4. Odorants as therapeutic ligands with EORs
Odorants with therapeutic potentials play a very crucial role in human
life (Denda et al., 2000; Kako et al., 2008; Lee,
Depoortere & Hatt, 2019). Several investigations have presented EORs
activations by odorants administration may have some help on a
physiological and psychological process in humans (Table 2), for
example, odorants can encourage skin barrier recovery by reducing the
stress responsible for homeostasis (Denda et al., 2000;
Angelucci et al., 2014).
From the literature review, we summarize the EORs activating odorants
(ligands) into three main groups. In this section, these three groups
have been elaborated with examples.
4.1 Fatty Acids
According to the research to date, fatty acids are a large group of
ligands that can activate EORs, mainly short-chain fatty acids (SCFAs)
and medium-chain fatty acids (MCFAs). In the human body, about 500–600
mmol of SCFAs are formed in the gut per day, but the amount of SCFAs
production depends on the fiber intake dose and sources. Some good
sources of dietary fiber are apples, apricots, milk, yogurt, see-weeds,
etc. (Dhingra et al., 2012; Dalile et al., 2019). Acetate
(C2) and propionate (C3) are the prominent SCFAs in the human body
(Macfarlane & Macfarlane, 2003). Acetate stimulates OR51E2 in the
kidney and induces renin secretion (Pluznick , 2013). Propionate
activates OR51E2 to mitigate airway contraction (Aisenberg et
al., 2016). Propionic acid, an SCFA metabolite generated from gut
microbiota fermentation can trigger OR51E2 and reduce anabolic and
proliferative signals in the prostate (Natarajan & Pluznick, 2016;
Pluznick, 2016; Rooks & Garrett, 2016; Abaffy et al., 2018).
Another receptor OR51E1, paralogous to OR51E2, can also be stimulated by
SCFA, but most prone to be activated by MCFA like nonanoic acid,
decanoic acid and valeric acid derivatives (Fujita et al., 2007;
Jovancevic et al., 2017a). MCFA can be released by the metabolism
of adipose tissue as well as direct dietary intake (Costa et al.,1998). MCFA is present in human plasma and epicardial adipose tissue,
which is a case in point to indicate the participation of ORs in heart
function. Because MCFA-activated OR51E1 can negatively induce cardiac
trabeculae in human explanted heart and results in chronotropic
negativity in human stem cell-derived cardiomyocytes (Jovancevic et
al., 2017a).
4.2 Essential oil oriented flavor compounds
EORs activating odorants are naturally found in plant essential oils
(EOs) (Lahlou, 2004). EOs are colorless smelling liquids consisting of
saturated and unsaturated hydrocarbons, alcohol, aldehydes, esters,
ethers, ketones, oxides phenols, and terpenes, which can be considered a
mixture of fragrance compounds (Schiller, & Schiller, 1994; Wildwood ,
1996). The human body could intake these odorants through the skin and
lungs by absorption and inhalation (Maßberg & Hatt, 2018). Furthermore,
Some of EOs can also be taken with drinks or foods as additives.
With small molecular weight, they are highly refractive. EOs are the
main therapeutic agents in aromatherapy, an age-old treatment system
that still possesses a very strong position in medical science (Ali et
al., 2015). As EOs are highly concentrated with fragrance
elements, they can work very effectively on pressure points even by
inhalation (Alok, Rakesh & Sushil, 2000). Besides relieving the stress,
rejuvenating and regenerating the individuals, EOs also has
antimicrobial and antioxidant characteristics (Guleria et al.,2013). For centuries, EOs are used by folklore professionals as powerful
treatment materials for diseases like Alzheimer’s, cardiovascular,
cancer and labor pain in pregnancy in different parts of the world
(Perry & Perry, 2006; Shiina et al., 2008; Jimbo et al.,2009; Smith, Collins & Crowther, 2011). Even recent medical science has
found that EOs can have a good effect on cancer treatment (Blowman et
al., 2018).
Volatile terpenes and terpenoids are the main components of EO
(Pichersky, Noel & Dudareva, 2006). Some of these volatiles viz.
citronellal (pelargonium), thymol (thyme), ionone (roses and berries),
geraniol (rose oil and citronella oil) and citronellal (citrus species)
can trigger ORs in non-chemosensory tissues and affect the cellular
process (Sanz et al., 2005; Braun et al., 2007; Saito et
al., 2009; Adipietro, Mainland & Matsunami, 2012; Gu &
Ben-Shahar, 2013; Wu et al., 2015; Zhao et al., 2013).
β-ionone, an endogenous ligand for OR51E2, is a very available component
of cosmetics because it has a good impact on melanogenesis and
dendritogenesis. It can also cut off the proliferation of melanocytes in
cell culture. OR51E2, formerly believed to be native in the prostate,
has shown its presence and effects on skin tissues too (Gelis et
al., 2016). In prostate cancer cells, β-ionone triggers OR51E2
and activates tyrosine kinase Src and increases Ca2+via transient receptor potential channel (TRVP6) (Spehr et al.,2011). This ligand retards the tumor suppressor N-myc
downstream-regulated gene 1 (NDRG1) by evoking the downstream
phosphorylation of tyrosine kinase 2 (PYK2), p38 MAPK, and JNK/SAPK. It
can also suppress the phosphorylation of ribosomal protein S6 kinase
(p70S6K) (Wiese et al., 2015).
Sandalore stimulates OR2AT4 and triggers cAMP-dependentt pathway
following Ca2+ increment and protein kinases
phosphorylation. This results in the proliferation and migration of
human keratinocytes. Keratinocyte proliferation and migration by
sandalore mediated OR2AT4 can develop healing in wounded human cells
by ex vivo system (Busse et al., 2014; Sondersorg et
al., 2014). Activation of OR2AT4 in human scalp hair follicles by
sandalore promotes hair growth by boosting the formation of
anagen-prolonging growth factor IGF-1 and reducing the amount of
apoptosis (Cheret et al., 2018). Italy has planned to use
sandalore clinically by making it an ingredient for shampoo and lotions
(Di Pizio, Behrens & Krautwurst, 2019).
Activation of OR2AT4 by Brahmanol and also by sandalore can induce a
strong reduction of hair matrix keratinocyte apoptosis by inhibiting
catagen development. OR2AT4 activation promotes anagen improvement
(active growth phase) of the hair follicle by boosting the production of
IGF1. That means OR2AT4-induced signaling has a significant role in the
hair growth cycle (Chéret et al., 2018).
OLFR16 activated by Lyral has a great impact on the regeneration of
muscle tissues (Griffin, Kafadar & Pavlath, 2009). This activation
causes a rise of intracellular cAMP leading to myocyte migration,
myofibre branching, and myogenesis. OLFR16 also modulates cell-cell
adhesion and myotube formation (Pichavant, Burkholder & Pavlath, 2015).
Troenan (5-methyl-2-pentan-2-yl-5-propyl-1, 3-dioxane) stimulates OR51B4
in colorectal cancer cells which results in apoptosis and inhibition of
cell proliferation (Weber et al., 2017). In German clinics,
suppository capsules with troenan have already been used to treat colon
cancer patients (Di Pizio, Behrens & Krautwurst, 2019).
Activation of OR2AG1 using amyl butyrate might inhibit the
histamine-inducedd contraction of human airway smooth muscle cells,
resulting in muscle relaxation. By contrast, stimulation of OR1D2 using
bourgeonal increased cell contractility and elicited the secretion of
interleukin-8 (IL-8) and granulocyte– macrophage colony-stimulating
factor (Kalbe et al., 2016a).
Eugenol and thymol from spices increase gut motility by activating some
ORs, e.g. OR1G1, OR1A1, OR3A1 (Braun et al., 2007). Thymol can
also induce angiogenesis via hOR17-7/11(Kim et al., 2015).
OR1A1 stimulated by the ligand (–)-carvone, a supreme compound in
spearmint essential oil, triggers PKA signaling pathway without
influencing intracellular Ca2+ levels. This
transduction helps in hepatic metabolism by reducing intracellular
triglyceride concentrations. α-cedrene activates OR10J5 and decreases
hepatic lipid concentrations (Wu et al., 2015).
Cyclohexyl salicylate can reduce intracellular cAMP (cyclic adenosine
monophosphate) and Ca2+ levels by activating
OR2A4/OR2A7. It can inhibit the growth of melanocyte and induce melanin
biosynthesis by reducing p42 MAPK (also known as MAPK1) and/or p44 MAPK
(also known as MAPK3) phosphorylation and promoting p38 MAPK signaling
(Tsai et al., 2017).
4.3 Metabolites
In animal cholesterol biosynthesis, terpenes are degraded into their
functional unit isoprene through mevalonate pathway (Goldstein & Brown,
1990). In addition, lots of metabolic intermediates of this pathway
generally contain similarities with OR activating terpenes in their
structure (Edwards & Ericsson, 1999). 19-Hydroxyandrostenedione is a
testosterone metabolite, which can activate OR51E2 and transduce
Neuroendocrine Trans-Differentiation of prostate cancer cells (Abaffy et
al., 2018)