Terpenes from Forests and Human Health

Abstract

Forest bathing has beneficial effects on human health via showering of forest aerosols as well as physical relaxation. Terpenes that consist of multiple isoprene units are the largest class of organic compounds produced by various plants, and one of the major components of forest aerosols. Traditionally, terpene-containing plant oil has been used to treat various diseases without knowing the exact functions or the mechanisms of action of the individual bioactive compounds. This review categorizes various terpenes easily obtained from forests according to their anti-inflammatory, anti-tumorigenic, or neuroprotective activities. Moreover, potential action mechanisms of the individual terpenes and their effects on such processes, which are described in various in vivo and in vitro systems, are discussed. In conclusion, the studies that show the biological effectiveness of terpenes support the benefits of forest bathing and propose a potential use of terpenes as chemotherapeutic agents for treating various human diseases.

Full text

97
Toxicol. Res.
Vol. 33, No. 2, pp. 97-106 (2017)
https://doi.org/10.5487/TR.2017.33.2.097
plSSN: 1976-8257 eISSN: 2234-2753 Review Article
Open Access
Terpenes from Forests and Human Health
Kyoung Sang Cho
1,2
, Young-ran Lim
1
, Kyungho Lee
1,2
, Jaeseok Lee
1,2
, Jang Ho Lee
1
and Im-Soon Lee
1,2
1
Department of Biological Sciences, Konkuk University, Seoul, Korea
2
Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
(Received February 6, 2017; Revised February 14, 2017; Accepted February 16, 2017)
Forest bathing has beneficial effects on human health via showering of forest aerosols as well as physical
relaxation. Terpenes that consist of multiple isoprene units are the largest class of organic compounds pro-
duced by various plants, and one of the major components of forest aerosols. Traditionally, terpene-con-
taining plant oil has been used to treat various diseases without knowing the exact functions or the
mechanisms of action of the individual bioactive compounds. This review categorizes various terpenes
easily obtained from forests according to their anti-inflammatory, anti-tumorigenic, or neuroprotective
activities. Moreover, potential action mechanisms of the individual terpenes and their effects on such pro-
cesses, which are described in various in vivo and in vitro systems, are discussed. In conclusion, the stud-
ies that show the biological effectiveness of terpenes support the benefits of forest bathing and propose a
potential use of terpenes as chemotherapeutic agents for treating various human diseases.
Key words: Cancer, Forest therapy, Health, Immune function, Neuronal health, Terpene
INTRODUCTION
Exposure to natural environment is beneficial to human
health (1). Among environmental exposures, the effects of
forest have been emphasized in many studies (2). Recently,
it has been shown that a short trip to forest environments
has therapeutic effects in children with asthma and atopic
dermatitis (3). Based on these studies, healthcare programs to
use forest have been developed in several countries (2,4,5).
For example, in the United States, “forest recreation” became
recognized as the most valuable use of forest in the 1960s in
light of social welfare (4). In Germany, a complementary
and alternative medicine practice called “Kneipp therapy” is
frequently used (6). Kneipp therapy includes five preven-
tive and curative methods created by Sebastian Kneipp, a
German priest (5), in which exercise in a forest is one of the
five core methods (2). Japan is one of the countries where
the forest usage programs for human health are well devel-
oped. The Forest Agency of the Japanese government intro-
duced the term “Shinrin-yoku,” defined as “taking in the
forest atmosphere or forest bathing” in 1982, and instituted
the “Therapeutic effects of forests plan” in 2005 (2).
Many studies have shown meaningful physiological effects
of forest atmosphere on people (2,7,8). These effects are
believed to be achieved by inhaling the forest atmosphere,
which includes various phytochemicals mainly produced by
trees. The major components of the forest atmosphere are
terpenes, which are the largest class of naturally occurring
organic compounds (9) with more than 40,000 structures
reported so far (9,10). Their basic chemical structure con-
sists of an isoprene unit (C
5
H
8
) (11). Depending on the number
of isoprene units, terpenes are classified as mono-, sesqui-,
and di-terpenes (C10, C15, and C20, respectively) (Fig. 1A)
(12). Terpenes have enormous chemical structural diversity
that is generated by various terpenoid metabolic pathways
as well as the specialized cell types that participate in their
biosynthesis (13). The biosynthesis of terpenes uses two
common C5 building blocks, dimethylallyl pyrophosphate
(DMAPP) and isopentenyl pyrophosphate (IPP), derived
from acetyl coenzyme A (14). Head-to-tail condensation of
DMAPP and IPP generates the monoterpene precursor, ger-
Correspondence to: Im-Soon Lee, Department of Biological Sci-
ences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul
05029, Korea
E-mail: islee@konkuk.ac.kr
The list of abbreviations: BCP, β-caryophyllene; GPP, geranyl pyro-
phosphate; DMAPP, dimethylallyl pyrophosphate; IPP, isopentenyl
pyrophosphate; MAPK, mitogen-activated protein kinase; NF-κB,
nuclear factor kappa B; IL, interleukin; TNF-α, tumor necrosis fac-
tor-α; NO, nitric oxide; LPS, lipopolysaccharide; MMP, matrix metal-
loproteinases; AD, Alzheimer’s disease; PD, Parkinson’s disease.
This is an Open-Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0) which permits unrestricted
non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.

98 K.S. Cho et al.
anyl pyrophosphate (GPP, C10) (Fig. 1B) (15). Furthermore,
sesquiterpenes and diterpenes are created by condensation
of additional IPP units to GPP (Fig. 1B) (15,16).
Terpenes are produced by various plants, particularly
conifers (13). Many of the terpenes are associated with not
only the defense mechanism of the plant against herbivores
and the environment (11,17) but also their developmental
physiology (9). Korean forests mainly consist of various
types of conifers, and many terpenes derived from them
have been detected, such as α-pinene, β-pinene, camphor,
camphene, sabinene, limonene, menthol, cymene, and
myrcene (18). Conifer oleoresins contain monoterpenes (e.g.,
pinene and camphor) and diterpenes (e.g., taxadiene and
phytane) as major components and sesquiterpenes (e.g.,
nerolidol and (E)-α-bisabolene) as minor components (17).
Given that the forest atmosphere is beneficial to human
health and that terpenes are the main components of forest
aerosols, we reviewed the effects of various terpenes from
Korean forests on human health, especially on immunity,
cancer, and neuronal health.
TERPENES WITH ANTI-INFLAMMATORY
FUNCTION
Studies in recent decades have demonstrated that ter-
penes exert anti-inflammatory effects by inhibiting various
proinflammatory pathways in ear edema, bronchitis, chronic
obstructive pulmonary disease, skin inflammation, and osteo-
arthritis (19-23).
α-Pinene, found in oils of coniferous trees and rosemary,
showed anti-inflammatory activity by decreasing the activ-
ity of mitogen-activated protein kinases (MAPKs), expres-
sion of nuclear factor kappa B (NF-κB), and production of
interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and
nitric oxide (NO) in lipopolysaccharide (LPS)-induced mac-
rophages (24). In ovalbumin-sensitized mouse model of
allergic rhinitis, pretreatment with α-pinene decreased clini-
cal symptoms and levels of immunoglobulin E and IL-4
(25). In human chondrocytes, α-pinene inhibited IL-1β-
induced inflammation pathway by suppressing NF-κB, c-
Jun N-terminal kinase (JNK) activation, and expression of
Fig. 1. Structures of various terpenes (A) and terpene biosynthesis pathway for pinenes (B). (A) Depending on the carbon number,
terpenes are classified as mono-, sesqui-, and di-terpenes. (B) Using DMAPP and IPP as building blocks, monoterpenes are produced
from GPP. Especially, α-pinene and β-pinene are generated via cyclisation of linaloyl pyrophosphate and the loss of a proton from the
carbocation equivalent.

Terpenes and Human Health 99
iNOS and matrix metalloproteinases (MMP)-1 and -13,
suggesting its role as an anti-osteoarthritic agent (19). Strong
anti-inflammatory activity was observed when α-pinene
was used in combination with two active ingredients of
frankincense, linalool and 1-octanol (22).
Another naturally occurring monoterpene d-limonene was
reported to reduce allergic lung inflammation in mice prob-
ably via its antioxidant properties (26). It also reduced car-
rageenan-induced inflammation by reducing cell migration,
cytokine production, and protein extravasation (27). Simi-
lar to α-pinene, d-limonene exerted an anti-osteoarthritic
effect by inhibiting IL-1β-induced NO production in human
chondrocytes (28). d-Limonene treatment reduced doxoru-
bicin-induced production of two proinflammatory cytokines,
TNF-α and prostaglandin E-2 (PGE
2
) (29).
Monoterpene p-cymene treatment reduced elastase-induced
lung emphysema and inflammation in mice. It reduced the
alveolar enlargement, number of macrophages, and levels
of proinflammatory cytokines such as IL-1β, IL-6, IL-8,
and IL-17 in bronchoalveolar lavage fluid (BALF) (30).
Similarly, p-cymene showed a protective effect in a mouse
model of LPS-induced acute lung injury by reducing the
number of inflammatory cells in the BALF and expression
of NF-κB in the lungs (31) and by reducing production of
proinflammatory cytokines and infiltration of inflammatory
cells (32). Mechanistically, p-cymene blocks NF-κB and
MAPK signaling pathways. It has been reported that p-
cymene reduces production of TNF-α, IL-6, and IL-β in
LPS-treated RAW 264.7 macrophages. In C57BL/6 mice,
TNF-α and IL-1β were downregulated and IL-10 was upreg-
ulated by p-cymene treatment. It also inhibited LPS-induced
activation of ERK 1/2, p38, JNK, and IκBα (32,33).
Treatment with linalool, a natural compound found in
essential oils of aromatic plants, inhibited cigarette smoke-
induced acute lung inflammation by inhibiting infiltration
of inflammatory cells and production of TNF-α, IL-6, IL-
1β, IL-8, and monocyte chemoattractant protein - 1 (MCP-
1), as well as NF-κB activation (20). In another lung injury
model, linalool attenuated lung histopathologic changes in
LPS-induced mice. In in vitro experiments, linalool reduced
production of TNF-α and IL-6 and blocked phosphorylation
of IκBα protein, p38, and JNK in LPS-stimulated RAW
264.7 macrophages (34). Similarly, linalool inhibited pro-
duction of TNF-α, IL-1β, NO, and PGE
2
in LPS-stimulated
microglia cells (35). Li et al. (35) showed that the anti-
inflammatory effect of linalool is involved in activation of
Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Frank-
incense oil extract, which contains linalool, exhibited anti-
inflammatory and analgesic effects in a xylene-induced ear
edema model and a formalin-inflamed hind paw model by
inhibiting COX-2 (22).
The monoterpene γ-terpinene, present in the essential oil
of many plants including Eucalyptus, reduced the acute
inflammatory response. It reduced carrageenan-induced paw
edema, migration of neutrophil into lung tissue, and IL-1β
and TNF-α production and inhibited fluid extravasation
(36). Terpinene-containing essential oil from Liquidambar
formosana leaves reduced inflammatory response in LPS-
stimulated mouse macrophages by reducing reactive oxy-
gen species (ROS), JNK, ERK, p38 MAP kinase, and NF-
κB (37). Another terpinene-containing essential oil from
Citrus unshiu flower or fingered citron (C. medica L. var.
sarcodactylis) reduced LPS-stimulated PGE
2
and NO pro-
duction in RAW 264.7 cells. Furthermore, production of
inflammatory cytokines, such as IL-1β, TNF-α, and IL-6,
was also reduced in macrophages (38,39).
Borneol, a bicyclic monoterpene present in Artemisia,
Blumea, and Kaempferia, has been used in traditional medi-
cine. Borneol alleviated acute lung inflammation by reduc-
ing inflammatory infiltration, histopathological changes, and
cytokine production in LPS-stimulated mice. It suppressed
phosphorylation of NF-κB, IκBα, p38, JNK, and ERK (40).
Oral administration and intrathecal injection of borneol
showed antihyperalgesic effects on inflammatory pain in
complete Freund’s adjuvant-induced hypersensitive animal
models by enhancing GABA
A
R (Gamma-Aminobutyric Acid
Type A Receptor)-mediated GABAergic transmission (41).
Borneol inhibited migration of leukocytes into the perito-
neal cavity in carrageenan-stimulated mice, suggesting its
anti-inflammatory function (42). In addition, borneol inhib-
ited TRPA1, a cation channel that is involved in inflamma-
tion and noxious-pain sensing, suggesting that its use as an
anti-inflammatory agent for neuropathic-pain and trigemi-
nal neuralgia (43).
A natural sesquiterpene β-caryophyllene (BCP) was re-
ported to protect against neuroinflammation in a rat model
of Parkinson’s disease (PD) by attenuating production of
proinflammatory cytokines and inflammatory mediators such
as COX-2 and iNOS (44). Chronic treatment with BCP
attenuated alcohol-induced liver injury and inflammation by
reducing the proinflammatory phenotypic switch of hepatic
macrophages and neutrophil infiltration. The beneficial
effects of BCP on liver injury are mediated by cannabinoid
2 (CB2) receptor activation (45). Prolonged administration
of BCP reduced proinflammatory cytokines in pancreatic
tissue of streptozotocin-induced diabetic rats (46). BCP
reduced expression of Toll-like receptor 4 and macrophage
inflammatory protein-2, and phosphorylation of ERK, p38,
JNK, and NF-κB in D-galactosamine and LPS-induced
liver injury mouse model (47).
Besides the aforementioned terpenes, anti-inflammatory
effects have been reported with sabinene itself or sabinene-
containing oil (48,49), bornyl acetate (50) and myrcene (28).
TERPENES AND TUMOR
Tumorigenesis is a multifaceted process, the progression
of which is associated with several hallmarks, including

100 K.S. Cho et al.
uncontrolled cell growth, dysregulation of apoptosis, activa-
tion of invasion, induction of angiogenesis, and metastasis.
Terpenes have been shown to exert anti-tumorigenic effects
against such processes in a number of in vivo and in vitro
systems, thus suggesting their potential uses as chemothera-
peutic agents for treating tumors.
A number of monoterpenes have been reported to exert
chemopreventive effects against tumors (51). Of these, the
anti-tumorigenic activity of d-limonene is well-established.
Numerous studies have demonstrated the protective effects
of d-limonene against chemical-induced tumors in various
tissue types such as breast, intestine, pancreas, liver, and
colon (52-57). Lu et al. (57) revealed that d-limonene could
inhibit the proliferation of human gastric cancer cells by
inducing apoptosis. Later, it was demonstrated that apopto-
sis of tumor cells by d-limonene could be mediated by the
mitochondrial death pathway via activated caspases and
PARP cleavage as well as by the suppression of the PI3K/
Akt pathway (58,59). In addition, positive effects on NK
(Natural Killer) activities were demonstrated not only in the
in vitro treatment of tumor cell lines with monoterpenes
released from trees, such as d-limonene and α-pinene, but
also in forest bathing trips by increasing intracellular levels
of anti-tumor proteins such as perforin, granulysin, and
granzymes A/B (60).
Anti-tumor effects of pinenes are well established on
tumor lymphocytes as well as tumor cell lines (61). Matsuo
et al. (62) identified proapoptotic and anti-metastatic activi-
ties of α-pinene in a melanoma model. Later, it was revealed
in human hepatoma Bel-7402 cells that the proapoptotic
effect of α-pinene is associated with induction of G2/M cell
cycle arrest (63). In addition, α-pinene triggers oxidative
stress signaling pathways in A549 and HepG2 cells (64).
However, Kusuhara et al. (65) reported that mice kept in a
setting enriched with α-pinene showed reduction in mela-
noma sizes, while in vitro treatment of melanoma cells with
α-pinene had no inhibitory effect on cell proliferation, sug-
gesting that the in vivo result may not be due to a direct
effect of α-pinene. Investigation of β-pinene also revealed
its cytotoxic activity against cancer and normal cell lines
with a more pronounced effect on neoplastic cells in the
majority of cases, showing acceptable chemotherapeutic
potency (66,67).
Perillyl alcohol is a naturally occurring monoterpene, and
a metabolite of limonene. Despite preclinical evidence of
anticancer activity, perillyl alcohol appeared to have no clini-
cal antitumor activity upon oral administration to patients
with advanced colorectal carcinoma (68). However, currently,
it is under preclinical development as a potential clinical
treatment for patients with brain tumor (69). Perillic acid is
a major metabolite of perillyl alcohol. Upon examining the
effects of perillic acid on lung metastasis induced by mela-
noma cells in mice, it was observed that administration of
perillic acid remarkably reduced the metastatic tumor nod-
ule formation by exerting an inhibitory effect on cell growth
by G1 arrest (70,71).
p-Cymene has been reported to have cytotoxic effects on
tumor cell lines (72). Recently, Li et al. (73) evaluated ben-
eficial effects of p-cymene on in vitro TPA-augmented inva-
siveness of HT-1080 cells, and found that it inhibits MMP-9
expression, but enhances TIMP-1 production along with the
suppression of ERK1/2 and p38 MAPK signal pathways in
tumor cells, suggesting that p-cymene is an effective candi-
date for the prevention of tumor invasion and metastasis.
Myrcene, the acyclic monoterpene, also exhibits signifi-
cant antiproliferative and cytotoxic effects in various tumor
cell lines such as MCF-7 (breast carcinoma), HeLa (human
cervical carcinoma), A549 (human lung carcinoma), HT-29
(human colon adenocarcinoma), P388 (leukemia), and Vero
(monkey kidney) as well as mouse macrophages (74,75).
Essential oil from Vepris macrophylla demonstrated a strong
cytotoxic effect, suggesting that the effect may be attributed
to the presence of specific components, among which is
myrcene (76).
Terpenes with more complex structures than monoterpenes,
including sesquiterpenoids derived from sesquiterpenes by
biochemical modifications, have demonstrated anticancer
ability as well. The anticancer effect of various sesquiter-
penoids is mediated via inhibition of inflammatory responses,
prevention of metastasis, and induction of apoptosis (77).
α-Caryophyllene, known as humulene, is a naturally occur-
ring monocyclic sesquiterpene. BCP, an isomer of α-caryo-
phyllene, has been identified as an active component of an
essential oil mixture that not only prevents solid tumor
growth and proliferation of cancer cell lines but also inhib-
its lymph node metastasis of melanoma cells in high-fat
diet-induced obese mice (78,79). Sarvmeili et al. (80) re-
ported that Pinus eldarica essential oil, of which BCP was
the major component, exerts cytotoxic effects on HeLa and
MCF-7 cell lines.
As described above, numerous in vitro and in vivo experi-
mental results have demonstrated that the toxicity of ter-
pene affects mainly cancer cells without harming healthy
ones, confirming their efficiency in chemotherapeutic treat-
ment of cancer. Thus, it is noteworthy that the use of ter-
pene and its derivatives can be considered to potentiate the
action of existing conventional therapies (81,82).
TERPENES AND NEURONAL HEALTH
Numerous studies have shown that essential oils derived
from various plants have neuroprotective effects against neu-
rodegenerative conditions in vivo and in vitro (83-90). There-
fore, as a main component of plant essential oils, terpenes
may be beneficial to human neuronal health. However, only
few studies have focused on the beneficial effects of ter-
pene components of plant essential oils on neuronal health.
So far, several terpenes, produced by a variety of plants,

Terpenes and Human Health 101
Tab le 1. Studies reporting the effects of terpenes on human health
Class Terpene Structure Effect Related literature
Mono- 1,8-Cineole Antioxidation
Neuroprotection
(106)
(106)
1-Octanol Anti-inflammation (73)
Borneol Anti-inflammation
Antioxidation
Neuroprotection
(40-43)
(91-101)
(91-94)
Bornyl acetate Anti-inflammation (50)
Cymene Anti-inflammation
Anti-cancer
Neuroprotection
(30-33)
(72,73)
(107)
Limonene Anti-inflammation
Antioxidation
Anti-cancer
(26-29)
(52-60)
(20,22,34,35)
Linalool Anti-inflammation (20,22,34,35)
Myrcene Anti-inflammation
Anti-cancer
(28)
(74-76)
Perillyl alcohol Anti-cancer (68-71)
Pinene Anti-inflammation
Anti-cancer
Antioxidation
Neuroprotection
(19,22,24,25)
(60-66)
(105)
(106)
Sabinene Anti-inflammation (48,49)
Terpinene Anti-inflammation (36-39)
Sesqui- Caryophyllene Anti-inflammation
Anti-cancer
Antioxidation
Neuroprotection
(31,44-47)
(78-80)
(44,103)
(44,103-105)

102 K.S. Cho et al.
have been associated with neuronal health. Among those,
borneol is a bicyclic monoterpene present in several medici-
nal plants (91-94). Previous studies showed that borneol has
free radical scavenging activity (95) and is a major compo-
nent of essential oil of SuHeXiang Wan (92) whose neuro-
protective function has been reported in in vivo and in vitro
models of Alzheimer’s disease (AD) (96-99). Moreover, a
recent study showed that borneol exerts a neuroprotective
effect against β-amyloid (Aβ) cytotoxicity via upregulation
of nuclear translocation of Nrf2 and expression of Bcl-2
(100). In addition, treatment with isoborneol, a monoter-
penoid alcohol, significantly reduced 6-hydroxydopamine-
induced ROS generation and cell death in human neuroblas-
toma SH-SY5Y cells, suggesting that isoborneol may be a
potential therapeutic agent for treatment of neurodegenera-
tive diseases associated with oxidative stress (101). Salvi-
anic borneol ester, a new compound synthesized from salvianic
acid A and borneol, also exerts anti-amyloid and neuropro-
tective effects in both SH-SY5Y cells and motor neuron
hybridoma VSC 4.1 cells (102).
BCP also has neuroprotective functions. It has been
reported that BCP has antioxidant effects (103), and func-
tions as a regulator of several neuronal receptors and shows
various pharmacological activities including neuroprotec-
tion (104). Neuroprotective effects of BCP have been reported
in both AD and PD animal models. Oral treatment with BCP
prevented AD-like phenotype such as cognitive impair-
ment and activation of inflammation through CB2 receptor
activation and the PPARγ pathway (105). As described above,
BCP administration also exerts neuroprotective effects in
rotenone-challenged rat model of PD by reducing neuro-
inflammation (44).
Other monoterpenes such as α-pinene and 1, 8-cineole
also exert neuroprotective effects by regulating gene expres-
sion. They protected PC12 cells against oxidative stress-
induced apoptosis through ROS scavenging and induction
of nuclear Nrf2 factor followed by enhanced expression of
antioxidant enzymes including catalase, superoxide dis-
mutase, glutathione peroxidase, glutathione reductase, and
HO-1 (106). Similarly, p-cymene has cholinergic effects
through regulation of expression of several genes in Caenor-
habditis elegans (107). Given that terpenes are major com-
ponents of essential oils of various medicinal plants with
neuroprotective functions, studies to find the beneficial roles
of terpenes in neurodegenerative diseases will provide a
promising way to develop therapeutics.
CONCLUSION AND PERSPECTIVES
Essential oils obtained from plants have been used in
diverse traditional medicines because of their broad benefi-
cial effects on human health (108). To date, many terpenes
from essential oils as well as forest bathing have been
reported to exhibit strong biological activities. This review
categorized the terpenes that have presented important results
in cell and animal systems according to their anti-inflamma-
tory, anti-tumorigenic, or neuroprotective activities (Table
1). Although data elucidating the possible action mecha-
nisms of these compounds are increasing, numerous stud-
ies still present only preliminary screening results. Thus, to
investigate the future chemotherapeutic uses of terpenes, it
is necessary to explore further the detailed action mecha-
nisms including signaling pathways that are associated with
their biological functions. In addition, understanding of the
relationship between the diverse chemical structures of ter-
penes and the in vivo physiological roles of these compounds
may provide critical insights for the future development of
therapeutics with enhanced selectivity and specificity.
So far, many studies have extensively reported the phar-
maceutical activities of monoterpenes among the terpenes.
Monoterpenes, formed from the coupling of two isoprene
units (C10), are the major molecules consisting 90% of the
essential oils (109). However, in recent years, small sub-
groups of other terpenes and terpenoids that exhibit diverse
biological activities have been isolated or synthesized, pro-
viding a source of novel chemotherapeutic molecules. The
use of various terpenes in clinical trials is currently limited
due to insufficient data from human studies. However, their
use as potent chemotherapeutic compounds alone, as well
as in combination with previously proven chemotherapeu-
tic drugs, to increase effectiveness and decrease doses is
expected to increase as data on their safety and efficacy in
in vivo and in vitro systems are accumulated.
CONFLICT OF INTEREST
The authors declare that they have no competing inter-
ests.
ACKNOWLEDGMENTS
This research was supported by the National Research
Foundation of Korea (NRF) funded by the Ministry of Sci-
ence, ICT and Future Planning (NRF-2016M3C1B6928005).
REFERENCES
1. Frumkin, H. (2001) Beyond toxicity: human health and the
natural environment. Am. J. Prev. Med., 20, 234-240.
2. Tsunetsugu, Y., Park, B.J. and Miyazaki, Y. (2010) Trends in
research related to “Shinrin-yoku” (taking in the forest atmo-
sphere or forest bathing) in Japan. Environ. Health Prev. Med.,
15, 27-37.
3. Seo, S.C., Park, S.J., Park, C.W., Yoon, W.S., Choung, J.T.
and Yoo, Y. (2015) Clinical and immunological effects of a
forest trip in children with asthma and atopic dermatitis. Iran
J. Allergy Asthma Immunol., 14, 28-36.
4. Douglass, R.W. (1982) Forest recreation (3rd edition), Perga-
mon Press.

Terpenes and Human Health 103
5. Spievogel, I. and Spalek, K. (2012) Medicinal plants uesed in
pediatric prophylactic method of Sebastian Kneipp. Nat. J.,
45, 9-18.
6. Joos, S., Rosemann, T., Szecsenyi, J., Hahn, E.G., Willich,
S.N. and Brinkhaus, B. (2006) Use of complementary and
alternative medicine in Germany: a survey of patients with
inflammatory bowel disease. BMC Complement. Altern. Med.,
6, 19.
7. Park, B.J., Tsunetsugu, Y., Kasetani, T., Kagawa, T. and
Miyazaki, Y. (2010) The physiological effects of Shinrin-yoku
(taking in the forest atmosphere or forest bathing): evidence
from field experiments in 24 forests across Japan. Environ.
Health Prev. Med., 15, 18-26.
8. Song, C., Ikei, H. and Miyazaki, Y. (2016) Physiological
effects of nature therapy: A review of the research in Japan.
Int. J. Environ. Res. Public Health, 13, E781.
9. Gershenzon, J. and Dudareva, N. (2007) The function of ter-
pene natural products in the natural world. Nat. Chem. Biol.,
3, 408-414.
10. Chappell, J. (2002) The genetics and molecular genetics of
terpene and sterol origami. Curr. Opin. Plant Biol., 5, 151-157.
11. Mewalal, R., Rai, D.K., Kainer, D., Chen, F., Külheim, C.,
Peter, G.F. and Tuskan, G.A. (2016) Plant-derived terpenes: A
feedstock for specialty biofuels. Trends Biotechnol., S0167-
7799(16)30128-7.
12. Kirby, J. and Keasling, J.D. (2009) Biosynthesis of plant iso-
prenoids: perspectives for microbial engineering. Annu. Rev.
Plant Biol., 60, 335-355.
13. Zulak, K.G. and Bohlmann, J. (2010) Terpenoid biosynthesis
and specialized vascular cells of conifer defense. J. Integr.
Plant Biol., 52, 86-97.
14. Lange, B.M. and Ahkami, A. (2013) Metabolic engineering of
plant monoterpenes, sesquiterpenes and diterpenes: current
status and future opportunities. Plant Biotechnol. J., 11, 169-196.
15. Dubey, V.S., Bhalla, R. and Luthra, R. (2003) An overview of
the non-mevalonate pathway for terpenoid biosynthesis in
plants. J. Biosci., 28, 637-646.
16. Matsuba, Y., Nguyen, T.T., Wiegert, K., Falara, V., Gonzales-
Vigil, E., Leong, B., Schäfer, P., Kudrna, D., Wing, R.A., Bol-
ger, A.M., Usadel, B., Tissier, A., Fernie, A.R., Barry, C.S.
and Pichersky, E. (2013) Evolution of a complex locus for ter-
pene biosynthesis in solanum. Plant Cell, 25, 2022-2036.
17. Martin, D.M., Gershenzon, J. and Bohlmann, J. (2003) Induc-
tion of volatile terpene biosynthesis and diurnal emission by
methyl jasmonate in foliage of Norway spruce. Plant Physiol.,
132, 1586-1599.
18. Lee, D.H., Kim, M.H., Park, O.H., Park, KS., An, S.S., Seo,
H.J., Jin, S.H., Jeong, W.S., Kang, Y.J., An, K.W. and Kim,
E.S. (2013) A study on the distribution characteristics of ter-
pene at the main trails of Mt. Mudeung. J. Environ. Health
Sci., 39, 211-222.
19. Rufino, A.T., Ribeiro, M., Judas, F., Salgueiro, L., Lopes,
M.C., Cavaleiro, C. and Mendes, A.F. (2014) Anti-inflamma-
tory and chondroprotective activity of (+)-α-pinene: struc-
tural and enantiomeric selectivity. J. Nat. Prod., 77, 264-269.
20. Ma, J., Xu, H., Wu, J., Qu, C., Sun, F. and Xu, S. (2015) Linalool
inhibits cigarette smoke-induced lung inflammation by inhibiting
NF-κB activation. Int. Immunopharmacol., 29, 708-713.
21. Rodrigues, K.A., Amorim, L.V., Dias, C.N., Moraes, D.F.C.,
Carneiro, S.M. and Carvalho, F.A. (2015) Syzygium cumini
(L.) Skeels essential oil and its major constituent α-pinene
exhibit anti-Leishmania activity through immunomodulation
in vitro. J. Ethnopharmacol., 160, 32-40.
22. Li, X.J., Yang, Y.J., Li, Y.S., Zhang, W.K. and Tang, H.B.
(2016) α-Pinene, linalool and 1-octanol contribute to the topi-
cal anti-inflammatory and analgesic activities of frankincense
by inhibiting COX-2. J. Ethnopharmacol., 179, 22-26.
23. Yu, P.J., Wan, L.M., Wan, S.H., Chen, W.Y., Xie, H., Meng,
D.M., Zhang, J.J. and Xiao, X.L. (2016) Standardized myrtol
attenuates lipopolysaccharide induced acute lung injury in
mice. Pharm. Biol., 54, 3211-3216.
24. Kim, D.S., Lee, H.J., Jeon, Y.D., Han, Y.H., Kee, J.Y., Kim,
H.J., Shin, H.J., Kang, J., Lee, B.S., Kim, S.H., Kim, S.J., Park,
S.H., Choi, B.M., Park, S.J., Um, J.Y. and Hong, S.H. (2015)
Alpha-pinene exhibits anti-inflammatory activity through the
suppression of MAPKs and the NF-κB pathway in mouse
peritoneal macrophages. Am. J. Chin. Med., 43, 731-742.
25. Nam, S.Y., Chung, C.k., Seo, J.H., Rah, S.Y., Kim, H.M. and
Jeong, H.J. (2014) The therapeutic efficacy of α-pinene in an
experimental mouse model of allergic rhinitis. Int. Immuno-
pharmacol., 23, 273-282.
26. Hansen, J.S., Nørgaard, A.W., Koponen, I.K., Sørli, J.B.,
Paidi, M.D., Hansen, S.W., Clausen, P.A., Nielsen, G.D.,
Wolkoff, P. and Larsen, S.T. (2016) Limonene and its ozone-
initiated reaction products attenuate allergic lung inflamma-
tion in mice. J. Immunotoxicol., 13, 793-803.
27. Amorim, J.L., Simas, D.L.R., Pinheiro, M.M., Moreno, D.S.,
Alviano, C.S., da Silva, A.J. and Fernandes, P.D. (2016) Anti-
inflammatory properties and chemical characterization of the
essential oils of four citrus species. PLoS ONE, 11, e0153643.
28. Rufino, A.T., Ribeiro, M., Sousa, C., Judas, F., Salgueiro, L.,
Cavaleiro, C. and Mendes, A.F. (2015) Evaluation of the anti-
inflammatory, anti-catabolic and pro-anabolic effects of E-
caryophyllene, myrcene and limonene in a cell model of
osteoarthritis. Eur. J. Pharmacol., 750, 141-150.
29. Rehman, M.U., Tahir, M., Khan, A.Q., Khan, R., Oday-O-
Hamiza, Lateef, A., Hassan, S.K., Rashid, S., Ali, N., Zee-
shan, M. and Sultana, S. (2014) D-limonene suppresses doxo-
rubicin-induced oxidative stress and inflammation via
repression of COX-2, iNOS and NFκB in kidneys of Wistar
rats. Exp. Biol. Med. (Maywood), 239, 465-476.
30. Games, E., Guerreiro, M., Santana, F.R., Pinheiro, N.M., de
Oliveira, E.A., Lopes, F.D., Olivo, C.R., Tibério, I.F., Mar-
tins, M.A., Lago, J.H. and Prado, C.M. (2016) Structurally
related monoterpenes p-Cymene, carvacrol and thymol iso-
lated from essential oil from leaves of lippia sidoides cham.
(Verbenaceae) protect mice against elastase-induced emphy-
sema. Molecules, 21, E1390.
31. Chen, L., Zhao, L., Zhang, C. and Lan, Z. (2014) Protective
effect of p-cymene on lipopolysaccharide-induced acute lung
injury in mice. Inflammation, 37, 358-364.
32. Xie, G., Chen, N., Soromou, L.W., Liu, F., Xiong, Y., Wu, Q.,
Li, H., Feng, H. and Liu, G. (2012) p-Cymene protects mice
against lipopolysaccharide-induced acute lung injury by inhib-
iting inflammatory cell activation. Molecules, 17, 8159-8173.
33. Zhong, W., Chi, G., Jiang, L., Soromou, L.W., Chen, N., Huo,
M., Guo, W., Deng, X. and Feng, H. (2013) p-Cymene modu-
lates in vitro and in vivo cytokine production by inhibiting

104 K.S. Cho et al.
MAPK and NF-κB activation. Inflammation, 36, 529-537.
34. Huo, M., Cui, X., Xue, J., Chi, G., Gao, R., Deng, X., Guan,
S., Wei, J., Soromou, L.W., Feng, H. and Wang, D. (2013)
Anti-inflammatory effects of linalool in RAW 264.7 macro-
phages and lipopolysaccharide-induced lung injury model. J.
Surg. Res., 180, e47-e54.
35. Li, Y., Lv, O., Zhou, F., Li, Q., Wu, Z. and Zheng, Y. (2015)
Linalool inhibits LPS-induced inflammation in BV2 microg-
lia cells by activating Nrf2. Neurochem. Res., 40, 1520-1525.
36. de Oliveira Ramalho, T.R., de Oliveira, M.T., de Araujo Lima,
A.L., Bezerra-Santos, C.R. and Piuvezam, M.R. (2015)
Gamma-terpinene modulates acute inflammatory response in
mice. Planta Med., 81, 1248-1254.
37. Hua, K.F., Yang, T.J., Chiu, H.W. and Ho, C.L. (2014) Essen-
tial oil from leaves of Liquidambar formosana ameliorates
inflammatory response in lipopolysaccharide-activated mouse
macrophages. Nat. Prod. Commun., 9, 869-872.
38. Kim, K.N., Ko, Y.J., Yang, H.M., Ham, Y.M., Roh, S.W.,
Jeon, Y.J., Ahn, G., Kang, M.C., Yoon, W.J., Kim, D. and Oda,
T. (2013) Anti-inflammatory effect of essential oil and its con-
stituents from fingered citron (Citrus medica L. var. sarcodac-
tylis) through blocking JNK, ERK and NF-κB signaling
pathways in LPS-activated RAW 264.7 cells. Food Chem.
Toxicol., 57, 126-131.
39. Kim, M.J., Yang, K.W., Kim, S.S., Park, S.M., Park, K.J., Kim,
K.S., Choi, Y.H., Cho, K.K. and Hyun, C.G. (2014) Chemical
composition and anti-inflammation activity of essential oils
from Citrus unshiu flower. Nat. Prod. Commun., 9, 727-730.
40. Zhong, W., Cui, Y., Yu, Q., Xie, X., Liu, Y., Wei, M., Ci, X.
and Peng, L. (2014) Modulation of LPS-stimulated pulmo-
nary inflammation by borneol in murine acute lung injury
model. Inflammation, 37, 1148-1157.
41. Jiang, J., Shen, Y.Y., Li, J., Lin, Y.H., Luo, C.X. and Zhu, D.Y.
(2015) (+)-Borneol alleviates mechanical hyperalgesia in
models of chronic inflammatory and neuropathic pain in mice.
Eur. J. Pharmacol., 757, 53-58.
42. Almeida, J.R., Souza, G.R., Silva, J.C., Saraiva, S.R., Júnior,
R.G., Quintans Jde, S., Barreto Rde, S., Bonjardim, L.R., Cav-
alcanti, S.C. and Quintans, L.J., Jr. (2013) Borneol, a bicyclic
monoterpene alcohol, reduces nociceptive behavior and
inflammatory response in mice. ScientificWorldJournal, 2013,
808460
43. Sherkheli, M.A., Schreiner, B., Haq, R., Werner, M. and Hatt,
H. (2015) Borneol inhibits TRPA1, a proinflammatory and
noxious pain-sensing cation channel. Pak. J. Pharm. Sci., 28,
1357-1363.
44. Ojha, S., Javed, H., Azimullah, S. and Haque, M.E. (2016)
β-Caryophyllene, a phytocannabinoid attenuates oxidative
stress, neuroinflammation, glial activation and salvages dopa-
minergic neurons in a rat model of Parkinson disease. Mol.
Cell. Biochem., 418, 59-70.
45. Varga, Z.V., Matyas, C., Erdelyi, K., Cinar, R., Nieri, D.,
Chicca, A., Nemeth, B.T., Paloczi, J., Lajtos, T., Corey, L.,
Hasko, G., Gao, B., Kunos, G., Gertsch, J. and Pacher, P.
(2017) Beta-caryophyllene protects against alcoholic steato-
hepatitis by attenuating inflammation and metabolic dysregu-
lation in mice. Br. J. Pharmacol. [Epub ahead of print].
46. Basha, R.H. and Sankaranarayanan, C. (2016) β-Caryophyl-
lene, a natural sesquiterpene lactone attenuates hyperglycemia
mediated oxidative and inflammatory stress in experimental
diabetic rats. Chem. Biol. Interact., 245, 50-58.
47. Cho, H.I., Hong, J.M., Choi, J.W., Choi, H.S., Kwak, J.H.,
Lee, D.U., Lee, S.K. and Lee, S.M. (2015) β-Caryophyllene
alleviates d-galactosamine and lipopolysaccharide-induced
hepatic injury through suppression of the TLR4 and RAGE
signaling pathways. Eur. J. Pharmacol., 764, 613-621.
48. Kim, M.J., Yang, K.W., Kim, S.S., Park, S.M., Park, K.J.,
Kim, K.S., Choi, Y.H., Cho, K.K., Lee, N.H. and Hyun, C.G.
(2013) Chemical composition and anti-inflammatory effects
of essential oil from Hallabong flower. EXCLI J., 12, 933-942.
49. Chaiyana, W., Anuchapreeda, S., Leelapornpisid, P., Phong-
pradist, R., Viernstein, H. and Mueller, M. (2016) Development
of microemulsion delivery system of essential oil from Zin-
giber cassumunar Roxb. Rhizome for improvement of stabil-
ity and anti-inflammatory activity. AAPS PharmSciTech, 1-11.
50. Yang, H., Zhao, R., Chen, H., Jia, P., Bao, L. and Tang, H. (2014)
Bornyl acetate has an anti-inflammatory effect in human chon-
drocytes via induction of IL-11. IUBMB Life, 66, 854-859.
51. Sobral, M.V., Xavier, A.L., Lima, T.C. and de Sousa, D.P.
(2014) Antitumor activity of monoterpenes found in essential
oils. ScientificWorldJournal, 2014, 953451.
52. Broitman, S.A., Wilkinson, J., 4th, Cerda, S. and Branch, S.K.
(1996) Effects of monoterpenes and mevinolin on murine
colon tumor CT-26 in vitro and its hepatic “Metastases” in
vitro. Adv. Exp. Med. Biol., 401, 111-13 0.
53. Uedo, N., Tatsuta, M., Iishi, H., Baba, M., Sakai, N., Yano, H.
and Otani, T. (1999) Inhibition by d-limonene of gastric car-
cinogenesis induced by N-methyl-N'-nitro-N-nitrosoguani-
dine in Wistar rats. Cancer Lett., 137, 131-136.
54. Stratton, S., Dorr, R. and Alberts, D. (2000) The state-of-the-
art in chemoprevention of skin cancer. Eur. J. Cancer, 36,
1292-1297.
55. Kaji, I., Tatsuta, M., Iishi, H., Baba, M., Inoue, A. and Kasugai,
H. (2001) Inhibition by D-limonene of experimental hepato-
carcinogenesis in Sprague-Dawley rats does not involve p21ras
plasma membrane association. Int. J. Cancer, 93, 441-444.
56. Guyton, K.Z. and Kensler, T.W. (2002) Prevention of liver
cancer. Curr. Oncol. Rep., 4, 464-470.
57. Lu, X.G., Zhan, L.B., Feng, B.A., Qu, M.Y., Yu, L.H. and Xie,
J.H. (2004) Inhibition of growth and metastasis of human gas-
tric cancer implanted in nude mice by d-limonene. World J .
Gastroenterol., 10, 2140-2144.
58. Ji, J., Zhang, L., Wu, Y.Y., Zhu, X.Y., Lv, S.Q. and Sun, X.Z.
(2006) Induction of apoptosis by d-limonene is mediated by a
caspase-dependent mitochondrial death pathway in human
leukemia cells. Leuk. Lymphoma, 47, 2617-2624.
59. Jia, S.S., Xi, G.P., Zhang, M., Chen, Y.B., Lei, B., Dong, X.S.
and Yang, Y.M. (2013) Induction of apoptosis by D-limonene
is mediated by inactivation of Akt in LS174T human colon
cancer cells. Oncol. Rep., 29, 349-354.
60. Li, Q. (2010) Effect of forest bathing trips on human immune
function. Environ. Health Prev. Med., 15, 9-17.
61. Bansal, A., Moriarity, D.M., Takaku, S. and Setzer, W.N.
(2007) Chemical composition and cytotoxic activity of the
leaf essential oil of Ocotea tonduzii from Monteverde, Costa
Rica. Nat. Prod. Commun., 2, 781-784.
62. Matsuo, A.L., Figueiredo, C.R., Arruda, D.C., Pereira, F.V.,
Scutti, J.A., Massaoka, M.H., Travassos, L.R., Sartorelli, P.

Terpenes and Human Health 105
and Lago, J.H. (2011) α-Pinene isolated from Schinus terebin-
thifolius Raddi (Anacardiaceae) induces apoptosis and con-
fers antimetastatic protection in a melanoma model. Biochem.
Biophys. Res. Commun., 411, 449-454.
63. Chen, W., Liu, Y., Li, M., Mao, J., Zhang, L., Huang, R., Jin,
X. and Ye, L. (2015) Anti-tumor effect of α-pinene on human
hepatoma cell lines through inducing G2/M cell cycle arrest.
J. Pharmacol. Sci., 127, 332-338.
64. Jin, K.S., Bak, M.J., Jun, M., Lim, H.J., Jo, W.K. and Jeong,
W.S. (2010) α-Pinene triggers oxidative stress and related sig-
naling pathways in A549 and HepG2 cells. Food Sci. Biotech-
nol., 19, 1325-1332.
65. Kusuhara, M., Urakami, K., Masuda, Y., Zangiacomi, V.,
Ishii, H., Tai, S., Maruyama, K. and Yamaguchi, K. (2012)
Fragrant environment with α-pinene decreases tumor growth
in mice. Biomed. Res., 33, 57-61.
66. Bakarnga-Via, I., Hzounda, J.B., Fokou, P.V.T., Tchokouaha,
L.R.Y., Gary-Bobo, M., Gallud, A., Garcia, M., Walbadet, L.,
Secka, Y., Dongmo, P.M.J., Boyom, F.F. and Menut, C. (2014)
Composition and cytotoxic activity of essential oils from
Xylopia aethiopica (Dunal) A. Rich, Xylopia parviflora (A.
Rich) Benth. and Monodora myristica (Gaertn) growing in
chad and cameroon. BMC Complement. Altern. Med., 14, 125.
67. Li, Y.L., Yeung, C.M., Chiu, L., Cen, Y.Z. and Ooi, V.E.
(2009) Chemical composition and antiproliferative activity of
essential oil from the leaves of a medicinal herb, Schefflera
heptaphylla. Phytother. Res., 23, 140-142.
68. Meadows, S.M., Mulkerin, D., Berlin, J., Bailey, H., Kolesar,
J., Warren, D. and Thomas, J.P. (2002) Phase II trial of peril-
lyl alcohol in patients with metastatic colorectal cancer. Int. J.
Gastrointest. Cancer, 32, 125-128.
69. Chen, T.C., Cho, H.Y., Wang, W., Wetzel, S.J., Singh, A.,
Nguyen, J., Hofman, F.M. and Schönthal, A.H. (2015) Chemo-
therapeutic effect of a novel temozolomide analog on nasopha-
ryngeal carcinoma in vitro and in vivo. J. Biomed. Sci., 22, 71.
70. Bardon, S., Foussard, V., Fournel, S. and Loubat, A. (2002)
Monoterpenes inhibit proliferation of human colon cancer
cells by modulating cell cycle-related protein expression.
Cancer Lett., 181, 187-194.
71. Yeruva, L., Pierre, K.J., Elegbede, A., Wang, R.C. and Carper,
S.W. (2007) Perillyl alcohol and perillic acid induced cell
cycle arrest and apoptosis in non small cell lung cancer cells.
Cancer Lett., 257, 216-226.
72. Ferraz, R.P., Bomfim, D.S., Carvalho, N.C., Soares, M.B., da
Silva, T.B., Machado, W.J., Prata, A.P.N., Costa, E.V., Moraes,
V.R.S., Nogueira, P.C.L. and Bezerra, D.P. (2013) Cytotoxic
effect of leaf essential oil of Lippia gracilis Schauer (Verbena-
ceae). Phytomedicine, 20, 615-621.
73. Li, J., Liu, C. and Sato, T. (2016) Novel antitumor invasive
actions of p-Cymene by decreasing MMP-9/TIMP-1 expres-
sion ratio in human fibrosarcoma HT-1080 cells. Biol. Pharm.
Bull., 39, 1247-1253.
74. Saleh, M., Hashem, F. and Glombitza, K. (1998) Cytotoxicity
and in vitro effects on human cancer cell lines of volatiles of
Apium graveolens var filicinum. Pharm. Pharmacol. Lett., 8,
97-99.
75. Silva, S.L.d., Figueiredo, P.M. and Yano, T. (2007) Cytotoxic
evaluation of essential oil from Zanthoxylum rhoifolium Lam.
leaves. Acta Amaz., 37, 281-286.
76. Maggi, F., Fortuné Randriana, R., Rasoanaivo, P., Nicoletti,
M., Quassinti, L., Bramucci, M., Lupidi, G., Petrelli, D.,
Vitali, L.A., Papa, F. and Vittori, S. (2013) Chemical composi-
tion and in vitro biological activities of the essential oil of
Vepris macrophylla (Baker) I. Verd. endemic to Madagascar.
Chem. Biodivers., 10, 356-366.
77. Kuo, Y.H., Kuo, Y.J., Yu, A.S., Wu, M.D., Ong, C.W., Kuo,
L.M.Y., Huang, J.T., Chen, C.F. and Li, S.Y. (2003) Two novel
sesquiterpene lactones, cytotoxic vernolide-A and-B, from
Vernonia cinerea. Chem. Pharm. Bull., 51, 425-426.
78. Dahham, S.S., Tabana, Y.M., Iqbal, M.A., Ahamed, M.B.,
Ezzat, M.O., Majid, A.S. and Majid, A.M. (2015) The anti-
cancer, antioxidant and antimicrobial properties of the sesquit-
erpene β-caryophyllene from the essential oil of Aquilaria
crassna. Molecules, 20, 11808-11829.
79. Jung, J.I., Kim, E.J., Kwon, G.T., Jung, Y.J., Park, T., Kim, Y.,
Yu, R., Choi, M.S., Chun, H.S., Kwon, S.H., Her, S., Lee,
K.W. and Park, J.H. (2015) β-Caryophyllene potently inhibits
solid tumor growth and lymph node metastasis of B16F10
melanoma cells in high-fat diet-induced obese C57BL/6N
mice. Carcinogenesis, 36, 1028-1039.
80. Sarvmeili, N., Jafarian-Dehkordi, A. and Zolfaghari, B. (2016)
Cytotoxic effects of Pinus eldarica essential oil and extracts on
HeLa and MCF-7 cell lines. Res. Pharm. Sci., 11 , 476-483.
81. Legault, J. and Pichette, A. (2007) Potentiating effect of β-
caryophyllene on anticancer activity of α-humulene, isocaryo-
phyllene and paclitaxel. J. Pharm. Pharmacol., 59, 1643-1647.
82. Lesgards, J.F., Baldovini, N., Vidal, N. and Pietri, S. (2014)
Anticancer activities of essential oils constituents and synergy
with conventional therapies: a review. Phytother. Res., 28,
1423-1446.
83. Savelev, S.U., Okello, E.J. and Perry, E.K. (2004) Butyryl-and
acetyl-cholinesterase inhibitory activities in essential oils of Sal-
via species and their constituents. Phytother. Res., 18, 315-324.
84. Liu, Z.B., Niu, W.M., Yang, X.H., Yuan, W. and Wang, W.G.
(2010) Study on perfume stimulating olfaction with volatile
oil of Acorus gramineus for treatment of the Alzheimer’s dis-
ease rat. J. Tradit. Chin. Med., 30, 283-287.
85. Majlessi, N., Choopani, S., Kamalinejad, M. and Azizi, Z.
(2012) Amelioration of amyloid β-induced cognitive deficits
by Zataria multiflora Boiss. essential oil in a rat model of Alz-
heimer’s disease. CNS Neurosci. Ther., 18, 295-301.
86. Cioanca, O., Hritcu, L., Mihasan, M., Trifan, A. and Hancianu,
M. (2014) Inhalation of coriander volatile oil increased anxio-
lytic-antidepressant-like behaviors and decreased oxidative
status in beta-amyloid (1-42) rat model of Alzheimer’s dis-
ease. Physiol. Behav., 131, 68-74.
87. Oboh, G., Olasehinde, T.A. and Ademosun, A.O. (2014)
Essential oil from lemon peels inhibit key enzymes linked to
neurodegenerative conditions and pro-oxidant induced lipid
peroxidation. J. Oleo Sci., 63, 373-381.
88. Abuhamdah, S., Abuhamdah, R., Howes, M.J., Al-Olimat, S.,
Ennaceur, A. and Chazot, P.L. (2015) Pharmacological and
neuroprotective profile of an essential oil derived from leaves
of Aloysia citrodora Palau. J. Pharm. Pharmacol., 67, 1306-
1315.
89. Ayaz, M., Junaid, M., Ullah, F., Sadiq, A., Khan, M.A.,
Ahmad, W., Shah, M.R., Imran, M. and Ahmad, S. (2015)
Comparative chemical profiling, cholinesterase inhibitions

106 K.S. Cho et al.
and anti-radicals properties of essential oils from Polygonum
hydropiper L: A Preliminary anti-Alzheimer’s study. Lipids
Health Dis., 14, 141.
90. Klein-Júnior, L.C., dos Santos Passos, C., Tasso de Souza, T.J.,
Gobbi de Bitencourt, F., Salton, J., de Loreto Bordignon, S.A.
and Henriques, A.T. (2016) The monoamine oxidase inhibitory
activity of essential oils obtained from Eryngium species and
their chemical composition. Pharm. Biol., 54, 1071-1076.
91. Mühlbauer, R., Lozano, A., Palacio, S., Reinli, A. and Felix,
R. (2003) Common herbs, essential oils and monoterpenes
potently modulate bone metabolism. Bone, 32, 372-380.
92. Koo, B.S., Lee, S.I., Ha, J.H. and Lee, D.U. (2004) Inhibitory
effects of the essential oil from SuHeXiang Wan on the cen-
tral nervous system after inhalation. Biol. Pharm. Bull., 27,
515-519.
93. Lima, B., López, S., Luna, L., Agüero, M.B., Aragón, L.,
Tapia, A., Zacchino, S., López, M.L., Zygadlo, J. and Feresin,
G.E. (2011) Essential oils of medicinal plants from the central
andes of Argentina: chemical composition, and antifungal,
antibacterial, and insect-repellent activities. Chem. Biodivers.,
8, 924-936.
94. El-Seedi, H.R., Khalil, N.S., Azeem, M., Taher, E.A., Görans-
son, U., Pålsson, K. and Borg-Karlson, A.K. (2012) Chemical
composition and repellency of essential oils from four medici-
nal plants against Ixodes ricinus nymphs (Acari: Ixodidae). J.
Med. Entomol., 49, 1067-1075.
95. Mkaddem, M., Bouajila, J., Ennajar, M., Lebrihi, A., Mathieu,
F. and Romdhane, M. (2009) Chemical composition and anti-
microbial and antioxidant activities of Mentha (longifolia L.
and viridis) essential oils. J. Food Sci., 74, M358-M363.
96. Hong, Y.K., Park, S.H., Lee, S., Hwang, S., Lee, M.J., Kim,
D., Lee, J.H., Han, S.Y., Kim, S.T., Kim, Y.K., Jeon, S., Koo,
B.S. and Cho, K.S. (2011) Neuroprotective effect of SuHeX-
iang Wan in Drosophila models of Alzheimer's disease. J. Eth-
nopharmacol., 134, 1028-1032.
97. Park, S.H., Lee, S., Hong, Y.K., Hwang, S., Lee, J.H., Bang,
S.M., Kim, Y.K., Koo, B.S., Lee, I.S. and Cho, K.S. (2013)
Suppressive effects of SuHeXiang Wan on amyloid-β42-
induced extracellular signal-regulated kinase hyperactivation
and glial cell proliferation in a transgenic Drosophila model of
Alzheimer’s disease. Biol. Pharm. Bull., 36, 390-398.
98. Liu, Q.F., Jeong, H., Lee, J.H., Hong, Y.K., Oh, Y., Kim,
Y.M., Suh, Y.S., Bang, S., Yun, H.S., Lee, K., Cho, S.M., Lee,
S.B., Jeon, S. Chin, Y.W., Koo, B.S. and Cho, K.S. (2016)
Coriandrum sativum suppresses Aβ42-induced ROS increases,
glial cell proliferation and ERK activation. Am. J. Chin. Med.,
44, 1325-1347.
99. Liu, Q.F., Lee, J.H., Kim, Y.M., Lee, S., Hong, Y.K., Hwang,
S., Oh, Y., Lee, K., Yun, H.S., Lee, I.S., Jeon, S., Chin, Y.W.,
Koo, B.S. and Cho, K.S. (2015) In vivo screening of tradi-
tional medicinal plants for neuroprotective activity against
Aβ42 cytotoxicity by using Drosophila models of Alzhei-
mer’s disease. Biol. Pharm. Bull., 38, 1891-1901.
100. Hur, J., Pak, S.C., Koo, B.S. and Jeon, S. (2013) Borneol
alleviates oxidative stress via upregulation of Nrf2 and Bcl-2
in SH-SY5Y cells. Pharm. Biol., 51, 30-35.
101. Tian, L.L., Zhou, Z., Zhang, Q., Sun, Y.N., Li, C.R., Cheng,
C., Zhong, Z.Y. and Wang, S.Q. (2007) Protective effect of
(±) isoborneol against 6-OHDA-induced apoptosis in SH-
SY5Y cells. Cell. Physiol. Biochem., 20, 1019-1032.
102. Han, M., Liu, Y., Zhang, B., Qiao, J., Lu, W., Zhu, Y., Wang,
Y. and Zhao, C. (2011) Salvianic borneol ester reduces β-
amyloid oligomers and prevents cytotoxicity. Pharm. Biol.,
49, 1008-1013.
103. Calleja, M.A., Vieites, J.M., Montero-Meterdez, T., Torres,
M.I., Faus, M.J., Gil, A. and Suárez, A. (2013) The antioxi-
dant effect of β-caryophyllene protects rat liver from carbon
tetrachloride-induced fibrosis by inhibiting hepatic stellate
cell activation. Br. J. Nutr., 109, 394-401.
104. Sharma, C., Al Kaabi, J.M., Nurulain, S.M., Goyal, S.N.,
Kamal, M.A. and Ojha, S. (2016) Polypharmacological
properties and therapeutic potential of β-caryophyllene: a
dietary phytocannabinoid of pharmaceutical promise. Curr.
Pharm. Des., 22, 3237-3264.
105. Cheng, Y., Dong, Z. and Liu, S. (2014) β-Caryophyllene
ameliorates the Alzheimer-like phenotype in APP/PS1 mice
through CB2 receptor activation and the PPARγ pathway.
Pharmacology, 94, 1-12.
106. Porres-Martínez, M., González-Burgos, E., Carretero, M.E.
and Gómez-Serranillos, M.P. (2016) In vitro neuroprotective
potential of the monoterpenes α-pinene and 1,8-cineole
against H2O2-induced oxidative stress in PC12 cells. Z.
Naturforsch., C, J. Biosci., 71, 191-199.
107. Sammi, S.R., Trivedi, S., Rath, S.K., Nagar, A., Tandon, S.,
Kalra, A. and Pandey, R. (2016) 1-Methyl-4-propan-2-ylben-
zene from Thymus vulgaris Attenuates Cholinergic Dysfunc-
tion. Mol. Neurobiol. [Epub ahead of print].
108. Lee, Y. (2016) Cytotoxicity evaluation of essential oil and its
component from zingiber officinale roscoe. Toxicol. Res., 32,
225-230.
109. Bakkali, F., Averbeck, S., Averbeck, D. and Idaomar, M.
(2008) Biological effects of essential oils-a review. Food
Chem. Toxicol., 46, 446-475.