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Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study

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  • FutureCeuticals Inc.
  • FutureCeuticals

Abstract and Figures

A pilot study by Reyes [1] previously showed that ingestion of single dose of whole coffee fruit concentrate (WCFC) powder increased blood levels of brain derived neurotrophic factor (BDNF) during the first 60 minutes after ingestion. In the present report, we performed a single dose, placebo-controlled, within-subject study to confirm and further investigate this effect. Twenty healthy subjects with ages ranging from 25 to 35 participated in this study. All fasted and resting subjects received placebo on Day 1, WCFC on Day 2, and a cup of freshly brewed coffee on Day 3. Treatment with WCFC resulted in a statistically significant increase in plasma BDNF compared to placebo (p = 0.0073) or coffee (p = 0.0219) during first 60 minutes. In addition, e isolated exosomes from serum and found that they contained BDNF. Furthermore, oral WCFC consumption acutely increased BDNF levels in serum exosomes. In summary, all presented results justify further clinical investigation of WCFC as a tool to manage BDNF-dependent health conditions.
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Food and Nutrition Sciences, 2013, 4, 984-990
http://dx.dor.org/10.4236/fns.2013.49127 Published Online September 2013 (http://www.scirp.org/journal/fns)
Stimulatory Effect of Whole Coffee Fruit Concentrate
Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects:
An Acute Within-Subject Clinical Study
Tania Reyes-Izquierdo1*, Ruby Argumedo1, Cynthia Shu1, Boris Nemzer2, Zb Pietrzkowski1
1Applied BioClinical Inc., Irvine, USA; 2FutureCeuticals Inc., Momence, USA.
Email: *Tania@abclinicaldiscovery.com
Received June 2nd, 2013; revised July 2nd, 2013; accepted July 9th, 2013
Copyright © 2013 Tania Reyes-Izquierdo et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
A pilot study by Reyes [1] previously showed that ingestion of single dose of whole coffee fruit concentrate (WCFC)
powder increased blood levels of brain derived neurotrophic factor (BDNF) during the first 60 minutes after ingestion.
In the present report, we performed a single dose, placebo-controlled, within-subject study to confirm and further inves-
tigate this effect. Twenty healthy subjects with ages ranging from 25 to 35 participated in this study. All fasted and
resting subjects received placebo on Day 1, WCFC on Day 2, and a cup of freshly brewed coffee on Day 3. Treatment
with WCFC resulted in a statistically significant increase in plasma BDNF compared to placebo (p = 0.0073) or coffee
(p = 0.0219) during first 60 minutes. In addition, e isolated exosomes from serum and found that they contained BDNF.
Furthermore, oral WCFC consumption acutely increased BDNF levels in serum exosomes. In summary, all presented
results justify further clinical investigation of WCFC as a tool to manage BDNF-dependent health conditions.
Keywords: Brain-Derived Neurotrophic Factor; Whole Coffee Fruit Concentrate; Coffee; Exosomes; Acute Effect
1. Introduction
Brain-derived neurotrophic factor (BDNF) is a member
of the neurotrophin family of growth factors, along with
nerve growth factor, neurotrophin N4/5, and neurotro-
phin NT6. BDNF has high affinity for the tropomy-
osin-related kinase B (TrkB) receptor [2,3]. This product
of the NTRK gene is expressed in several types of cells
and tissues with major expression in neural cells and car-
diomyocytes [4]. BDNF exerts several effects in the cen-
tral nervous system; it regulates the development and
differentiation of new neurons [5-7] and promotes neuron
survival [8-10]. Influences mood and depression [11-13],
sleep control [14] and modulates appetite [15,16]. In ad-
dition, alterations in BDNF have been identified in vari-
ous chronic neurodegenerative diseases [17]. Blood
BDNF declines during aging [18] and decreased levels
may be associated with depression [19]. Preclinical stud-
ies demonstrate that both BDNF and TrkB receptor ago-
nists have antidepressant effects in an animal model of
depression [20-23]. In humans suffering from depression,
blood levels of BDNF are lower than in healthy controls
[24].
BDNF may act through TrkB receptors not only in
brain cells, but also in several peripheral tissues. Blood
circulating BDNF and BDNF found in peripheral organs
and tissues may interact with the TrkB receptor to mo-
dulate glucose metabolism [25-27], energy expenditure
[25,27], total food intake [25], and stimulation of Glut 4
expression in muscle tissue [28]. Both central and pe-
ripheral administration of BDNF lowers blood glucose
and increases energy expenditure in diabetic animals [29].
Conversely, haploinsufficiency of the BDNF gene results
in hyperphagy and obesity [30,31].
Several types of cells within the human body express
BDNF mRNA [32] and the corresponding BDNF pep-
tides are stored for rapid release. BDNF can be rapidly
released from various types of blood cells including
platelets [33-35] peripheral blood mononuclear cells [36],
*Corresponding author.
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Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
985
eosinophils [37-39], monocytes [40]. Interestingly, all of
these cells can release exosomes [41,42]. Exosomes are
40 - 50 nm vesicles found in various cell types (for re-
view, see Simons and Raposo [43]. Blood-circulating
exosomes carry mRNA, microRNA, and proteins char-
acteristic of the cells that release the exosomes.
Circulating exosomes can fuse with other cells and
transmit internal macromolecules, such as microRNA or
peptides [43,44]. Therefore, exosomes may function as a
communication vehicle between different cells and tis-
sues [45]. Recently, researchers were able to detect
exosomes in blood that had been released from brain
cells [46,47] indicating that exosomes can cross the
brain-blood barrier (BBB) [46,47]. Likewise, exosomes
released into blood may pass the BBB and deliver their
exosomal content [48]. Such an arrangement would sug-
gest that exosomes are of potential therapeutic value as a
means to deliver substances to brain that do not normally
cross the BBB [49].
We previously reported that WCFC acutely increases
blood levels of BDNF in a small number of healthy sub-
jects [1]. This preliminary study was limited by the small
number of participants and by the fact that the chosen
placebo, silica oxide, unexpectedly reduced BDNF levels
in blood. We now report the results of a larger clinical
trial that further clarifies the effect of WCFC on BDNF.
We also provide evidence that blood exosomes contain
BDNF and that treatment with WCFC may increase
exosomal BDNF content.
2. Materials and Methods
2.1. Materials
WCFC is a patented extract of whole coffee fruit (coffee
cherries) from Coffeaarabica. WCFC tested in this study
was provided by Future Ceuticals, Inc., Momence, IL,
USA. Chemical composition and polyphenol profile of
this material was previously reported [1]. Dulbecco’s
phosphate buffered saline (PBS) and water were pur-
chased from Sigma Chem. Co. (St. Louis, MO, USA).
Protein Low Binding microtubes were obtained from
Eppendorf (Hauppauge, NY, USA) and RC DC Protein
Assay Kit II was from Bio-Rad (Palo Alto, CA, USA).
Human BDNF Quantikine ELISA kits were from R&D
Systems (Minneapolis, MN USA). Heparin blood collec-
tion tubes were obtained from Ram Scientific Inc.
(Yonkers, NY) and lancets were purchased from Med-
lance® (Ozorkow, Poland). Placebo was empty gelatin
capsules obtained from Capsuline, Inc. (Pompano Beach,
FL, USA). Coffee was prepared in a Platinum B70
Keurig® brewer (Keurig Incorporated, Reading MA,
USA) and brewed to 150 mL cup size. Afterwards, 150
mL cold water was added per cup to cool down the cof-
fee for fast consumption. The pre-packed selected coffee
was San Francisco Bay Coffee One Cup for Keurig
K-Cup Brewers, French Roast (San Francisco, CA, USA)
which contains 130 ± 10 mg of caffeine.
This study was conducted according to the guidelines
put forth in the Declaration of Helsinki and all proce-
dures involving human subjects were approved by the
Institutional Review Board at Vita Clinical S.A. Aveni-
daCircunvalacion Norte #135, Guadalajara, JAL, Mexico
44,270 (Study protocol ABC-WCFC). All study subjects
were generally healthy and did not use any type of
medication or supplement for a period of 15 days prior to
the start of the study. The inclusion criteria required par-
ticipants to be between the ages of 25 and 35 and have a
body mass index between 18.5 and 24.9 kg/m² [50]. At
the time of the study, participants were free of rhinitis,
influenza, and any other symptoms of upper respiratory
infection. Participants were excluded if they had diabetes
mellitus, a known allergy to any of the test ingredients or
were using any anti-inflammatory, analgesic, anti-allergy,
anti-depressant medication or multivitamins. Participants
received oral and written information about the experi-
mental procedures and written consent was obtained be-
fore administration of any study treatment.
2.2. Study Description
Twenty (20) subjects meeting inclusion criteria were
treated with placebo on Day 1, a single dose of WCFC
on Day 2, and 300 mL of freshly brewed coffee on the
Day 3. In all cases, subjects fasted for 12 h prior to the
first blood collection. Other than consuming one of the
given materials, patients had no intake per os during the
study period and remained calm and resting. One hun-
dred µL of finger blood were collected by finger punc-
ture and placed in Safe-T-Fill® Lithium heparin capillary
blood collection tubes (Ram Scientific Inc. Yonkers, NY)
at baseline (T0). Subsequent samples were collected
every 60 min (T60 and T120) after treatment.
2.3. BDNF Detection and Quantification
Heparin plasma was isolated from collected blood sam-
ples using centrifugation at 1000 × g for 10 min. Human
mature BDNF (aa129-247) was detected using a quanti-
tative sandwich ELISA immunoassay (R&D Systems;
Minneapolis, MN, USA) following the instructions pro-
vided. Final reactions were measured using a Molecular
Devices spectrophotometer (Sunnyvale, CA, USA) and
BDNF concentrations were determined based on a stan-
dard curve as described in the instruction.
2.4. Determination of Exosomal BDNF
(Clinical Case Experimentation)
For exosome isolation, 500 μL of blood were collected
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
986
from finger puncture in serum collections tubes. Blood
was spun down at 1000 g for 10 min. Two-hundred fifty
µL of serum were used for exosome separation by pre-
cipitation using ExoQuick™ Exosome Precipitation Kit
(System Biosciences, Mountain View CA, USA) follow-
ing the instructions from the manufacturer. Briefly, 63
µL of exosome precipitation solution were added to 250
µL of serum. The samples were gently mixed to ensure
uniformity and then incubated at 4˚C for 30 min. After-
wards, samples were centrifuged at room temperature for
30 min at 1500 g. The supernatant was collected in a
clean tube while the pellet was spun again for 5 min at
1500 g and any remaining supernatant was removed.
Finally, the pellet was resuspended in 250 µL of Exo-
some Binding buffer (System Biosciences, Mountain
View, CA, USA) and incubated in an ice bath for 5 min
to complete the lytic process. BDNF contained in the
exosomal lysate was measured using the quantitative
sandwich ELISA immunoassay (R&D Systems; Min-
neapolis, MN, USA) previously described.
2.5. Lactate and Glucose Measurements
Blood lactate was measured using an Accutrend® Lactate
Point of Care (Roche, Mannheim, Germany) and BM-
Lactate Strips® (Roche, Mannheim, Germany). Twelve
µL of blood were loaded onto the strip and lactate was
read according to the instructions provided by the manu-
facturer. Glucose was measured using an Accu-Chek®
Compact Plus glucometer (Roche Diagnostics, Indian-
apolis, IN, USA) and Accu-Chek® test strips (Roche Di-
agnostics, Indianapolis, IN, USA). After blood was col-
lected for BDNF assays, fingers were wiped off and a
glucose test was performed on fresh blood. Glucose was
read according to the instructions provided by the manu-
facturer.
2.6. Statistical Analysis
As previously described [1], BDNF levels were com-
pared to a reference standard curve and each subject was
normalized to their own value measured at time zero (T0).
Results from each group were pooled and standard error
of the mean was used for each separate analysis. Plasma
BDNF levels for 60 and 120 minutes after treatment were
compared within experimental groups to baseline and
between experimental groups using a one-way ANOVA
with Tukey’s post hoc analysis. Descriptive analyses
were run in GraphPad® to derive mean and standard de-
viation for each group.
3. Results
Twenty healthy volunteers were recruited for this within-
subject crossover clinical study. On Day 1, participants
consumed an empty capsule labeled as placebo. On Day
2, 100 mg of WCFC was administered orally and on Day
3, they consumed fresh-brewed coffee. On each day,
blood samples were drawn at baseline and at 60 and 120
minutes after treatment. As shown in Figure 1, a single
100 mg dose of capsulated WCFC increased plasma
BDNF by 91% at 60 minutes and 66% at 120 minutes
compared to baseline (p < 0.001). Placebo increased
plasma BDNF by 5% (p = 0.5) at T60 and 26% (p = 0.02)
at T120 over baseline. Treatment with fresh coffee re-
sulted in 21% and 15% change at T60 (p = 0.1) and T120
(p = 0.2) over baseline, respectively (Figure 1). At 60
minutes, plasma BDNF in subjects treated with WCFC
was higher than those treated with placebo (p = 0.0073).
This difference diminished at 120 min (p = 0.1127).
WCFC treatment also increased BDNF levels signifi-
cantly more than fresh coffee consumption at 60 min (p =
0.02) and 120 min (p = 0.04). The coffee treatment did
not significantly alter BDNF levels when compared to
placebo at 60 min (p = 0.23) or 120 min (p = 0.138).
Blood levels of glucose (Figure 2A) and lactate (Figure
2B) were not changed by any of the three treatments
(placebo, WCFC, coffee) compared to baseline.
We were interested in determining whether treatment
with WCFC increases only free BDNF levels in the
blood or whether exosomal BDNF levels change as well.
After the within-subject crossover study, we selected one
participant at random to receive an additional dose of
WCFC. We collected serum samples at T0, T60 and
T120 as before. The exosome fraction was isolated using
standard procedures provided with the exosome isolation
kit. BDNF levels in the exosome fraction and remaining
serum from one volunteer are presented in Figure 3.
0%
50%
100%
150%
200%
250%
300%
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
BDNF[%Change]
Treatments
T0
T60
T120
**
*
Figure 1. The effect of WCFC on BDNF. Plasma BDNF le-
vels were measured at baseline (T0), 60 (T60) and 120 (T120)
min after treatment. Subjects were treated with Placebo
(Day 1), 100 mg WCFC (Day 2) and 300 mL of diluted cof-
fee (Day 3). Data are presented as the average percentage
difference compared to baseline. *Mean value of WCFC
treatment was significantly different when compared with
placebo (p = 0.007) and coffee (p = 0.02) at T60. Results
were not significant at T120 when compared to the placebo
(p = 0.11), however, they are significant when compared to
coffee (p = 0.04).
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
987
0
25
50
75
100
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
Glucose(dl/L)
Treatments
T0
T60
T120
0%
50%
100%
150%
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
Lactate[%Change]
Trea tm ent s
T0
T60
T12
0
A
B
Figure 2. Blood glucose levels (A) and lactate levels (B) re-
mained unchanged at baseline, 60 and 120 min after treat-
ment with placebo (Day 1), WCFC (Day 2) and coffee (Day
3). No significant differences were observed between treat-
ments or over time.
0
100
200
300
400
500
t0 t60 t120
BDNF(pg/mL)
TimePoints
Serum
Exosome
s
Figure 3. Exosomal BDNF after treatment with WCFC.
Exosomes were isolated from serum of one volunteer at
baseline and at 60 and 120 minutes after treatment with
WCFC. Preliminary results suggest that exosomal BDNF is
increased after treatment.
BDNF was present in exosomes before treatment at T0.
After 60 minutes, one dose of WCFC increased serum
BDNF by 54% and exosomal BDNF by 206%. The ini-
tial WCFC-induced increase in serum BDNF declined at
120 minutes (32% over baseline) as did exosomal BDNF
(39% over baseline). This clinical case result suggests
that acute treatment with WCFC may increase the
amount of exosomal BDNF in blood; however this re-
quires further investigation since data presented here are
from a single study participant.
4. Discussion
We report that a single dose of WCFC nearly doubles the
amount of BDNF in the blood after 60 minutes with sus-
tained effects for at least two hours after treatment. This
confirms and extends the results of our previous work [1].
This effect was not seen with freshly brewed coffee over
the same time, a control that was not tested previously.
This result is consistent, however, with our previous ob-
servation that coffee beans or green coffee extracts con-
taining various amounts of caffeine do not raise BDNF
levels in blood [1]. Since WCFC is an extract of whole
coffee fruit, it does not contain BDNF. Thus, WCFC
could be considered to be a stimulator of endogenous
BDNF release from cells. As previously described, there
are several types of mammalian cells capable of releasing
BDNF. However, it remains to be determined which cells
are stimulated by WCFC and by what mechanism.
In a previous study, we reported that the use of silica
oxide as a placebo, slightly decreased levels of blood
BDNF [1]. In the current study, empty gelatin capsules
were used as placebo, showing a slight, but not signifi-
cant increase in plasma BDNF (5%) at T60, whilst
BDNF blood levels increased up to 28% at T120. Coffee
had no significant effect on BDNF at T60 and T120.
While fasting is known to increase BDNF levels in brain
[51,52], this effect for serum in healthy individuals has
not been clearly shown. In addition, studies of long term
fasting on serum BDNF levels have yielded conflicting
results [53,54].
Since study participants fasted 12 hours prior to the
start of the study, we monitored blood glucose for hypo-
glycemia. We also wanted to learn if WCFC affects
blood levels of glucose or lactate. We confirmed our pre-
vious finding that WCFC does not affect glucose or lac-
tate [1]. It is important to mention, that this study was
conducted on healthy subjects. It is unclear what effect
WCFC would have on subjects with chronic conditions,
until additional trials have been conducted.
An acute increase in blood levels of BDNF may indi-
cate that BDNF is released into bloodstream from cells
[43]. Therefore, we hypothesized that at least part of the
plasma BDNF detected was released from exosomes de-
rived from blood cells. We report for the first time that
blood-circulating BDNF may exist as both free BDNF
and contained within exosomes. Free BDNF sharply in-
creased one hour after WCFC treatment and began to
return to baseline after two hours, as did exosomal
BDNF. Further studies are needed to confirm that BDNF
circulates in blood as both free BDNF and exosomal
BDNF since this was the result obtained in a single sub-
ject (clinical case experiment). However, the initial result
is encouraging. Since exosomes have the ability to cross
the BBB [43], it would be interesting to study the effect
of WCFC on BDNF-mediated brain functionalities such
as cognitive activity [47], appetite control [55], or modu-
lation of neurodegenerative conditions [47,49,56,57].
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
988
5. Acknowledgements
The present study was funded by Futureceuticals, Inc. T.
R.-I. conducted the experimental work, analysed the data
and led the manuscript writing. R. A. and C. S. per-
formed serum tests and helped in the data analysis. B. N.
designed and conducted all the chemical analysis. Z. P.
designed and directed the study. We express our grati-
tude to John Hunter and Brad Evers (Future Ceuticals)
for their comments and suggestions in the preparation of
this article. We would like to thank Michael Sapko for
his help in editing the manuscript. All authors declare
that they have no conflicts of interest.
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... Whole coffee cherry extract (WCCE), is a proprietary, safe [8], powdered extract of whole coffee cherries from Coffea arabica with high levels of polyphenols and substantially low (<2%) levels of caffeine (for a detailed composition profile, please see Table 1 of the study by Reyes-Izquierdo et al. (2013b) [9]). WCCE has been previously associated with increased serum concentrations of both circulating and exosomal brain-derived neurotrophic factor (BDNF), in addition to increased alertness and decreased fatigue [4,[9][10][11][12]. BDNF is a protein synthesized in neurons and other types of cells, and it is associated with a range of neural (e.g., plasticity) [13][14][15][16] and psychological processes [17][18][19][20]. ...
... MCI is marked by problems with memory, language, thinking, and judgment that are greater than normal age-related changes. Given that earlier studies reported that WCCE may stimulate increases in BDNF [9,11], one remaining question was whether WCCE, potentially through increases in BDNF, could acutely improve cognitive function or provide protective effects in older adults who may be on the verge of or have MCI. To this end, BDNF has been associated with such changes via its effects on N-methyl-D-aspartate-type (NMDA) receptors [32][33][34]. ...
... For a detailed composition profile, please see Table 1 and Figure 1. Dosage, as well as post-administration scan timing, was chosen based on previous research demonstrating significant effects on BDNF [9,11], as well as reductions in mental fatigue and higher levels of alertness [10]. Furthermore, a dosage of 100 mg of WCCE was later corroborated in a longitudinal, double-blind, placebo-controlled study in which cognitive effects were noted in as little as 7 days and persisted throughout a 28-day study period [35]. ...
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Bioactive plant-based compounds have shown promise as protective agents across multiple domains including improvements in neurological and psychological measures. Methodological challenges have limited our understanding of the neurophysiological changes associated with polyphenol-rich supplements such as whole coffee cherry extract (WCCE). In the current study, we (1) compared 100 mg of WCCE to a placebo using an acute, randomized, double-blind, within-subject, cross-over design, and we (2) conducted a phytochemical analysis of WCCE. The primary objective of the study was to determine the neurophysiological and behavioral changes that resulted from the acute administration of WCCE. We hypothesized that WCCE would increase brain-derived neurotrophic factor (BDNF) and glutamate levels while also increasing neurofunctional measures in cognitive brain regions. Furthermore, we expected there to be increased behavioral performance associated with WCCE, as measured by reaction time and accuracy. Participants underwent four neuroimaging scans (pre- and post-WCCE and placebo) to assess neurofunctional/metabolic outcomes using functional magnetic resonance imaging and magnetic resonance spectroscopy. The results suggest that polyphenol-rich WCCE is associated with decreased reaction time and may protect against cognitive errors on tasks of working memory and response inhibition. Behavioral findings were concomitant with neurofunctional changes in structures involved in decision-making and attention. Specifically, we found increased functional connectivity between the anterior cingulate and regions involved in sensory and decision-making networks. Additionally, we observed increased BDNF and an increased glutamate/gamma-aminobutyric acid (GABA) ratio following WCCE administration. These results suggest that WCCE is associated with acute neurophysiological changes supportive of faster reaction times and increased, sustained attention.
... Polyphenol-rich, caffeine-containing extracts, such as whole coffee fruit extract (WCFE), are also potential candidates for maintaining biological systems that underpin neurocognitive function [10]. Recent research has shown that an acute 100 mg WCFE dose in healthy adults significantly increases measures of Brain-derived neurotrophic factor (BDNF), which is a neurotrophin that is important for learning and memory processes. ...
... Each study day comprised of a practice module, a pre-supplement baseline testing session on mood and cognitive measures, followed immediately by a pre-supplement blood glucose measurement, and administration of supplement. A 45-minute absorption time was used based on the average absorption time and pharmacokinetic profile used for the extracts in previous studies [10,17]. ...
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Objective: This study assessed whether a multi-ingredient herbal supplement containing Bacopa monniera (BM), Panax quinquefolius ginseng (PQ) and whole coffee fruit extract (WCFE) could enhance cognitive performance and cerebral-cortical activation during tasks of working memory and attention. Method: In a randomised, double-blind, placebo-controlled, between-group study, 40 healthy adults between 18–60 years (M = 34.46 SD = 12.95) completed tasks of working memory and attention at baseline and 45 min post active or placebo supplement consumption. During the cognitive testing, changes in hemodynamic response in the prefrontal cortex (PFC) were continuously measured using functional near-infrared spectroscopy (fNIRS). Results: Working memory task performance on the N-back task was significantly improved following active supplement consumption compared to placebo in terms of accuracy (p < .01) and response time (p < .05). Improved performance was associated with a reduction of PFC activation (p < .001) related to effortful mental demand, reflecting increased neural efficiency concomitant with improved cognitive performance. The effects were independent of background demographics variables and changes in blood glucose response and mood. Discussion: This is the first report of acute effects on cognitive performance in healthy adults following intake of a combined, multi-ingredient herbal supplement with concomitant changes in cerebral haemodynamic response. The potential synergistic effects of polyphenolic compounds on neurocognitive function and fNIRS use in nutritional intervention studies, poses a significant increase in the capacity to understand the effects of dietary compounds on the brain.
... In a non-exercise context, single doses of coffee berry extracts have been shown to increase the synthesis of neurotrophic factors such as BDNF [155][156][157], and a range of coffee berry extract doses (100, 300, 1100 mg) reduced the mental fatigue, and attenuated the decreased alertness, associated with extended performance of demanding cognitive tasks [158,159]. A follow-up study contrasting the cognitive and psychological state effects of 1100 mg coffee berry extract alone, and combined with apple polyphenol extract, found that coffee berry alone increased alertness and vigour and decreased fatigue across the 6 h of post-dose assessments. ...
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The plant defence compound caffeine is widely consumed as a performance enhancer in a sporting context, with potential benefits expected in both physiological and psychological terms. However, although caffeine modestly but consistently improves alertness and fatigue, its effects on mental performance are largely restricted to improved attention or concentration. It has no consistent effect within other cognitive domains that are important to sporting performance, including working memory, executive function and long-term memory. Although caffeine’s central nervous system effects are often attributed to blockade of the receptors for the inhibitory neuromodulator adenosine, it also inhibits a number of enzymes involved both in neurotransmission and in cellular homeostasis and signal propagation. Furthermore, it modulates the pharmacokinetics of other endogenous and exogenous bioactive molecules, in part via interactions with shared cytochrome P450 enzymes. Caffeine therefore enjoys interactive relationships with a wide range of bioactive medicinal and dietary compounds, potentially broadening, increasing, decreasing, or modulating the time course of their functional effects, or vice versa. This narrative review explores the mechanisms of action and efficacy of caffeine and the potential for combinations of caffeine and other dietary compounds to exert psychological effects in excess of those expected following caffeine alone. The review focusses on, and indeed restricted its untargeted search to, the most commonly consumed sources of caffeine: products derived from caffeine-synthesising plants that give us tea (Camellia sinensis), coffee (Coffea genus), cocoa (Theabroma cacao) and guaraná (Paullinia cupana), plus multi-component energy drinks and shots. This literature suggests relevant benefits to mental performance that exceed those associated with caffeine for multi-ingredient energy drinks/shots and several low-caffeine extracts, including high-flavanol cocoa and guarana. However, there is a general lack of research conducted in such a way as to disentangle the relative contributions of the component parts of these products.
... Various genes are involved in obesity phenotypes like PCSK1, MCR4, BDNF and POMC [39,[78][79][80][81][82][83]. FTO was one of the sixth gene missed in fused toe mice on1.6-Mb chromosome segment, therefore it is rational to determine the FTO deficient phenotype (Figure 1). ...
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Obesity has become a genuine global pandemic due to lifestyle and environmental modifications and is associated with chronic lethal comorbidities. Various environmental factors such as lack of physical activity due to modernization and higher intake of energy‐rich diets are primary obesogenic factors in pathogenesis of obesity. Genome‐wide association study has identified the crucial role of FTO (fat mass and obesity) in human obesity. A bunch of SNPs in the first intron of FTO has been identified and subsequently correlated to body mass index and body composition. Findings of in silico, in vitro, and in vivo studies have manifested the robust role of FTO in regulation of energy expenditure and food consumption. Numerous studies have highlighted mechanistic pathways behind concomitant functions of FTO in adipogenesis and body size. Current investigation has also revealed the link of FTO neighboring genes i.e., RPGRIP1L, IRX3 and IRX5 and epigenetic factors with obesity phenotypes. The motive behind this review is to cite the consequences of FTO on obesity vulnerability.
... Many genes that control the same phenotypes with lipid storage and obesity have been identified, such as PCSK1 [108,109], MCR4 [110][111][112], BDNF [113], and POMC [114][115][116]. Therefore, it was reasonable to determine the phenotype of FTO deficiency. ...
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In the 21st century, obesity has become a serious problem because of increasing obese patients and numerous metabolic complications. The primary reasons for this situation are environmental and genetic factors. In 2007, FTO (fat mass and obesity associated) was the first gene identified through a genome-wide association study (GWAS) associated with obesity in humans. Subsequently, a cluster of single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene was discovered to be associated with BMI and body composition. Various studies have explored the mechanistic basis behind this association. Thus, emerging evidence showed that FTO plays a key role regulating adipose tissue development and functions in body size and composition. Recent prevalent research topic concentrated in the three neighboring genes of FTO: RPGRIP1L, IRX3 and IRX5, as having a functional link between obesity-associated common variants within FTO and the observed human phenotypes. The purpose of this review is to present a comprehensive picture of the impact of FTO on obesity susceptibility and to illuminate these new studies of FTO function in adipose tissue.
... Coffee as phosphodiesterases inhibitor inhibited adenosine receptor leading to increases NE, dopamine levels, and serotonin [59]. Moreover, black pepper and its main component piperine led to increased NE, dopamine, and serotonin levels [60], resulted in the inhibition of food intake and decreasing body weight by stimulating thermogenesis and energy expenditure through the sympathetic nervous system. ...
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Objective: This study aims to evaluate the effect of black pepper and coffee extracts on chronic and acute experimental-induced obesity and energy homeostasis. Methods: Rats were divided into 10 groups including control, high-fat diet (HFD), triton, HFD+triton, black pepper+HFD, black pepper+HFD+triton, coffee+HFD, coffee+HFD+triton, mixture+HFD, and mixture+HFD+triton groups. Blood glucose, serum insulin, and insulin resistance were estimated. Body mass index, food efficiency intake, and body weight gain were calculated. Lipid profile, liver and kidney functions were measured, serum and brain cyclic adenosine monophosphate (cAMP) was estimated, and brain neurotransmitters were measured by high-performance liquid chromatography. Furthermore, histopathology of liver was performed. Results: Findings showed that blood glucose, insulin resistance, lipid profile, kidney and liver functions as well as brain cAMP and neurotransmitters were significantly increased, concomitant with a significant decrease in insulin resistance and serum cAMP in both HFD and triton-induced obesity groups compared to control. Conclusion: Supplementation with black pepper extract, coffee extract, and a mixture of both significantly improved these findings. In conclusion, black pepper and coffee extracts are overlooked as promising weight reduction and antihyperlipidemic agents.
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There has been increasing interest in food- and dietary supplement-based materials that may support healthy cognition. However, few studies have quantitatively measured bioavailability, bioactivity, or cognitive short- and long-term effects of these materials against placebo. Earlier clinical studies reported ability of coffee cherry extract (CCE) to a.) reduce levels of reactive oxygen species (ROS) in human blood and b.) to increase serum and exosomal levels of brain-derived neurotrophic factor (BDNF), a neuroprotein essential for neurogenesis. Here, we examined CCE influence on cognitive performance. Seventy-one adults with mild cognitive decline completed this double blind, randomized, placebo-controlled, 28-day regimen. Participants engaged in a cognitive challenge that involved working memory processes. Our results suggest that effects of CCE were notable during the first week and persisted throughout the study period. Specifically, participants on the CCE regimens had significant reductions in reaction time compared to placebo when comparing baseline to days 7 and 28 (p = 0.040, partial η2 = 0.130). A main effect of group was not identified for accuracy; however, strong trends were noted between the placebo group and two of the three CCE groups. These results suggest CCE, when taken in the morning or twice per day, is associated with improvements in reaction times and trends toward indications of improved accuracy. Although further research is required, these observations may be indicative of underlying processes such as increased processing speed, sustained attention, and/or focus.
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The present single-dose study was performed to assess the effect of whole coffee fruit concentrate powder (WCFC), green coffee caffeine powder (N677), grape seed extract powder (N31) and green coffee bean extract powder (N625) on blood levels of brain-derived neurotrophic factor (BDNF). Randomly assorted groups of fasted subjects consumed a single, 100 mg dose of each material. Plasma samples were collected at time zero (T 0) and at 30 min intervals afterwards, up to 120 min. A total of two control groups were included: subjects treated with silica dioxide (as placebo) or with no treatment. The collected data revealed that treatments with N31 and N677 increased levels of plasma BDNF by about 31 % under these experimental conditions, whereas treatment with WCFC increased it by 143 % (n 10), compared with baseline. These results indicate that WCFC could be used for modulation of BDNF-dependent health conditions. However, larger clinical studies are needed to support this possibility.
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Chapter
Since the discovery of short interfering RNAs (siRNAs), their potential as a therapeutic platform has been widely recognized. However, clinical translation has been stalled by inefficient delivery in vivo. While some success has been achieved with cationic lipids and lipid-like materials for therapeutic RNAi delivery to liver, delivery across the blood–brain barrier (BBB) to the central nervous system for the treatment of neurological disorders such as Parkinson’s, Alzheimer’s, and Huntington’s disease remains a challenge. To address the problem of inefficient delivery across the BBB, our laboratory exploited one of nature’s mechanisms for intercellular communication, named exosomes. They are a class of membrane vesicles derived from the endolysosomal compartment implicated in cell–cell communication by shuttling various proteins, lipids, and RNAs between cells. We have developed a method to target exosomes with brain-specific peptides and subsequently load them with siRNA for targeted delivery to brain. This chapter aims at providing an insight into membrane vesicle-mediated RNA delivery and how these vectors can be utilized for RNAi therapy.
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Epidemiological studies have demonstrated a close relationship between depression and cardiovascular disease (CVD). Although it is known that the central nervous system (CNS) contributes to this relationship, the detailed mechanisms involved in this process remain unclear. Recent studies suggest that the endoplasmic reticulum (ER) molecular chaperone sigma-1 receptor and brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of CVD and depression. Several meta-analysis studies have showed that levels of BDNF in the blood of patients with major depressive disorder (MDD) are lower than normal controls, indicating that blood BDNF might be a biomarker for depression. Furthermore, blood levels of BDNF in patients with CVD are also lower than normal controls. A recent study using conditional BDNF knock-out mice in animal models of myocardial infarction highlighted the role of CNS-mediated mechanisms in the cardioprotective effects of BDNF. In addition, a recent study shows that decreased levels of sigma-1 receptor in the mouse brain contribute to the association between heart failure and depression. Moreover, sigma-1 receptor agonists, including the endogenous neurosteroid dehydroepiandosterone (DHEA) and the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, show potent cardioprotective and antidepressive effects in rodents, via sigma-1 receptor stimulation. Interestingly, agonist activation of sigma-1 receptors increased the secretion of mature BDNF from its precursor proBDNF via chaperone activity in the ER. Given the role of ER stress in the pathophysiology of CVD and MDD, the author will discuss the potential link between sigma-1 receptors and BDNF-TrkB pathway in the pathophysiology of these two diseases. Finally, the author will make a case for potent sigma-1 receptor agonists and TrkB agonists as new potential therapeutic drugs for depressive patients with CVD.
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