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)