinase 1/2; p-ERK1/2, phospho-extracellular signal-regulated kinases 1/2; ERK1/2, extracellular signal-regulated kinases 1/2; p-p90RSK, phospho-p90 ribosomal s6 kinase; RIP3, receptor-interacting serine/threonine-protein kinase 3; HMBG1, high-mobility group box 1; Bcl2, B-cell lymphoma 2; Bcl-xl, B-cell lymphoma xl; Bax, bcl2-associated x protein; Bak, Bcl-2 homologous antagonist/killer.
... Curcumin is considered a folk medicine in MAFLD therapy primarily because of its antioxidant and anti-inflammatory properties. Treating patients between the age of 25 and 50 with supplementation of curcumin PLGA-NPs at 40 mg capsules/day after meals for three months leads to improved glucose, lipids, inflammation, and nesfatin, hepatic transaminases, and fatty liver degree indices [107,108]. These curcumin PLGA-NPs were initially patented turmeric-based colloidal dispersion technology named THERACURMIN, with a limited pharmaceutical characterization of PS 0.19 µm and stability of 28 days in comparison to 1 h for pure curcumin powder. ...
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Current research indicates that the next silent epidemic will be linked to chronic liver diseases, specifically non-alcoholic fatty liver disease (NAFLD), which was renamed as metabolic-associated fatty liver disease (MAFLD) in 2020. Globally, MAFLD mortality is on the rise. The etiology of MAFLD is multifactorial and still incompletely understood, but includes the accumulation of intrahepatic lipids, alterations in energy metabolism, insulin resistance, and inflammatory processes. The available MAFLD treatment, therefore, relies on improving the patient’s lifestyle and multidisciplinary pharmacotherapeutic options, whereas the option of surgery is useless without managing the comorbidities of the MAFLD. Nanotechnology is an emerging approach addressing MAFLD, where nanoformulations are suggested to improve the safety and physicochemical properties of conventional drugs/herbal medicines, physical, chemical, and physiological stability, and liver-targeting properties. A wide variety of liver nanosystems were constructed and delivered to the liver, only those that addressed the MAFLD were discussed in this review in terms of the nanocarrier classes, particle size, shape, zeta potential and offered dissolution rate(s), the suitable preparation method(s), excipients (with synergistic effects), and the suitable drug/compound for loading. The advantages and challenges of each nanocarrier and the focus on potential promising perspectives in the production of MAFLD nanomedicine were also highlighted.
... The use of polymeric nanoparticles called nanocurcumin has been shown to increase curcumin bioavailability up to 22 times [48]. Polymeric nanoparticles are very small in size which increase their surface area for interaction with epithelial cells [49]. ...
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Over the past decades, the worldwide prevalence of obesity has dramatically increased, thus posing a serious public health threat. Obesity is associated with the development of comorbid conditions and psychological disorders. Several lifestyle interventions have been proposed to tackle obesity; however, long-term maintenance of these interventions often proves challenging. In addition, among the different types of diets there is still a debate about the optimal macronutrient composition that will achieve the best results in weight loss. Recently, several commonly used spices such as pepper, ginger, and curcumin have been shown to play a beneficial role in obesity management. Therefore, exploring the effects of certain herbs or dietary spices on obesity may be promising. Among these spices, curcumin, which is the primary component of the spice turmeric, has gained great interest for its multiple health benefits. Several randomized controlled trials have investigated the potential favorable effects of curcumin supplementation on anthropometric measures. The aim of this review is to evaluate the effect of curcumin supplementation on the anthropometric indices among overweight or obese adults.
... Hyperandrogenism and insulin resistance are two main pathological characteristics of PCOS, and recent studies have shown that these two factors are associated with NALFD [5]. Several clinical studies found that hyperandrogenism alone can lead to NAFLD [5][6][7], and there is evidence that women with PCOS along with insulin resistance or obesity are more likely to be diagnosed with NAFLD [8][9][10]. However, the mechanisms through which PCOS and NAFLD are connected remain unclear. ...
Article
Full-text available
Objective Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51% of women with PCOS suffer from non-alcoholic fatty liver disease (NAFLD). Investigation into the pathological mechanism behind this association will provide insights for the prevention and treatment of this complication. Methods Dihydrotestosterone (DHT), a nonaromatic androgen, was used to mimic the pathological conditions of hyperandrogenism and insulin resistance. Hematoxylin and eosin staining, Oil Red O staining, immunofluorescent staining, Western blots, and qRT-PCR were used to verify the hepatic steatosis and inflammation, and the latter two methods were also used for energy and mitochondrion-related assays. ELISA was used to measure the level of reactive oxygen species. Results Twelve weeks of DHT exposure led to obesity and insulin resistance as well as hepatic steatosis, lipid deposition, and different degrees of inflammation. The expression of molecules involved in respiratory chain and aerobic respiration processes, such as electron transfer complex II, pyruvate dehydrogenase, and succinate dehydrogenase complex subunit A, was inhibited. In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver. Conclusions Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.
Article
The aim of the study is the assessment of the food security status and its association with some risk factors of chronic obesity-related diseases in Ardabil-Iran population. METHODS: This cross-sectional study was done between 500 adults of Ardabil that were selected by random sampling from Persian cohort study participants, in January 2019. Food insecurity of study participants was measured using the United States Department of Agriculture 18-item questionnaire. Some risk factors of chronic diseases including fasting blood glucose, lipid profile, liver enzymes, and dietary information were measured on the day of the interview. To assess the association between variables the correlation and linear regression tests were used. RESULTS: Forty-eight and six percent of the study participants were food secure and 51.4% were in food insecurity status. There were a significant difference in weight, blood glucose, blood pressure, and serum triglyceride levels between the food security status groups (P < 0.05). The food insecurity score had significant association with participants, weight (p = 0.005,β= 1.66), serum triglycerides (p = 0.022,β= 0.027), body mass index (p = 0.003,β= 0.645) and fasting blood sugar (p = 0.0001,β= 0.664). CONCLUSION: About half of the participants were in food insecurity status. Food insecurity status can be associated with obesity and some risk factors of chronic obesity-related diseases. This problem requires main food policies to reduce food insecurity in the community.
Article
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Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that can lead to end-stage liver disease needing a liver transplant. Many pharmacological approaches are used to reduce the disease progression in NAFLD. However, current strategies remain ineffective to reverse the progression of NAFLD completely. Employing nanoparticles as a drug delivery system has demonstrated significant potential for improving the bioavailability of drugs in the treatment of NAFLD. Various types of nanoparticles are exploited in this regard for the management of NAFLD. In this review, we cover the current therapeutic approaches to manage NAFLD and provide a review of recent up-to-date advances in the uses of nanoparticles for the treatment of NAFLD. 1. Introduction Nonalcoholic fatty liver disease (NAFLD) is the deposition of fat (steatosis) in the liver, excluding the secondary causes of fatty liver, such as excessive alcohol consumption, viral hepatitis, or certain medications. NAFLD is commonly associated with metabolic syndromes such as obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. Studies have shown that NAFLD-related liver diseases are escalating as a public health issue. Because of the increasing prevalence of obesity and type 2 diabetes worldwide, NAFLD is emerging as the critical risk factor for end-stage liver disease and liver cancer. NAFLD is expected to become one of the most common indications for liver transplantation in the next decade [1–4]. NAFLD encompasses a spectrum of liver abnormalities. Various histological grades have been described in the evaluation of NAFLD, including simple steatosis (grade 1), steatosis with lobular inflammation and ballooned hepatocytes (grade 2), and lobular inflammation, ballooned hepatocytes, and fibrosis (grade 3). NAFLD can progress to cirrhosis, hepatocellular carcinoma, and liver failure [5, 6]. 1.1. Pathogenesis of NAFLD Multiple factors are involved in the pathogenesis of NAFLD [7]. Genes, hormones, and nutrition can contribute to the development of NAFLD. It is well established that hepatic fat accumulation is related to insulin resistance, leading to steatosis development [8]. The pathophysiology of NAFLD and its development is a complex process with many unsolved topics. One prevailing model for describing the pathogenesis of NAFLD and NASH (nonalcoholic steatohepatitis) is the “two-hit hypothesis.” Triglyceride accumulation in the liver is attributed as the first hit. The second hit which can make NAFLD progress to severe liver injuries is mediated by several factors, including oxidative stress, cytokines, and mitochondrial dysfunction [9, 10]. The original “two-hit” approach cannot fully explain the pathophysiology of NAFLD, which incorporates several variables. Many studies in recent decades have revealed that the gut microbiota plays an essential role in NAFLD development via the gut-liver axis (GLA). Furthermore, significant progress has been made in the previous decade, with the involvement of inflammation and high-sugar diets emerging as key players in the etiology of NAFLD. With the advancement of technology, more researchers have focused on genetic predispositions and discovered several gene variations that may modify lipid and sugar metabolism in the liver and other tissues, such as adipose tissue (Figure 1) [10, 11].
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Background: The prevalence of non-alcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases risks of liver cirrhosis, hepatocellular carcinoma, and the requirement for liver transplantation. Uncertainty surrounds relative benefits and harms of various nutritional supplements in NAFLD. Currently no nutritional supplement is recommended for people with NAFLD. Objectives: • To assess the benefits and harms of different nutritional supplements for treatment of NAFLD through a network meta-analysis • To generate rankings of different nutritional supplements according to their safety and efficacy SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, the World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or status) for people with NAFLD, irrespective of method of diagnosis, age and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: We performed a network meta-analysis with OpenBUGS using Bayesian methods whenever possible and calculated differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios with 95% credible intervals (CrIs) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. Main results: We included in the review a total of 202 randomised clinical trials (14,200 participants). Nineteen trials were at low risk of bias. A total of 32 different interventions were compared in these trials. A total of 115 trials (7732 participants) were included in one or more comparisons. The remaining trials did not report any of the outcomes of interest for this review. Follow-up ranged from 1 month to 28 months. The follow-up period in trials that reported clinical outcomes was 2 months to 28 months. During this follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. We did not calculate effect estimates for mortality because of sparse data (zero events for at least one of the groups in the trial). None of the trials reported that they measured overall health-related quality of life using a validated scale. The evidence is very uncertain about effects of interventions on serious adverse events (number of people or number of events). We are very uncertain about effects on adverse events of most of the supplements that we investigated, as the evidence is of very low certainty. However, people taking PUFA (polyunsaturated fatty acid) may be more likely to experience an adverse event than those not receiving an active intervention (network meta-analysis results: OR 4.44, 95% CrI 2.40 to 8.48; low-certainty evidence; 4 trials, 203 participants; direct evidence: OR 4.43, 95% CrI 2.43 to 8.42). People who take other supplements (a category that includes nutritional supplements other than vitamins, fatty acids, phospholipids, and antioxidants) had higher numbers of adverse events than those not receiving an active intervention (network meta-analysis: rate ratio 1.73, 95% CrI 1.26 to 2.41; 6 trials, 291 participants; direct evidence: rate ratio 1.72, 95% CrI 1.25 to 2.40; low-certainty evidence). Data were sparse (zero events in all groups in the trial) for liver transplantation, liver decompensation, and hepatocellular carcinoma. So, we did not perform formal analysis for these outcomes. The evidence is very uncertain about effects of other antioxidants (antioxidants other than vitamins) compared to no active intervention on liver cirrhosis (HR 1.68, 95% CrI 0.23 to 15.10; 1 trial, 99 participants; very low-certainty evidence). The evidence is very uncertain about effects of interventions in any of the remaining comparisons, or data were sparse (with zero events in at least one of the groups), precluding formal calculations of effect estimates. Data were probably because of the very short follow-up period (2 months to 28 months). It takes follow-up of 8 to 28 years to detect differences in mortality between people with NAFLD and the general population. Therefore, it is unlikely that differences in clinical outcomes are noted in trials providing less than 5 to 10 years of follow-up. Authors' conclusions: The evidence indicates considerable uncertainty about effects of nutritional supplementation compared to no additional intervention on all clinical outcomes for people with non-alcohol-related fatty liver disease. Accordingly, high-quality randomised comparative clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (study design in which multiple interventions are trialed within large longitudinal cohorts of patients to gain efficiencies and align trials more closely to standard clinical practice) comparing interventions such as vitamin E, prebiotics/probiotics/synbiotics, PUFAs, and no nutritional supplementation. The reason for the choice of interventions is the impact of these interventions on indirect outcomes, which may translate to clinical benefit. Outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource utilisation measures including costs of intervention and decreased healthcare utilisation after minimum follow-up of 8 years (to find meaningful differences in clinically important outcomes).
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