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Endurance exercise induces IL-6 production from myocytes that is thought to impair intracellular defence mechanisms. Curcumin inhibits NF-κB and activator protein 1, responsible for cytokine transcription, in cell lines. The aim of this study was to investigate the effect of curcumin supplementation on the cytokine and stress responses following 2 h of cycling. Eleven male recreational athletes (35.5 ± 5.7 years; Wmax 275 ± 6 W; 87.2 ± 10.3 kg) consuming a low carbohydrate diet of 2.3 ± 0.2 g/kg/day underwent three double blind trials with curcumin supplementation, placebo supplementation, and no supplementation (control) to observe the response of serum interleukins (IL-6, IL1-RA, IL-10), cortisol, c-reactive protein (CRP), and subjective assessment of training stress. Exercise was set at 95% lactate threshold (54 ± 7% Wmax) to ensure that all athletes completed the trial protocol. The trial protocol elicted a rise in IL-6 and IL1-RA, but not IL-10. The supplementation regimen failed to produce statistically significant results when compared to placebo and control. IL-6 serum concentrations one hour following exercise were (Median (IQR): 2.0 (1.8-3.6) Curcumin; 4.8 (2.1-7.3) Placebo; 3.5 (1.9-7.7) Control). Differences between supplementation and placebo failed to reach statistical significance (p = 0.18) with the median test. Repeated measures ANOVA time-trial interaction was at p = 0.06 between curcumin supplementation and placebo. A positive correlation (p = 0.02) between absolute exercise intensity and 1 h post-exercise for IL-6 concentration was observed. Participants reported "better than usual" scores in the subjective assessment of psychological stress when supplementing with curcumin, indicating that they felt less stressed during training days (p = 0.04) compared to placebo even though there was no difference in RPE during any of the training days or trials. The limitations of the current regimen and trial involved a number of factors including sample size, mode of exercise, intensity of exercise, and dose of curcumin. Nevertheless these results provide insight for future studies with larger samples, and multiple curcumin dosages to investigate if different curcumin regimens can lead to statistically different interleukin levels when compared to a control and placebo.
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R E S E A R C H A R T I C L E Open Access
The effect of turmeric (Curcumin) supplementation
on cytokine and inflammatory marker responses
following 2 hours of endurance cycling
Joseph N Sciberras
1*
, Stuart DR Galloway
2
, Anthony Fenech
3
, Godfrey Grech
5
, Claude Farrugia
4
,
Deborah Duca
4
and Janet Mifsud
3
Abstract
Background: Endurance exercise induces IL-6 production from myocytes that is thought to impair intracellular
defence mechanisms. Curcumin inhibits NF-κB and activator protein 1, responsible for cytokine transcription, in cell
lines. The aim of this study was to investigate the effect of curcumin supplementation on the cytokine and stress
responses following 2 h of cycling.
Methods: Eleven male recreational athletes (35.5 ± 5.7 years; W
max
275 ± 6 W; 87.2 ± 10.3 kg) consuming a low
carbohydrate diet of 2.3 ± 0.2 g/kg/day underwent three double blind trials with curcumin supplementation,
placebo supplementation, and no supplementation (control) to observe the response of serum interleukins (IL-6,
IL1-RA, IL-10), cortisol, c-reactive protein (CRP), and subjective assessment of training stress. Exercise was set at 95%
lactate threshold (54 ± 7% W
max
) to ensure that all athletes completed the trial protocol.
Results: The trial protocol elicted a rise in IL-6 and IL1-RA, but not IL-10. The supplementation regimen failed to
produce statistically significant results when compared to placebo and control. IL-6 serum concentrations one
hour following exercise were (Median (IQR): 2.0 (1.8-3.6) Curcumin; 4.8 (2.1-7.3) Placebo; 3.5 (1.9-7.7) Control).
Differences between supplementation and placebo failed to reach statistical significance (p = 0.18) with the
median test. Repeated measures ANOVA time-trial interaction was at p = 0.06 between curcumin supplementation
and placebo. A positive correlation (p = 0.02) between absolute exercise intensity and 1 h post-exercise for IL-6
concentration was observed. Participants reported better than usualscores in the subjective assessment of
psychological stress when supplementing with curcumin, indicating that they felt less stressed during training
days (p = 0.04) compared to placebo even though there was no difference in RPE during any of the training days
or trials.
Conclusion: The limitations of the current regimen and trial involved a number of factors including sample size,
mode of exercise, intensity of exercise, and dose of curcumin. Nevertheless these results provide insight for future
studies with larger samples, and multiple curcumin dosages to investigate if different curcumin regimens can lead
to statistically different interleukin levels when compared to a control and placebo.
Keywords: Immunity, Interleukins, Natural polyphenols
* Correspondence: sciberras.n.joseph@gmail.com
1
Sport Nutrition graduate from the University of Stirling, 74, San Anton Court,
Pope John XXIII street, Birkirkara BKR1033, Malta
Full list of author information is available at the end of the article
© 2015 Sciberras et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5
DOI 10.1186/s12970-014-0066-3
Background
Research supports a role for nutritional interventions to
maintain immune function in the post-exercise period
[1-5] It is also widely recognized that endurance exercise
stimulates an increase in circulating cytokines in the
post-exercise period [6,7]. These cytokines include inter-
leukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8
(IL-8), interleukin 10 (IL-10), and interleukin 1 receptor
antagonist (IL1-RA). These cytokine responses following
exercise do not mainly originate from circulating mono-
cytes, but may influence secretion of other cytokines
from cells which form part of the immune system [8,9].
The post-exercise rise in IL-6 is unrelated to muscle
damage, but serves as a messenger from myocytes to in-
crease hepatic glycogenolysis [10-12]. Interestingly, the
release of IL-6 in the post-exercise period appears to be
dependent upon carbohydrate availability [12].
IL-6 is a cell messenger which affects many cells and
systems, such as lymphocytes, leads to the release of the
anti-inflammatory hormone cortisol, and stimulates re-
lease of acute phase proteins and glucose from the liver
[13] IL1-RA and IL-10 transcription are mediated by
high IL-6 concentrations [14]. These immunomodula-
tory mechanisms result in a decreased amount of circu-
lating Type 1 T-helper (Th1) cells [15]. This suggests
that regular high volume exercise shifts the CD4 positive
T lymphocyte profile from Th1 towards Th2. Th1 cells
help neutralize intracellular infective agents like viruses
and bacteria which are responsible for upper respiratory
tract infections (URTI). Specific interleukins, involved in
cellular immunity, are also inhibited by the increase in
IL-6 [16]. Inhibition of IL-1 is mediated through IL1-
RA, and IL-6 appears to blunt the effect of TNF-α, while
the effects of interleukin 12 are countered by IL-10 [17].
Thus, factors that can modify the post-exercise cytokine
response could assist in maintenance of immune func-
tion in athletes.
Cytokine transcription is mediated by the transcription
factors NF-κB and activator protein 1 (AP-1) [18]. Acti-
vation of NF-κB is induced by several immunity media-
tors, cell signaling intermediates, and reactive oxygen
species [19]. Curcumin found in the rhizome Curcuma
longa (turmeric), is an anti-oxidant and anti-inflammatory,
long used as a traditional herbal medicine [20-22]. It at-
tenuates the activation of NF-κB and IκB kinase in cancer
cell lines [23]. Researchers observed that curcumin in-
hibits the activity of IκB kinase and decreases the activity
of NF-κB in intestinal epithelial cells [24]. Shisodia et al.,
reported that the activity of curcumin also affects the AP-
1 pathway, and Akt signaling [25]. In a study on rats, cur-
cumin was shown to reduce IL-6, IL-1β, and TNFαlevels
following eccentric exercise [26]. These authors concluded
that curcumin may promote recovery following repeated
strenuous activity. Curcumin has also been shown to affect
numerous physiological pathways, including inflammation,
and play important roles in pathological conditions, includ-
ing diabetes and arthritis, as reviewed elsewhere [27-29].
These observations with curcumin in cell and animal
models, leads us to hypothesize that curcumin supple-
mentation in humans could reduce cytokine release fol-
lowing exercise. An acute blunting of the cytokine
response to exercise may provide a strong basis for lon-
ger term studies examining a role for curcumin on im-
mune function and recovery during periods of strenuous
exercise training. The current study, therefore, aimed to
observe the effects of curcumin supplementation on
interleukin and other inflammatory marker responses
following two hours of cycling in a low glycogen state.
Methods
Eleven recreationally active males (regular weekly aer-
obic activity during the last year for at least 3 h, mean
age 35.5 ± 5.7 years; mean W
max
275 ± 56 W; mean
weight 87.2 ± 10.3 kg; mean height 1.78 ± 0.07 m) volun-
teered to participate in the study. All of the participants
gave their written informed consent to participate in the
study which was approved by the ethics committees of
the University of Stirling and University of Malta. Athletes
were recruited from those attending talks held at sport
clubs in Malta. Participants were screened for suitability
prior to the experimental trials, including a medical visit
by a licensed general practitioner. None reported a history
of auto-immune disorders or medical conditions which
could affect the results. Moreover they were not on medi-
cation or high dose vitamin C and/or vitamin E intake.
Participants reported being free from infection for at least
4 weeks prior to the trial, and were in a steady period of
endurance training. The number of participants needed
was calculated by sample size testing based on literature
review. Power was set at 80%, p < 0.05, with a difference in
population means of 2 pg for interleukin 6, and standard
deviation of 2 pg. This gave an approximate sample size of
810. The sample sizes and results obtained in studies
listed in the review of Fischer, 2006 [30], on interleukins
and exercise were also taken as a guide.
Participants were taught how to use diabetic nutritional
exchanges to comply with the pre-trial prescribed diet.
Preliminary measurement of lactate threshold and max-
imum workload were obtained together using a Compu-
trainer lab ergometer (Racermate, Seattle, USA) and
Lactate Scout (EKF-Diagnostics, Magdeburg, Germany).
The Lactate Scout was validated prior to each test using
the standard solution provided by the manufacturer. Lac-
tate was measured by skin pricking every three minutes
on the computrainer® lab; following which power was in-
creased by 30 W. This continued until volitional fatigue or
until the athlete was unable to maintain a cadence of
70 rpm. This was defined as the maximum workload.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 2 of 10
Subjects were then allocated either to the curcumin
supplement or placebo in a double blind randomized
cross-over fashion. Subjects performed three trials in total
(supplement/placebo and control) in which they exercised
for 2 h at a power output equivalent to 95% of their lactate
threshold, to ensure completion of the trial task. Supple-
ment or placebo was taken for three days prior to the trial
day, and finally on arrival at the clinic for the trial. Follow-
ing a one week wash-out period the trial was repeated
with supplementation/placebo accordingly. An identical
further trial served as a control and was held following a
further week without any supplementation. The control
arm of the study was scheduled after the two experimental
trials in an effort to minimize data loss from curcumin
and placebo trials, through athlete drop out. In addition,
participants undertook a supervised one hour interval
training session on a cycle ergometer in the afternoon,
two days prior to each trial, in an attempt to lower muscle
glycogen stores. Participants were then assigned a diet
containing 2.3 ± 0.2 g/kg carbohydrate, 1.0 ± 0.2 g/kg fat,
and 1.3 ± 0.2 g/kg protein. This diet was aimed at mini-
mising carbohydrate replenishment following training two
days prior to the trial. Participants returned to their habit-
ual diet immediately after the trial. Participants were re-
quested to refrain from strenuous physical activity for
24 h prior to trials.
Upon arrival at the laboratory for the trials a cannula
was inserted in an antecubital vein. Blood samples
(20 ml, 4 serum and 2 EDTA tubes) were taken just be-
fore the exercise trial, immediately after completing the
two hours cycling, and one hour following the cessation
of exercise (Figure 1). A pedaling cadence of 70 rpm
was maintained during trials using the Computrainer®
ergometer, which was calibrated as per manufacturer's
instructions. Prior to all training and trial sessions par-
ticipants completed a daily analysis of life demands
(DALDA) questionnaire to assess stress sources (part 1)
and stress symptoms (part 2) [31].
Trials, conducted at St James Highway Clinic, com-
menced between 1 pm and 6 pm, at least 4 h following
their last meal. Heart rate was measured using a Timex®
(Middlebury, USA) telemetry strap. Temperature and
humidity, measured with a calibrated thermo-hygrometer
(TFA-Dostmann, Mannheim, Germany), were maintained
close to 20°C and 60% RH, respectively. Rating of per-
ceived exertion was reported after 15 min into the trial
and thereafter every 30 minutes. Only water was permit-
ted during the trial. One athlete dropped out following the
second trial, and did not complete the control trial. The
curcumin supplement (Meriva®Curcumin) and corre-
sponding identical placebo, together with respective cer-
tificate of analysis (CoA) were donated by Indena Spa.
(Milan, Italy). Meriva® curcumin was chosen because of its
superior bioavailability to other curcumin products. Re-
searchers concluded that a single dosage of 376 mg of
Meriva® curcumin was eighteen times superior to a stand-
ard curcumin dose of 2 g, giving a maximum plasma con-
centration of 207 ng/ml four hours following supplement
ingestion [32]. Dosage for the present study subjects was a
single dose of 500 mg of Meriva® curcumin (5 tablets) with
midday meal for three days, and then 500 mg ingested just
before exercise. Samples for plasma curcumin analysis
were taken at the final blood sampling time only in this
study, three hours post ingestion to coincide with assess-
ment of post-exercise interleukin response.
Plasma and serum samples obtained after centrifuging
were frozen at 80°C. Plasma samples for curcumin ana-
lysis were incubated for 4 hours with helix pomatia glu-
curonidase (Sigma Aldrich®, Delaware, USA) in a pH 5
sodium acetate buffer. This was followed by extraction
with chloroform. The organic chloroform was dried under
a nitrogen stream, and reconstituted in 4 ml curcumin
spiked acetonitrile. These samples were then analysed for
curcumin using a Waters HPLC (Milford, USA) using a
method reported in literature [33]. The method was vali-
dated for identification and linearity using curcumin
standard (Sigma Aldrich, Delaware, USA). Interleukins 6,
1RA, and 10 were assayed on all serum samples using
ELISA kits supplied by R&D Systems Ltd (Minneapolis,
USA). Haematocrit, haemoglobin concentration, white
blood cell (WBC count), neutrophil proportion, cortisol
concentration, and c-reactive protein concentration were
Figure 1 Trial flow chart detailing sequence of events, supplementation days, and blood sampling. DALDA daily analysis of life
demands in athletes, HR heart rate, RPE rating of perceived exertion.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 3 of 10
all measured on blood taken immediately after exercise
only (analyses were conducted by MLS laboratories,
St James Hospital, Malta).
Repeated measures ANOVA was conducted with the
values obtained for time, trial, and time x trial interac-
tions. Any outliers in datasets were dealt with using
Grubbs method [34]. Any significant within subject ef-
fects were then examined with the median test when
data was not normally distributed (IL-6 conc.), otherwise
student t-test was used. Ratings from the DALDA ques-
tionnaire were analysed with the wilcoxon test for paired
non parametric data. Parametric results are tabulated as
mean ± standard deviation, 95% confidence intervals are
also given in brackets for Tables 1 and 2. Further results
are graphically plotted as mean ± standard error of the
mean. Median and inter-quartile range are reported when
continuous data is not normally distributed. Spearmans
correlation coefficient was calculated where associations
were expected. The intra-assay coefficient of variation was
9.4% for IL-6; 6.4% for IL-1RA and 3.4% for the HPLC
assay of curcumin.
Results
All participants undertook the trial at 95% lactate
threshold. Relative to W
max
the mean power output sus-
tained during the 2 hour ride was 54 ± 7% of the mean
maximum workload (range 39% to 63% of W
max
). The
humidity, temperature, and ergometer calibration values
were all similar between trials (Table 1). Initial body
mass and training volume were also not different be-
tween each trial (Table 1). None of the participants re-
ported any adverse effect to supplementation or placebo
ingestion. All participants reported adhering to their
pre-trial diets on all trials. Participants completed all the
trials in three weeks. Five participants started the trials
with placebo and six with curcumin supplementation.
HPLC analysis confirmed the presence of curcumin in
plasma of all participants when taking the curcumin sup-
plement. No curcumin was detected in plasma samples on
other trials. Mean ± SD (range) curcumin concentration ob-
tained was 79.7 ± 26.3 ng/ml (50.7 ng/ml to 125.5 ng/ml).
The reported perceived exertion increased significantly
every 30 minutes during the 2 hour ride on all trials (mean
(SD) RPE was: 9 ± 1; 10 ± 2; 11 ± 2 & 12 ± 2 at 15, 45, 75
and 105 minutes during exercise; p < 0.01). There were no
significant differences in RPE ratings obtained during exer-
cise between trials (11 ± 1; 11 ± 1; 11 ± 1 for curcumin, pla-
cebo and control trials, respectively). Mean (SD) heart rate
during the exercise period was also not different between
trials (118 ± 12; 117 ± 10; 117 ± 13 for curcumin, placebo
and control trials, respectively). Whole blood analysis of the
post-exercise samples revealed no differences in cortisol, c-
reactive protein, haematocrit, haemoglobin, WBC, or neu-
trophil proportion between trials (Table 2).
Serum IL-6 data demonstrated a tendency for an inter-
action effect (time x trial interaction p = 0.06; F = 4.03)
between curcumin and placebo trials (Figure 2). Curcu-
min only appeared to lower the concentration of IL-6 re-
leased one hour following exercise when compared to
placebo, but this failed to reach statistical significance
(p = 0.18; n = 10; 95% C.I. 1.63 ×3.81) (Figure 3). Es-
timation of size of effect proves difficult because one set
of data is not normally distributed. Nonetheless Cohens
d is of 0.84 hinting at a possibly large effect (Figure 4).
The correlation analysis revealed a significant association
(p = 0.02) between IL-6 elevation and percentage W
max
power output sustained during the exercise task (correl-
ation coefficient rho 0.41 (dƒ= 30)). No association was
observed between attenuation of IL-6 response following
exercise with the plasma concentration levels of curcu-
min (p = 0.92; correlation coefficient rho 0.04 (dƒ= 9)).
There was no difference between the trials for IL1-RA
(time x trial interaction p = 0.85, (F = 0.44) when analys-
ing the ANOVA for repeated measures. Correlation co-
efficient between percentage W
max
power and change in
IL1-RA concentration was 0.34 (dƒ= 30), but failed to
reach statistical significance (p = 0.06). There was no de-
tectable increase in IL-10 on any of the trials.
The DALDA questionnaire (Table 3) revealed a higher
number of better than usualresults on the training day
when ingesting curcumin compared to placebo and con-
trol. This was statistically significant between placebo
Table 1 Ambient conditions, ergometer calibration setting and initial body mass on the day of each trial
Curcumin Placebo Control
Mean ambient humidity (% RH) 63 ± 6 (5967) 62 ± 7 (5866) 62 ± 6 (5866)
Mean ambient temperature (°C) 19.9 ± 0.6 (19.5-20.3) 20.0 ± 0.4 (19.8-20.2) 20.1 ± 0.5 (19.8-20.4)
Calibration value of computrainer 2.7 ± 0.1 (2.6-2.8) 2.7 ± 0.1 (2.6-2.8) 2.8 ± 0.1 (2.7-2.9)
Body mass (kg) 86.7 ± 10.5 (80.5-92.9) 86.6 ± 10.4 (80.4-92.8) 87.5 ± 11.0 (80.7-94.3)
Training (Hours×Intensity) 11 ± 10 (517) 13 ± 9 (818) 13 ± 6 (917)
Habitual training load during the previous week was assessed using duration and intensity information. Training is reported in hours multiplied by intensity. Intensity
was classified as low (1) medium (2) & high (3) Data are mean (± SD). Standard deviation and 95% confidence intervals are also reported following each value. No
differences were noted between trials groups. Calibration value of the Computrainer is the value given to the ergometer as instructed by the manufacturer.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 4 of 10
Table 2 Physiological parameters means (± SD) measured during trial, grouped by trial type
Curcumin Placebo Control
Cortisol (nMol) 308 ± 200 (190426) 266 ± 200 (148384) 289 ± 228 (148430)
C-Reactive protein (mg/l) 0.5 ± 0.3 (0.3-0.7) 0.9 ± 0.9 (0.4-1.4) 0.7 ± 0.6 (0.3-1.1)
Haematocrit (%) 43 ± 2 (4244) 43 ± 3 (4145) 43 ± 2 (4243)
Haemoglobin (g/dl) 15.0 ± 0.7 (14.6-15.4) 14.0 ± 0.9 (13.5-14.5) 15.1 ± 0.8 (14.6-15.6)
WBC (10
9
/L) 10.1 ± 2.7 (8.5-11.7) 9.6 ± 2.5 (8.1-11.1) 10.4 ± 2.6 (8.8-12.0)
Neutrophil (%) 61.9 ± 9.8 (56.1-67.7) 61.4 ± 9.2 (56.0-66.8) 63.5 ± 9.5 (57.6-69.4)
Confidence intervals 95% are also reported following each value.
Parameters show no significant difference between trials. These parameters were measured only at the end of exercise. Cortisol and C - reactive protein were measured to
investigate any possible effects from the active compound curcumin. Haematocrit & Haemoglobin were measured to ensure that the athletes were in similar hydration
status, while white blood cell and neutrophil percentage were needed to confirm that the athlete was not suffering from an infection at the time of the trial.
Figure 2 Mean (±SEM) IL-6 concentration obtained before exercise, immediately after exercise, and one hour following exercise on
each trial day. *indicates significant difference from pre-exercise on all trials. No statistical significant difference between interleukin 6 values was
observed. Table shows mean cytokine levels, standard deviation, and 95% confidence intervals during trials. Median and interquartile range IQR
are also shown for 1 hour post exercise.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 5 of 10
Figure 3 Mean (±SEM) IL1-RA concentration obtained before exercise, immediately after exercise, and one hour following exercise on
each trial day. *indicates significant difference from pre-exercise. Table shows mean cytokine levels, standard deviation, and 95% confidence
intervals during trials.
Figure 4 Median IL-6 concentration and range one hour post exercise for curcumin, placebo and control trials. Note curcumin dataset
still positively skewed (towards low values) despite removing an outlier.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 6 of 10
and supplementation in both stress sources (Part 1, p =
0.04) and stress symptoms (Part 2, p = 0.04). The num-
ber of better than usualresults obtained between cur-
cumin and control on the training day was also higher
but not statistically significant (Part 1,p = 0.06; and Part
2, p = 0.14). There were no differences in scoring on Part
1 or Part 2 of the DALDA questionnaire between treat-
ments on the trial days.
Discussion
The current study has not revealed a statistically signifi-
cant difference between the supplementation with curcu-
min vs. placebo or control. However these results suggest
that a positive inhibitory effect of curcumin on IL-6 pro-
duction/release or an enhanced uptake in vivo could occur
at higher supplementation doses, and under different trial
conditions (suggested underneath). These observations, al-
though again not statistically significant, lend some sup-
port to the previous cell and animal model data, and
suggest that further studies in humans may be warranted.
The lack of statistical significance in our dataset suggests
that sample size, mode of exercise, intensity of exercise,
dose of curcumin, or sample collection times are interest-
ing issues for discussion and further investigation.
Sample size estimates using the mean difference 1 hr
post-exercise, and standard deviation, from the present
study indicate that adequate power could be obtained
with 26 participants. Given the large variance in re-
sponse of IL-6 post-exercise within the current study it
would be of interest to analyse responses in a similar
trial on a group who may provide a more homogeneous
response. The recruitment of cyclists also may have lim-
ited our ability to observe any possible effect of curcu-
min on post-exercise cytokine concentration, due to the
absence of eccentric contractions or weight bearing im-
pact during the exercise task. A two hour long exercise
regimen was chosen because duration of exercise is
considered a better predictor of serum interleukin eleva-
tion than intensity. Running is associated with a higher
rise in cytokine concentration post-exercise than ob-
served following cycling [30], and may therefore be a
mode of choice in future studies.
Despite the light exercise intensity examined in the
present study a response in IL-6 and IL1-RA was still elic-
ited, primarily because the exercise was of sufficient dur-
ation. We deliberately adopted a low carbohydrate diet in
an attempt to exacerbate the cytokine response to pro-
longed cycling exercise [12], and this seems to have been
effective. Participants whose trial was at a higher workload
intensity relative to their maximum workload capacity had
a greater increase in IL1-RA and IL-6 concentration one
hour after exercise. This was statistically significant for IL-
6, and close to statistical significance for IL1-RA. It is
important to note that some studies observing higher
cytokine responses employed a performance time/distance
trial following a period of cycling at a submaximal steady
state intensity [12]. This type of protocol would enhance
the cytokine response post-exercise, and indicates that
higher intensity bouts may be of most interest in future
studies examining curcumin effects on cytokine response.
Although our data indicate no statistically significant
effect of curcumin supplementation on IL-6 and IL1-RA
response to exercise, this could be due to the curcumin
dose and plasma curcumin response. Cuomo and col-
leagues previously indicated that serum micro-molar
concentrations of curcumin would likely be necessary
for pharmacological in vivo effects [32]. Indeed, it is pos-
sible that a significant effect on post-exercise interleukin
concentrations would have been achieved with a higher
plasma curcumin concentration in the present study.
The curcumin concentration achieved in the present
study was almost 80 ng/ml (0.22 μmoles/L). A recent
paperobservedaneffectofcurcuminonplasmaoxidative
stress markers following exertion in humans when plasma
Table 3 DALDA (Daily Analysis of Life Demands on Athletes) questionnaire responses (median & range) for both
training and trial days
DALDA part 1 (training day) stress sources DALDA (part 2 training day) stress symptoms
RESPONSE A (Worse) B (Same) C (Better) A (Worse) B (Same) C (Better)
CURCUMIN (n = 11) 0 (03) 4 (49) 3 (05)
1(04) 21(425) 3 (019)
PLACEBO (n = 11) 1 (05) 7 (29) 1 (06) 2 (07) 20 (825) 2 (015)
CONTROL (n = 10) 2 (03) 6 (29) 0 (07) 2 (09) 22 (525) 2 (018)
DALDA part 1 (trial day) stress sources DALDA part 2 (trial day) stress symptoms
RESPONSE A (Worse) B (Same) C (Better) A (Worse) B (Same) C (Better)
CURCUMIN (n = 11) 2 (04) 6 (29) 1 (07) 2 (05) 22 (525) 1 (020)
PLACEBO (n = 11) 1 (05) 8 (29) 0 (06) 1 (06) 23 (525) 0 (018)
CONTROL (n = 10) 2 (03) 7 (39) 0 (06) 3 (08) 22 (425) 1 (019)
Data is grouped according to trial type. A Worse than usual; B Same as usual; C Better than usual.
indicates statistical significant difference between
curcumin and placebo trials, p-value in both parts between curcumin and placebo is 0.04 using Wilcoxon signed ranks.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 7 of 10
curcumin concentration was elevated to around 100 ng/ml
[35]. Recent work [36] has demonstrated that intraperito-
neal injection of curcumin counteracts muscle atrophy in
rats possibly also through anti-oxidant actions. It is unclear
if such effects can be demonstrated in a human model and
what dose of curcumin would be required to achieve this,
but translation to a human model could provide relevant
outcomes for sport or clinical practice. It is, therefore, rec-
ommended that future studies quantify the plasma con-
centration of curcumin required to achieve significant
clinically relevant outcomes and investigate any possible
association with anti-oxidant activity. Furthermore, blood
sampling after 2, 16, & 24 hours following exercise would
have provided further data on cortisol, C-reactive protein,
and interleukin 10 responses which are known to be influ-
enced by circulating IL-6 concentration, but at a later time
than the last blood sample taken in our study.
Ratings of perceived exertion significantly increased
throughout the exercise period on all trials. Given the
prior glycogen depleting exercise during the training day,
and prescribed low carbohydrate diet, it is likely that
glycogen depletion contributed towards increased ratings
of exertion during the exercise period. The DALDA re-
sults indicate that participants felt better on the second
day of curcumin supplementation (the training day). The
number of better than usualresponses was higher than
placebo and control on the second day of supplementa-
tion. It is important to note that DALDA is a retrospective
tool of psychological causes and symptoms [31], while that
ratings of perceived exertion (RPE) is a prospective tool
assessing the extent of exercise difficulty. The study was
aimed to provide the same repeatable exercise stressor
every time the trial was repeated conducted with curcu-
min, placebo, and control. The fact that the RPE has did
not changed to the extent of its sensitivity, between ex-
perimental variables provides evidence that the study
managed to reproduce similar exercise conditions in all
trials. A study on patients suffering from osteoarthritis
taking 1 g of curcumin supplementation for eight months
showed less pain and better movement reported by pa-
tients taking the supplementation versus placebo [37].
Moreover our views are supported by a recent study on
curcumin supplementation and delayed muscle onset
soreness (DOMS). This study has demonstrated that, par-
ticipants taking 400 mg curcumin supplementation for
2 days, report less DOMS than participants taking placebo
[38]. The authors suggest that potentially acute curcumin
supplementation may be of use to help participants with
higher intensity training workloads.
Interestingly, researchers have recently described sig-
nificant anti-inflammatory effects of curcumin, and have
confirmed that curcumin acts to inhibit lipopolysaccharide
stimulated NF-κB, reduce IL-6, and reduce PMA induced
reactive oxygen species (ROS) production, in human
neutrophils [39]. Furthermore, others [40] have noted a
significant attenuation in skeletal muscle IL-6 mRNA dur-
ing exercise with anti-oxidant vitamin supplementation
(vitamin C and E); and lead to significantly decreased
plasma IL-6 concentration. Starkie and colleagues note a
significant reduction in plasma IL-6 but not in skeletal
muscle IL-6 mRNA following carbohydrate intake [41].
These observations suggest that measurement of early
events in cytokine production are important to monitor in
future human studies, and that concurrent supplementa-
tion of carbohydrate alongside an anti-oxidant like curcu-
min might have a superior effect to that of carbohydrate
on its own on attenuation of cytokine response following
exercise. It must be noted that subjects in our study were
glycogen depleted, and that further studies are needed to
confirm or refute similar findings or trends in athletes
who are carbohydrate replete. As such the usefulness of
curcumin supplementation during competition or training
needs to be studied separately.
The present study also included a control arm, intended
to identify any placebo effects, especially in subjective
measures and to help confirm any trends observed with
curcumin supplementation. No statistical difference be-
tween placebo and control values was found for any vari-
ables and no difference was observed from control in
those who commenced the study with either curcumin
supplementation, or placebo supplementation. This sug-
gests both that the washout period was sufficiently long
between trials with our present protocol and that trial
stress was adequately reproduced.
Conclusion
There is considerable debate concerning the impact of
blunting cytokine and inflammatory marker responses to
exercise on the adaptive stimulus to exercise [42], and fur-
ther work is required to determine the effects of blunting
cytokine and inflammatory marker responses to exercise on
incidence of infection, and training adaptation in athletes.
Given that the limited bioavailability of the polyphenol cur-
cumin has been now improved with new preparations as
used in the present study, it would seem prudent to direct
more research towards athletic and clinical populations. In
conclusion, the results from the present study did not re-
veal any statistical difference between intervention and pla-
cebo. However our interpretation based on the findings
presented in this paper does not exclude the possibility of
an attenuating effect on IL-6 by curcumin. This is sup-
ported by the results obtained in this study and corrobo-
rated by findings in other published studies. We conclude
that the effect of curcumin supplementation on interleukins
and other inflammatory markers needs to be further inves-
tigated with observations in a larger sample including
examination of exercise mode, intensity effects, and curcu-
min dose effects.
Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 8 of 10
Competing interests
The authors declare that they have no competing interests.
Authorscontributions
JNS designed the study including trials & analysis, collected, analysed
samples & data, prepared the manuscript; SG designed the study, supervised,
reviewed data, & prepared manuscript;. AF designed and supervised analysis &
reviewed manuscript, GG supervised cytokine analysis, CF supervised HPLC
analysis, DD designed and supervised HPLC analysis & JM supervised the study
and reviewed manuscript. All authors read and approved the final manuscript.
Acknowledgements
Analysis was carried out at the department of pharmacology and
therapeutics, and department of chemistry laboratories. The help of the
respective laboratory officers is acknowledged. A special thanks to
Dr. Bridgette Ellul, Dr. Neville Calleja, Dr. Christian Saliba, Pro-Rector Richard
Muscat & Professor Roger Ellul Micallef for their support and mentorship.
Many thanks to Dr. Gregory Attard & St James Highway Clinics This study
was aided by a grant from the Maltese Sports Council.
Author details
1
Sport Nutrition graduate from the University of Stirling, 74, San Anton Court,
Pope John XXIII street, Birkirkara BKR1033, Malta.
2
Health and Exercise
Sciences Research Group, School of Sport, University of Stirling, Stirling,
Scotland.
3
Department of Clinical Pharmacology and Therapeutics, University
of Malta, Msida, Malta.
4
Department of Chemistry, University of Malta, Msida,
Malta.
5
Department of Pathology, University of Malta, Msida, Malta.
Received: 12 August 2014 Accepted: 18 December 2014
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Sciberras et al. Journal of the International Society of Sports Nutrition (2015) 12:5 Page 10 of 10
... Several studies [22,23,25,52,53] that investigated the effect of curcumin on exercise-induced inflammatory and oxidative stress markers also evaluated plasma curcumin concentration post-supplementation. All studies [22,23,25,52,53] observed an increase in plasma curcumin concentration post-supplementation at time points ranging from 2 h to 1-4 days ( Table 3). ...
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Background Delayed onset of muscle soreness (DOMS) and its physiological consequences has an important influence on the individual’s adherence to the exercise routine. Objective This study aimed to evaluate the efficacy, safety, and tolerability of TurmXTRA ® 60N (WDTE60N) on DOMS in comparison with placebo in recreationally active healthy subjects. Methods The present study was a randomized, double-blind, placebo-controlled parallel group study. Thirty healthy and recreationally active subjects (average age: 28.23±4.20 years) were randomized to receive WDTE60N (WDTE60N group; n=15) or placebo (placebo group; n=15). Study treatments were initiated 29 days prior to the eccentric exercise and continued for 4 days after the exercise. Primary endpoint was the change in pain intensity measured by the visual analog scale (VAS) at the end of study treatment (at 96 hours after eccentric exercise) from baseline (measured immediately after exercise). Results The VAS score indicated that subjects from the WDTE60N group reported significantly less pain after eccentric exercise compared to placebo group (AUC 0-96h : 286.8±46.7 vs. 460±40.5, respectively; p<0.0001). Wellbeing status, assessed using the adapted version of Hooper & MacKinnon questionnaire, calculated as individual and cumulative scores of the domains - fatigue, mood, general muscle soreness, sleep quality and stress demonstrated significant improvement in all domains as well as in overall wellbeing in WDTE60N group as compared to placebo group (p<0.0001). Serum lactate dehydrogenase (LDH) was significantly lower in the WDTE60N group compared to placebo group (AUC 0-96h : 23623.7±2532.0 vs. 26138.6±3669.5, respectively; p=0.0446). Conclusion The WDTE60N intake before and after eccentric exercise significantly reduced subjective perception of muscle soreness and serum LDH activity, and increased psychological wellbeing after eccentric exercise in recreationally active subjects.
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In recent years, many efforts have been made to identify micronutrients or nutritional strategies capable of preventing, or at least, attenuating, exercise-induced muscle damage and oxidative stress, and improving athlete performance. The reason is that most exercises induce various changes in mitochondria and cellular cytosol that lead to the generation of reactive species and free radicals whose accumulation can be harmful to human health. Among them, supplementation with phenolic compounds seems to be a promising approach since their chemical structure, composed of catechol, pyrogallol, and methoxy groups, gives them remarkable health-promoting properties, such as the ability to suppress inflammatory processes, counteract oxidative damage, boost the immune system, and thus, reduce muscle soreness and accelerate recovery. Phenolic compounds have also already been shown to be effective in improving temporal performance and reducing psychological stress and fatigue. Therefore, the aim of this review is to summarize and discuss the current knowledge on the effects of dietary phenolics on physical performance and recovery in athletes and sports practitioners. Overall, the reports show that phenolics exert important benefits on exercise-induced muscle damage as well as play a biological/physiological role in improving physical performance.
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Background Prolonged or unaccustomed eccentric exercise may cause muscle damage and depending from its extent, this event negatively affects physical performance. Objectives The aim of the present investigation was to evaluate, in humans, the effect of the flavonoid quercetin on circulating levels of the anabolic insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 2 (IGF-II), produced during the recovery period after an eccentric-induced muscle damage (EIMD). Methods A randomized, double-blind, crossover study has been performed; twelve young men ingested quercetin (1 g/day) or placebo for 14 days and then underwent an eccentric-induced muscle damaging protocol. Blood samples were collected, and cell damage markers [creatine kinase (CK), lactate dehydrogenase (LDH) and myoglobin (Mb)], the inflammatory responsive interleukin 6 (IL-6), IGF-I and IGF-II levels were evaluated before the exercise and at different recovery times from 24 hours to 7 days after EIMD. Results We found that, in placebo treatment the increase in IGF-I (72 h) preceded IGF-II increase (7 d). After Q supplementation there was a more marked increase in IGF-I levels and notably, the IGF-II peak was found earlier, compared to placebo, at the same time of IGF-I (72 h). Quercetin significantly reduced plasma markers of cell damage [CK (p<0.005), LDH (p<0.001) and Mb (p<0.05)] and the interleukin 6 level [IL-6 (p<0.05)] during recovery period following EIMD compared to placebo. Conclusions Our data are encouraging about the use of quercetin as dietary supplementation strategy to adopt in order to mitigate and promote a faster recovery after eccentric exercise as suggested by the increase in plasma levels of the anabolic factors IGF-I and IGF-II.
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Background Delayed onset muscle soreness (DOMS) due to eccentric muscle activity is associated with inflammatory responses and production of reactive oxygen species (ROS) that sustain both inflammation and oxidative stress. Curcumin, a powerful promoter of anti-oxidant response, is one of the best-investigated natural products, and is now commercially available as a lecithin delivery system (Meriva®, Indena SpA, Milan) with improved bio-availability. The aim of this study was to test whether curcumin could attenuate damage from oxidative stress and inflammation related to acute muscle injury induced by eccentric continuous exercise Methods This was a randomised, placebo-controlled, single-blind pilot trial. Twenty male healthy, moderately active volunteers were randomised to curcumin given as the Phytosome® delivery system 1 g twice daily (200 mg curcumin b.i.d.) or matching placebo. Supplementation was initiated 48 hours prior to a downhill running test and was continued for 24 hours after the test (4 days in total). Muscle damage was quantified by magnetic resonance imaging, laboratory tests and histological analyses on muscle samples obtained 48 hours after the test. Patient-reported pain intensity was also recorded. Results Subjects in the curcumin group reported less pain in the lower limb as compared with subjects in the placebo group, although significant differences were observed only for the right and left anterior thighs. Significantly fewer subjects in the curcumin group had MRI evidence of muscle injury in the posterior or medial compartment of both thighs. Increases in markers of muscle damage and inflammation tended to be lower in the curcumin group, but significant differences were only observed for interleukin-8 at 2 h after exercise. No differences in markers of oxidative stress and muscle histology were observed Conclusions Curcumin has the potential for preventing DOMS, as suggested by its effects on pain intensity and muscle injury. Larger studies are needed to confirm these results and further clarify the mechanism of action of curcumin.
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Overtraining syndrome (OTS) occurs where an athlete is training vigorously, yet performance deteriorates. One sign of OTS is suppressed immune function, with an increased incidence of upper respiratory tract infection (URTI). An increased incidence of URTIs is also associated with high volume/intensity training, as well as with excessive exercise (EE), such as a marathon, manifesting between 3–72 hours post-race. Presently, there is no encompassing theory to explain EE and altered immune competence. Recently, it has been conclusively established that T helper lymphocytes (TH), a crucial aspect of immune function, represent two distinct functional subsets: TH1 and TH2 lymphocytes. TH1 lymphocytes are associated with cell-mediated immunity (CMI) and the killing of intracellular pathogens, while TH2 lymphocytes are associated with humoral immunity and antibody production. When TH-precursor cells are activated, the balance is tipped in favour of one or the other. Furthermore, the most appropriate means of determining the TH-subset, is by the prevailing cytokine ‘pattern’. This paper hypothesises that exercise-related immunosuppression is due to tissue trauma sustained during intense exercise, producing cytokines, which drive the development of a TH2 lymphocyte profile. A TH2 cell response results in simultaneous suppression of CMI, rendering the athlete susceptible to infection. Additionally, increased levels of circulating stress hormones (cortisol and catecholamines), as well as prostaglandin E2, support up-regulation of TH2 lymphocytes. Marathon-related data are presented to support this hypothesis. It is concluded that an increased incidence of illness associated with OTS and in response to EE is not due to immunosuppression per se, but rather to an altered focus of immune function, with an up-regulation of humoral immunity and suppression of CMI.
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Anti-oxidant administration aimed to antagonise development and progression of disuse muscle atrophy provided controversial results. Here we investigated the effects of curcumin, a vegetal polyphenol with pleiotropic biological activity, because of its ability to upregulate Grp94 expression in myogenic cells. Grp94 is a sarco-endoplasmic reticulum chaperone, the levels of which decrease significantly in unloaded muscle.Rats were injected intraperitoneally with curcumin and soleus muscle was analysed after 7 days of hindlimb unloading or standard caging. Curcumin administration increased Grp94 protein level about twofold in muscles of ambulatory rats (P < 0.05) and antagonised its decrease in unloaded ones. Treatment countered loss of soleus mass and myofibre cross-sectional area by approximately 30% (P ≤ 0.02) and maintained force-frequency relationship closer to ambulatory levels. Indexes of muscle protein and lipid oxidation, such as protein carbonylation, revealed by Oxyblot, and malondialdheyde, measured with HPLC, were significantly blunted in unloaded treated rats compared to untreated ones (P = 0.01). Mechanistic involvement of Grp94 was suggested by the disruption of curcumin-induced attenuation of myofibre atrophy after transfection with antisense grp94 cDNA and by the drug positive effect on the maintenance of the subsarcolemmal localization of active nNOS molecules, which were displaced to the sarcoplasm by unloading. The absence of additive effects after combined administration of a nNOS inhibitor further supported curcumin interference with this pro-atrophic pathway.In conclusion, curcumin represents an effective and safe tool to upregulate Grp94 muscle levels and to maintain muscle function during unweighting.This article is protected by copyright. All rights reserved
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The purpose of this study was to investigate the effects of curcumin supplementation on exercise-induced oxidative stress in humans. 10 male participants, ages 26.8±2.0 years (mean±SE), completed 3 trials in a random order: (1) placebo (control), (2) single (only before exercise) and (3) double (before and immediately after exercise) curcumin supplementation trials. Each participant received oral administration of 90 mg of curcumin or the placebo 2h before exercise and immediately after exercise. Each participant walked or ran at 65% of V˙2max on a treadmill for 60min. Blood samples were collected pre-exercise, immediately after exercise and 2h after exercise. The concentrations of serum derivatives of reactive oxygen metabolites measured immediately after exercise were significantly higher than pre-exercise values in the placebo trial (308.8±12.9 U. CARR, P<0.05), but not in the single (259.9±17.1 U. CARR) or double (273.6±19.7 U. CARR) curcumin supplementation trials. Serum biological antioxidant potential concentrations measured immediately after exercise were significantly elevated in the single and double curcumin supplementation trials compared with pre-exercise values (P<0.05). These findings indicate that curcumin supplementation can attenuate exercise-induced oxidative stress by increasing blood antioxidant capacity.
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Curcumin, extracted from the rhizome of Curcuma longa, is known to possess anti-inflammatory activities. Despite the fact that neutrophils are key player cells in inflammation, the role of curcumin on neutrophil cell biology is not well documented and, in particular, how curcumin can alter primed neutrophils is unknown. In addition, the effect of curcumin on agent-induced neutrophilic inflammation is not well documented. Here, we demonstrated that curcumin inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)- or lipopolysaccharide (LPS)-induced suppression of human neutrophil apoptosis. In addition, we found that curcumin reversed the ability of phorbol myristate acetate (PMA) to induce reactive oxygen species as assessed by flow cytometry using the CM-H2DCF-DA probe. Using an antibody array approach, curcumin was found to inhibit LPS-induced cytokine production, including MIP-1α, MIP-1β, IL-6, IL-8 (CXCL-8) and GRO-α. The inhibitory effect of curcumin on IL-8 production was confirmed by ELISA. Using both an electrophoretic mobility shift assay and a TransFactor p50 NF-κB ELISA, we demonstrated that curcumin inhibited LPS-induced NF-κB activation. In vivo, using the murine air pouch model of acute inflammation, we demonstrated that intraperitoneal administration of curcumin inhibited LPS-induced neutrophilic infiltration in vivo. As assessed by a murine antibody array approach, curcumin was found to decrease the local production of several cytokines/chemokines induced by LPS, including, but not limited to, MIP-1α and MIP-1β. We conclude that curcumin possesses potent modulatory activities on primed or agent-induced human neutrophils in vitro and that it possesses important anti-inflammatory activities in vivo by inhibiting LPS-induced neutrophilic inflammation.