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Abstract

α-(-)-bisabolol is a natural oily monocyclic sesquiterpene alcohol present in the essential oil has generated considerable interest in chemical and pharmaceutical industries and currently in used in various formulations, mainly in cosmetics. This study was undertaken to evaluate its therapeutic profile against skin inflammation using in-vitro, in-vivo and in silico assays. Lipopolysachharide (LPS) and12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced production of pro-inflammatory cytokines (TNF-α and IL-6) inflammation in macrophage cells as well as in TPA-induced skin inflammation in mice was significantly inhibited by α-(-)-bisabolol. TPA-induced ear thickness, ear weight and lipid production and histopathological damage in ear tissue was also significantly inhibited by topical application of α-(-)-bisabolol in dose dependant manner. In-vitro and in-vivo toxicity profile indicates that it is safe for topical application on skin. Molecular docking study also revealed its strong binding affinity to the active site of the pro-inflammatory proteins. These findings suggested that α-(-)-bisabolol may be a useful therapeutic candidate for the treatment of skin inflammation.
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Current Pharmaceutical Biotechnology, 2014, 15, 173-181 173
α-(-)-bisabolol Reduces Pro-inflammatory Cytokine Production and
Ameliorates Skin Inflammation
Anil K. Maurya, Monika Singh, Vijaya Dubey, Suchita Srivastava, Suaib Luqman and
Dnyaneshwar U. Bawankule*
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow-226015,
India
Abstract: α-(-)-bisabolol is a natural monocyclic sesquiterpene present in the essential oil has generated considerable in-
terest in the chemical and pharmaceutical industries and currently in use in various formulations, mainly in cosmetics.
This study was undertaken to evaluate its therapeutic profile against skin inflammation using in-vitro, in-vivo and in-silico
assays. Lipopolysachharide (LPS) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced production of pro-
inflammatory cytokines (TNF-α and IL-6) in macrophage cells as well as in TPA-induced skin inflammation in mice was
significantly inhibited by α-(-)-bisabolol. TPA-induced ear thickness, ear weight and lipid peroxidation and histopa-
thological damage in the ear tissue were also significantly inhibited by topical application of α-(-)-bisabolol in a dose de-
pendent manner. In-vitro and in-vivo toxicity profiles indicate that it is safe for topical application on skin. Molecular
docking study also revealed its strong binding affinity to the active site of the pro-inflammatory proteins. These findings
suggested that α-(-)-bisabolol may be a useful therapeutic candidate for the treatment of skin inflammation.
Keywords: α-(-)-bisabolol, anti-inflammatory, macrophage, 12-O-tetradecanoylphorbol-13-acetate, mice, LPS.
1. INTRODUCTION
Inflammation is the common biological reaction to a va-
riety of stimuli and local injury [1]. It is a complex patho-
physiological process mediated by a variety of signaling
molecules produced by activated leukocytes, which bring
edema formation as a result of extravasation of fluid and
cells at the inflammatory site [2]. Skin plays a central role in
host defenses and regulation of defense mechanism is vital
for immunity [3]. Skin diseases linked with inflammation are
the most common problem in dermatology. They are in
many forms, from occasional rashes accompanied by skin
itching and redness, to chronic conditions such as dermatitis,
rosacea, seborrheic dermatitis, and psoriasis [4]. Pathogene-
sis of psoriasis is not fully understood. Several researches
have demonstrated that keratinocytes are known to partici-
pate in inflammatory reactions by producing a variety of
inflammatory cytokines. Psoriasis is a non-contagious skin
disorder which has a physical impact includes itching to the
skin, pain and restricted motion in their joints, but also ad-
versely affects the psychological feelings of the sufferers
leading to anxiety, anger, embarrassment, low self-esteem
and even depression [5]. Experimental evidences has shown
that exposure of skin to 12-O-tetradecanoylphorbol-13-
acetate (TPA) induces a pleiotropic tissue response encom-
passing a strong inflammatory reaction similar to that ob-
served in skin diseases [6].
*Address correspondence to this author at the Molecular Bioprospection
Department, CSIR-Central Institute of Medicinal and Aromatic Plants
(CSIR-CIMAP), Lucknow, India; Tel: +91-522-2718646;
Fax: +91-522-2342666; E-mail: du.bawankule@cimap.res.in
α-(-)-bisabolol is an unsaturated, optically active ses-
quiterpene alcohol found as a major component of essential
oil of chamomile. Chamomile, one of the most recognized
herbs to mankind which has been used traditionally as an
anti-inflammatory, antispasmodic, carminative, mild astrin-
gent and healing medicine [7]. Pharmacological study re-
vealed that α-(-)-bisabolol has anti-microbial [8], nematicidal
and gastroprotective effect against ethanol and indometha-
cin-induced ulcer in mice [9], and skin inflammation [10].
In this study, we examined the impact of α-(-)-bisabolol
on the production of pro-inflammatory cytokine in macro-
phage cells stimulated with lipopolysaccharide (LPS) and
12-O-tetradecanoylphorbol-13-acetate (TPA) as an in-vitro
study. We have further validated our finding in in-vivo sys-
tem in TPA-induced skin inflammation in mice as well as
molecular docking interaction study with pro-inflammatory
cytokines. We also examined the safety study (in-vitro and
in-vivo) of α-(-)-bisabolol. Our results reveal that α-(-)-
bisabolol reduces pro-inflammatory cytokine production and
ameliorates skin inflammation without any toxic effect.
2. MATERIALS AND METHODS
2.1. Materials
α-(-)-bisabolol, RPMI 1640 medium, dexamethasone and
12-o-tetradecanoylphorbol-13-acetate (TPA) were purchased
from Sigma- Aldrich USA. TNF-α and IL-6 were from BD
Biosciences, USA, and fetal bovine serum was from Gibco,
USA.
18-/14 $58.00+.00 © 2014 Bentham Science Publishers
174 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 Maurya et al.
2.2. In-vitro Study
2.2.1. Primary Cell Culture
Isolation of peritoneal macrophage cells was done as
described previously [11]. In brief, the macrophage cells
were isolated from the peritoneal cavities of female Swiss
albino mice after an intra-peritoneal injection of 1.0 mL of
1% peptone (BD Biosciences, USA) 3 days before harvest-
ing. Mice were euthanized by cervical dislocation under
ether anesthesia and peritoneal macrophage cells were ob-
tained by intra-peritoneal injection of phosphate buffer saline
(PBS). Cell viability was determined by trypan blue exclu-
sion and the concentration of 0.5 × 106 live cells/mL was
used for the study. The cells were suspended in RPMI 1640
medium (Sigma–Aldrich, USA) containing 10% heat-
inactivated fetal bovine serum (Gibco, USA), 100 U/mL of
penicillin and 100 µg/mL of streptomycin and incubated in a
culture plate (Nunc, Germany) at 370 C in 5% CO2 in an in-
cubator. Non-adherent cells were removed after 4 h by re-
moving the culture media and the adherent cells were re-
suspended in the media without antibiotic.
2.2.2. Cell Toxicity
Effect of α-(-)-bisabolol on cell cytotoxicity was carried
out in peritoneal macrophage cells using 3-(4, 5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay
as described by Sharma et al., (2012). Peritoneal macrophage
cells (0.5 x 106 cells/well) isolated from mice were sus-
pended in RPMI 1640 medium (Sigma, USA) containing
10% heat-inactivated fetal bovine serum (Gibco, USA) and
incubated in a 96 well plate at 37ºC in 5% CO2 in an incuba-
tor and left overnight to get attached. Cells treated with 1%
DMSO served as a vehicle control for cell cytotoxicity study.
α-(-)-bisabolol was dissolved in DMSO. Cells were treated
(1, 3, 10, 30 and 100µg/mL) and incubated for 24 h at 37ºC
in 5% CO2. After incubation 20 μL of MTT solution
(5mg/mL in PBS) were added to each well and left for 4 h
followed by media removal and cell solubilization in DMSO
(100µL) for 10 min. Absorbance was measured at 570nm
using micro-plate reader (Spectramax; Molecular Devices,
USA). The amount of color produced is directly proportional
to the number of viable cells. Cytotoxicity was calculated as
follows: Percentage (%) of survival = (mean experimental
absorbance/mean control absorbance×100).
2.2.3. Quantification of Pro-inflammatory Cytokines
Culture macrophage cells were pre-treated with 1, 3 and
10 µg/mL of α-(-)-bisabolol and/or dexamethasone, a stan-
dard anti-inflammatory drug (Sigma Aldrich, USA) at
1µg/mL for 30 min. The in-vitro anti-inflammatory study
was performed in two sets. The cells were stimulated with
LPS (0.5µg/mL) and TPA (10µg/mL), respectively for 24 h,
and collected supernatants were immediately frozen at
−80oC. Pro-inflammatory mediators (TNF-α and IL-6) were
quantified from supernatant using ELISA method according
to the manufacturer’s instructions (BD Biosciences, USA).
The values of TNF-α, and IL-6 were expressed as pg/mL.
2.3. In-vivo Study
2.3.1. Experimental Animals
Female BALB/c mice (25–35g), housed at 22±2oC (60–
80% humidity) under a 12h light/12h dark cycle and with
access to food and water ad libitum, were used for this study.
The animals were allowed to adapt to the laboratory for a
week before testing. Experiments were performed according
to the ethical guidelines suggested by the Institutional Ani-
mal Ethics Committee (IAEC) and Committee for the Pur-
pose of Control and Supervision of Experiments on Animals
(CPCSEA), Government of India.
2.3.2. TPA-induced Mouse Ear Inflammation
Topical inflammation was induced in right ears of female
BALB/c mice by the topical application of TPA (2.5μg) dis-
solved in acetone (20μL). A volume of 10μL was delivered
to both the inner and outer surface of the ear. α-(-)-bisabolol
was diluted in acetone in the ratio of 0.1%, 0.3% and 1.0%
for topical anti-inflammatory study. α-(-)-bisabolol was ap-
plied to the right ears at the dose of 20μL/ear/time 30 min
after TPA administration. For comparison, two other groups
were treated with TPA (vehicle control and dexamethasone
200μg/ear).
2.3.3. Ear Edema and Tissue Weight Measurement
Ear ed ema was expressed as the increase in ear thickness
due to the inflammatory challenge. Ear thickness was meas-
ured before and after induction of the inflammatory response
by using an electronic digital micrometer (Aerospace In-
struments). At 6 h, when TPA-induced inflammation was
maximal, animals were euth anized by ether anesthesia and
1cm diameter punch of ear tissue wet weight was taken for
quantification of inflammatory mediators from tissue ho-
mogenate. These tissues were quickly placed in a beaker
containing ice-cold Tris- HCl buffer (pH 7.4) and minced
into small pieces on ice and homogenized immediately in
tissue homogenizer (Pro Scientific Inc, USA). The ho-
mogenate (5%) was frozen and stored at -80°C till it’s used
for biochemical estimation. The tissue homogenate was
processed for the estimation of malondialdehyde (MDA) and
pro-inflammatory cytokines.
2.3.4. Quantification of Lipid Peroxidation and Inflamma-
tory Cytokines
Quantification of lipid peroxidation was performed fol-
lowing the thiobarbituric acid (TBA) test. The amount of
MDA formed was quantitated by reaction with TBA and
used as an index of lipid peroxidation. The results were
expressed as µM MDA/mL tissue homogenate. Pro-
inflammatory cytokines (TNF-α and IL-6) were quantified
from tissue homogenate using commercially available mouse
specific enzyme immune assay (EIA) k its (BD Biosciences,
USA) as per the manufactures instructions.
2.3.5. Histopathology
After fixation of the ear tissues in 10% buffered formalin.
The tissues were rinsed with water, dehydrated with graded
concentration of ethanol and embedded in paraffin wax. The
samples were sectioned into 4-5 μm thickness and mounted
α-(-)-bisabolol Reduces Pro-inflammatory Cytokine Production Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 175
on glass slides and stained with hematoxylin and eosin (H&E
stain). A representative area was selected for qualitative light
microscopic analysis (200× magnification).
2.3.6. Primary Skin Irritation
Primary skin irritation study was performed for the topi-
cal application of α-(-)-bisabolol in four healthy New Zea-
land white rabbits (1500±250g body weight) as per the ap-
proved protocol by the Institutional Animal Ethical Commit-
tee of CSIR-CIMAP, Lucknow, India.
α-(-)-bisabolol @ 1% was applied to the previously
shaved skin of rabbits on one inch square area. Normal saline
(1%) was applied as vehicle control at opposite side of skin.
Observations were made at 1, 4, 24, 48 and 72 h to assess
individual erythema and edema. The primary irritation index
(PII) was determined using the following formula; PII = Test
site score – Control site score [12].
2.4. In-silico Study
2.4.1. Molecular Docking
The methodology utilized was previously described [13]
for automated docking of flexible ligands with receptor using
Lamarckian genetic algorithm. The binding interaction of
α-(-)-bisabolol and dexamethasone was calculated by using
the freely available software AUTODOCK TOOLS 1.5.4.
The 3D structure of receptor (protein) was obtained from
protein data bank (http://www.rcsb.org/pdb/home/home.do).
The 3D structure of ligand (molecule) in sdf format was ob-
tained from Pubchem (http://pubchem.ncbi.nlm.nih.gov/)
and converted into 3D PDB structure by Open Babel Soft-
ware 2.0.2. Grid parameter file of the dimensions (60 X 60 X
60) for the receptor was prepared. Docking parameter file
based on Lamarckian genetic algorithm was prepared.
Command for docking was given on cygwin terminal (pro-
vides Unix/Linux like environment and command interface
for windows) supported by autogrid4 and autodock4 exten-
sion files. Results of the full run of a docking experiment
were collected from the dlg file obtained on full completion
of the single run of the software. The docking score in terms
of binding energy and inhibition constant values were ob-
tained for the ligand and receptor interaction. Usually, more
negative binding energy (Kcal/mol) is considered good for
effective interaction of the ligand with the receptor.
2.5. Statistical Analysis
Results are presented as th e Mean±SE and analysed using
GraphPad Prism 4. The one-way ANOVA followed by
Tukey’s multiple comparison test was used to assess the sta-
tistical significance of vehicle vs treatment groups. Probabil-
ity (P) values less than 0.05 were considered significant.
3. RESULTS
3.1. In-vitro Study
3.1.1. Cell Toxicity
Effect of α-(-)-bisabolol on cell viability in peritoneal
macrophage cells was evaluated using MTT assay. The sig-
nificant change in percent cell survival was not observed at
any concentration of the treatment when compared with
normal cells. Results are summarized in (Fig. 1).
3.1.2. Quantification of Pro-inflammatory Cytokines
Production of pro-inflammatory cytokines was signifi-
cantly decreased (p < 0.05) in α-(-)-bisabolol treated cells in
LPS as well as TPA-induced inflammation in macrophage
cells in a dose dependent manner. Representative results ar e
depicted in (Fig. 2).
Table 1. Grading score for primary skin irritation test in rabbit.
Skin Irritation score Score
Erythema formation
No erythema
Very slight erythema (barely perceptible)
Well defines erythema
Moderate erythema
Severe erythema (beet redness)
Edema formation
No edema
Very slight edema (barely perceptible)
Well defined edema (edges of area well defined by definite raising)
Moderate edema (raised approximately 1 mm)
Severe edema (raised more than 1 mm and extending beyond exposure area)
0
1
2
3
4
0
1
2
3
4
176 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 Maurya et al.
Fig. (2). % Cell viability of α-(-)-bisabolol using MTT assay.
3.2. In-vivo Study
3.2.1. Ear Thickness and Ear Weight
Ear edema was observed in all TPA-treated animals at 6h
after treatment. Mice treated with vehicle (Acetone), initial
ear thickness was 0.22mm. Ear thickness increased to
0.47mm by 6 h after TPA treatment. α -(-)-bisabolol treated
experimental mice showed significant reduction of ear
edema when compared with vehicle treated mice. α -(-)-
bisabolol and dexamethasone treatment exhibited the signifi-
cant reduction in ear edema when comp ared with the mice
treated with vehicle (Fig. 3 A). Ear punch biopsy weight at
6h was significantly lower in α-(-)-bisabolol and dexametha-
sone treated mice groups compared to the TPA treated vehi-
cle control group (Fig. 3 B).
3.2.2. Pro-inflammatory Cytokines
The mice treated with vehicle in TPA-induced ear in-
flammation showed the significant (P<0.05) increase in pro-
inflammatory cytokines (TNF-α and IL-6) production when
compared with the normal mice treated with vehicle,
whereas α -(-)-bisabolol showed the inhibition of pro-
inflammatory cytokines levels. Significant (P<0.05) inhibi-
tion of pro-inflammatory cytokines production was observed
in 1.0% α -(-)-bisabolol and dexamethasone treated mice
(Fig. 4).
3.2.3. Lipid Peroxidation
MDA was measured from the homogenate of ear punch
biopsies taken 6h after TPA administration as an index
of lipid peroxidation. The ears treated with 0.3%, 1.0%
α-(-)-bisabolol and dexamethasone doses had significantly
reduced the MDA activity (Fig. 5).
3.2.4. Histopathology
Ear sections obtained from vehicle treated mice resulted
in a marked increase in ear thickness with clear evidence of
edema, and inflammatory cell (infiltrated leukocyte) infiltra-
tion in the dermis with accompanying connective tissue dis-
ruption. By histological comparison, the ears treated with
α-(-)-bisabolol 1.0% and dexamethasone doses had shown
significant changes in ear section (Fig. 6).
Fig. (1). Dose-response effect of α -(-)-bisabolol on LPS and TPA induced inflammation in Macrophages. (A) LPS induced (B) TPA in-
duced. Results are Mean±SEM; n= 4; * P<0.05 (Vehicle vs Treatment).
(A)
(B)
α-(-)-bisabolol Reduces Pro-inflammatory Cytokine Production Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 177
Fig. (3). Dose-response effect of α-(-)-bisabolol on TPA-induced inflammatory ear swelling in BALB/c mice (A) Change in ear thickness (B)
Ear weight. Results are Mean±SEM; n=8; * P<0.05 (Vehicle vs Treatment).
Fig. (4). Effect of α-(-)-bisabolol on inflammatory mediators on TPA-induced ear inflammation in BALB/c mice (A) Ear homogenateTNF-α
(B) Ear homogenate IL-6. Data are expressed as Mean±SEM; n= 4; * P<0.05 (Vehicle vs Treatment).
(A)
(B)
(A)
(B)
178 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 Maurya et al.
Fig. (5). Dose-response effect of α-(-)-bisabolol on TPA-induced oxidative stress mediators quantification from ear tissue homogenate, MDA
formation expressed in μM/ml tissue homogenate. Results are Mean±SEM; n= 4; * P<0.05 (Vehicle vs Treatment).
Fig. (6). Representative photomicrograph of transverse sections of mice ears sensitized with topical application of TPA stained with hema-
toxylin–eosin and examined under light microscopy (magnification: 200×). Treatments: (A) Normal (B) Vehicle (C) α-(-)-bisabolol 0.1%,
(D) α-(-)-bisabolol 0.3%, (E) α-(-)-bisabolol 1% and (F) Dexamethasone 0.1 % . Arrows indicate the epidermis and arrowheads indicate the
inflammatory cells (infiltrated leukocyte). The shown sections are representative of five animals per group.
3.2.5. Primary Skin Irritation
Skin Irritation test was conducted to determine the
primary skin irritation on rabbit skin. 72 hr after the applica-
tion of α -(-)-bisabolol on rabbit skin. Significant erythema
and odema formation were observed in α-(-)-bisabolol treat-
ment site compared to vehicle treated site (Table 2). Pigmen-
tation, blood oozing and rough skin were also not observed
in both the control and treatment site. According to Federal
Hazardous Substances Act (FHSA) regulations, a material
with a PII of less than 5.00 is generally not considered a pri-
mary irritant to the skin. The PII result concluded that the
application of α-(-)-bisabolol is not irritant to the rabbit skin.
3.3. Molecular Docking
Molecular interaction study revealed that α -(-)-bisabolol
and dexamethasone when docked with pro-inflammatory
targets (IL-6 and TNF-α) show good docking scores in terms
of Binding energy and Inhibition constant (Ki) values. Thus
both the ligands possess high affinity for the receptors
(Table 3). Several previous reports also concluded that the
α-(-)-bisabolol Reduces Pro-inflammatory Cytokine Production Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 179
molecules having high binding affinity with targeted protein
exhibited therapeutic efficacy.
4. DISCUSSION
Treatment of most inflammatory skin diseases are domi-
nated by topical or oral corticosteroids. These are typically
used for only short periods of time because they exert some
negative side effects on skin, including immunosuppression,
hyperglycemia etc [14].
α-(-)-bisabolol is a natural monocyclic sesquiterpene pre-
sent in the essential oil of different plants, including chamo-
mile flowers. α-(-)-bisabolol has generated considerable eco-
nomic interest because it possesses a delicate floral odour
and has been shown to have several pharmacological activi-
ties [15]. Pharmaceutical industries currently use α-(-)-
bisabolol in various formulations, mainly in cosmetics as
aftershave lotions, moisturisers, emulsions for sensitive skin
and creams for children. In this study, we examined the im-
pact of α-(-)-bisabolol on the production of pro-inflammatory
cytokine in macrophage cells stimulated with lipopolysac-
charide (LPS) and 12-O-tetradecanoylphorbol-13-acetate
(TPA) as an in-vitro study. We have further validated our
finding in in-vivo system in TPA-induced skin inflammation
in mice as well as molecular docking interaction study with
pro-inflammatory cytokines as well as its safety profile.
In-vitro results demonstrate that the production of pro-
inflammatory cytokines was significantly decreased (p <
0.05) in α-(-)-bisabolol treated cells in LPS as well as TPA-
induced inflammation in macrophage in dose dependant
manner without any cytotoxic effect. Our findings are similar
with the previous observation that α-(-)-bisabolol can inhibit
the production of pro-inflammatory cytokines [9]. The con-
trol of overproduction of the inflammatory mediators may
greatly facilitate the treatment of many inflammation linked
diseases [16].
To substantiate its efficacy to make it best suited for
clinical indications that can be treated with topical therapeu-
tics, we examined its therapeutic efficacy in TPA-induced
skin inflammation in mouse model. The induction of ear skin
inflammation in mice by TPA represents a promising animal
model for elucidating the mechanism of clinical dysfunctio n
and for evaluating the efficacy of topical anti-inflammatory
agents [17, 18]. The results of the study exhibits that the
topical application of TPA increased the ear thickness and
ear weight significantly when compared to the normal mice
treated with acetone alone. Increased skin thickening is often
the first hallmark of skin irritation and local inflammation.
This parameter is indicative of a number of processes that
occur during skin inflammation, including increased vascular
permeability, edema and swelling within the dermis, and
proliferation of the epidermal keratinocytes. The mice
treated with α-(-)-bisabolol exhibited the reduction of oxida-
tive stress and pro-inflammatory markers level [19]. An im-
balance between oxidants and antioxidants can lead to oxida-
tive stress, characterized by escalating cell damage [20].
Oxidative stress is characterized by increased lipid peroxida-
tion and/or altered non enzymatic and enzymatic antioxidant
systems [21]. Pro-inflammatory cytokines (TNF-α and IL-6)
in ear tissue homogenate was significantly increased in TPA
challenged vehicle treated mice when compared with normal
mice. Topical application of α-(-)-bisabolol is able to reduce
(p<0.05) the production of pro-inflammatory cytokines
(TNF-α and IL-6) in dose dependant manner when compared
with vehicle treated mice. It is widely recognized that the
secretions of cytokines by keratinocytes in response to injury
Table 2. Effects of α-(-)-bisabolol on primary skin irritation in rabbit.
Average score
Hours After treatment
Control site Treatment Site
Irritant Intensity
1 0 0 No
4 0.25 0.75 No
24 0 0.75 No
48 0 0 No
72 0 0 No
Table 3. Binding affinity score of α-(-)-bisabolol w ith resp ect to th e inflammatory targets; IL-6 and TNF-α.
Ligand Details Receptors
Mice Interleukin 6 (2L3Y) Tumor Necrosis Factor- α
α
(2TNF)
Name CID Code
BE Ki BE Ki
α-(-)-bisabolol 1549992 -5.7 65.82 -4.73 341.75
Dexamethasone 5743 -5.88 48.56 -6.31 28.83
BE: Binding energy expressed in terms of Kcal/mol; Inhibition constant (Ki): Expressed in μM.
180 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 2 Maurya et al.
are key mediators of the cutaneous inflammatory response
[22]. In this study, it has been clearly demonstrated topical
treatment with α-(-)-bisabolol inhibits the secretion of TNF-α
and IL-6. Primary skin irritation study in rabbits revealed
that it is safe for topical application on skin.
In-vitro and in-vivo anti-inflammatory profile of α -(-)-
bisabolol was further confirmed by molecular docking study.
The aim of the molecular interaction study was to explore
the interaction of α -(-)-bisabolol with pro-inflammatory cy-
tokine receptors. The interaction study was compared with
dexamethasone, a standard steroidal anti-inflammatory drug.
Molecular interaction study of α -(-)-bisabolol with pro-
inflammatory cytokines through docking showed high bind-
ing affinity i.e. low docking energy with pro-inflammatory
cytokines. Several previous reports also conclude that the
molecules having high binding affinity with targeted protein
exhibited therapeutic efficacy [23].
CONCLUSION
The present work conclude through in-vitro, in-vivo and
in-silico study that α-(-)-bisabolol reduces pro-inflammatory
cytokine production and ameliorates skin inflammation. This
study confirms the suitability of α -(-)-bisabolol as a candi-
date for further studies to obtain a suitable prototype drug for
chronic skin inflammatory disorders.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The study was financially supported by CSIR-CIMAP
under OLP-17 project. The authors are grateful to the Direc-
tor of the institute for kind support during the progress of the
work.
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Received: April 14, 20 14 Revised: May 23, 2014 Accepted: May 26, 2014
... Based on these data, the non-toxic range was deemed to be from 1.6 µ g/mL to 50.0 µ g/mL. The non-toxic concentration of β-bisabolol and α-bisabolol was selected following the anti-inflammatory assay of Maurya et al. [49], who reported that concentrations as high as 100 µ g/mL were non-toxic to peritoneal macrophages. To confirm these reports, cell viability assays were performed using a similar concentration range (1.6 µ g/mL to 100.0 µg/mL). ...
... Based on these data, the non-toxic range was deemed to be from 1.6 µg/mL to 50.0 µg/mL. The non-toxic concentration of β-bisabolol and α-bisabolol was selected following the anti-inflammatory assay of Maurya et al. [49], who reported that concentrations as high as 100 µg/mL were non-toxic to peritoneal macrophages. To confirm these reports, cell viability assays were performed using a similar concentration range (1.6 µg/mL to 100.0 µg/mL). ...
... β-Bisabolol has not been investigated for any anti-inflammatory activities prior to this study, even though its isomer α-bisabolol has been extensively studied for anti-inflammatory and other biological activities. Activities associated with α-bisabolol include anti-inflammatory [49,54], anti-oxidant [70], and anti-cancer [71,72]. α-Bisabolol limits the secretion of pro-inflammatory mediators during chronic inflammation [49,54] and in this study, it was demonstrated that β-bisabolol, which differs from α-bisabolol by the position of a hydroxyl group (-OH), also has anti-inflammatory properties. ...
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... As CP exerts inflammatory and oxidative actions, and BIS has antioxidant and antiinflammatory activities [21,22], we thought it would be interesting to evaluate whether BIS could mitigate or prevent CP nephrotoxicity in mice. To the best of our knowledge, such a study has not been reported before. ...
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... The anti-inflammatory effect of α-Bisabolol was envisaged to be mediated by the inhibition of NF-κB and activator protein-1 (AP-1) signaling cascade, and it was further elucidated by α-Bisabolol-induced suppression of ERK and p38 phosphorylation [125]. The topical application of α-Bisabolol demonstrated a remarkable inhibition of pro-inflammatory cytokines in 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced skin inflammation in mice [126]. ...
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α-Bisabolol is one of the important monocyclic sesquiterpenes, derived naturally from essential oils of many edible and ornamental plants. It was first obtained from Matricaria chamomilla, commonly known as chamomile or German chamomile. The available literature indicates that this plant along with other α-Bisabolol containing plants is popularly used in traditional medicine for potential health benefits and general wellbeing. Nutritional studies are indicative of the health benefits of α-Bisabolol. Numerous experimental studies demonstrated pharmacological properties of α-Bisabolol including anticancer, antinociceptive, neuroprotective, cardioprotective, and antimicrobial. This review aims to collectively present different pharmacological activities based on both in vitro and in vivo studies. In the present review using synoptic tables and figures, we comprehensively present that α-Bisabolol possesses therapeutic and protective activities, therefore, it can be used for potential health benefits based on pharmacological effects, underlying molecular mechanism, and favorable pharmaceutical properties. Based on the studies mostly performed in cell lines or animal models, it is evident that α-Bisabolol may be a promising nutraceutical and phytomedicine to target aberrant biological mechanisms which result in altered physiological processes and various ailments. Given the polypharmacological effects and pleiotropic properties, along with favorable pharmacokinetics, and dietary availability and safety, α-Bisabolol can be used as a dietary agent, nutraceutical or phytopharmaceutical agent or as an adjuvant with currently available modern medicines. The regulatory approval of this molecule for use as food additives, and in cosmetics and fragrance industry is also supportive of its human usage. Moreover, further studies are necessary to address pharmaceutical, pharmacological, and toxicological aspects before clinical or nutritional usage in humans. The pharmacological effects and biological actions opens up opportunities on the pharmacological basis of its use in future therapeutics.
... 21 It Reduces Pro-inflammatory Cytokine Production and Ameliorates Skin Inflammation. 22 d-Limonene demonstrates significant anti-inflammatory effects in murine dermal inflammation and wound-healing. 23 Nowadays, thymol was used for wound healing. ...
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... In addition, as one of the four stereoisomers of α-bisabolol, (+)-α-bisabolol, 40 (−)-α-bisabolol, 28,41−44 (+)-epi-α-bisabolol, 45 and (−)-epi-α-bisabolol, 46 (−)-α-bisabolol, which is a monocyclic sesquiterpene alcohol, is highly valued and widely used as an active ingredient in the cosmetics and pharmaceutical industries. 28,47 The productivity of (−)-αbisabolol has been improved by using engineered microbes and high-efficiency BOS for the industrial production. To obtain BOS with better activity and selectivity, the researcher combined three strategies: (1) use the identified enzyme homology search, (2) build a phylogenetic tree to lock a smaller one, and (3) multiple sequence alignments and finally obtained a higher yield of CcBOS from Cynara cardunculus var. ...
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A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .
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Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human keratinocytes (HNK) and human epidermoid carcinoma cell lines (KB, A431) were tested both in a TNF-alpha-specific ELISA and a bioassay. In supernatants of untreated epidermal cells, no or minimal TNF-alpha activity was found, while after stimulation with lipopolysaccharide (LPS) or ultraviolet (UV) light, significant amounts were detected. Western blot analysis using an antibody directed against human TNF-alpha revealed a molecular mass of 17 kD for keratinocyte-derived TNF-alpha. These biological and biochemical data were also confirmed by Northern blot analysis revealing mRNA specific for TNF-alpha in LPS- or ultraviolet B (UVB)-treated HNK and KB cells. In addition, increased TNF-alpha levels were detected in the serum obtained from human volunteers 12 and 24 h after a single total body UVB exposure, which caused a severe sunburn reaction. These findings indicate that keratinocytes upon stimulation are able to synthesize and release TNF-alpha, which may gain access to the circulation. Thus, TNF-alpha in concert with other epidermal cell-derived cytokines may mediate local and systemic inflammatory reactions during host defense against injurious events caused by microbial agents or UV irradiation.
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A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1. error of 9.11 kJ mol 2.177 kcal mol and was chosen as the new energy
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This work examined the gastroprotection of (-)-α-bisabolol, an unsaturated optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants. (-)-α-Bisabolol has been described as a compound capable of reducing the gastric ulcer area in response to absolute ethanol. We evaluated the gastroprotection of (-)-α-bisabolol in ethanol-induced gastric lesions model through histopathological assessment, measurement of the membrane lipids peroxidation (MDA), myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, catalase (CAT) activity and the nitrite amount. Our results showed that (-)-α-bisabolol was able to reduce injuries associated with the administration of ethanol and the formation of thiobarbituric acid reactive substances (MDA) was also able to increase SOD activity and reduce the influx of cells inflammatory (neutrophils) in the gastric mucosa. The effect of (-)-α-bisabolol seems to be unrelated to the nitric oxide. (-)-α-Bisabolol caused a reduction of catalase activity. These findings show that (-)-α-bisabolol is able to decrease oxidative stress and inflammatory event associated with the lesions induced by ethanol.