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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 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 ].
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) [51,52,53]. 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 .
Open in a separate window(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 .
Open in a separate windowThe 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.
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 [12,46,48,61,62,63,64,65].
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 [66,67,68,69,70]. 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 [73,74,75]. 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 another 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 . The mechanisms of gastroprotection, anti-cancer, anti-tumor, anti-inflammation, anti-microbial, and lipolytic actions of citrus EO components are summarized in .
Open in a separate windowOpen in a separate windowThe 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].
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 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 carrageenan-induced 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 [109,110,111,112]. 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 .
Open in a separate windowTerpenes 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].
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