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antioxidants
Review
Citrus Essential Oils in Aromatherapy: Therapeutic Effects
and Mechanisms
Pooja Agarwal 1,† , Zahra Sebghatollahi 2,† , Mehnaz Kamal 3,† , Archana Dhyani 4,† , Alpana Shrivastava 5 ,
Kiran Kumari Singh 6 , Mukty Sinha 7 , Neelima Mahato 8 , Awdhesh Kumar Mishra 9, * and
Kwang-Hyun Baek 9, *
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Citation: Agarwal, P.; Sebghatollahi,
Z.; Kamal, M.; Dhyani, A.;
Shrivastava, A.; Singh, K.K.; Sinha,
M.; Mahato, N.; Mishra, A.K.; Baek,
K.-H. Citrus Essential Oils in
Aromatherapy: Therapeutic Effects
and Mechanisms. Antioxidants 2022,
11, 2374. https://doi.org/10.3390/
antiox11122374
Academic Editors: Delia Mirela Tit
and Simona Bungau
Received: 25 October 2022
Accepted: 25 November 2022
Published: 30 November 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
*
†
Division of Chemistry, School of Basic and Applied Sciences, Galgotias University,
Greater Noida 203 201, Uttar Pradesh, India
Department of Plant Breeding and Biotechnology, Faculty of Agricultural Sciences and Food Industries,
Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University,
Al Kharj 11942, Saudi Arabia
Department of Applied Sciences, School of Engineering, University of Petroleum and Energy Studies,
Dehradun 248 007, Uttarakhand, India
Department of Botany, Sri Shankar College, (A Constituent Unit of V.K.S.U., Ara); Rohtas,
Sasaram 821 115, Bihar, India
Department of Geography, Central University of South Bihar, Gaya 151001, Bihar, India
Department of Medical Devices, National Institute of Pharmaceutical Education and Research,
Ahmedabad 382 355, Gandhinagar, India
School of Chemical Engineering, Yeungnam University, Gyeongsan,
Gyeongsangbuk-do 38541, Republic of Korea
Department of Biotechnology, Yeungnam University, Gyeongsan,
Gyeongsangbuk-do 38541, Republic of Korea
Correspondence: awdhesh@ynu.ac.kr (A.K.M.); khbaek@ynu.ac.kr (K.-H.B.); Tel.: +82-53-810-3029 (A.K.M.);
Fax: +82-53-810-4769 (A.K.M.)
These authors contributed equally to this work.
Abstract: Citrus is one of the main fruit crops cultivated in tropical and subtropical regions worldwide.
Approximately half (40–47%) of the fruit mass is inedible and discarded as waste after processing,
which causes pollution to the environment. Essential oils (EOs) are aromatic compounds found in
significant quantities in oil sacs or oil glands present in the leaves, flowers, and fruit peels (mainly
the flavedo part). Citrus EO is a complex mixture of ~400 compounds and has been found to be
useful in aromatic infusions for personal health care, perfumes, pharmaceuticals, color enhancers
in foods and beverages, and aromatherapy. The citrus EOs possess a pleasant scent, and impart
relaxing, calming, mood-uplifting, and cheer-enhancing effects. In aromatherapy, it is applied either
in message oils or in diffusion sprays for homes and vehicle sittings. The diffusion creates a fresh
feeling and enhances relaxation from stress and anxiety and helps uplifting mood and boosting
emotional and physical energy. This review presents a comprehensive outlook on the composition,
properties, characterization, and mechanism of action of the citrus EOs in various health-related
issues, with a focus on its antioxidant properties.
published maps and institutional affiliations.
Keywords: citrus essential oils; aromatherapy; natural aromatic compounds; therapeutic effects of
citrus EOs; characterization of citrus EOs
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1. Introduction
Citrus is one of the world’s most abundant fruits containing substantial amounts of
beneficial secondary metabolites [1]. Among them, citrus essential oils (EOs) are important
secondary metabolites; they are usually aromatic compounds found in oil glands present in
the flowers, leaves, and fruit peels. However, most citrus EOs are extracted from fruit peels,
viz., fruit rind, or flavedo (green part) and albedo (white part). These citrus EOs contain
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https://www.mdpi.com/journal/antioxidants
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85–99% volatile and 1–15% non-volatile components [2] and their content as well as chemical composition depend on species and extraction methods [3–5]. These volatile constituents
contain large amounts of monoterpene hydrocarbons (70–95%) and d-limonene, a good
source of antioxidants, in all the reported orange species [6].
Aromatherapy using citrus EOs has been practiced as a treatment method since
ancient times. Aromatherapy is utilized to relieve many symptoms, such as body pain,
nausea, vomiting, anxiety, depression, stress, insomnia, etc. [7]. Several scientific reports
have been published regarding the use of EOs in the treatment of a number of medical
issues, including hypertension, hypotension, cognitive dysfunction [8–12], physical and
psychological stress, and exhaustion [13]. EOs are extracted from plants and used in a
controlled manner in aromatherapy with few or no side effects. Currently, EOs are hugely
popular as safe and natural agents with medicinal and therapeutic properties and have
been approved by the US Food and Drug Administration (FDA).
Citrus EOs are fragrant volatile molecules, which upon inhalation can alter hemodynamic parameters or blood flow in the body by controlling circulation through the
autonomous nervous system. Citrus EOs have also been investigated for their antimicrobial [14] and antioxidant activities [15,16]. Many citrus EOs, such as orange [17] and
bitter orange [18,19] have shown anxiolytic, antidepressant, anticonvulsant, analgesic, and
sedative effects and influence overall emotional behavior. Major components in the citrus
EOs include bioactive compounds, such as monoterpenes and its derivatives, aldehydes,
ketones, esters, alcohols, limonene, β-pinene, and γ-terpinene [20].
Global Production and Consumption of Citrus
Natural products are popular globally due to their nutritional value and little or no
side effects. The demand for citrus EOs has been continuously increasing to produce higher
quality nutraceuticals, food and beverages, bakery, natural preservatives for vegetables,
meat and fish, pharmaceuticals, aromatherapy, perfumes, toiletries, and personal care,
blending ingredients for herbal tea, cosmetic ingredients, and so on [21]. The major citrusproducing countries, climate sustainability, and annual production of the different citrus
fruits in different geographical regions are shown in Figure S1 (Supplementary Materials).
The global market of citrus EOs in the year 2018 was 6.31 billion USD, which is
predicted to grow at a rate of 6.5% by the year 2025. The market has been estimated to grow
up to 9.43 billion by the year 2028 [22,23]. The market segregation of citrus essential oils and
the global market for citrus EOs based on its major applications (in %; up to the year 2018)
are shown in Figure S2 (Supplementary Materials). Global citrus oil market by application
(by the year 2018) [22,24] and citrus EO market value forecast [25] are shown in Figure S3a,b
(Supplementary Materials). The market of EOs obtained from citrus fruits (data year 2020)
and its market value forecast for the decade are displayed in the world map in Figure 1.
Many countries in the Asia-Pacific region have a high demand for citrus EOs because of
their use in various food and beverages, cosmetic preparations, and therapeutics. Similarly,
the demand is expected to increase in Europe and the US due to their higher usage in the
food and beverage industry and the substantial use of these products in aromatherapies. In
addition, citrus EOs are also becoming a preferred ingredient material in green repellents
and pesticides against insects and pests [26].
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Figure 1. Market of essential oils obtained from citrus fruits, (2020) (Note: Bar graph was created for major countries involved in import and export; the map was
Figure 1. Market of essential oils obtained from citrus fruits, (2020) (Note: Bar graph was created for major countries involved in import and export; the map was
created using ArcGIS 10.8.1 with UTM projection taking WGS84 datum) [24].
created using ArcGIS 10.8.1 with UTM projection taking WGS84 datum) [24].
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2. Extraction, Characterization, and Authentication Methods for Citrus EOs
EOs are present in the oil glands in the peel and cuticles of the citrus fruit peel
or pericarp. The EOs are released when oil sacs are crushed during juice extraction or
under pressure during cold pressing of the peel waste. The major component of the
EOs is d-limonene [14,20]. Cold pressing has been a traditional method of extracting essential oils and the yield is a watery emulsion. The latter is centrifuged to recover the
EOs [27]. Alternately, the extraction of EOs is also carried out using stream stripping
and distillation methods. These methods have been found effective and efficient in removing oil components from oil-milled sludge. Modern methods include distillation
techniques, e.g., Microwave Steam Distillation (MSD), Microwave Hydrodiffusion and
Gravity (MHG), and Instant Controlled Pressure Drop Technique (DIC). Instant controlled
pressure drop (DIC) technology facilitates the extraction of essential oil as well as the
expansion of the plant matrix. This improves the extraction of the oil significantly. In this
method, a high-steam pressure (~0.6–1.0 MPa) is applied constantly for a short time (~5–60
s) followed by an instantaneous drop in the pressure towards vacuum 5 kPa with a rate
≥0.5 MPa s−1 . This treatment results in the rapid expansion of the sample matrix, auto evaporation, and faster cooling, enabling the extraction of volatile compounds and EOs within
1–4 min. The EOs obtained by distillation have been observed to deteriorate easily and develop off-odor because of the instability of the terpene hydrocarbons,
e.g., d-limonene [28]. Supercritical fluid extraction (SFE) is an emerging and inexpensive technique of extraction and isolation of EOs [29]. By this method, efficient and fast
extraction can be done at ambient temperatures, without incorporating clean-up steps in
absence of harmful organic solvents. Carbon dioxide (CO2 ) is used in the SFE method
because of its non-explosive, non-toxic nature along with the ease availability. CO2 can be
considered an ideal solvent and can be easily eliminated from extracted products [30,31].
MHG is a highly efficient method as it accelerates the extraction process many times
over. In addition, it also enables the recovery of EOs without any changes in the oil
composition. MSD techniques have an edge over MSD as it causes more rapid rupture of
the cell wall of the plant material under strong microwaves which quickly releases the cell
cytoplasm containing oils. The main extraction methods/techniques for obtaining citrus
EOs are summarized in Table S1 (Supplementary Materials) [4].
The extraction process yields a matrix containing a mixture of phytochemicals which
ought to undergo separation, purification, and isolation to obtain individual compounds.
Citrus EO is a complex mixture of ~400 volatile and semi-volatile compounds. Column chromatography, high-speed counter current chromatography (HSCC), and high-performance
liquid chromatography (HPLC) are generally employed involving solvent combinations,
such as hexane:n-butanol, ethyl acetate:hexane, butanol:water, chloroform:methanol, etc.,
in the basic process of purification and separation of compounds. The different compounds
are detected and quantitatively determined using a combination of modern instruments,
viz., UV–visible, mass spectroscopy, and HPLC. GC and its extensions such as MDGC,
enantioselective capillary gas chromatography (eCGC), ultra-high performance liquid chromatography, etc. are the most extensively employed for EO separation, identification, and
quantitative characterization due to its volatility and complexity of most natural oils [32].
Gas chromatography (GC) is one of the most popular methods for the characterization
of single-phase vapor samples and is suitable for samples with 2 (molecular hydrogen) to
1500 mass units. Almost all EOs fall within this mass range. A combination of GC and
MDGC with other techniques, such as mass spectroscopy (MS) and Raman spectroscopy
is employed to improve the efficiency of the separating power of chromatography and
analyze more complex structures. Such coupled analyses improve data quality and exhibit
good separation performance [33]. The use of two or more techniques detects adulteration in EOs extracted from the citrus peels and waste more accurately [34]. Researchers
used simultaneous distillation and extraction (SDE)-GC-MS and MDGC-MS techniques to
study and authenticate the enantiomeric ratios of chiral compounds present in the citrus
EOs. These techniques helped in the identification of 67 volatile compounds, including
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limonene, γ-terpinene, and linalool, as the major compounds and sabinene, camphene, and
β-phellandrene as minor and chiral aromatic components in lemon and lime. A combination
of MDGC and GCC-IRMS is employed to determine the authenticity of the EOs extracted
from neroli (Egyptian bitter orange flower) and lime [35]. A comparative analysis was performed for lime (Citrus aurantifolia Swingle and Citrus latifolia Tanaka)-based Eos following
two different approaches using MDGC and gas chromatography–combustion-isotope ratio
mass spectrometry (GC–C-IRMS). This study is the first to differentiate Eos extracted from
Persian lime and key lime. A series of components were identified including limonene,
geranial, β-caryophyllene, trans-α-bergamotene, α and β-pinene, and germacrene B, using
GC–C-IRMS. MDGC determined the enantiomeric distribution of camphene, limonene,
linalool, α-phellandrene, β-phellandrene, β-pinene, terpinen-4-ol, α-terpineol, sabinene,
and α-thujene in lime oils. Such hyphenated techniques are also used successfully in the
investigation of citrus oil-based flavored drinks. Italian alcoholic syrup was examined by
comparing carbon isotope ratios to identify the presence of genuine cold-pressed peel oils.
For this purpose, solid phase microextraction was performed, followed by GC with IRMS.
GC was used to determine the enantiomeric distribution of the selected volatile chiral samples, whereas qualitative analyses of the samples were performed by mass spectrometry.
The results were confirmed using enantioselective gas chromatography [36].
Ultra-high-performance liquid chromatography–time-of-flight–mass spectrometry
(UHPLC–TOF–MS) profiling and 1 H nuclear magnetic resonance (NMR) near-infrared
spectroscopy are employed for the fingerprinting of lemon oil [37]. Metabolite variations
have been also investigated in lemon oil samples. Such analysis has high demand in
the fragrance and flavor industries for terpenoids, citropten, bergamottin, furocoumarins,
flavonoids, and fatty acids. Characterization based on quantitative analysis of substances
present in EOs is an important process in essential oil-based industries. The different methods/techniques of characterization/authentication of citrus EOs have been summarized in
Table S2 (Supplementary Materials).
3. Components of Citrus EOs
Citrus species are rich in various EOs, with many chemical components of interest
for aromatherapy. Several ingredients used in pharmaceuticals and cosmetics are procured from citrus EOs [38–41]. Around 400 compounds, which cover 85–99% of the total
oil fraction, have volatile and semi-volatile properties [38,39,42,43]. Citrus EOs can be
grouped into five major classes: hydrocarbon monoterpenes, oxygenated monoterpenes,
hydrocarbon sesquiterpenes, and oxygenated sesquiterpenes. The major component of
citrus Eos is limonene, which can be found in quantities ranging from 32% to 98% [44].
Hydrocarbons, aliphatic aldehydes, and oxygen-containing mono- and sesquiterpenes are
the next most significant classes of compounds present in citrus EOs which show antioxidant properties. Several terpenes are present as their functionalized derivatives, which
are volatile compounds, and flavonoids, diterpenoids, sterols, coumarins, and fatty acids
are some of the non-volatile compounds [45]. Several studies have reported the chemical
composition of EOs derived from the citrus flower, leaf, and peel. The composition of
citrus EOs varies with citrus species, origin, climatic and geographical conditions, ripening,
method of extraction, etc. [14]. The molecular structures of the volatile and non-volatile
compounds present in citrus EOs are displayed in Figure S4 (Supplementary Materials).
The composition of the aromatherapeutic components present in the EOs of common citrus
species [3,14] are summarized in Figure S5 (Supplementary Materials).
4. Aromatherapy: Mechanisms
4.1. Evolution of Aromatherapy
Stress conditions alter the respiration process, and an altered respiration activates
the limbic system (amygdala, hippocampus, and hypothalamus) in the brain and induces
psycho-physiological responses. The latter can alter the emotional responses. This is how
respiration relates to emotional behavior and brain functions. Furthermore, pulmonary
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diseases have been observed to affect brain-cell growth, reduce oxygen supply in the body
and brain causing neurophysiological and neurobehavioral disorders, namely anxiety and
depression. Moreover, the systemic circulation carrying blood with insufficient oxygen
supply also transports lung-induced inflammation mediators. The latter induces adaptive
responses in the brain and the body. Applications of EOs have been observed to impart
neuroprotective and anti-aging effects, and relief from respiratory congestion, pain, insomnia, anxiety, depression, stress, and other psychological and physiological disorders
mostly due to its antioxidant properties [46]. When inhaled, the EOs can stimulate the
olfactory, respiratory, and gastrointestinal systems, and the EOs release endorphins to
initiate a feeling of well-being and an analgesic effect [7]. Citrus EOs have been reported to
be safe and effective for treating insomnia. Moreover, these can decrease the side effects
of drugs and sleep illnesses owing to their short- or long-term usage [47]. The EOs have
gained attention in clinical and scientific research because they are harmless and do not
have any side effects [46]. There are three ways by which EOs can reach and act directly
on the respiratory, circulatory, and central nervous systems, viz., (i) inhalation through the
respiratory tract; (ii) oral intake in the form of capsules, drops, or food; and (iii) topical
absorption through the skin [48].
4.2. Mechanism
4.2.1. Inhalation
A human can differentiate more than 10,000 types of aromas. Humans possess ~400
functional gene coding for olfactory sensory neurons (OSNs). Each receptor expresses a
specific type of odorant reception [49,50]. Inhalation is the fastest and most effective way
to induce responses in the central nervous system within a few seconds. The inhalation
of the EO molecules delivers active volatile compounds to the brain and the circulatory
system via (a) the olfactory lobe and (b) the respiratory system, respectively. The olfactory
system begins with the nasal cavity which leads to the olfactory lobe located close to the
brain. The olfactory lobe is connected to several brain areas, e.g., the hypothalamus and
hippocampus. The volatile molecules in the citrus EOs enter through the nasal cavity, pass
through the olfactory lobe, activate the sensory neurons present in the olfactory mucosa,
and the axons of the sensory neuron cells ultimately deliver the signals to the central
nervous system (CNS) [51–53]. The ‘activation’ is the initiation of electrical signals (by the
odorant molecules) in the olfactory lobe. The signal is transmitted from the olfactory lobe
to the olfactory cortex. The stimuli modulate specific physiological responses involving
mood and behavioral actions (emotion and cognition), hormone production, regulation of
body temperature, digestive reactions, memory, stress responses, sedation, sex stimulation,
blood pressure, heart rate, etc. [54,55]. It has been observed that if the sense of smell is lost
in patients with anxiety and depression, inhaled volatile molecules enter the lungs through
the circulatory system via gas exchange and trigger the healing process. Another pathway
of the EOs post inhalation is through the respiratory system involving gaseous exchange
via diffusion into the blood circulation in the alveoli [49]. The EOs action toward brain
functioning has been explained to take place via three basic mechanisms: (a) Activation of
nasal olfactory chemoreceptors, (b) direct absorption of the EO active molecules into the
neuronal pathway, (c) absorption of EO active molecules in the alveolar blood circulation.
The pathways followed by citrus EOs are illustrated in Figure 2.
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Figure
Figure2.2.Pathways
Pathwaysfollowed
followedby
bycitrus
citrusEOs
EOsfor
foraromatherapy.
aromatherapy.
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(a) Activation of nasal olfactory chemoreceptors
This involves the activation of nasal olfactory chemoreceptors and the consequent
effects of the olfactory signals on the respective brain segments. The EO, upon inhalation,
travels through the interiors of the nasal passage where the endothelium in the inner
lining is thin and located close to the brain. Therefore, the EO molecules readily enter the
local circulation and the brain. A particular odorant can activate a single or a set of OSN
receptors and generate an electrophysiological signal for transmission into the brain. This
is how different odors can be identified and differentiated. The olfactory epithelial layer
is facilitated by different types of OSNs. A smell is identified by the activation of nasal
olfactory chemoreceptors. The odorant molecules approach the olfactory epithelium and
bind with the dendrite receptors present in the OSNs. This generates an electrophysiological
signal via induction of an action potential. The axons of the OSNs extend and converge
into the corresponding glomerulus cell. The latter is associated with a specific mitral and
tufted cell. The signals are transmitted via dendrites of the glomerulus through connected
mitral and tufted cells and eventually to the pyramidal neurons present in the olfactory
cortex. In the cortex region, the transmitted electrophysical signals further stimulate the
target regions in the brain [56,57]. The olfactory cortex of the brain is divided into other
smaller regions, namely the piriform cortex, olfactory tubercle, and entorhinal cortex. Each
of these regions project information to the amygdala (regulates aggression, eating, drinking,
sexual behavior), hippocampus (regulates emotion, learning, memory, odor memory), and
hypothalamus (regulates blood glucose levels, salt, blood pressure, and hormones) or
‘limbic system’. The olfactory signals directly transmits into the cortex and responses to the
stimuli are expressed in terms of odor, memory, emotions, and endocrine functions [58].
(b) Direct absorption of the EO active molecules into the neuronal pathway
The small and volatile molecules present in the EOs can be transported either by
extracellular or by intracellular transport mechanisms. In the intracellular mechanism, the
EO active molecules directly pass through the neuronal pathway in the olfactory lobe and
transmitted to the brain. The molecules bind with the olfactory receptor surface of the
neurons and initiate receptor-mediated endocytosis (cells take in substances present outside
the cell body by engulfing them in a vesicle which reopens inside the cell and the substance
becomes a part of the cytoplasm). The molecules absorbed in the OSN are transported to the
olfactory bulb along the axons by endosomes. In the extracellular transport mechanism, the
EO active molecules pass through the paracellular cleft between the OSN and supporting
cells and enter the lamina propria (connective tissues) through movement in the fluid.
From lamina propria, the EO active molecules are further transported to perineural space
along the axons and eventually arrive at the brain parenchyma. Finally, the EO active
molecules enter across the blood–brain barrier and blood–cerebrospinal fluid barrier to
spread into different regions in the brain. The EO active molecules now interact with the
neurotransmitter receptors, namely transient receptor potential (TRP) channel proteins,
glutamate, and γ-amino-butyric acid (GABA), 5-hydroxytryptamine (5-HT), and dopamine
(DA), and produce anxiolytic and antidepressant effects [58].
(c) Absorption of EO active molecules in the alveolar blood circulation
The EO vapor molecules, upon inhalation, travel to the lungs and induce an immediate
and easing impact on breathing difficulties that appear during cold and congestion. The
EO active molecules present in the inhaled vapor pass through the respiratory tract, enter
the lungs, and reach the alveolar sacs where gaseous exchange between the cells of the
alveoli and blood cells in the capillaries take place. Simultaneously, some molecules are
also absorbed by the inner mucous linings of the respiratory tract, bronchi, and bronchioles.
Deep breathing tends to increase the quantity of any EO components absorbed into the
body by this route. EO active molecules enter the neuronal pathway, and absorption of the
EO active molecules in the alveolar blood circulation is illustrated in Figure 3.
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Figure 3. Inhalation of the citrus EOs and response delivery to the central nervous system through the olfactory lobe and respiratory and circulatory system.
Figure 3. Inhalation of the citrus EOs and response delivery to the central nervous system through the olfactory lobe and respiratory and circulatory system. (a)
(a)
Activation
of nasal
olfactory
chemoreceptors
Direct
absorptionofofthe
theEO
EOactive
activemolecules
moleculesinto
intothe
theneuronal
neuronalpathway
pathway(c)
(c)Absorption
Absorption of
of EO
EO active
active molecules
molecules in
Activation
of nasal
olfactory
chemoreceptors
(b)(b)
Direct
absorption
in
the
alveolar
blood
circulation.
the alveolar blood circulation.
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The soluble molecules present in the EO vapor carried with the inhaled air can cross
the air–blood barrier. A majority of the EO components are lipophilic and hydrophobic in
nature (lipid soluble terpene family). Lipophilic EO components can cross the blood–brain
barrier and transport to the CNS [58] The EO action in aromatherapy through the inhalation
process towards the brain functioning has been explained to take place via three basic
mechanisms, viz., activation of nasal olfactory chemoreceptors and direct absorption of the
active molecules. Aromatherapy is known to improve mood and certain mild symptoms of
stress-related disorders, such as anxiety, depression, loss of appetite, loss of concentration,
and chronic pain. The benefits of aromatherapy have been established by both the physiological and psychological effects upon inhalation of volatile EO components. The EO active
components act via the limbic system, namely the hippocampal, the hypothalamus, and
the pyriform cortex.
4.2.2. Oral Intake
Citrus and its juice have been a major medicinal recipe for abdominal problems since
ancient times in tropical and subtropical countries besides its use in foods, bakeries, and
confectionaries. The lime fruits have been used for making anti-odorant agents due to
the fragrance and freshness effects of their aromatic volatiles. Bergamot essential oils are
utilized in pharmaceutical industries to absorb unpleasant odors of medicinal products
and add antiseptic and antibacterial properties. In addition, the juice is added to drinking
water, alcoholic, and non-alcoholic beverages to enhance flavor and antioxidants. The
characteristic flavor of citrus oils is mainly due to the presence of certain components,
namely linalool, citral, and linalyl acetate [59]. However, limonene and pinene present in
the EO composition have not been much favored. Moreover, they are relatively unstable
compounds and decompose when exposed to heat and light and they are removed from the
oil to enhance the life of the products [59,60]. The roots of the lime tree have been used as a
febrifuge and antipyretic in traditional medicine. The bark of the lemon tree is often boiled
in water to obtain a decoction and taken as a remedy for gonorrhea and related disorders.
In many tribal populations, the roots of the plant are dried and chewed for headache
and vermifuge effects in the stomach and the intestines. The citrus EO components have
several benefits when taken orally due to their antiviral, antiseptic, antimicrobial, astringent,
restorative, stimulant, and antioxidant properties [12,46,48,61–65].
Bergamot EO possesses a bitter aromatic taste and a characteristic pleasant aroma. It is
a popular pharmacopoeias in many countries. It has been also reported for its hypolipemic
and hypoglycemics activities, anti-inflammatory, and anti-cancer properties [66–70]. In folk
medicine in many countries, it has been popularly used for fever and parasitic diseases.
Due to its significant antimicrobial properties, it has been found useful in treating infections
in the mouth, skin, respiratory and urinary tract, gonococcal infections, leucorrhea, vaginal
pruritus, tonsillitis, and sore throats [71]. BEO and vapors have been observed to exhibit
resistance against common food-borne pathogens. The EO component linalool is reported
to be the most effective antibacterial component [72]. BEO has also been reported for its
antibacterial and anti-fungal activities against several microbial strains, such as Campylobacter jejuni, Escherichia coli O157, Listeriamono cytogenes, Bacillus cereus, Staphylococcus
aureus, dermatophytes, and Candida species-induced infections [73–75]. BEO-incorporated
chitosan-based films with concentrations, viz., 0.5, 1, 2, and 3% w/w have been reported to
exhibit a significant dose-dependent inhibitory effect against Penicillium italicum [76].
Bergamottine (5-geranoxypsoralen), an important component in the Eos, is a natural
furanocoumarin. It can be extracted from the pulp of pomelos and grapefruits and the
peel and pulp of bergamot oranges. It has been found to decrease the electrocardiographic
changes significantly during experimental studies in guinea pigs. The latter is typical of
coronary arterial spasms and cardiac arrhythmias provoked by pitressin. Bergamottine
is also found to increase the dose of ouabain required to induce ventricular premature
beats, ventricular tachyarrhythmias, and death. The experimental studied suggest that
bergamottine possesses potential anti-anginal and antiarrhythmic properties [77]. In an-
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other experimental model of rat angioplasty, a pretreatment with a volatile fraction of
bergamot EO in a dose-dependent manner has been observed to reduce the neointima
proliferation, together with the free radical formation and LOX-1 expression. Lectin-like
oxy LDL receptor-1(LOX-1) is known to be involved in smooth muscle cell proliferation and
neo-intima formation occurring in injured blood vessels [66]. Furthermore, the bergamot
EO has also been observed to induce vasorelaxation of the mouse aorta by activating K+
channels and inhibiting Ca2+ influx [78]. The latter differentially modulates intracellular
Ca2+ levels in vascular endothelial and smooth muscle cells [79]. These research findings
altogether indicate that bergamot EO possesses potential activity as a vasodilator agent
in cardiovascular diseases. Citrus EOs in oral administration has been observed to be
beneficial in treating anxiety [80].
The citrus EOs undergo significant biotransformation after being absorbed in the
digestive system which has been observed to alter their effects on health. When ingested
orally, the EOs enter the digestive system and its components begin a wide range of actions.
Primarily the monoterpenoids, namely d-limonene, carvone, cis- and trans- carveol (CAR),
perillyl alcohol (POH), and geraniol have been observed to alleviate the carcinogenesis
of exogenous substances. Other EO components, such as linalool and citral along with
carvone and geraniol have been found to impart antimicrobial activities in the digestive
system. The antimicrobial properties of the citrus EOs are attributed to the presence of
abundant amounts of limonene and flavonoids in their composition [81]. Liver CYPs
(Cytochrome P450) transform limonene into a variety of products. The CYPs act on various
types of substrates or target molecules, and it has been observed that more than one P450
can act on the same type of substrate which produces multiple products from the same
substrate. In human beings, the biotransformation of limonene occurs via four pathways,
namely oxidation of endo- and exocyclic double bonds, oxidation of methyl side chain, and
allylic oxidation of C6-ring [82]. The oxidation of the exocyclic double bond present in the
limonene molecule produces Limonene (LMN)-8,9-OH, whereas the other three pathways
produce perillyl alcohol (POH), perillic acid (PA), and cis- and trans- carveol (CAR).
The biotransformation of α-pinene, the second major component of citrus EOs produces myrtenol, cis- and trans- verbenol. In addition, carene is transformed into caren-10-ol,
caren-10-carboxylic acid and caren-3,4-diol [82]. Biotransformation of the citrus EOs alters
its bioavailability. For example, the major component in the citrus Eos, limonene, is readily
absorbed into the blood from the digestive tract. It is reported that the d-limonene (labeled
with radioactive substance) is absorbed in the liver in 1.0 h with a peak concentration
of 45.1 dpm (disintegration per min)/mg. Within the next 1.0 h, the peak concentration of the labeled d-limonene in adrenal glands and kidney was found to be 77.3 and
21.8 dpm/mg, respectively [83]. The biotransformation of limonene is a rapid process and
the concentration of limonene, and its metabolites become undetectable within 24 h of
ingestion (oral intake). The products of biotransformation of limonene (in citrus EOs) are
excreted from the body via urine (~60%), feces, and breath after oral consumption [83].
The products of the citrus EOs post biotransformation exhibit certain health-promoting
effects. Perillyl alcohol has been observed to reduce the incidence and diversity of colonic
invasive adenocarcinoma in rats (induced by injecting methoxymethane (or azoxymethane
(AOM) carcinogen). Furthermore, perillyl alcohol has been found to be more effective
compared with limonene in terms of chemoprotection against malignant cancer [84]. The
metabolism of d-limonene and α-pinene in the liver, and absorption of citrus EO components
into the circulatory system through the intestinal villi is shown in Figure 4. The mechanisms
of gastroprotection, anti-cancer, anti-tumor, anti-inflammation, anti-microbial, and lipolytic
actions of citrus EO components are summarized in Figure 5.
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Figure 4. Metabolism of d-limonene and α-pinene in the liver, absorption of citrus EO components into the circulatory system through the intestinal villi.
Figure 4. Metabolism of d-limonene and α-pinene in the liver, absorption of citrus EO components into the circulatory system through the intestinal villi.
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Figure
5. Mechanisms
Mechanismsofof
gastroprotection,
anti-cancer,
anti-tumor,
anti-inflammation,
anti-microbial,
and lipolytic
actions
of EO
citrus
EO components.
Figure 5.
gastroprotection,
anti-cancer,
anti-tumor,
anti-inflammation,
anti-microbial,
and lipolytic
actions
of citrus
components.
Caspase Cas(key
pase
(key
apoptosis-inducing
protein)
[85–92].
Abbreviations;
PPAR-α
(Peroxisome
proliferator-activated
receptor
alpha),
bcl
2
(B-cell
lymphoma
protein
apoptosis-inducing protein) [85–92]. Abbreviations; PPAR-α ( Peroxisome proliferator-activated receptor alpha), bcl 2 (B-cell lymphoma protein 2), Bax
( bcl 2),
2Bax
(bcl 2-associated
NF-KB (Nuclear
factor-κB),
LXR-β
X receptor
beta),
TG8
LDL (Triglycerides
8 Low-density
lipoprotein),
FBG (fasting
glucose),
associated
X), NF-ΚBX),
(Nuclear
factor-κB),
LXR-β (Liver
X (Liver
receptor
beta), TG8
LDL
(Triglycerides
8 Low-density
lipoprotein),
FBG (fasting
bloodblood
glucose),
ROS
(Reactive
Oxygen
Species),
TNF-α
(tumor
necrosis
factorfactor
alpha),
ILs (Interleukins),
ATP ATP
(Adenosine
triphosphate).
ROS
(Reactive
Oxygen
Species),
TNF-α
(tumor
necrosis
alpha),
ILs (Interleukins),
(Adenosine
triphosphate).
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The mechanism of chemoprotection by monoterpenes has been explained via several
hypotheses, viz., G1block, induction of cell apoptosis or cell death, aggravation of stressed
condition inside endoplasmic reticulum, and alteration in mevalonate metabolism pathway.
Perillyl alcohol is believed to mainly block the modification of Ras oncoproteins; inhibit
farnesyl-protein transferase (FPTase) and geranylgeranyl protein transferases (GGPTases),
whereas other metabolites of limonene biotransformation, viz., cis- and trans-carveol (CAR)
induce anti-inflammatory activity by suppressing the generation of superoxide dismutase
(SOD) and nitric oxide and NF-κB signaling pathway. Furthermore, myrtenol and cis- and
trans-verbenol (products of α-pinene biotransformation) have been observed to induce
gastroprotective and anti-ischemic effects [82,93].
4.2.3. Applications on Skin
Skin is the largest organ of the human body. Cell cytoplasm contains 90% of its
composition as water, and therefore the skin acts as a protective barrier to resist water loss.
However, the skin is semi-permeable to water and water-soluble substances. The barrier
protection is attributed to the stratum corneum (the epidermis). It is an outer tough, durable
keratinized layer with a thickness up to 20 layers of dead cells, and self-repairing. Beneath
the epidermis is the dermis, a complex structure comprising lymph, blood vessels and
capillaries, nerves, sweat and oil glands, hair follicles, collagen, elastin, fibroblasts, mast
cells, and so on. Due to the lipids present in all cell membranes, the penetration of molecules
through the dermis is relatively easier. The fundamental physicochemical properties
of the external molecules which decide the rate and quantity of external molecules to
penetrate the skin are the molecular weight of the molecule, its spatial structure and
arrangement of functional groups, polarity, optical activity, liposolubility, coefficients of
diffusion, dissociation, and so on. Due to the presence of lipids in the stratum corneum,
the liposoluble compounds in the EOs make their way into the inner layers of the skin and
finally reach into the blood stream.
Once the EO components penetrate the epidermis and enter the dermis, they are
absorbed into the blood circulation and carried to every cell in the body. The hydrophilic
and lipophilic molecules present in the citrus Eos can penetrate the skin through sweat
gland openings, hair follicles, and sebaceous glands, respectively. The EO molecules
progress through the passage between cells, i.e., fatty cement of the skin layers as well
as through the cells themselves by intervening through the cell’s membrane made of
phospholipids. The skin epidermis thickness is uneven in different parts of the body. For
example, the skin epidermis of the forehead and scalp is relatively thinner and contains a
large number of oil glands. Therefore, lipophilic molecules penetrate readily through the
partial barrier and enter the blood stream.
The lipophilic EO components are lipid soluble and tend to accumulate in lipid-rich
areas of the body to form reservoir(s) and possibly to be sequestrated [94,95]. The EO constituent molecule reservoirs present in the outer layers of the epidermis and subcutaneous
fat are retained in the fat for some time and do no disperse to the adjacent layers of the
skin because of poor blood supply in this region [94]. Furthermore, the enzymes present in
the skin participate in regulating (activation/inactivation) the natural chemicals present in
the body, such as hormones, steroids, and inflammatory mediators as well as externally
applied chemicals, such as medicines/drugs and EO components. In addition, the enzymes
also participate in the metabolism of EO components which may result in the change of
molecular structure of the original compound. The latter changes the effect on the body.
The skin enzymatic activities vary differently in different age group individuals which
define skin elasticity, dehydration, damage, broken, pigmentation, inflammation, diseases,
and so on [94].
Bergamot EOs (BEO) have been a part of homemade ointments, soaps, toiletries,
bodywash, shampoos, anti-dandruff and hair care products, masks and cleansers, candles,
and massage oils (a mixture of oils) employed for skin disinfection [96], as an astringent [97],
antiseptic or aid for healing minor wounds [98], insect bites, sunburn, aromatherapy
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massage, and cosmetics [99]. BEO aromatherapy massage as a complementary therapy to
the patients suffering from cancer has been observed to induce relaxation from symptoms
of clinical anxiety and depression for up to two weeks [100]. Furthermore, aromatherapy
involving BEO has been observed to help in improving mood, and symptoms of mild stress
and facilitating sleep induction [101]. The commonly used EOs from citrus in aromatherapy
(in the form of aroma-sticks) in clinical studies are lemon (Citrus limon (L.) Osbeck) [102],
bergamot (Citrus bergamia) [103] and orange sweet (Citrus sinensis (L.) Osbeck) [104] along
with EOs from other herbs, such as lavender (Lavandula angustifolia Mill.), frankincense
(Boswellia carterii), and peppermint (Mentha piperita) [105,106].
BEO is reported to exhibit anti-inflammatory activity while conducting a carrageenaninduced rat paw edema test. The optimal response for the anti-inflammatory activity was
observed with a 0.10 mL/kg dosage injected intraperitoneally while the median effective
dose was 0.079 mL/kg [73]. The absorbed EO and its components penetrated the skin
and can be detected in exhaled air of the breath within 20–60 min. For example, the times
taken to detect citrus EO components in exhaled breath post penetration into the skin are
1,8-cineole and α-pinene (20 min); linalyl acetate, geranyl acetate (between 20 and 40 min),
bergamot, and lemon oils (40 and 60 min, respectively), and geraniol and citral (up to
2 h) [94,107].
Lemon EO has antioxidant properties, i.e., fighting free radicals which cause premature
aging of the skin, and is therefore a popular ingredient in skincare products. The antibacterial property of lemon EOs is attributed to its components, viz., citric acid, limonene,
and pinene. This makes it a suitable component in formulating cleansers, body washes,
and soaps, as it helps in removing bacteria, and other microbes from pores of the skin of
acne-prone oily skin. Furthermore, lemon EOs also possess astringent properties which are
effective in closing the pores in the skin and preventing the blockages from being inflamed.
For a typical formulation to be utilized in topical applications, citrus EOs in a blend with
other EOs, such as lavender and chamomile EOs, are employed for calming skin inflammation and reducing redness. In skin lotions and ointments, the citrus EOs are mixed with
a carrier oil, such as jojoba oil or olive oil to dilute the potency of the oil for applications
at sensitive areas such as the face, neck, and chest. Some citrus EOs, e.g., EOs from bergamot, lemon, and grapefruit exhibit phototoxic effects (e.g., skin-irritation, damage) upon
exposure to sunlight/UV rays in the Sun’s radiation owing to furanocoumarins, especially
5-MOP (5-methoxypsoralen or bergapten) present in the EO composition. Removal of
psoralen (the parent compound in a family of naturally occurring linear furanocoumarins)
from the citrus EOs-containing formulations has been found to eliminate the possibility of
phototoxicity [108].
The volatile constituents in the EOs penetrate the skin through deeper layers of
the skin via different mechanisms of action, viz., interaction with the highly ordered
intercellular lipid structure in stratum corneum (SC), and interaction with intercellular
proteins resulting in conformational changes, and the latter increases permeability of the
skin [109]. The penetration of the EO components also forms a pathway for different
drugs (hydrophobic and hydrophilic), and vitamins in the topical formulation to enter
lower skin layers [109–112]. Furthermore, the EO components are rapidly metabolized, not
accumulated in the skin and the body, and rapidly excreted after application to the skin;
therefore, regarded as safe penetration enhancers [109]. The absorption of citrus EOs to the
deeper layers of the skin, molecular structures of the skin penetration enhancers (frequently
employed in topical lotions/ointments for facilitating transdermal drug delivery), and
molecules participating in anti-inflammatory, anti-microbial, and anti-carcinoma activities
are displayed in Figure 6.
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Figure6. 6.Absorption
Absorptionofofcitrus
citrusEOs
EOsto
to the
the deeper
deeper layers
layers of
of the
the skin, molecular structures
Figure
structures of
of the
the skin
skin penetration
penetrationenhancers
enhancers(frequently
(frequentlyemployed
employedinintopical
topicallotions/ointments
for
facilitating
transdermal
drug
delivery),
and
molecules
participating
in
anti-inflammatory,
anti-microbial,
and
anti-carcinoma
activities.
lotions/ointments for facilitating transdermal drug delivery), and molecules participating in anti-inflammatory, anti-microbial, and anti-carcinoma activities.
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Terpenes in citrus EOs are proven as promising nontoxic, non-irritating penetration
enhancers for both hydrophilic and lipophilic drugs [113,114]. Some of the well-known penetration enhancer molecules present in the citrus EOs are d-limonene, α-pinene, α-terpineol,
carvone, and 1,8-cineole. The terpenes exhibit a significantly efficient fluidizing effect on the
lipid bilayer structure. Limonene has been found to induce change in the barrier structure
of the skin in the presence of ethanol and facilitate the permeation of EO components and
drug molecules utilizing its affinity with alcohol. In addition, sesquiterpenes also have
been found to increase the penetrability of the skin by altering the structure of intercellular
lipid bilayer and formation of a complex with the drug molecule [109,111].
5. Aromatherapy Using Citrus EOs for Health and Treatment of Diseases
5.1. Oxidative Stress
Free radicals, such as reactive oxygen species (ROS), and reactive nitrogen species
(RNS) are produced during cellular aerobic respiration in mitochondria (endogenous).
ROS are also produced when skin is exposed to ultraviolet (UV) light (UV-A; 320–400 nm,
and UV-B; 290–320 nm) and this is known as the exogenous origin of free radicals. In
addition to the ROS, superoxide anion radical (*O2 •– ), hydrogen peroxide (H2 O2 ), hydroxyl
radical (*OH), singlet oxygen (*O2 ), lipid peroxides (LOOH), and their radicals (LOO*)
are also formed which participate in the process of skin aging, phototoxicity, induction of
inflammation, and inflammation-induced malignant tumors [115–119]. The free radicals
attack and degenerate structural molecules, such as collagen; and functional biomolecules,
such as RNA and DNA, fatty acids, proteins, and other essential molecules. This gives rise
to several complications which result in aging, inflammation, cancer, Alzheimer’s disease,
Parkinson’s disease, diabetes, atherosclerosis, liver disease, etc. Oxidative stress is one of
the main reasons behind allergic and inflammatory skin diseases, e.g., atopic dermatitis,
urticaria, and psoriasis. Furthermore, microbial infections, e.g., that are caused by S. aureus,
may worsen the damaged and lesioned skin by the production of ROS [120].
Aerobic respiration at the cellular level takes place in the mitochondria. The latter
is a double-walled organelle (in eukaryotic cells) which carries out aerobic respiration
and produces adenosine triphosphate (ATP). ATP is the utilizable form of the chemical
energy consumed by the cell in its various functions. In diseased conditions, such as
Alzheimer’s disease, dementia, or aging, the mitochondria undergo a dysfunctional stage
during which oxidizing free radicals are generated in excessive amounts which eventually
leads to oxidative stress and oxidative damages to essential molecules in the cell and
ultimately pathological abnormalities. Beta-amyloid (Aβ) is an initiator of reactive oxygen
species (ROS) and reactive nitrogen species (RNS). The free radicals attack and damage the
essential molecules present in the cell including membrane lipids, and cellular organelles
and generate mitochondrial toxins, such as hydroxynonenal (HNE) and malondialdehyde.
When the membrane bound ion selective ATPase is damaged because of oxidative stress,
it stimulates the NMDA receptors, membrane attack complex (MAC), and ion-specific
Aβ pore formation. As a result, an influx of calcium ions increases and consequently
cytosolic and mitochondrial calcium load. In the next stage, cellular amyloid targets essential enzymes, namely cytochrome-C oxidase, α-ketoglutarate dehydrogenase, pyruvate
dehydrogenase, and manganese superoxide dismutase (MnSOD). This causes damage
to the mitochondrial DNA and ultimately fragmentation of the structure. Aβ stimulates
stress-induced protein kinases-p38, c-jun N-terminal kinase (JNK), and tumor suppressor
protein (P53 ) leading to apoptosis or cellular damage.
In natural and healthy physiological conditions, the free radicals generated are neutralized to non-radical forms under the action of certain enzymes, e.g., catalase (CAT)
and hydroxy peroxidase. In acute and chronic cases or low immunity, the production of
free radicals becomes radically high. To elaborate on this, products of lipid peroxidation
stimulate phosphorylation and aggregation of tau proteins. The latter inhibits complex-I
in a cell under oxidative stress, and excessive quantities of ROS and RNS are produced at
complexes I and III. In the final stage, mitochondrial membrane potential (MMP) drops,
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and the permeability-transition pores (ψm) opens. The latter results in the activation of
caspases and cellular damage. Ultimately, the reactive species (ROS and RNS) readily
initiate oxidative degradation of somatic and brain cells (neural, microglial, and cerebrovascular cells). In such conditions, supplementary administration of free radical scavengers is
recommended [58,121].
The citrus EOs possess antioxidative properties due to the ability of the component
molecules to donate a hydrogen atom, or an electron to the free radicals which can delocalize the unpaired electrons (in conjugated/aromatic structure), thus neutralizing the
free radicals and protecting the biological molecules from being damaged by oxidation or
oxidative stress. The EO components also interfere with lipid metabolism in animal tissues
by upregulating the activities of antioxidative enzymes, such as superoxide dismutase,
catalase, and glutathione peroxidase. This results in the inhibition of the formation of
reactive oxygen species and oxidation of polyunsaturated fatty acids which give rise to
off-flavors in the food materials [122,123]. Inhalation of Citrus EOs can increase the amount
of GSH and cause a reduction in lipid peroxidation in the brain, and it helps prevent
DNA cleavage and cell apoptosis by scavenging free radicals (ROS) via antioxidant effects.
Inhalation of EOs augments the level of antioxidant enzymes involved in the immune
system, e.g., superoxide dismutase (SOD), glutathione peroxidase, and catalase (CAT). It
has been found that terpenes present in the citrus EOs can reduce inflammation symptoms by decreasing/inhibiting the release of pro-inflammatory cytokines, such as NF-κB
(nuclear transcription factor-kappa B), IL-1β (interleukin-1β), and TNF-α (tumor necrosis
factor-alpha) [124].
In addition to monoterpene hydrocarbons, limonene can also inhibit the production of
pro-inflammatory cytokines in lipopolysaccharide (LPS)-induced inflammation symptoms,
and the production of ROS in H2 O2 -induced oxidative stress and wound healing. EOs
obtained from bergamot and sweet orange have been found to heal acne vulgaris caused
by excessive secretion of androgen by reducing the growth rate of as well as secretion from,
sebaceous glands. This activates the inhibition of triglyceride (TG) accumulation and the
release of inflammatory cytokines in the sebaceous glands. This results in apoptosis in
sebaceous glands leading to a decrease of T/E2 ratio. The EOs act to lower the IL-1α levels
in sebaceous glands which help in improving acne lesions by alleviating inflammatory responses [121,125,126]. Another study investigating limonene’s anti-inflammatory response
on human eosinophilic leukemia HL-60 clone 15 cells revealed interesting results. Hirota
et al. [127] reported that a low concentration of limonene (7.34 mmol/L) can inhibit ROS
production for eotaxin-stimulated HL-60 clone 15 cells.
A higher limonene concentration of 14.68 mmol/L was found to diminish diesel
exhaust particles (DEP)-induced MCP-1 production significantly, indicating that the antioxidant activity of limonene can help restrict monocyte infiltration into the lungs and prevent
migration of eosinophil, protecting asthmatic lungs and prevent damage from DEPs in the
lung. Furthermore, NF-κB formation was also diminished upon the addition of proteasome
inhibitor MG132. The limonene can inhibit DEP induced p38 MAPK signaling pathway and
inhibit eotaxin-induced chemotaxis by eosinophils [127]. Citrus EO components exhibit
antioxidative activities against the oxidation of linoleic acid. In addition, antioxidant activities have also been reported against in vitro oxidation of human low-density lipoprotein
induced by Cu2+ , and 2, 20 -azobis (2-aminopropane) hydrochloride [128]. The antioxidant
properties of citrus EOs are attributed to the presence of phenolic compounds in their composition. Monoterpene hydrocarbons (limonene, thujene), and oxygenated monoterpenes
(monoterpenes with different functional groups, such as phenols, alcohols, aldehydes,
ethers, esters, and ketones) contribute significantly to the antioxidant properties of the
citrus EOs [129]. The events and consequences of oxidative stress in a somatic and nerve
cell, and the therapeutic effects of citrus EO aromatherapy are displayed in Figures 7–9.
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Figure 7. Oxidative stress in the cell: Events and consequences-I: Somatic cell.
Figure 7. Oxidative stress in the cell: Events and consequences-I: Somatic cell.
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Figure
Figure8.8.Oxidative
Oxidativestress
stressininthe
thecell:
cell:Events
Eventsand
andconsequences-II:
consequences-II:Nerve
Nervecell.
cell.
20 of 44
20 of 45
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x FOR
Figure
Therapeutic
effect
citrus
EOs
aromatherapy.
Figure
9. 9.
Therapeutic
effect
ofof
citrus
EOs
aromatherapy.
21 21
of of
4445
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Thujene, a monoterpene, has been reported to exhibit good antioxidant activity due to
its ability to quench singlet oxygen efficiently [130]. The alcohol compounds, e.g., carveol
and perillyl alcohol; ketones, e.g., carvone and aldehydes, perillyl aldehyde; esters, e.g.,
citronellyl acetate, geranyl acetate, neryl acetate exhibit good antioxidant activities. Among
the compounds, γ-terpinene, geranial, R-(+) limonene, and β-pinene have been reported
for possessing the highest antioxidant capacities [131–133].
5.2. Stress-Related Disorders/Mood Disorders
Stress-related disorders or mood disorders have become very common in everyday
life. Mood disorders include several psychiatric illnesses which significantly (sometimes
severely) impact the mood related function of an individual (patient). The disorders
are characterized by cognitive deficits such as impaired learning, loss of memory, and
inability to focus/concentrate. Sudden, significant, and persistent changes in emotions or
state of mind, sadness, anxiety, depression, sleep disorders, and insomnia are symptoms
associated with chronic stress or trauma. Mood disorders originate from physiological,
psychological disturbances, organic damage, nerve injury, side effects of medications,
chronic stress, etc. Depression is characterized by a combination of symptoms associated
with traumatic emotions (sadness and anhedonia), cognition deficit, and somatic symptoms
(change in appetite, such as over/under eating), sleep disorders, insomnia, melancholy,
hopeless, despair, detachment from daily life/routine activities, fatigue, and even suicidal
tendencies. Anxiety is mainly caused by physiological and psychological disturbances,
e.g., emotional, behavioral, environmental, somatic, and social elements. When any of
these elements invoke unpleasant situation or sensations, fret, phobias, disquietedness, or
restlessness, the human mind enters a stressed condition or anxiety. Prolonged stressed
conditions lead to a stage when the person faces the onset of anxiety symptoms, such as
unusual panic situations characterized by hypertension, sweating, palpitation, chest pain,
migraine, papillary dilation, shortness of breath, and so on [134,135]. According to a WHO
report, more than 260 million people are suffering from depression with varying levels and
approximately 800,000 people die by committing suicide every year [136]. Furthermore,
more than 50 million people are known to be suffering from dementia/Alzheimer’s disease
which is projected to rise in number up to 82 to 152 million by the years 2030 and 2050,
respectively. A stressed or diseased person finds it difficult to perform his/her daily life and
respond approximately to the problems, challenges, or important events on time. Moreover,
the disease further progresses with loss of memory. In the pathological aspect, the diseased
person is diagnosed by the presence of amyloid plaques, neurofibrillary tangles, and loss of
neural transmission in the brain [137,138]. Insomnia patients have common symptoms of
depression and anxiety, and no single medication is known to cure this condition accurately.
Insomnia is also characterized by acute sleep disorder. Prolonged disturbance in sleep
patterns may result in high blood pressure, cardiovascular diseases, and severe risks of
acute mental illnesses [139–141].
Bergamot oil has been found to reduce blood pressure and heart rate and help induce
sleep and relief from restlessness. EOs extracted from sweet orange and lavender EO have
been observed to improve sleep quality and provide relief from tiredness in hemodialysis
patients [142]. Takeda et al. carried out a study on inhalation aromatherapy in elderly
dementia patients by applying EO drop on towels covering their pillows during their sleep
time. The researchers recorded a better sleep latency and improved total sleep time and effectiveness of sleep among the treated people [143]. The aromatic EO molecules enter limbic
system in the brain via nasal passages and stimulate GABA receptors in the hypothalamus.
The overall process induces and maintains restful sleep [144]. Citrus EO (with 95% citral in
the composition) has been observed to induce a pleasant mood in people suffering from
sadness [145]. The molecular pathways involved in the pathophysiology of depression
include the hypothalamic–pituitary–adrenal axis, sympathetic nervous system, monoamine
neurotransmission system (e.g., serotonergic (5-HT), dopaminergic (DA), and GABAergic
pathways), cyclic adenosine monophosphate (c-AMP) response element-binding (CREB)
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protein signaling pathway [58,146–152]. According to neurotropic hypothesis, depression
is associated with a deficit of neurotropic factors caused by prolonged exposure to stress
which results in loss of neural plasticity [153]. Brain-derived neurotropic factors (BDNF),
a protein in the brain produced by BDNF gene, and neurotrophins, a class of growth
factors, promote the growth of the neurons and maintain adequate neural plasticity. During
depression, the level of BDNF in the serum decreases. Therefore, deficiency of neurogenesis or production of new neurons in the brain hippocampus is a major reason behind
depression. EO-based aromatherapy involving EOs of lavender, lemon, and bergamot
has been reported to prevent negative symptoms of depression, such as deficiency of
neurogenesis, suppressed dendritic growth of immature neurons, and low serum BDNF
levels in the brain hippocampus [154–157]. In a clinical study involving patients diagnosed
with stress- and depression-related symptoms, such as attention deficit and hyperactivity
disorder, four weeks employing EO-based aromatherapy resulted in a decrease in the
level of anxiety and depression and a simultaneous increase in blood plasma BDNF levels
in the brain hippocampal tissues [157]. Moreover, regarding neurogenic and enhancing
neurotropic factors in the human brain, citrus EOs have also been observed to participate
in the regulation of the neuroendocrine system. Depression and anxiety disorder release
the stress hormone cortisol. Aromatherapy involving lavender EO has been observed to
downregulate the release of stress hormones and a decrease in salivary and serum cortisol
levels was recorded [48,158]. In addition, bergamot EO and grapefruit seed EO have also
been reported to induce lowering of cortisol levels in the blood, thereby lower stress related
symptoms. There have also been recorded improved coronary flow velocity and enhancement in relaxation. Bergamot EOs have been observed to cause an alteration of HPA axis
and attenuate the rise of corticosterone levels in the blood [159]. Lemon EOs have been
recorded to produce antidepressant effects in terms of accelerated turnover of dopamine in
the brain hippocampal region establishing therapeutic effects of EOs in healing the patients
from depression and related symptoms [58].
Anshen EO, a mixture of EOs from lavender, sweet orange, and sandalwood, has been
observed to have anxiolytic, antidepressant, sedative, and hypnotic effects. Researchers have
performed sleep latency and sleep duration experiments, where they compared diazepam—
generally used to treat insomnia—with anshen EOs [160]. Mouse brain responses were
analyzed using ELISA test to detect changes in 5-HT and GABA levels. The results showed a
significant decrease in impulsive activities and reduced sleep potential. An increase in the
levels of 5-HT and GABA was observed in the mouse brain. Anxiolytic effects of BEO (1.0, 2.5,
and 5.0% w/w) were studied by administering it to rats subjected to anxiety-related behaviors,
the elevated plus-maze, and the hole-board tests, and then measuring the stress-induced
levels of plasma corticosterone in comparison with the effects of diazepam. BEO (2.5%) and
diazepam exhibited anxiolytic-like effects and attenuated the corticosterone response to acute
stress [159]. After perfusion into the hippocampus via the dialysis probe (having volumetric
flow rate 20 µL/min), BEO produced a dose-dependent and Ca2+ -independent increase of
extra cellular aspartate, glycine, taurine, GABA, and glutamate [161]. Inhalation of orange
EO for 90 s has been observed to cause a significant decrease in oxyhemoglobin concentration
in the right prefrontal cortex of the brain which increases comfortable, relaxed, and natural
feelings [104]. Osbeck EO from Citrus sinensis Osbeck is found to exert antidepressant effects,
being suitable to treat minor stress. The effects of Osbeck EO inhalation on CUMS (Chronic
Unpredictable Mild Stress) mice were found to tackle depression along with decreased body
weight, interest, movement, and dyslipidemia. Limonene is not metabolized in the brain
immediately after inhalation. An in-depth study revealed that limonene is significantly effective as an antidepressant and shows healing progress in the neuroendocrine, neurotrophic,
and monoaminergic systems [17].
Moradi et al. [162] conducted a study on patients who underwent coronary angiography.
The patients were divided into two intervention groups, each comprising 40 patients. Patients
of the test group inhaled EO from Citrus aurantium for 15–20 min about 60 min before the
procedure. In the control group, distilled water was used instead of EO. Following Citrus
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aurantium EO inhalation, noticeable responses were observed. Vital signs of anxiety such as
pulse rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly
decreased after the intervention [162]. Li et al. [163] compared the effects of an essential oil
mixture (EOM) (a mixture of Citrus sinensis L., Mentha piperita L., Syzygium aromaticum L.
and Rosmarinus officinalis L.), with peppermint EO on physical exhaustion in two rat groups.
After swimming, the two rat groups were maintained in an environment of EOM and
peppermint EO, respectively. Various body parameters were studied after three continuous
days of nebulization. Blood lactic acid (BLA) and malondialdehyde (MDA) levels were
found to decrease in both groups. An improved duration of fatigue and increased superoxide
dismutase (SOD) activity were observed in both groups. The results observed in the EOM
group were noticeable, such as an increase in blood glucose and a reduction of blood urea
nitrogen (BUN) and glutathione peroxidase (GSH-PX). This study determined that exerciseinduced fatigue can be effectively relieved by inhalation of EOs [163]. Another study was
performed on Swiss male mice to observe the neurotransmission contribution of nitric oxide
when C. sinensis EO was used for its anxiolytic effects. To perform this study, mice were
placed in an environment of C. sinensis for inhalation of EOs at different concentrations. Nitric
oxide was used as a precursor to observe the mediation behavior of the nitrergic system, and
it was found to play a significant role in the anxiolytic effect of C. sinensis. Bergamot essential
oil (BEO), obtained from the fruit of Citrus bergamia, is used in aromatherapy as a pain reliever,
improves sleep disorders, and reduces anxiety. BEO can induce neurotransmission which is
associated with its anxiolytic-relaxant effects. Anxiolytic effects are shown to be the result
of the collaborative action of BEO and the 5-hydroxytryptamine (5-HT) 1A along with the
involvement of multiple and complex mechanisms [19].
5.3. Diseased Conditions
5.3.1. Neurogenic Inflammation
Neurogenic inflammation is inflammation in neurons caused by the release of proinflammatory mediators, namely Substance P, calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). The release of pro-inflammatory mediators in
the neurons is stimulated by the activation of ion channels (transient receptor potential ion
channel-1 or TRPA-1) in response to harmful/unpleasant environmental stimuli. Acute
neurogenic inflammation is caused by the activation of TRPA-1 channels induced by LPS.
Following the release of inflammation causing neuropeptides is the release of histamine from
the mast cells present in the vicinity of the affected neurons. The latter stimulates release
of Substance P and calcitonin gene-related peptide, thereby establishing a bidirectional link
between histamine and neuropeptide in the causation of neurogenic inflammation. Approximately 25% of migraine cases lead to temporary dysfunction of the central nervous
system associated with visual field disturbances, sensitivity to light/sound, nausea, and/or
vomiting [164].
Terpenes and terpene derivatives have been investigated for anti-inflammatory bioactivities. In this regard, limonene, α-pinene, β-caryophyllene, and β-myrcene have been most
preferred for migraine cases [165]. Alpha-pinene (α-pinene) present in citrus EOs has been
found to reduce NF-κB/p65 nucleus of LPS-stimulated THP-1 cells and increase the cytoplasmic concentration of Iκ-Bα protein. Alpha-pinene (α-pinene) also significantly decreases
the levels of IL-6, TNF-α, and NO, as well as the expression of iNOS and Cox-2 induced
by LPS. An in vitro study on d-limonene activity revealed an increase in IL-10/IL-2 ratio,
consequently enhancing IL-10 levels. The latter is a cytokine synthesis inhibitory factor and
inhibits proinflammatory Th1 cytokine production (IL-2) [166]. Furthermore, d-limonene
epoxide has been observed to prevent the release of inflammatory mediators, inhibit vascular
permeability, reduce migration of neutrophils, and display systematic and peripheral analgesic effects towards the brain’s opioid system (associated with regulating pain, reward, and
addictive behavior) [167]. The pathophysiological mechanism of migraine induced by 5-HT
and neuroprotective mechanisms of α-pinene in migraine are displayed in Figures 10 and 11,
respectively.
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Figure 10. The pathophysiological mechanism of migraine induced by 5-HT. (1) Platelet aggregation trigger release of 5-HT and ADP in blood plasma. (2) High
Figure 10. The pathophysiological mechanism of migraine induced by 5-HT. (1) Platelet aggregation trigger release of 5-HT and ADP in blood plasma. (2) High
level of plasma 5-HT causes reversible vasoconstriction followed by conversion of 5-HT to its metabolite 5-HIAA. The latter is excreted in urine. (3) Low level
level of plasma 5-HT causes reversible vasoconstriction followed by conversion of 5-HT to its metabolite 5-HIAA. The latter is excreted in urine. (3) Low level of
of plasma 5-HT stimulates perivascular neurons to release neuropeptides (NO, PG, SP, NKA, CGRP) causing vasodilation of cerebral veins. The latter leads to
plasma 5-HT stimulates perivascular neurons to release neuropeptides (NO, PG, SP, NKA, CGRP) causing vasodilation of cerebral veins. The latter leads to
migraine
migraine symptoms.
symptoms.
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Figure
Neuroprotective
mechanismsof
ofα-pinene
α-pinene in
in migraine
migraine [168].
Figure
11. 11.
Neuroprotective
mechanisms
[168]. The
The α-pinene
α-pinenecan
canreduce
reduce LPSLPS-induced inflammation in macrophages. α-pinene can block phosphorylation of MAPKs
induced inflammation in macrophages. α-pinene can block phosphorylation of MAPKs (ERK/JNK)
(ERK/JNK) in macrophages and reduce the level of active (soluble IKK). This can prevent degradain macrophages
and reduce
theAlso,
levelα-pinene
of active
(soluble
IKK). phosphorylation
This can prevent
tion of the NF-ĸB/IĸB
complex.
can
hinder NF-ĸB
anddegradation
formation of of the
NF-kB/IkB
complex.complex
Also, α-pinene
can
phosphorylation
formation of the
the P65/p50/NF-ĸB
that leads to
its hinder
nuclear NF-kB
translocation
and inductionand
of inflammatory
genes to generate
cytokines.
TNF-α translocation
(tumor necrosisand
factor
alpha), IL-1β
(Interleukin- genes
P65/p50/NF-kB
complex
thatAbbreviations;
leads to its nuclear
induction
of inflammatory
1β), IL-6 (Interleukin), Cox-2 (Cyclooxygenase-2), Inos (Inducible nitric oxide synthase).
to generate
cytokines. Abbreviations; TNF-α (tumor necrosis factor alpha), IL-1β (Interleukin-1β),
IL-6 (Interleukin), Cox-2 (Cyclooxygenase-2), Inos (Inducible nitric oxide synthase).
5.3.2. Dementia, Alzheimer’s Disease (AD), and Parkinson’s Disease (PD)
Alzheimer’s
disease is anfurther
age-related
neurodegenerative
characterized
by other
Neurogenic
inflammation
causes
conditions for thedisorder
pathogenesis
of several
gradual
memory
loss
and
dementia.
It
also
shows
cognitive
dysfunctions
and
turbulent
neurogenic diseases, namely multiple sclerosis, migraine, psoriasis, asthma, vasomotor rhiniAt a the
physio-chemical
level,
is diagnosed
by scarcity
in cholinergic
tis, behavioral
and so on. patterns.
In migraine,
stimulation of
the ittrigeminal
nerve
takes place
which releases
neurotransmission in the cranial (brain) nerves, cognitive dysfunction, behavioral turbuneuropeptides, such as Substance P, nitric oxide, 5-HT, vasoactive intestinal polypeptide,
lence, gradual memory loss, accumulation of amyloid plaques (amyloid-β, Aβ) and neuneurokinin A, and CGRP which eventually results in “sterile neurogenic inflammation”. The
rofibrillary tangles (NFTs) in the specific brain areas, reduced glutathione (GSH) content
release
of Substance P stimulates the production of several other pro-inflammatory cytokines,
in the hippocampus, mitochondrial dysfunction in the cells, and excess production of free
namely
interleukins
IL-6),
and[169].
TNF-alpha
(TNF-α). Migraine
is characterized
radicals
leading to (IL-1,
oxidative
stress
The cholinesterase
(ChEs) enzyme
hydrolyses by a
strong
headache(Ach)
accompanied
with
nausea,
and sensitivity
to light
which may peracetylcholine
into choline
and
acetatevomiting,
and the concentration
of Ach
neurotransmitsistter
upmolecules
to 72 h orin
longer.
Thedrops
phases
in migraine
be explained
to take place in four
the brain
resulting
in thecan
termination
of neurotransmission.
Ace-stages,
viz.,tylcholine
(a) prodrome:
this in
stage
persists
for of
a few
hours
few days
is characterized
by
is involved
the key
function
learning
andtomemory.
In and
addition,
monoamines, viz.,depression,
dopamine and
serotonin
(5HT),fatigue,
releasedmuscle
in the brain
are also
attributed
to learnirritability,
yawning,
nausea,
stiffness,
difficulty
in concentration
and (b)
memory.
A decrease
the
dopamine
amount
in the brain, and
consequently,
anding
sleep;
aura: this
persistsinfor
5 to
60 min and
is characterized
by visual
disturbances,
functional
degradation
of dopamineinreceptors
has feet,
been and
identified
as one
of the common
temporary
loss
of sight, numbness
hands and
tingling
sensations
in the body;
causes of Parkinson’s
disease
and
disease [170].byFor
symptomatic
(c) headache;
this persists
for 4 to
72Alzheimer’s
h and is characterized
throbbing
pain,managesensitivity to
ment of AD, inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)
light,
noise, odors, nausea, vomiting, giddiness, insomnia, neck and body pain and stiffness,
enzymes responsible for the degradation of the essential neurotransmitter acetylcholine
and burning; and (d) postdrome: this is characterized by an inability to concentrate, fatigue,
(ACh) are considered for the development of anti-AD drugs. The choline esterase inhibi-
and lack of comprehension.
5.3.2. Dementia, Alzheimer’s Disease (AD), and Parkinson’s Disease (PD)
Alzheimer’s disease is an age-related neurodegenerative disorder characterized by
gradual memory loss and dementia. It also shows cognitive dysfunctions and turbulent
behavioral patterns. At a physio-chemical level, it is diagnosed by scarcity in cholinergic neurotransmission in the cranial (brain) nerves, cognitive dysfunction, behavioral turbulence,
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gradual memory loss, accumulation of amyloid plaques (amyloid-β, Aβ) and neurofibrillary tangles (NFTs) in the specific brain areas, reduced glutathione (GSH) content in the
hippocampus, mitochondrial dysfunction in the cells, and excess production of free radicals
leading to oxidative stress [169]. The cholinesterase (ChEs) enzyme hydrolyses acetylcholine
(Ach) into choline and acetate and the concentration of Ach neurotransmitter molecules in
the brain drops resulting in the termination of neurotransmission. Acetylcholine is involved
in the key function of learning and memory. In addition, monoamines, viz., dopamine
and serotonin (5HT), released in the brain are also attributed to learning and memory. A
decrease in the dopamine amount in the brain, and consequently, functional degradation
of dopamine receptors has been identified as one of the common causes of Parkinson’s
disease and Alzheimer’s disease [170]. For symptomatic management of AD, inhibitors
of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes responsible for
the degradation of the essential neurotransmitter acetylcholine (ACh) are considered for
the development of anti-AD drugs. The choline esterase inhibitors reversibly bind to the
active sites of acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) enzymes. As a
result, the hydrolytic degradation of ACh neurotransmitter molecules into choline and
acetate is inhibited. Consequently, the concentration of ACh increases at the synaptic gaps in
cholinergic neurons in the hippocampus cerebral cortex and some parts of the new striatum.
Other neurodegenerative pathological conditions in patients suffering from AD include
an increase in monoamine oxidase (MAO) activity and lipid oxidation induced by Fe2+
ions. The increase of MAO deactivates neuroactive amines, such as serotonin, dopamine,
and norepinephrine, and enhances the production of free radicals (or ROS) in the patient’s
brain [171]. Fe2+ ions have the ability to cross the blood–brain barrier which induces lipid
oxidation via Fenton’s reaction. This leads to an abundance of polyunsaturated fatty acids
in the brain tissues and causes vulnerability to free radical attacks. The latter causes the formation of radical species, e.g., MDA which participates in neurodegeneration. As a remedy,
if an antioxidant mechanism stops or inhibits the lipid peroxidation products (MDA), it is
possible to deplete the concentration of free Fe2+ ions in the cytosol. Consequently, the level
of oxidative stress decreases in the brain as well as in the entire body [172–177].
Most of the drugs employed in the treatment for AD are synthesized chemically and
have been observed to cause side effects, e.g., nausea or vomiting, hepatotoxicity, dyspepsia, myalgia, dizziness, anorexia, and so on. EOs have been observed to interact with a
range of neurotransmitter pathways, namely noradrenergic (related to norepinephrine),
5-HTergic (related to serotonin), GABAergic (related to γ-aminobutyric acid), DAergic or
dopaminergic (related to dopamine), etc. Furthermore, the specific compounds present in
the EOs participate in specific action mechanisms, e.g., benzyl benzoate activates 5-HTergic
and dopaminergic pathways and consequently exerts anxiolytic and anti-depressant effects [178]. Linalool and β-pinene interact with GABAergic pathway to produce similar
effects. In this direction, other EO components, namely limonene benzyl alcohol has also
been found to produce anxiolytic and anti-depressant effects. EOs can inhibit enzymes
linked with hydrolysis of neurotransmitters, such as monoamine oxidase (MAO). Moreover,
EOs possess antioxidative properties and can penetrate the blood–brain barrier. In this
direction, Ademosun et al. carried out carried out inhibition assays of AChE and BChE,
MAO, and lipid peroxidation [173]. The pathophysiological targets in diseased conditions
of dementia, Alzheimer’s, and Parkinson’s are summarized in Figure 12. The Mechanism of
action of citrus EOs to inhibit acetylcholinesterase (AChE), thereby increasing levels and
duration of acetylcholine in the brain and assisting with cognition (learning and memory
retention) is shown in Figure 13. The syntheses of different neurotransmitter molecules
in the brain, namely GABA, dopamine, and serotonin, and the mechanism of neurotransmission are shown in Figure 14. The neurotransmission pathways in GABAergic, DAergic
(dopaminergic), and 5-HTergic (serotoninergic) neurons and citrus EO components that
activate neurotransmission and exhibit anti-proliferative effects on human neuroblastoma
cell growth are shown in Figure 15.
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Figure
Figure12.
12.Pathological
Pathologicaltargets
targetsinindiseased
diseasedconditions
conditionsof
ofdementia,
dementia,Alzheimer’s,
Alzheimer’s,and
andParkinson’s.
Parkinson’s.
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.
Figure 13. Mechanism of action of citrus EOs to inhibit acetylcholinesterase (AChE), thereby increasing levels and duration of acetylcholine in the brain and
Figure 13. Mechanism of action of citrus EOs to inhibit acetylcholinesterase (AChE), thereby increasing levels and duration of acetylcholine in the brain and
assisting with cognition (learning and memory retention). Abbreviation; ACh—acetylcholine; AChE—acetylcholinesterase; nAChr—nicotinic acetylcholine receptors;
assisting with cognition (learning and memory retention). Abbreviation; ACh—acetylcholine; AChE – acetylcholinesterase; nAChr - nicotinic acetylcholine recepEOs—Citrus
essential
oil components.
tors;
EOs—Citrus
essential
oil components.
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11,x2374
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45
Figure 14. Syntheses of neurotransmitter molecules, viz., GABA (γ- Aminobutyric acid), dopamine, and serotonin (also called as 5-HT) and the mechanism
Figure 14. Syntheses of neurotransmitter molecules, viz., GABA (γ- Aminobutyric acid), dopamine, and serotonin (also called as 5-HT) and the mechanism of
of neurotransmission. AADC also known as DDC. Abbreviations; GAD (glutamate decarboxylase), TH (Tyrosine hydroxylase), AADC (aromatic amino acid
neurotransmission. AADC also known as DDC . Abbreviations; GAD (glutamate decarboxylase), TH (Tyrosine hydroxylase), AADC (aromatic amino acid
decarboxylase),DDC
DDC(DOPA
(DOPA decarboxylase),
decarboxylase), TPH2
TPH2 (s
(s tryptophan
tryptophan hydroxylase
hydroxylase 2).
2).
decarboxylase),
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Figure 15.
15. Neurotransmission pathways in GABAergic, DAergic, and 5-HTergic
5-HTergic neurons
neurons and
and Citrus
Citrus EO
EO components
components that
that activate
activate neurotransmission
neurotransmission and exhibit
exhibit
Figure
anti-proliferative effects
effects on
on human
human neuroblastoma
neuroblastomacell
cellgrowth.
growth.
anti-proliferative
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The EO has been observed to inhibit AChE, BChE, and MAO in a dose-dependent
manner. However, the EOs extracted from peels exhibited a significantly higher inhibition
towards AChE compared with the EOs extracted from the seeds. On the other hand, the
EOs from seeds exhibited a higher inhibition towards MAO activity compared with the
peel EOs. Furthermore, the EOs also exhibited a decreasing effect on malondialdehyde
(MDA) production which is present inside the brain homogenates. MAO activity is a
crucial determinant in deactivating main neurotransmitters, such as serotonin, dopamine
in the brain cells. This affects the overall behavior and mood of the patients suffering from
Alzheimer’s disease. Zhou et al. [179] carried out passive avoidance test (PA) and open
field habituation test (OFT) employing lemon EO components, viz., s-limonene and its
derivatives-perillyl alcohol to investigate the effect of EOs on memory in rats. The rats were
fed with s-limonene (100 mg/kg), s-perillyl alcohol (50 mg/kg) in their diets and scopolamine (1 mg/kg) was injected subcutaneously 30 min before the training test [179]. The
lemon EO components showed a strong ability to improve learning and memory impaired
by scopolamine in rats. BEO has been reported to exhibit antiproliferative activities in terms
of inhibition against the survival and proliferation of SH-SY5Y neuroblastoma cells by
activating multiple pathways resulting into necrosis and apoptotic cell death [69,180,181].
A summary of the studies on the application of citrus EOs in aromatherapy is presented
in Table 1.
Table 1. Pharmacological behavior of citrus EOs in aromatherapy.
Citrus Type
Bergamot orange
(C. bergamia)
essential oil (CBEO)
Particulars
In Vitro/In Vivo/Animal
Model
Activity
References
Antioxidant behavior
In vivo model
obtained from mouse
hearts
Increase in transcription of genes involved
in antioxidant responses
Having lower IC50 O2 •− value in
scavenging activity test than ascorbic acid
and higher FRAP activity
[182]
Mood disorder
BEO aromatherapy in
alleviating depressive
mood in postpartum
women
Significantly improve the depressive mood
Sleep quality was not significantly different
[103]
Acclimatization of the
rats was performed
Relieve symptoms of stress-induced anxiety
No overlapping between BEO and
benzodiazepines behavioral effects
Integrated effect on both 5-HT and GABA-A
receptors
[183]
Usefulness in neuroprotection
Chronic pain control
Management of stress, anxiety, and
anxiety-related conditions
[184]
Effect of inhalation
BEO on
formalin-induced
nociceptive response
in mice.
Inhalation of BEO exerted antinociceptive
activity.
reduces formalin-induced licking/biting
behavior.
chronic pain relief in a stepwise therapeutic
manner
[161]
Evaluated against the
ROS-generating
compound
Activity in DPPH assay was in a range of
6–23% for C. sinensis
Decreased apoptosis in HaCat cells
stimulated with H2O2.
The levels of intracellular superoxide ion
found to be lower
[185]
Diseased condition
The elevated
plus-maze and the
Neuropharmacological
hole-board tests were
studies
performed to study of
BEO on rats
Antinociceptive effect
Sweet orange or
navel orange
(C. sinensis L.)
essential oil (CSEO)
Antioxidant behavior
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Table 1. Cont.
Citrus Type
Particulars
Activity
References
Mood disorder
Aromatherapy
during dental
treatment
Lower degree of anxiety and a more
cheerful attitude.
To reduce salivary cortisol and pulse rate
[104]
Physiological and
psychological effect
Measurements were
performed in a
chamber with an
artificial climate with
20 females
Significant decrease in oxyhemoglobin
concentration in the right prefrontal cortex
of the brain.
Increases comfortable, relaxed, and natural
feelings.
[104]
Anxiolytic effect
Forty (40) male
volunteers were
allocated for the
inhalation
Decreases the symptoms of anxiety
Improves the mood
[186]
Unpredictable mild
stress
Randomized
three-arm controlled
trial
Significantly improved depression-like
behaviors in CUMS mice by lowering
sucrose preference, body weight, curiosity,
and mobility
Reducing immobility time and
dyslipidemia
[17]
Antioxidant behavior
DPPH scavenging
test
contribute to the prevention of oxidation as
antioxidants and free radical scavengers
[187]
Mood
disorder/anxiolytic
effect
Collection of
medullary material in
patients with chronic
myeloid leukemia
(CML)
Anxiolytic effect and reduces the signs and
symptoms associated with anxiety
Decrease in the SBP and DBP
[188]
Diseased condition/premenstrual
syndrome (PMS)
Inhalation of 0.5
percent CAEO during
the luteal phase of the
menstrual cycle
Improved the symptoms of PMS
Effective as a new and complementary
therapeutic method for the emotions PMS
symptoms in female.
[18]
Sedative and
hypnotic effects
Spielberger’s
State-Trait Anxiety
Inventory (STAI) was
used after giving
bitter orange flower
powder capsule to
post-menopausal
women
Inhaling the CAEO greatly reduced anxiety
[189]
Reduces pain
Study was a
randomized clinical
trial conducted with
126 eligible
primiparous patients
Controls the enzymes in prostaglandins and
reduces pain; controls the contractions
caused by oxytocin and prostaglandins and
exert anti-uterine pain effects
[190]
Antioxidant behavior
DPPH radical
scavenging assay
Lemon peel EO showed 55.09% inhibition
of DPPH
considerable antioxidant properties both
in vitro and barley soup as food model
[191]
Mood
disorder/Anxiety
Thirty-nine
sophomore nursing
students (35 female
and 4 males)
Positive effect on cognitive test anxiety
[192]
Bitter orange
(C. aurantium)
essential oil (CAEO)
Lemon
(C. limon) essential
oil (CLEO)
In Vitro/In Vivo/Animal
Model
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Table 1. Cont.
Citrus Type
Mandarin
(C. reticulata)
essential oil
(CREO)
Kaffir lime
(C. hystrix) essential
oil (CHEO)
Particulars
In Vitro/In Vivo/Animal
Model
Activity
References
Diseased
condition/anxiolyticlike
effect
Swiss mice model
Induce an anxiolytic behavior in mice
no toxicity in vitro
[193]
Treatment of
dysmenorrhea
Population of this
study amounted to
185
Psychological and physical benefits
[194]
Effect on nausea
among pregnant
women
Control trial on 90
pregnant women
Effective in reducing pregnancy nausea and
vomiting
[195]
Antioxidant behavior
DPPH),
3-(N-morpholino)
propane sulfonic acid
(ABTS)
Exhibited moderate radical scavenging
activity
[196]
Mood
disorder/mood and
as a relaxing hypnotic
agent
Frontal and parietal
skulls of male Wistar
rats implanted with
electrodes for electroencephalographic
(EEG)
CREO reduces REM sleep latency and
enhanced the overall time and number of
REM sleep episodes
[197]
Anti-proliferative
Protective effects on
bleomycin
(BLM)-induced lung
fibrosis in rats
Preventive effects on BLM-induced
pulmonary fibrosis in rats
Anti-proliferative effect against human
embryonic lung fibroblasts
[198]
Antioxidant behavior
DPPH free radical
scavenging assay
Potential antioxidant activity
[199]
Stimulating effect
Forty healthy
volunteers
participated in the
experiments
Reducing depression and stress in humans
more alert, attentive, cheerful attitude
[200]
Antioxidant behavior
DPPH free radical
scavenging test
Mature yuzu contains higher amounts of
vitamin C and phenolics than other citrus
fruits
Significant dietary source of antioxidants
[201]
Mood disorder
Inhaled
administration (i.h.)
of EOCJ for 90 min on
mouse
Increased locomotor activity
The anxiolytic-like effect
[202]
Autonomic nervous
system (ANS)
Study on seventeen
women with
subjective
premenstrual
symptoms
Therapeutic effects of yuzu fragrance on
premenstrual symptoms (PMS)
Can reduce premenstrual emotional
symptoms
Increased parasympathetic activity
[203]
Physiological effect
Effect of 10-min
inhalation of the yuzu
scent on 21 women
Reduced heart rate (HR) and enhanced
high-frequency power of heart rate
variability (HRV), exhibiting
parasympathetic nervous system activation,
alleviation of negative emotional stress
[204]
Yuzu
(C. junos)
essential oil (CJEO)
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Table 1. Cont.
Citrus Type
References
32 healthy
participants enrolled
in the study (16 men
and 16 women, aged
20–24 years)
Oxyhemoglobin concentration in the
prefrontal cortex increased
Task performance improved after inhaling
yuzu essential oil
[203]
Antioxidant behavior
DPPH test
Prevention of oxidation as antioxidants and
free radical scavengers.
Essential oils in the old leaves had the
maximum antioxidant activity
[43]
Diseased condition/neurological
disorder
Study on
scopolamineinduced learning and
memory deficit in rats
Repairing effects on memory and
behavioral disorders
Treatment of AD, insomnia, anxiety, and
epilepsy
[205]
Mood
disorder/anxiolytic
Effect
Study on patients
with chronic myeloid
leukemia (CML)
Diastolic pressure decreases
Exhibits an anxiolytic effect and reduces the
signs and symptoms associated with
anxiety in patients with CML
[188]
Antiseizure and
anticonvulsant effect
Assessed in
pentylenetetrazole
(PTZ)-induced in
mice
Anticonvulsant activity which supports the
ethnomedicinal claims of the use of the
plant in the management of seizure
[206]
Effect on anxiety and
perceived pain in
women during labor
Study on 88 women
during labor
Used as an alternative tool to relieve anxiety
and perceived pain in women during all
stages of labor
[207]
Human psychology
Neroli
(C. aurantium)
essential oil
(CAEO)
In Vitro/In Vivo/Animal
Model
Activity
Particulars
6. Summary
Citrus EOs are economical, eco-friendly, and natural alternatives to the synthetic
compounds used in aromatherapy. Citrus-based EOs are mainly obtained from the leaves,
flowers, and peels of young and ripened fruits, indirectly emphasizing waste management
to save the environment from pollution and prevent contamination of the underground
water table. Citrus EOs from waste peels used in aromatherapy help in relieving stress and
stress-related disorders/diseases. The majorly occurring components present in citrus EOs
and their therapeutic effects in aromatherapy have been summarized pictorially as below
(Figure 16).
Antioxidants 2022, 11, x FOR PEER REVIEW
36 of 44
Antioxidants 2022, 11, 2374
36 of 45
Figure 16. Therapeutic effects of majorly occurring component in citrus essential oil [202,208–211].
Figure 16. Therapeutic effects of majorly occurring component in citrus essential oil [202,208–211].
Antioxidants 2022, 11, 2374
37 of 45
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/antiox11122374/s1, Figure S1: Climate sustainability and the
annual production of citrus fruits in different geographical regions across the globe; Figure S2: Market
segmentation of citrus essential oils; Figure S3: (a) Global citrus oil market by application, by the
year 2018, (b) Citrus essential oil market value forecast (Citrus Oil Market by Product Type, 2022);
Figure S4: Molecular structures of the volatile and non-volatile components present in Citrus EOs;
Figure S5: Composition of EOs in different Citrus varieties; Table S1: Methods/Techniques of
extracting Citrus essential oils; Table S2: Methods/techniques of characterization/authentication of
Citrus essential oils. References [3,4,14,21,22,24,25,34–37,42,170,212–219] are cited in Supplementary
Materials.
Author Contributions: P.A.: conceptualization, writing original draft; Z.S.: designing the schematic
diagrams and creating figures; M.K.: conceptualization, writing original draft; A.D.: writing
original draft; A.S.: writing—reviewing and editing; K.K.S.: maps and graphical content; M.S.:
writing—reviewing; N.M.: content collection, reconstructing text and figures, and editing; A.K.M.:
reviewing and editing and resources; K.-H.B.: reviewing, editing, and supervision. All authors have
read and agreed to the published version of the manuscript.
Funding: This research was funded by the Rural Development Administration, Republic of Korea,
grant number PJ0157260.
Acknowledgments: This work was supported by the Cooperative Research Program for Agriculture
Science and Technology Development (project no. PJ015726), Republic of Korea.
Conflicts of Interest: The authors declare that there is no conflict of interest.
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