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Ginger Extract Ameliorates Obesity and Inflammation via Regulating MicroRNA-21/132 Expression and AMPK Activation in White Adipose Tissue

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Ginger is a plant whose rhizome is used as a spice or folk medicine. We aimed to investigate the effect of ginger root extract on obesity and inflammation in rats fed a high-fat diet. Sprague-Dawley rats were divided into three groups and fed either a 45% high-fat diet (HF), HF + hot-water extract of ginger (WEG; 8 g/kg diet), or HF + high-hydrostatic pressure extract of ginger (HPG; 8 g/kg diet) for 10 weeks. The HPG group had lower body weight and white adipose tissue (WAT) mass compared to the HF group. Serum and hepatic lipid levels of HPG group were lower, while fecal lipid excretion of the HPG group was higher than that of the HF group. In the WAT of the WEG and HPG groups, mRNA levels of adipogenic genes were lower than those of the HF group. Moreover, HPG group had lower mRNA levels of pro-inflammatory cytokines than did the HF group. MicroRNA (miR)-21 expression was down-regulated by both WEG and HPG. Additionally, miR-132 expression was down-regulated by HPG. The adenosine monophosphate-activated protein kinase (AMPK) activity of HPG group was greater than that of the HF group. HPG may have beneficial effects on obesity and inflammation, partially mediated by regulation of miR-21/132 expression and AMPK activation in WAT.
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nutrients
Article
Ginger Extract Ameliorates Obesity and Inflammation
via Regulating MicroRNA-21/132 Expression and
AMPK Activation in White Adipose Tissue
Seunghae Kim 1, , Mak-Soon Lee 1 ,† , Sunyoon Jung 1, , Hye-Yeon Son 1, Seonyoung Park 1,
Bori Kang 1, Seog-Young Kim 1, In-Hwan Kim 2, Chong-Tai Kim 3and Yangha Kim 1,*
1Department of Nutritional Science and Food Management, Ewha Womans University, 52 Ewhayeodae-gil,
Seodaemun-gu, Seoul 03760, Korea; shkyr1120@naver.com (S.K.); troph@hanmail.net (M.-S.L.);
cococosy@naver.com (S.J.); shyfree@gmail.com (H.-Y.S.); rain9125@naver.com (S.P.);
pasodi00@naver.com (B.K.); saraha9390@gmail.com (S.-Y.K.)
2Department of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, Korea;
k610in@korea.ac.kr
3Research Group of Bioprocess Engineering, Korea Food Research Institute, Wanju-gun,
Jeollabuk-do 55365, Korea; ctkim@kfri.re.kr
*Correspondence: yhmoon@ewha.ac.kr; Tel.: +82-2-3277-4425
These authors contributed equally to this work.
Received: 12 September 2018; Accepted: 19 October 2018; Published: 23 October 2018

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Abstract:
Ginger is a plant whose rhizome is used as a spice or folk medicine. We aimed to
investigate the effect of ginger root extract on obesity and inflammation in rats fed a high-fat
diet. Sprague-Dawley rats were divided into three groups and fed either a 45% high-fat diet (HF),
HF + hot-water
extract of ginger (WEG; 8 g/kg diet), or HF + high-hydrostatic pressure extract of
ginger (HPG; 8 g/kg diet) for 10 weeks. The HPG group had lower body weight and white adipose
tissue (WAT) mass compared to the HF group. Serum and hepatic lipid levels of HPG group were
lower, while fecal lipid excretion of the HPG group was higher than that of the HF group. In the WAT
of the WEG and HPG groups, mRNA levels of adipogenic genes were lower than those of the HF
group. Moreover, HPG group had lower mRNA levels of pro-inflammatory cytokines than did the
HF group. MicroRNA (miR)-21 expression was down-regulated by both WEG and HPG. Additionally,
miR-132 expression was down-regulated by HPG. The adenosine monophosphate-activated protein
kinase (AMPK) activity of HPG group was greater than that of the HF group. HPG may have
beneficial effects on obesity and inflammation, partially mediated by regulation of miR-21/132
expression and AMPK activation in WAT.
Keywords: ginger extract; obesity; inflammation; microRNA-21; microRNA-132; AMPK
1. Introduction
Obesity refers to excessive body fat accumulation. It induces systemic low-grade inflammation,
which increases the risk of type 2 diabetes, hypertension, cardiovascular diseases, and certain
cancers. Obesity-induced inflammation occurs because of the continuous lipid accumulation in
adipose tissue [
1
]. Pro-inflammatory molecules produced by adipose tissue are active participants
in the development of insulin resistance and increase the risk of metabolic disease associated with
obesity [
1
]. To address these issues, many studies have been conducted to inhibit lipid accumulation
and pro-inflammatory cytokine synthesis using food materials. Typical functional food components
such as curcumin, quercetin, resveratrol, Camellia sinensis, and green tea were found to alleviate lipid
accumulation and inflammation induced by metabolic diseases such as obesity and hypertension [
2
4
].
Nutrients 2018,10, 1567; doi:10.3390/nu10111567 www.mdpi.com/journal/nutrients
Nutrients 2018,10, 1567 2 of 12
Ginger (Zingiber officinale Roscoe) is a herbaceous plant widely cultivated as a spice or for natural
food therapy. In traditional medicine, ginger has been used for diseases such as indigestion, vomiting,
joints and muscle pain, and cold [
5
]. Moreover, its various pharmacological effects have been reported,
including anti-obesity, anti-inflammatory, and anticancer effects [
6
]. The currently known ginger
extraction methods are hot water extract, ultra-sonication assisted extract and more [
7
]. While the
heating method has a high possibility of losing functional compounds in food, the high-hydrostatic
pressure (HHP) method, a non-thermal food processing technology, extracts functional compounds
with higher ease without damaging them by destroying their covalent bonds and cell membrane
structures [8].
In this study, we examined the effect of high-hydrostatic pressure extract of ginger (HPG)
on high-fat (HF) diet-induced obesity and inflammation, and measured the expression levels of
genes involved in adipogenesis and pro-inflammatory cytokines in white adipose tissue (WAT).
In addition, we evaluated the microRNA (miR)-21 and miR-132 expression, as well as adenosine
monophosphate-activated protein kinase (AMPK) activity in WAT.
2. Materials and Methods
2.1. Preparation of Materials
HPG and hot water extract of ginger (WEG) were kindly supplied by Korea Food Research
Institute (Songnam, Gyeonggi, Korea). The WEG was used as a reference. The ginger root used
in the preparation of HPG and WEG was purchased from the local market of Muan (Muan-gun,
Jeollanam-do, Korea). Fresh ginger root was added in distilled water, followed by pulverization
with a waring blender. The ginger root suspension was used for the preparation of HPG and WEG.
The preparation of HPG and WEG were in accordance with the method by Jung et al. [
9
]. Briefly,
the ginger root suspension was poured into plastic bags with 25 mL of each enzyme (Thermamyl
120 L, Celluclast 1.5 L andViscozyme L; Novo Nordisk, Bagsvaerd, Denmark) and transferred to
a programmable high-pressure treatment apparatus (TFS-10 L; Innoway Co., Bucheon, Korea) set
at a pressure of 100 MPa for 24 h at 50
C. After incubation, the extract was heated at 100
C for
10 min to inactivate the enzymes. After cooling, the extract was centrifuged at 11,000
×
gfor 10 min.
The supernatant was filtered using No. 4 filter paper and the filtrate was freeze-dried and used as
HPG. The WEG was prepared as follows [
9
]: Ginger root suspension was placed into a round-bottom
flask fitted with a cooling condenser, and extraction was performed at 100
C for 3 h. The extract was
followed by centrifugation at 11,000
×
gfor 10 min, and the supernatant was filtered using No. 4 filter
paper. The filtrate was freeze-dried and used as WEG.
2.2. Determination of 6-Gingerol, 6-Shogaol and Total Saponin
The 6-gingerol and 6-shogaol were analyzed by high-performance liquid chromatography (HPLC)
using a JASCO HPLC system (Tokyo, Japan), according to a method by Moon et al. [
10
]. Standard
6-gingerol and 6-shogaol were purchased from Sigma-Aldrich (St. Louis, MO, USA).
Total saponin content of each extract was determined using the method described by
Moon et al.
[
10
]. The ginsenoside Re (Wako Chem. Co., Osaka, Japan) was used as a reference standard.
2.3. Animals and Experimental Design
All experimental procedures were approved by the Institutional Animal Care and Use Committee
(IACUC) of Ewha Womans University, Korea (IACUC No. 15-002). Twenty-seven Sprague–Dawley
(male, 3-week-old) rats were housed individually in stainless steel wire mesh cages under controlled
environment with a temperature of 22
±
2
C, humidity of 55
±
5%, and a 12-h light and dark cycle.
After a week of adaptation, the animals were randomly divided into three groups (n= 9/group) and
fed the following experimental diet for 10 weeks: a high-fat diet (HF), high-fat diet containing WEG
(8 g/kg diet), and high-fat diet containing HPG (8 g/kg diet). The diet compositions are shown in
Nutrients 2018,10, 1567 3 of 12
supplementary Table S1. During the experimental period, body weight and food intake were measured
twice a week using a digital scale. Average daily intake was determined by dividing total food intake
by the number of days fed. After fasting for 12 h, the rats were anesthetized with a mixture of Zoletil 50
(Virbac Laboratories, Carros, France) and Rompun (Bayer Korea, Seoul, Korea), and euthanized. Blood
was collected by cardiac puncture and serum was separated by centrifugation. The collected serum,
liver and epididymal adipose tissue were stored at 70 C until analysis.
2.4. Serum Biochemical Measurements
Serum concentrations of triglyceride (TG), total cholesterol (TC), high-density lipoprotein
cholesterol (HDL-C), aspartate transaminase (AST), and alanine transaminase (ALT) were measured
based on enzymatic colorimetric method using a commercial kit (Asan pharmaceutical, Seoul, Korea)
in accordance with the manufacturer’s instructions. Low-density lipoprotein cholesterol (LDL-C) was
calculated by the Friedewald formula (LDL-C (mg/dL) = TC HDL-C (TG/5)) [11].
2.5. Hepatic and Fecal Lipid Analysis
Hepatic and fecal lipids were extracted using the method of Bligh and Dyer [
12
] with slight
modifications. Levels of TG and TC in the liver and feces were analyzed by the enzymatic colorimetric
method described for serum lipid analysis.
2.6. Histological Analysis
Epididymal adipose tissue was fixed in 10% formalin solution overnight. The fixed tissue was
processed using an automatic tissue processor (TP1020, Leica, Mannheim, Germany). The processed
tissues were infiltrated with paraffin (Paraplast Plus, Leica), cut into 7-
µ
m-thick sections, and then
stained with hematoxylin and eosin (H&E). Image of H&E sections were obtained using a microscope
(Olympus, Tokyo, Japan) at 200
×
magnification. To determine adipocyte size, H&E staining images
were analyzed using Image J software. Thirty cells per sample were included in the analysis for
each group.
2.7. Quantitative Real-Time PCR (qRT-PCR)
Total RNA was extracted from epididymal adipose tissue using TRIzol reagent (GeneAll
Biotechnology, Seoul, Korea) according to the manufacturer’s instructions. cDNA was synthesized from
total RNA using a Moloney Murine Leukemia Virus (M-MLV) Reverse Transcriptase kit (Bioneer Co.,
Daejeon, Korea). Real-time qPCR was performed using Rotor Gene 3000 (Corbett Research, Mortlake,
N.S.W., Australia) and AccuPower 2X Greenstar qPCR MasterMix (Bioneer Co., Daejon, Korea).
Primers used for real-time qPCR analysis are described in Supplementary Table S2. Data analysis was
conducted by the 2∆∆Ct method. β-actin was used as the reference gene for normalization.
For the analysis of miR expression, cDNA was synthesized using a miRNA cDNA Synthesis Kit
with Poly (A) Polymerase Tailing (ABM Inc., Richmond, BC, Canada). The synthesized cDNA was
amplified using the EvaGreen miRNA qPCR Master Mix (ABM Inc.). Quantification of miRs was
carried out using miR-21, miR-132, and U6 specific primers (ABM Inc). Real-time qPCR amplification
was performed using the Rotor Gene 3000 (Corbett Research). Levels of miR-21 and miR-132 were
normalized to U6 snRNA and determined using the 2∆∆Ct method.
2.8. AMP-Activated Protein Kinase (AMPK) Activity
AMPK activity was evaluated using an AMPK Kinase Assay kit (Cyclex, Nagano, Japan) according
to the manufacturer’s instructions. Protein levels were determined using a bicinchoninic acid (BCA)
protein assay kit (Thermo Scientific, Waltham, MA, USA). AMPK activity was normalized to protein
concentration and expressed as fold change relative to the control group.
Nutrients 2018,10, 1567 4 of 12
2.9. Statistical Analysis
Data are expressed as mean
±
standard error of the mean (SEM). The SPSS software (version 22;
IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. Data were tested for normal
distribution by the Kolmogorov–Smirnov normality test. Then the comparisons between groups were
made by one-way analysis of variance (ANOVA) and Tukey’s post hoc multiple comparison tests.
p-values less than 0.05 were considered statistically significant.
3. Results
3.1. Contents of 6-Gingerol, 6-Shogaol and Total Saponin of Ginger Extracts
The chemical structures of 6-gingerol and 6-shogaol are shown in Figure 1a. The HPLC
chromatogram of the 6-gingerol and 6-shogaol is presented in Figure 1b–d.
Nutrients 2018, 10, x FOR PEER REVIEW 4 of 12
2.9. Statistical Analysis
Data are expressed as mean ± standard error of the mean (SEM). The SPSS software (version 22;
IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. Data were tested for
normal distribution by the Kolmogorov–Smirnov normality test. Then the comparisons between
groups were made by one-way analysis of variance (ANOVA) and Tukey’s post hoc multiple
comparison tests. p-values less than 0.05 were considered statistically significant.
3. Results
3.1. Contents of 6-Gingerol, 6-Shogaol and Total Saponin of Ginger Extracts
The chemical structures of 6-gingerol and 6-shogaol are shown in Figure 1a. The HPLC
chromatogram of the 6-gingerol and 6-shogaol is presented in Figure 1b–d.
(a) (b)
(c) (d)
Figure 1. High-performance liquid chromatography (HPLC) analysis of ginger extracts. (a) Chemical
structures of 6-gingerol and 6-shogaol; HPLC chromatogram of (b) standard, (c) hot water extract of
ginger (WEG), and (d) high-hydrostatic pressure extract of ginger (HPG).
The quantities of 6-gingerol in the WEG and HPG were 1.894 ± 0.02 and 3.067 ± 0.09 mg/g,
respectively (p < 0.001), and 6-shogaol amounts were 0.620 ± 0.01 and 0.652 ± 0.01 mg/g, respectively
(Figure 2a). The total saponin amounts of the WEG and HPG were 27.86 ± 1.97 and 32.89 ± 4.65 g/100
g, respectively (Figure 2b).
(a) (b)
Figure 2. Bioactive compositions of WEG and HPG. (a) 6-gingerol and 6-shogaol of WEG and HPG and (b)
total saponin of WEG and HPG. Values are expressed as mean ± SEM (n = 3) of three independent
experiments. *** p < 0.001 compared to the WEG. WEG: hot water extract of ginger; HPG: high-hydrostatic
pressure extract of ginger.
Figure 1. High-performance liquid chromatography (HPLC) analysis of ginger extracts. (a) Chemical
structures of 6-gingerol and 6-shogaol; HPLC chromatogram of (
b
) standard, (
c
) hot water extract of
ginger (WEG), and (d) high-hydrostatic pressure extract of ginger (HPG).
The quantities of 6-gingerol in the WEG and HPG were 1.894
±
0.02 and 3.067
±
0.09 mg/g,
respectively (p< 0.001), and 6-shogaol amounts were 0.620
±
0.01 and 0.652
±
0.01 mg/g, respectively
(Figure 2a). The total saponin amounts of the WEG and HPG were 27.86
±
1.97 and 32.89
±
4.65 g/100 g,
respectively (Figure 2b).
Nutrients 2018, 10, x FOR PEER REVIEW 4 of 12
2.9. Statistical Analysis
Data are expressed as mean ± standard error of the mean (SEM). The SPSS software (version 22;
IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. Data were tested for
normal distribution by the Kolmogorov–Smirnov normality test. Then the comparisons between
groups were made by one-way analysis of variance (ANOVA) and Tukey’s post hoc multiple
comparison tests. p-values less than 0.05 were considered statistically significant.
3. Results
3.1. Contents of 6-Gingerol, 6-Shogaol and Total Saponin of Ginger Extracts
The chemical structures of 6-gingerol and 6-shogaol are shown in Figure 1a. The HPLC
chromatogram of the 6-gingerol and 6-shogaol is presented in Figure 1b–d.
(a) (b)
(c) (d)
Figure 1. High-performance liquid chromatography (HPLC) analysis of ginger extracts. (a) Chemical
structures of 6-gingerol and 6-shogaol; HPLC chromatogram of (b) standard, (c) hot water extract of
ginger (WEG), and (d) high-hydrostatic pressure extract of ginger (HPG).
The quantities of 6-gingerol in the WEG and HPG were 1.894 ± 0.02 and 3.067 ± 0.09 mg/g,
respectively (p < 0.001), and 6-shogaol amounts were 0.620 ± 0.01 and 0.652 ± 0.01 mg/g, respectively
(Figure 2a). The total saponin amounts of the WEG and HPG were 27.86 ± 1.97 and 32.89 ± 4.65 g/100
g, respectively (Figure 2b).
(a) (b)
Figure 2. Bioactive compositions of WEG and HPG. (a) 6-gingerol and 6-shogaol of WEG and HPG and (b)
total saponin of WEG and HPG. Values are expressed as mean ± SEM (n = 3) of three independent
experiments. *** p < 0.001 compared to the WEG. WEG: hot water extract of ginger; HPG: high-hydrostatic
pressure extract of ginger.
Figure 2.
Bioactive compositions of WEG and HPG. (
a
) 6-gingerol and 6-shogaol of WEG and HPG
and (
b
) total saponin of WEG and HPG. Values are expressed as mean
±
SEM (n= 3) of three
independent experiments. *** p< 0.001 compared to the WEG. WEG: hot water extract of ginger; HPG:
high-hydrostatic pressure extract of ginger.
Nutrients 2018,10, 1567 5 of 12
3.2. Body Weight, Intakes, and Fat Accumulation
The initial body weights were not significantly different among the three groups. At 10 weeks of
treatment, the body weight and body weight gain of HPG group were 11.5% and 13.4% lower than
those of the HF group (p< 0.05) (Table 1and Figure 3a).
Table 1. Effects of WEG and HPG on physiological variables.
Variables HF HF + WEG HF + HPG
Initial body weight (g) 73.25 ±1.33 73.66 ±1.26 72. 46 ±1.30
Final body weight (g) 472.64 ±9.49 a438.31 ±10.36 ab 418.25 ±11.98 b
Body weight gain (g) 399.40 ±9.32 a364.65 ±9.46 ab 345.79 ±13.16 b
Food intake (g/day) 18.15 ±0.25 16.97 ±0.37 17.06 ±0.41
Food efficiency (g gained/g consumed) 0.301 ±0.006 a0.293 ±0.002 a0.278 ±0.005 b
Energy intake (kcal/day) 84.23 ±1.16 78.75 ±1.73 79.15 ±1.91
Energy efficiency (g gained/kcal consumed) 0.065 ±0.001 a0.063 ±0.000 ab 0.060 ±0.001 b
Values are expressed as mean
±
SEM (n= 9/group).
a,b
Mean values with unlike superscript letters are statistically
different at p< 0.05. HF: high fat; WEG: hot water extract of ginger; HPG: high-hydrostatic pressure extract of ginger.
1
(a)
(c)
(e)
Figure 3. Effects of WEG and HPG on diet-induced obesity. (a) Body weight and (b) adipose tissue weight
of rats fed WEG and HPG diets for 10 weeks; (c) Representative histological sections of epididymal adipose
tissue; hematoxylin and eosin stain, scale bar = 100 μm; (d) Average adipocyte size was presented as pixels;
(e) Liver weight and (f) serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. Values
are expressed as mean ± SEM (n = 9 /group). * p < 0.05 compared to the HF group. a,b Mean values with
unlike superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot water extract of ginger;
HPG: high-hydrostatic pressure extract of ginger.
Figure 3.
Effects of WEG and HPG on diet-induced obesity. (
a
) Body weight and (
b
) adipose tissue
weight of rats fed WEG and HPG diets for 10 weeks; (
c
) Representative histological sections of
epididymal adipose tissue; hematoxylin and eosin stain, scale bar = 100
µ
m; (
d
) Average adipocyte
size was presented as pixels; (
e
) Liver weight and (
f
) serum aspartate transaminase (AST) and alanine
transaminase (ALT) levels. Values are expressed as mean
±
SEM (n= 9/group). * p< 0.05 compared
to the HF group.
a,b
Mean values with unlike superscript letters are statistically different at
p< 0.05.
HF: high fat; WEG: hot water extract of ginger; HPG: high-hydrostatic pressure extract of ginger.
Nutrients 2018,10, 1567 6 of 12
During the experimental period, food efficiency and energy efficiency in the HPG groups were
lower than those in the HF group (p< 0.05), while food intake and energy intake did not significantly
differ among the three groups (Table 1).
The total weight of WAT containing epididymal and perirenal adipose tissue mass of the HPG
group was lower than that of the HF group (p< 0.05) (Figure 3b). As the representative images of
adipose tissue show, the sizes of epididymal adipocytes were significantly smaller in both WEG and
HPG groups than those in the HF group (Figure 3c,d).
3.3. Liver Weight and Serum AST and ALT Activities
To test whether ginger extracts induce liver toxicity, the liver weight and serum AST and ALT
levels were measured. There were no significant differences among the three groups in the relative
liver weight and serum AST and ALT levels (Figure 3d,e).
3.4. Serum, Liver, and Fecal Lipid Profiles
The levels of serum TG, TC, and LDL-C were significantly lower in the HPG group than in the
HF group (p< 0.05) (Figure 4a). On the other hand, the levels of HDL-C in the WEG and HPG groups
was significantly higher than those in the HF group (p< 0.05) (Figure 4a).
Nutrients 2018, 10, x FOR PEER REVIEW 6 of 12
During the experimental period, food efficiency and energy efficiency in the HPG groups were
lower than those in the HF group (p < 0.05), while food intake and energy intake did not significantly
differ among the three groups (Table 1).
The total weight of WAT containing epididymal and perirenal adipose tissue mass of the HPG
group was lower than that of the HF group (p < 0.05) (Figure 3b). As the representative images of
adipose tissue show, the sizes of epididymal adipocytes were significantly smaller in both WEG and
HPG groups than those in the HF group (Figure 3c,d).
3.3. Liver Weight and Serum AST and ALT Activities
To test whether ginger extracts induce liver toxicity, the liver weight and serum AST and ALT
levels were measured. There were no significant differences among the three groups in the relative
liver weight and serum AST and ALT levels (Figure 3d,e).
3.4. Serum, Liver, and Fecal Lipid Profiles
The levels of serum TG, TC, and LDL-C were significantly lower in the HPG group than in the
HF group (p < 0.05) (Figure 4a). On the other hand, the levels of HDL-C in the WEG and HPG groups
was significantly higher than those in the HF group (p < 0.05) (Figure 4a).
(a) (b)
(c) (d)
(e) (f)
Figure 4. Effects of WEG and HPG on lipid profiles of serum, liver and feces. (a) Serum lipid profiles;
(b, c) liver lipid profiles; (d) total fecal excretion; and (e,f) fecal lipid profiles. Values are expressed as
mean ± SEM (n = 9/group). a,b Mean values with unlike superscript letters are statistically different at
p < 0.05. HF: high fat; WEG: hot water extract of ginger; HPG: high-hydrostatic pressure extract of
ginger; TG: triglyceride; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C:
low-density lipoprotein cholesterol.
Hepatic total lipid level of the HPG group was lower than that of the HF group (p < 0.05) (Figure
4b). The hepatic TG and TC levels of the HPG group were also lower than those of the HF group (p <
Figure 4.
Effects of WEG and HPG on lipid profiles of serum, liver and feces. (
a
) Serum lipid profiles;
(
b
,
c
) liver lipid profiles; (
d
) total fecal excretion; and (
e
,
f
) fecal lipid profiles. Values are expressed as
mean
±
SEM (n= 9/group).
a,b
Mean values with unlike superscript letters are statistically different
at p< 0.05. HF: high fat; WEG: hot water extract of ginger; HPG: high-hydrostatic pressure extract of
ginger; TG: triglyceride; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C:
low-density lipoprotein cholesterol.
Hepatic total lipid level of the HPG group was lower than that of the HF group (p< 0.05)
(Figure 4b). The hepatic TG and TC levels of the HPG group were also lower than those of the HF
Nutrients 2018,10, 1567 7 of 12
group (p< 0.05) (Figure 4c). In feces, total lipid level in the HPG group was higher than that in the
HF group (p< 0.05), whereas the total fecal matter excretion amount was not significantly different
(Figure 4d,e). Moreover, HPG enhanced the fecal TG and TC excretion compared to the HF group
(p< 0.05) (Figure 4f).
3.5. mRNA Expression of Genes Related to Adipogenesis and Pro-Inflammatory Cytokines in WAT
The mRNA expression of genes related to adipogenesis and pro-inflammatory cytokines in WAT
were analyzed. The mRNA levels of peroxisome proliferator-activated receptor-
γ
(PPAR-
γ
) and
adipocyte protein 2 (aP2) were lower in both the WEG and HPG groups than those in the HF group
(p< 0.05) (Figure 5a). The mRNA levels of tumor necrosis factor-
α
(TNF-
α
), interleukin-6 (IL-6), and
monocyte chemoattractant protein-1 (MCP-1) were lower in the HPG group than in the HF group
(p< 0.05), whereas WEG treatment did not affect these levels significantly (Figure 5b).
Nutrients 2018, 10, x FOR PEER REVIEW 7 of 12
0.05) (Figure 4c). In feces, total lipid level in the HPG group was higher than that in the HF group (p
< 0.05), whereas the total fecal matter excretion amount was not significantly different (Figure 4d,e).
Moreover, HPG enhanced the fecal TG and TC excretion compared to the HF group (p < 0.05) (Figure
4f).
3.5. mRNA Expression of Genes Related to Adipogenesis and Pro-Inflammatory Cytokines in WAT
The mRNA expression of genes related to adipogenesis and pro-inflammatory cytokines in WAT
were analyzed. The mRNA levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) and
adipocyte protein 2 (aP2) were lower in both the WEG and HPG groups than those in the HF group
(p < 0.05) (Figure 5a). The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and
monocyte chemoattractant protein-1 (MCP-1) were lower in the HPG group than in the HF group (p
< 0.05), whereas WEG treatment did not affect these levels significantly (Figure 5b).
(a)
(b)
Figure 5. Effects of WEG and HPG on mRNA expression of genes related to adipogenesis and pro-
inflammatory cytokines in white adipose tissue (WAT). The mRNA levels of (a) adipogenesis and (b)
pro-inflammatory cytokines were measured using real-time qPCR. Values represent fold changes
compared to the control. Values are expressed as mean ± SEM (n = 9/group). a,b Mean values with
unlike superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot water extract of
ginger; HPG: high-hydrostatic pressure extract of ginger; PPAR-γ: peroxisome proliferator-activated
receptor-γ; aP2: adipocyte protein 2; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; MCP1:
monocyte chemoattractant protein-1.
3.6. miR-21 and miR-132 Expression in WAT
To elucidate the molecular mechanisms underlying the regulation of lipid metabolism and
inflammation of HPG, miR-21 and miR-132 expression levels were analyzed in WAT. miR-21
expression in the WEG and HPG groups was down-regulated by 33.9% and 64.1%, respectively,
compared to that in the HF group (p < 0.05) (Figure 6a). Moreover, the miR-21 level in the HPG group
was 45.7% lower than that in the WEG group (p < 0.05) (Figure 6a). The expression of miR-132 was
57.1% lower in the HPG group compared to that in the HF group (p < 0.05) (Figure 6b).
(a) (b)
Figure 6. Effects of WEG and HPG on microRNA(miR)-21 and miR-132 in WAT. The levels of (a) miR-21
and (b) miR-132 were measured using real-time qPCR. Values are expressed as mean ± SEM (n = 9/group).
a,b Mean values with unlike superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot
water extract of ginger; HPG: high-hydrostatic pressure extract of ginger.
Figure 5.
Effects of WEG and HPG on mRNA expression of genes related to adipogenesis and
pro-inflammatory cytokines in white adipose tissue (WAT). The mRNA levels of (
a
) adipogenesis and
(
b
) pro-inflammatory cytokines were measured using real-time qPCR. Values represent fold changes
compared to the control. Values are expressed as mean
±
SEM (n= 9/group).
a,b
Mean values with
unlike superscript letters are statistically different at p< 0.05. HF: high fat; WEG: hot water extract of
ginger; HPG: high-hydrostatic pressure extract of ginger; PPAR-
γ
: peroxisome proliferator-activated
receptor-
γ
; aP2: adipocyte protein 2; TNF-
α
: tumor necrosis factor-
α
; IL-6: interleukin-6; MCP1:
monocyte chemoattractant protein-1.
3.6. miR-21 and miR-132 Expression in WAT
To elucidate the molecular mechanisms underlying the regulation of lipid metabolism and
inflammation of HPG, miR-21 and miR-132 expression levels were analyzed in WAT. miR-21 expression
in the WEG and HPG groups was down-regulated by 33.9% and 64.1%, respectively, compared to that
in the HF group (p< 0.05) (Figure 6a). Moreover, the miR-21 level in the HPG group was 45.7% lower
than that in the WEG group (p< 0.05) (Figure 6a). The expression of miR-132 was 57.1% lower in the
HPG group compared to that in the HF group (p< 0.05) (Figure 6b).
Nutrients 2018, 10, x FOR PEER REVIEW 7 of 12
0.05) (Figure 4c). In feces, total lipid level in the HPG group was higher than that in the HF group (p
< 0.05), whereas the total fecal matter excretion amount was not significantly different (Figure 4d,e).
Moreover, HPG enhanced the fecal TG and TC excretion compared to the HF group (p < 0.05) (Figure
4f).
3.5. mRNA Expression of Genes Related to Adipogenesis and Pro-Inflammatory Cytokines in WAT
The mRNA expression of genes related to adipogenesis and pro-inflammatory cytokines in WAT
were analyzed. The mRNA levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) and
adipocyte protein 2 (aP2) were lower in both the WEG and HPG groups than those in the HF group
(p < 0.05) (Figure 5a). The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and
monocyte chemoattractant protein-1 (MCP-1) were lower in the HPG group than in the HF group (p
< 0.05), whereas WEG treatment did not affect these levels significantly (Figure 5b).
(a)
(b)
Figure 5. Effects of WEG and HPG on mRNA expression of genes related to adipogenesis and pro-
inflammatory cytokines in white adipose tissue (WAT). The mRNA levels of (a) adipogenesis and (b)
pro-inflammatory cytokines were measured using real-time qPCR. Values represent fold changes
compared to the control. Values are expressed as mean ± SEM (n = 9/group). a,b Mean values with
unlike superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot water extract of
ginger; HPG: high-hydrostatic pressure extract of ginger; PPAR-γ: peroxisome proliferator-activated
receptor-γ; aP2: adipocyte protein 2; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; MCP1:
monocyte chemoattractant protein-1.
3.6. miR-21 and miR-132 Expression in WAT
To elucidate the molecular mechanisms underlying the regulation of lipid metabolism and
inflammation of HPG, miR-21 and miR-132 expression levels were analyzed in WAT. miR-21
expression in the WEG and HPG groups was down-regulated by 33.9% and 64.1%, respectively,
compared to that in the HF group (p < 0.05) (Figure 6a). Moreover, the miR-21 level in the HPG group
was 45.7% lower than that in the WEG group (p < 0.05) (Figure 6a). The expression of miR-132 was
57.1% lower in the HPG group compared to that in the HF group (p < 0.05) (Figure 6b).
(a) (b)
Figure 6. Effects of WEG and HPG on microRNA(miR)-21 and miR-132 in WAT. The levels of (a) miR-21
and (b) miR-132 were measured using real-time qPCR. Values are expressed as mean ± SEM (n = 9/group).
a,b Mean values with unlike superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot
water extract of ginger; HPG: high-hydrostatic pressure extract of ginger.
Figure 6.
Effects of WEG and HPG on microRNA(miR)-21 and miR-132 in WAT. The levels of
(
a
) miR-21 and (
b
) miR-132 were measured using real-time qPCR. Values are expressed as
mean ±SEM
(n= 9/group). a,b
Mean values with unlike superscript letters are statistically different at
p< 0.05.
HF:
high fat; WEG: hot water extract of ginger; HPG: high-hydrostatic pressure extract of ginger.
Nutrients 2018,10, 1567 8 of 12
3.7. AMPK Activity in WAT
We determined the activity of AMPK, an important metabolic regulator, which affects the
regulation of genes related to adipogenesis and inflammation in WAT. The AMPK activity was
significantly enhanced by 1.8-fold in the HPG group compared to the HF group (p< 0.05) (Figure 7).
Nutrients 2018, 10, x FOR PEER REVIEW 8 of 12
3.7. AMPK Activity in WAT
We determined the activity of AMPK, an important metabolic regulator, which affects the
regulation of genes related to adipogenesis and inflammation in WAT. The AMPK activity was
significantly enhanced by 1.8-fold in the HPG group compared to the HF group (p < 0.05) (Figure 7).
Figure 7. Effects of WEG and HPG on adenosine monophosphate-activated protein kinase (AMPK)
activity in WAT. Values are expressed as mean ± SEM (n = 9/group). a,b Mean values with unlike
superscript letters are statistically different at p < 0.05. HF: high fat; WEG: hot water extract of ginger;
HPG: high-hydrostatic pressure extract of ginger.
4. Discussion
Natural foods have a variety of physiologically active substances that help prevent/treat
diseases. High-hydrostatic pressure (HHP) technology has attracted attention as a low-temperature
extraction method that does not destroy or denature the active substances by heat during the
extraction process of various natural products [8]. Therefore, we evaluated the effects of HHP extract
of ginger (HPG) on high-fat diet-induced obesity, as well as the molecular factors involved in lipid
metabolism and inflammation of the white adipose tissue (WAT). The dose of the ginger extracts
used in the study was well tolerated by rats, demonstrated by the fact that the relative liver weight
and serum levels of AST and ALT were unaffected by ginger supplementation. Significant reduction
of body weight in the HPG group was observed at 5 weeks after beginning the HPG diet. The total
fat mass containing epididymal and perirenal adipose tissue was lower in the HPG group than that
in the HF group. These results suggested that HPG efficiently inhibited body weight gain in HF diet-
fed rats.
Studies have reported that dietary ginger improves lipid metabolism. Hot water extract of ginger
improved the serum lipid profiles by lowering TG, TC, and LDL-C and increasing HDL-C in HF diet
fed rats [13]. Additionally, supplementation of white ginger powder for 3 days reduced the plasma
levels of TC, TG, VLDL-C, and LDL-C in cholesterol-enriched diet fed Wistar rats [14]. Likewise,
HPG, in our study, improved the lipid profiles in serum and liver. Specifically, HPG enhanced fecal
excretion of total lipids, TG and TC. These results indicate that HPG could exerts beneficial effects on
lipid profiles in serum and liver in rats fed HF diet. In addition, it can be postulated that enhancement
of lipid excretion by HPG could be one of the mechanisms that inhibit accumulation of lipids in serum
and liver.
To understand the mechanism underlying obesity-induced lipid metabolism and inflammatory
response, we measured mRNA levels of the adipogenic genes and inflammatory cytokines in WAT.
PPAR-γ is a ligand-activated transcription factor that acts on the differentiation and development of
adipocytes [15]. aP2 is a marker protein for the mature adipocytes, involved in fat accumulation by
acting on lipid biosynthesis pathways [15]. Chronic inflammation in obesity is manifested by
abnormal expression of the genes that encode pro-inflammatory cytokines [16]. Weight loss, on the
other hand, has been shown to alter the expression of genes involved in the production of cytokines
in obesity [16]. TNF-α and IL-6 are pro-inflammatory cytokines synthesized when the lipid content
increases in WAT, contributing to the pathogenesis of obesity-linked complications [1]. Adipocytes
secrete chemotactic signals such as MCP-1, which trigger the recruitment of macrophages [1]. A study
Figure 7.
Effects of WEG and HPG on adenosine monophosphate-activated protein kinase (AMPK)
activity in WAT. Values are expressed as mean
±
SEM (n= 9/group).
a,b
Mean values with unlike
superscript letters are statistically different at p< 0.05. HF: high fat; WEG: hot water extract of ginger;
HPG: high-hydrostatic pressure extract of ginger.
4. Discussion
Natural foods have a variety of physiologically active substances that help prevent/treat diseases.
High-hydrostatic pressure (HHP) technology has attracted attention as a low-temperature extraction
method that does not destroy or denature the active substances by heat during the extraction process
of various natural products [
8
]. Therefore, we evaluated the effects of HHP extract of ginger (HPG)
on high-fat diet-induced obesity, as well as the molecular factors involved in lipid metabolism and
inflammation of the white adipose tissue (WAT). The dose of the ginger extracts used in the study
was well tolerated by rats, demonstrated by the fact that the relative liver weight and serum levels of
AST and ALT were unaffected by ginger supplementation. Significant reduction of body weight in
the HPG group was observed at 5 weeks after beginning the HPG diet. The total fat mass containing
epididymal and perirenal adipose tissue was lower in the HPG group than that in the HF group. These
results suggested that HPG efficiently inhibited body weight gain in HF diet-fed rats.
Studies have reported that dietary ginger improves lipid metabolism. Hot water extract of ginger
improved the serum lipid profiles by lowering TG, TC, and LDL-C and increasing HDL-C in HF diet
fed rats [
13
]. Additionally, supplementation of white ginger powder for 3 days reduced the plasma
levels of TC, TG, VLDL-C, and LDL-C in cholesterol-enriched diet fed Wistar rats [
14
]. Likewise, HPG,
in our study, improved the lipid profiles in serum and liver. Specifically, HPG enhanced fecal excretion
of total lipids, TG and TC. These results indicate that HPG could exerts beneficial effects on lipid
profiles in serum and liver in rats fed HF diet. In addition, it can be postulated that enhancement of
lipid excretion by HPG could be one of the mechanisms that inhibit accumulation of lipids in serum
and liver.
To understand the mechanism underlying obesity-induced lipid metabolism and inflammatory
response, we measured mRNA levels of the adipogenic genes and inflammatory cytokines in WAT.
PPAR-
γ
is a ligand-activated transcription factor that acts on the differentiation and development of
adipocytes [
15
]. aP2 is a marker protein for the mature adipocytes, involved in fat accumulation by
acting on lipid biosynthesis pathways [
15
]. Chronic inflammation in obesity is manifested by abnormal
expression of the genes that encode pro-inflammatory cytokines [
16
]. Weight loss, on the other hand,
has been shown to alter the expression of genes involved in the production of cytokines in obesity [
16
].
TNF-
α
and IL-6 are pro-inflammatory cytokines synthesized when the lipid content increases in WAT,
contributing to the pathogenesis of obesity-linked complications [
1
]. Adipocytes secrete chemotactic
Nutrients 2018,10, 1567 9 of 12
signals such as MCP-1, which trigger the recruitment of macrophages [
1
]. A study have reported that
ethanol extract of ginger ameliorated obesity and inflammation through inhibition of adipose tissue
accumulation and mRNA expression of pro-inflammatory cytokines such as IL-6 and TNF-
α
in WAT
of mice fed high-fat diet [
17
]. In our study, mRNA levels of PPAR-
γ
and aP2 were reduced in the
WEG and HPG groups. In addition, HPG reduced the mRNA levels of TNF-
α
, IL-6, and MCP-1. Thus,
decreased adipogenic gene expression might explain the reduction of WAT mass by HPG, and HPG
might have effects on the inhibition of inflammatory cytokine expression in WAT.
The pungent fragrance of the ginger is mainly attributed to volatile oils, primarily composed of
gingerols and shogaols [
18
]. Among them, 6-gingerol is the major constituent of the gingerols along
with 6-shogaol [
18
]. In our study, HPG showed excellent efficacy against weight loss and inflammation
suppression compared with the conventional ginger extract. In a previous study, 6-gingerol showed
anti-obesity effect by reducing lipid accumulation in mice fed a high-fat diet [
19
]. Further, rats fed
a high-fat diet and treated with purified gingerol showed significant decrease in body weight and
liver lipids compared to the control group [
20
]. An
in vivo
study has also reported that gingerol-and
shogaol-enriched ginger extract increases fecal lipids including TG and TC [
21
]. Meanwhile, studies
performed
in vitro
have reported that bioactive constituent of ginger such as 6-shogaol prevents
adipogenesis and stimulates lipolysis in 3T3-L1 adipocytes [
22
]. In addition, 6-gingerol has been
reported to block the action of PPAR-γto prevent adipogenesis and the accumulation of cytoplasmic
lipid droplets during the differentiation in 3T3-L1 preadipocytes as well as decreases the protein levels
of fatty acid synthase and aP2 [
23
]. Moreover, 6-gingerol has been reported to inhibit TNF-
α
mediated
c-Jun N-terminal kinases (JNK) phosphorylation, and 6-shogaol up-regulates PPAR-
γ
target gene
expression in adipocytes [
24
]. Therefore, the amounts of 6-gingerol and 6-shogaol in both extracts were
measured and compared to determine whether the superior effect of the HPG was due to increased
6-gingerol and 6-shogaol or not. As the data indicate, the amount of 6-gingerol in the HPG was
significantly higher relative to that in the WEG, while total saponin and 6-shogaol amounts of the
WEG and HPG were not statistically different, implying that 6-gingerol in HPG may have contributed
in part to the inhibition of obesity and inflammation in rats fed the HF diet.
MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that regulate gene expression
at the post-transcriptional level. The miRNA binds to the complementary sequence of the target
mRNAs to form a physical barrier or induce cleavage or degradation of the transcripts, thereby
silencing the target transcripts. In particular, miRNAs are important regulators of development and
function of adipose tissue. The expression of miR-21 increased during adipogenic differentiation in
mesenchymal stem cells derived from the human adipose tissue [
25
]. Similarly, the expression of
miR-21 increased in WAT, and correlated with the number of adipocytes in the epididymal fat [
26
].
Moreover, miR-132 has effects on activating NF-
κ
B and transcription of IL-8 and MCP-1 in primary
human pre-adipocytes and in differentiated adipocytes
in vitro
[
27
]. In this study, amelioration of
adipogenic gene expression by ginger extract was accompanied by reduction of miR-21 expression in
both WEG and HPG groups. The level of miR-132 was decreased in the HPG supplemented rats, and it
was consistent with a decrease in the gene expression of cytokines such as TNF-
α
, IL-6, and MCP-1.
Recently, Ahn et al. have reported that zerumbone, a cyclic sesquiterpene present in the rhizomes
of wild ginger, ameliorates high-fat diet-induced adiposity by microRNA-146b/SIRT1-mediated
adipogenesis [
28
]. However, the mechanism of regulation of ginger extracts on miRNA expression has
not been reported so far. This study first demonstrated that ginger extracts regulate the expression of a
variety of miRNAs such as miR-21 and miR-132 in WAT. Further, it is assumed that reduced miR-21
and miR-132 may be associated with post-translational regulation of genes related to adipogenesis and
inflammation in rats fed a high-fat diet.
AMPK activation reduces lipogenesis and triglyceride synthesis, and prevents the expression and
secretion of pro-inflammatory cytokines [
29
]. In a high-fat high-carbohydrate diet-fed rat model, ginger
extract increased AMPK
α
phosphorylation and total AMPK
α
in skeletal muscle [
30
].
Hashem et al.
have reported that 6-gingerol treatment in rats fed high-fat diet improves inflammatory state and
Nutrients 2018,10, 1567 10 of 12
metabolic disorders via targeting the AMPK-NF-
κ
B pathway [
31
]. In the present study, AMPK activity
was enhanced by the HPG supplementation in WAT of HF diet fed rats. Therefore, it appears that
anti-obesity and anti-inflammatory effect of HPG is partially mediated by AMPK activation.
5. Conclusions
Our findings suggest that HPG inhibits body weight gain and adipose tissue in rats fed the HF
diet. Additionally, HPG reduces lipid levels in serum and liver, promotes lipid excretion through
feces, and causes down-regulation in the mRNA expression of genes related to adipogenesis and
pro-inflammatory cytokines. Therefore, we concluded that HPG would be useful for application as
a functional food for the prevention of obesity and inflammation. Specifically, this study has first
reported that HPG inhibits miR-21/132 expression and activates AMPK in adipose tissue. Thus, further
studies are needed to investigate the target-signaling pathways due to miR-21/132 down-regulation
and AMPK activation by HPG.
Supplementary Materials:
The following are available online at http://www.mdpi.com/2072-6643/10/11/1567/s1.
Table S1: compositions of experimental diets, Table S2: primers used for quantitative real-time PCR.
Author Contributions:
Conceptualization, S.K., M.-S.L. and Y.K.; Formal Analysis, S.K., M.-S.L. and S.J;
Investigation, S.K., M.-S.L., S.J., H.-Y.S., S.P., B.K, S.-Y.K.; Resources, I.-H.K. and C.-T.K.; Writing—Original
Draft Preparation, S.K.; Writing—Review and Editing, M.-S.L. and S.J.; Visualization, M.-S.L. and S.J; Project
Administration, Y.K.; Funding Acquisition, Y.K.
Funding:
This research was supported by the National Research Foundation of Korea (NRF) funded by the
Ministry of Science & ICT (numbers 2012M3A9C4048761 and 2016R1A2B4011021).
Conflicts of Interest: The authors declare no conflict of interest.
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... Ginger also showed potential functions in prevention of obesity through the alleviation of inflammation. When Sprague-Dawley rats were fed the high-fat diet with ginger extract, body weight gain and total weight of white adipose tissue mass were significantly decreased and serum and liver lipids were also reduced (Kim et al., 2018). Ginger extracts suppressed the expression of genes related to adipogenesis and pro-inflammatory cytokines, such as peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte protein 2 (aP2) (for adipogenesis) and TNFα, interleukin-6 (IL-6) and MCP-1 (for pro-inflammatory cytokines). ...
... * represents a significant difference at p < .05 when compared to week 1 samples Ginger has been considered as a potential agent in prevention and treatment of many oxidative stress-related diseases, including obesity and diabetes (Han et al., 2005;Kim et al., 2018;Suk et al., 2016). ...
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We determined the phenolic content and anti-oxidation properties of ginger at different harvesting time and tested its effects on lipid droplet formation and glucose uptake in HepG2 cells. Ginger samples at different stages of maturity were harvested every two weeks starting from mid-October for 16 weeks. Our data indicate that ginger has the highest phenolic contents and superior anti-oxidation activity when harvested early (immature baby ginger); however, the concentration of phenolic contents and its anti-oxidation activity were progressively reduced up to 50% as ginger matures. Furthermore, the data indicate that baby ginger extract inhibits lipid accumulation and triglyceride content in oleic acid-induced HepG2 cells up to 20% in a dose-dependent manner. Baby ginger exhibited significant inhibition of α-amylase enzyme activity by 29.5% and ameliorated glucose uptake in HepG2 cell at similar level. Our results suggest that harvesting ginger at an appropriate (early) time may be beneficial for optimizing its biological active contents and qualitative properties. The data also suggest that a regular use of ginger can potentially lower incidences of obesity and diabetes.
... Studies on animal models identified a probable mechanism of action involving the suppression of pro-inflammatory cytokines at the expression level (Kim et al., 2018). ...
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Potential Benefits of Ginger in Maintenance of Oral Health
... That is because ginger has prevention and it can treat various prevalent diseases, for instance, soothing the stomach, colds, dysmenorrhea, nausea, carsickness, and headaches (Mao et al., 2019). Recently, ginger and its compounds has been confirmed to bio-activities, contain antioxidant (Stoilova et al., 2007), anti-inflammatory (Ezzat et al., 2018), anticancer (Habib et al., 2008), neuroprotective (Mohd Sahardi & Makpol, 2019;Seow et al., 2017), antiobesityactivities (Kim et al., 2018). Previous studies found that 6-shogaol neuroprotective effects on the oxidative stress induced with 6-OHDA in the PC12 cells (Kabuto et al., 2005;Peng et al., 2015). ...
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Abstract To explore the protective impact of the ginger root ethanol extract (GRE) against the oxidative stress induced by 6-hydroxydopamine (6-OHDA) and apoptotic and its mechanism. Parkinson's disease (PD) model was established using 6-OHDA in the cells of rat adrenal pheochromocytoma (PC12). The GRE pretreatment increased PC12 cell viability of injury induced by 6-OHDA. The GRE effectively suppressed 6-OHDA-induced death, apoptosis through decreased Bax and cleaved-caspase 3 expression, and up-regulated expression of B-cell lymphoma 2 (Bcl-2). GRE also inhibited 6-OHDA-inducel oxidative stress, decreased reactive oxygen species (ROS) and up-regulates the heme oxygenase (HO-1), antioxidant enzymes, catalase and, glutathione (GSH), superoxide dismutase (SOD), 8-oxoguanine glycosylase1 (OGG1) and NAD(P)H quinone oxidoreductase1 (NQO1). Besides, GRE up-regulating Protein kinase B (Akt), nuclear erythroid 2-related factor 2 (Nrf2), down-regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation, together with the mitogen-activated protein kinase (MAPK) phosphorylation. In conclusions, the GRE prevented apoptosis and oxidative stress in 6-OHDA-induced PC12 cells. The ginger ethanol extract could be treatment and prevention of PD.
... 37 Our previous research also confirmed that AMPK is involved in the pathological process of intimal thickening in carotid artery ligation animal models. 38 However, several studies have suggested that the effects of ginger extracts [39][40][41] or gingerols 42,43 involved in the development of diseases may partly be due to the activation of AMPK, but it is unclear which component is responsible for this. Recently, computer-aided drug design technology has been widely used in functional food study. ...
Article
10-Gingerol inhibits neointimal hyperplasia and suppresses VSMC proliferation by the activation of AMPK in vivo and in vitro and acts as a natural AMPK agonist.
... Ginger rhizome is applied for the prevention and treatment of numerous common diseases, such as nausea, emesis, dysmenorrhea, carsickness, headaches and colds (Beristain-Bauza et al., 2019). Recently, ginger has been proven to possess multiple biological activities, including anti-inflammatory (Lantz et al., 2007), antioxidant (Si et al., 2018;Stoilova et al., 2007), anticancer (Habib et al., 2008), antimicrobial (Sebiomo et al., 2011), neuroprotective (Hussein et al., 2017;Sahardi & Makpol, 2019), cardiovascular protective (Attyah & Ismail, 2012), and anti-obesity activities (Kim et al., 2018). Ginger's therapeutic effect mainly stems from its active constituents, which include paradols, shogaols, and gingerols (Mao et al., 2019). ...
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Abstract To explore the protective activity of ginger (Zingiber officinale) root ethanol extract (GRE) on the neuroinflammation induced by lipopolysaccharide in microglial cells. Ginger has been investigated as a neuroprotective and anti-aging agent. Nevertheless, ginger extract attenuates neuroinflammation in microglia have not been discovered in depth. The results showed that GRE had high total phenolic and (55.63 ± 0.16 mg GAE/g) and total flavonoid content (4.33 ± 0.17 mg QUE/g), and antioxidant activity. GRE inhibited the release of cytokines and inflammatory mediators including COX-2, PGE2, Nitric oxide, interleukin-6, TNF-α, and iNOS. GRE ameliorated microglia-mediated neuronal insults via upregulating the expression of Bax and reducing the expression of Bcl-2. GRE suppressed NF-κB and AKT/STAT3, and the MAPK pathway in the neuroinflammatory response. In conclusions, GRE positively affected anti-neuroinflammatory and neuroprotective activity without serious side effects, which might be used as a functional food additive and/or therapeutic material for the management and prevention of neurodegenerative diseases.
Article
Ginger (Zingiber officinale) is a famous dietary spice rich in bioactive components like gingerols, and it has been used for a long time as food and medicine. Indeed, clinical studies have confirmed the anti-inflammatory and antioxidant properties of ginger. Thus, ginger seems to be an excellent complementary nutritional strategy for non-communicable diseases (NCD) such as obesity, diabetes, cardiovascular disease and chronic kidney disease. This narrative review aims to discuss the possible effects of ginger on the mitigation of common complications such as inflammation, oxidative stress, and gut dysbiosis in NCD.
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Background and aims: To evaluate the expression of microRNA 132 (miR-132) in fetuses with normal growth and in fetuses with late-onset growth restriction (FGR). Methods: In a prospective cohort study, 48 fetuses (24 with late-onset FGR and 24 with normal growth) were scanned with Doppler ultrasound after 34 weeks to measure the umbilical artery and middle cerebral artery pulsatility indices and followed until birth. Subsequently, blood samples from the umbilical cord were collected to evaluate the expression of miR-132 by means of Real-time quantitative polymerase chain reaction, determining the existence of normality cut-offs and associations with birth weight (BW) centile, cerebroplacental ratio multiples of the median (CPR MoM), and intrapartum fetal compromise (IFC). Results: In comparison with normal fetuses, late-onset FGR fetuses showed upregulation of miR-132 (33.94 ± 45.04 vs. 2.88 ± 9.32 2-ddC t, p < 0.001). Using 5 as a cut-off we obtained a sensitivity of 50% and a specificity of 96% for the diagnosis of FGR, while for IFC these values were respectively 27% and 73%. Expression of miR-132 was associated with BW centile but not with CPR MoM. Finally, the best detection of IFC was achieved combining miR-132 expression and CPR MoM (AUC = 0.69, p < 0.05). Conclusion: Fetuses with late-onset FGR show upregulation of miR-132. Further studies are needed to investigate the role of miR-132 in the management of late-onset FGR.
Chapter
Zingiber officinale Roscoe is a well-recognized herbal plant throughout the world. Ginger is not only consumed as dietary spice but has also been employed in the traditional medicinal systems as herbal remedy since antiquity. Ginger offers health benefits mainly attributable to many bioactive phytochemicals including phenolic compounds, terpenes, flavonoids, carbohydrates, proteins, minerals, and many more. The principle phenolic compounds in ginger that lead to a plethora of biological activities are gingerols, shogaols, and paradols. Rhizome is an essential nutritional and medicinal component of ginger. The volatile components impart characteristic aroma or fragrance to ginger. This spice is traditionally used to relieve pain, constipation, digestive troubles, fever, cramps, inflammation, hypertension, dementia, and infections. Accumulated evidences have illustrated that ginger and its derivatives exhibit multiple pharmacological effects including antioxidant, anti-inflammatory, antidiabetic, antiemetic, anti-obesity, antimicrobial, anticancer, cardioprotective, and neuroprotective. Ginger thus can be used as potent and innovative therapeutic alternative for the prevention and management of acute and chronic disorders. This chapter highlights current knowledge about the ethanobotanical uses, phytochemicals, and biological activities of ginger and suggests that this updated information will be fruitful for researchers to investigate novel and unexplored applications.
Chapter
Since the prehistoric times, at least 60,000 years back as per fossil records, humans have been using natural products, such as plants, animals, microorganisms, and marine organisms, in medicines to alleviate and treat diseases. The use of natural products as medicines must have a great challenge to early humans because when seeking food in forests and hills, early humans often consumed poisonous plants, which led them to vomiting, diarrhea, coma, or other toxic reaction-even death. Subsequently, they were able to develop knowledge about edible plant materials and to use many plants as natural medicines for treatment of diseases and ailments, which are the basis of traditional medicine. Such forms of traditional medicines, namely, traditional Chinese medicine (TCM), Indian Ayurveda, Greek-Arabic Unani, Japanese Kampo, and traditional Korean medicine, known as Sasang constitutional medicine (SCM) have been practiced worldwide for more than thousands of years and have blossomed into the present systems of modern medicines. The advancement of modern technology helped us to evaluate the pharmacology and mechanism of action of many medicinal herbs in treatment of diseases and to use them as cornerstones of modern medicine. In the historic year 1805, German pharmacist Friedrich Serturner isolated morphine from the opium plant, Papaver somniferum L., and laid the foundation of modern medicine. Subsequently, countless active natural molecules, known as phytochemicals have been separated from natural plant and microbial extracts, and many of them have potential anticancer, antihypertensive, hypolipidemic, antiobese, antidiabetic, antiviral, antileishmanial, and antimigraine medicative properties. These phytochemicals, which have evolved over millions of years, have a unique chemical structural diversity, which results in the diversity of their biological actions to alleviate and treat critical human diseases. A group of evidence advocates that a “multidrugs” and “multi-targets” approach would be more effective compared to a “single-drug” and “single-target” approach in the treatment of complex diseases like obesity, diabetes, cardiovascular disease, and cancer. Phytochemicals present in a single herb or in a herbal formulation can function alone or synergistically with other phytochemicals in a “multi-targets” approach to produce desired pharmacological effect in prevention and cure of complex diseases. The optimal efficacy of the herbal/polyherbal extract depends on its correct dosage containing the optimal concentration of bioactive phytochemical (s) and the method of preparing and processing of the herbal/polyherbal composition and the appropriate time of collection of plant parts. Therefore, the research on natural products is a thrust area for future research in drug discovery (Yuan et al. 2016). This chapter summarizes the current progress in the study of the antiobesity and antidiabetic potentials of natural products and their main bioactive phytochemicals, major molecular mechanisms in preventing and treating obesity and diabetes, and their associated complications.
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In a prospective study, 48 fetuses were evaluated with Doppler ultrasound after 34 weeks and classified, according to the cerebroplacental ratio (CPR) and estimated fetal weight (EFW), into fetuses with normal growth and fetuses with late-onset fetal growth restriction (LO-FGR). Overexpression of miRNAs from neonatal cord blood belonging to LO-FGR fetuses, was validated by real-time PCR. In addition, functional characterization of overexpressed miRNAs was performed by analyzing overrepresented pathways, gene ontologies, and prioritization of synergistically working miRNAs. Three miRNAs: miR-25-3p, miR-185-5p and miR-132-3p, were significantly overexpressed in cord blood of LO-FGR fetuses. Pathway and gene ontology analysis revealed over-representation of certain molecular pathways associated with cardiac development and neuron death. In addition, prioritization of synergistically working miRNAs highlighted the importance of miR-185-5p and miR-25-3p in cholesterol efflux and starvation responses associated with LO-FGR phenotypes. Evaluation of miR-25-3p; miR-132-3p and miR-185-5p might serve as molecular biomarkers for the diagnosis and management of LO-FGR; improving the understanding of its influence on adult disease.
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Green tea extract exerts favorable influence on the lipid profile and insulin resistance in the high-sodium intake arterial hypertension. A high-sodium diet (HSD) was introduced to thirty Wistar rats to create a model of hypertension. Rats were randomized into three groups, 10 animals each. The SK group consumed HSD. The SH2 group consumed HSD with 2 g of green tea extract in kg of diet. The SH4 group was fed HSD with 4 g of green tea extract in kg of diet. After six-week trial blood samples were collected. The serum concentrations of glucose, insulin and lipids were estimated, and insulin sensitivity was calculated using homeostatic model assessment (HOMA). Neither the high-sodium diet nor supplementation with green tea extract had any significant influence on the body mass of the animals in either group. Total cholesterol (TCH) and low-density lipoproteins (LDL) cholesterol serum concentrations were significantly smaller in both supplemented groups than in the SK group. The insulin level in the SH2 rats and HOMA in SH2 and SH4 groups were found to be significantly smaller than in the SK group. There were no differences in glucose concentrations between groups. Within the whole population, statistically significant positive correlations between HOMA and LDL, TCH were found. We conclude that in NaCl-induced hypertensive Wistar rats, supplementation with green tea extract produced a dose-independent beneficial and parallel effect on the lipid profile and insulin resistance.
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Stress contributes to physiological changes such as weight loss and hormonal imbalances. The aim of the present study was to investigate antistress effects of high hydrostatic pressure extract of ginger (HPG) in immobilization-stressed rats. Male Sprague-Dawley rats (n = 24) were divided into three groups as follows: control (C), immobilization stress (2 h daily, for 2 weeks) (S), and immobilization stress (2 h daily, for 2 weeks) plus oral administration of HPG (150 mg/kg body weight/day) (S+G). Immobilization stress reduced the body weight gain and thymus weight by 50.2% and 31.3%, respectively, compared to the control group. The levels of serum aspartate transaminase, alanine transaminase, and corticosterone were significantly higher in the stress group, compared to the control group. Moreover, immobilization stress elevated the mRNA levels of tyrosine hydroxylase (Th), dopamine beta-hydroxylase (Dbh), and cytochrome P450 side-chain cleavage (P450scc), which are related to catecholamine and corticosterone synthesis in the adrenal gland. HPG administration also increased the body weight gain and thymus weight by 12.7% and 16.6%, respectively, compared to the stress group. Furthermore, the mRNA levels of Th, Dbh, phenylethanolamine-N-methyltransferase, and P450scc were elevated by the HPG treatment when compared to the stress group. These results suggest that HPG would have antistress effects partially via the reversal of stress-induced physiological changes and suppression of mRNA expression of genes related to corticosterone and catecholamine synthetic enzymes.
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Obesity is characterized by increased fat mass, as adipose tissue serves as a storage site for excess energy from food consumption. In obesity, altered lipid metabolism of adipose tissue, characterized by fatty acid uptake, de novo lipogenesis, and lipolysis, are induced. In this study, we examined the effect of zerumbone, a major sesquiterpene from wild ginger, on high-fat diet (HF)-induced obesity and dysregulated lipid metabolism in the white adipose tissues (WAT) of C57BL/6N mice. Dietary supplementation with zerumbone ameliorated HF-induced obesity and improved impaired lipid metabolism in WAT. Zerumbone additionally induced AMPK activation and phosphorylation of acetyl-CoA carboxylase, and effectively decreased adipogenic differentiation, in a concentration-dependent manner in the 3T3-L1 cells. Dysregulated microRNAs in obese WAT and adipocytes were examined, and zerumbone treatment was found to effectively reverse the robust upregulation of microRNA-146b. An increase in the levels of SIRT1, the direct target of microRNA-146b, was observed in zerumbone-treated differentiated adipocytes. This increase was additionally observed in WAT of zerumbone-supplemented mice. The antiadipogenic effect of zerumbone was found to be abolished in SIRT1-silenced 3T3-L1 cells. The increase in SIRT1 levels induced by zerumbone led to deacetylation of FOXO1 and PGC1α in WAT and differentiated 3T3-L1 cells. These findings indicate that zerumbone ameliorated diet-induced obesity and inhibited adipogenesis, and that the underlying mechanisms involved AMPK and the microRNA-146b/SIRT1 pathway. Zerumbone may represent a potential therapeutic candidate for the prevention and treatment of metabolic diseases, particularly obesity.
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Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications.
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Background: Recent studies indicate the important role of chronic inflammation and oxidative stress in the pathogenesis of hypertension. Green tea, due to the high content of catechins, shows high antioxidant activity. Objective: To determine the effect of supplementation with green tea extract on the blood pressure, on the concentration of selected parameters of inflammation and antioxidant status in the model of high-sodium-diet induced hypertension. Design: The study lasted 42 days. The experimental population consisted of 30 rats. The rats were divided into three groups. The rats in the control group were fed a standard diet with 35 g of NaCl per kg of diet, in the second group hypertensive rats were fed a standard diet with NaCl (35 g/kg diet) and with an extract of green tea (2 g/kg diet). The third group consisted of hypertensive rats fed a standard diet with NaCl (35 g/kg diet), and 4 g of green tea extract/kg diet. Results: Supplementation with green tea had no effect on body mass of rats on a high-sodium diet. At the end of the experiment systolic blood pressures in SH2 and SH4 groups were significantly lower than in the control group SK. The SH4 group was characterized by a significantly lower diastolic blood pressure value and concentration of TNF-α in comparison to the SK group. The rats from both SH2 and SH4 groups were characterized by higher total antioxidant status values compared to the control group. Discussion: The mechanism of the beneficial effects of green tea on blood pressure is not clear, but it is believed that it is related to its omnidirectional properties. Conclusions: Supplementation of green tea has a beneficial effect on blood pressure, markers of inflammation and antioxidant status in an experimental model of hypertension.
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The AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways and may have therapeutic importance for treating obesity, insulin resistance, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Given the ubiquitous expression of AMPK, it has been a challenge to evaluate which tissue types may be most beneficially poised for mediating the positive metabolic effects of AMPK-centered treatments. In this review we evaluate the metabolic phenotypes of transgenic mouse models in which AMPK expression and function have been manipulated, and the impact this has on controlling lipid metabolism, glucose homeostasis, and inflammation. This information may be useful for guiding the development of AMPK-targeted therapeutics to treat chronic metabolic diseases.
Article
Objectives: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in metabolic homeostasis and regulation of inflammatory responses through attenuation of nuclear factor kappa-B (NF-κB), Thus AMPK may be a promising pharmacologic target for the treatment of various chronic inflammatory diseases. We examined the effect of 6-gingerol, an active ingredient of ginger on AMPK-NF-κB pathway in high fat diet (HFD) rats in comparison to fish oil. Methods: Protein levels of AMPK-α1 and phosphorylated AMPK-α1 were measured by western blot while Sirtuin 6 (Sirt-6), resistin and P65 were estimated by RT-PCR, TNF-α was determined by ELISA, FFAs were estimated chemically as well as the enzymatic determination of the metabolic parameters. Results: 6-Gingerol substantially enhanced phosphorylated AMPK-α1 more than fish oil and reduced the P65 via upregulation of Sirt-6 and downregulation of resistin, and resulted in attenuation of the inflammatory molecules P65, FFAs and TNF-α more than fish oil treated groups but in an insignificant statistical manner, those effects were accompanied by a substantial hypoglycemic effect. Conclusion: Gingerol treatment effectively modulated the state of inflammatory privilege in HFD group and the metabolic disorders via targeting the AMPK-NF-κB pathway, through an increment in the SIRT-6 and substantial decrement in resistin levels.
Article
Mitochondrial dysfunction and dyslipidemia are associated with obesity-linked metabolic disorders. The aim of this study was to investigate the effects of ginger extract on muscle mitochondrial biogenesis and high-density lipoprotein-cholesterol (HDL-C) metabolism in high-fat diet-fed rats. Supplementation with ginger extract reduced final body weight and epididymal adipose tissue mass without affecting energy intake (p < 0.05). Ginger extract increased mitochondrial size and mitochondrial DNA (mtDNA) content as well as key genes expression related to mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF-1) and transcription factor A (Tfam) in skeletal muscle (p < 0.05). In addition, ginger extract elevated serum HDL-C along with up-regulating ATP-binding cassette transporter A1 (ABCA1), apolipoprotein A-1 (ApoA-1) and lecithin-cholesterol acyltransferase (LCAT) mRNA in liver (p < 0.05). These results suggest that ginger extract may have a beneficial effect against obesity-related metabolic disorders with elevating muscle mitochondrial biogenesis and serum HDL-C level.