Botaceuticals

Immunity x Essential oils

These articles are not intended to provide treatment recommendations for the ongoing COVID-19 pandemic.
Aromatherapy has probably become the most popular branch of phytotherapy in Western Europe. Essential oils have a myriad of properties that give them undeniable health potential: anxiolytic, antibacterial, anti-inflammatory, ... 

There are many areas where they can "make a difference". Among these many areas, winter ailments and their immune dimension are obviously at the center of attention. As a matter of fact, according to some, certain essential oils are considered to have powerful immunostimulatory properties.

Let us discover the scientific data available, as well as the molecules and mechanisms involved. As we will see, essential oils deserve their reputation as powerful plant active ingredients in the context of winter ailments and immunity. They seem to do it by sometimes surprising and often particular ways.

1. A MOLECULAR APPROACH


In a large majority of cases, we will base ourselves on the molecules that make up essential oils and not on the totum (except in the case of specific data). Why?
Because all purists will tell you: the activity of essential oils is revealed thanks to the subtle synergy of aromatic molecules in precise proportions. Indeed, many studies confirm this increased activity of the totum.

In addition to the fact that the composition of the same essential oil varies from one distillation to another, the totum approach ignores a crucial aspect: essential oils are commonly associated with each other. But if we consider the fact that they often have common molecules, combining two essential oils engender a new totum, whose properties would be unknown according to this "totum approach".

If it is entirely correct to consider that an essential oil is more than the addition of the properties of its components, the evaluation based on these same components is, with rare exceptions, the only valid approach in the current state of available scientific data. This is an opinion and not a fact. I am therefore entirely open to debate on this point.


2. ESSENTIAL OILS & IMMUNITY 

2.1. Essential oils & macrophages

2.1.1. Anti-inflammatory activity

The anti-inflammatory activity is obviously a widespread property in the field of essential oils. We find experimental data on a large majority of aromatic molecules. This activity has a limiting effect on the activity of macrophages. An effect which is found in particular with linalool [1-3], 1,8-cineol [4-7], terpinen-4-ol [8-9], geraniol [10], citral: geranial & neral [11-15], eugenol [16-21], cinnamaldehyde [22-24], turmerones [25-26], α-pinene [27] or limonene [28].
However, it would be simplistic to consider that the underlying molecular mechanisms are identical for all of these molecules. Even if there are many common points, such as the inhibition of the NF-κB and other MAPK pathways, certain aromatic molecules also seem to intervene via PPAR-γ [29-33] or endocannabinoid receptors [33-34]. The two pathways often linked.
As mentioned in previous articles, limiting inflammation is not necessarily negative for the immune system since it allows the immune cells to "last a long time". This effect has above all the advantage of limiting specific symptoms associated with inflammation. However, this is not strictly speaking immunostimulation. 

2.1.2. Modulation of phagocytosis

Studies reporting a modulating effect of essential oils on the phenomenon of phagocytosis are sparse and less numerous than those referring to anti-inflammatory properties. Nevertheless, they deserve to be highlighted in order to better assess the impact of a molecular profile. Depending on the molecules, phagocytosis seems to be able to be stimulated or inhibited. 

The molecules and essential oils that have been reported to stimulate the phenomenon of phagocytosis are: 
  • essential oil of eucalyptus (Eucalyptus globulus). Note that a study reports that this property does not seem to apply to pure 1,8-cineol. Therefore, this phagostimulant effect would not be transposable to other cineole oils [35].
  • limonene [36-37] is a molecule found in many citrus fruits; one of its main metabolites is perillyl alcohol, which also seems to have immunostimulatory properties on the respiratory level [38].
  • bornyl acetate [39], a molecule found in the fragrant Stinkwort (Dittrichia graveolens) & Black spruce (Picea mariana).
  • thymoquinone [40-41], a molecule found in the Nigella also named Love-in-a-mist (Nigella sativa)
  • a-phellandrene [42], a molecule found in the leaves of Turmeric (Curcuma longa) or certain chemotypes obtained from the aerial parts of Dill (Anethum graveolens).

Conversely, the molecules and essential oils that have been reported to inhibit the phenomenon of phagocytosis are:
  • Cinnamon essential oil [43]
  • Oregano essential oil [43] and its major component carvacrol [39 & 44]
  • Mint essential oil [43]
  • Clove essential oil [39] and its major component eugenol [39]
  • Tea tree essential oil [39] 

Finally, for thymol, the data seem to contradict each other since one study highlights its stimulating effect [45] while another considers it as an inhibitor [39].

2.1.3. Macrophage polarization

Few essential oil molecules show an impact on the phenotype of macrophages. Note the following publications:

  • a study reports a favoring effect on the M2 phenotype by β-caryophyllene [46], note that this goes for microglia and we do not know if this effect extends to other categories of macrophages
  • one study reports a stimulating effect on the M1 phenotype by β-elemene [47].
  • one study describes an effect favoring the M2 phenotype by thymoquinone [48]. 

2.2. Essential oils & dendritic cells


There are fewer data that demonstrate the potential activating effect of essential oils on dendritic cells than those referring to the activity of macrophages. Note, however, that some aromatic molecules are an exception:

  • ar-turmerone [49], one of the main molecules in essential oil of Turmeric (Curcuma longa), that has previously been identified as an anti-inflammatory.
  • calamenene [50-51], which is found in Manuka essential oil (Leptospermum scoparium), which could partially explain the interest of Manuka honey in the context of immune health (associated with triketones and their antiviral activity).
  • T-cadinol [50-51], a molecule that can be found in significant quantities in the essential oil from Sugi wood or Japanese cedar (Cryptomeria japonica), which should not be confused with the oil from its branches.
  • Conversely, some studies indicate an inhibitory activity of certain aromatic molecules and essential oils:
  • thymol [52], the main molecule in essential oil of Common thyme (Thymus vulgaris) or Ajowan (Trachyspermum ammi).
  • carvacrol [52], the main molecule of the essential oil of Oregano (Origanum vulgare), Mountain savory (Satureja montana) or Compact oregano (Origanum compactum), the latter also containing thymol.
  • essential oil of Litsea citrata [53].
  • sesame essential oil rich in sesamol, not to be confused with its vegetable oil [54].


2.3. Essential oils & lymphocytes 

If scientific publications reporting an influence of essential oils on lymphocyte populations are relatively disparate (whether they are T or B lymphocytes), there are still some potentially interesting mentions: 

  • Clove essential oil (Eugenia caryophyllus) seems to stimulate the humoral response: B-lymphocytes. [55] 
  • Ginger essential oil (Zingiber officinale) seems to stimulate B-lymphocytes as well. [55] 
  • a singular chemotype of Frankincense (Boswellia carterii) essential oil seems to cause the differentiation of T-lymphocytes [56]. 
  • Niaouli essential oil (Melaleuca quinquenervia) seems to promote activation of cellular immunity: T-lymphocytes in vivo [57]. 
  • since β-caryophyllene is a CB2 receptor agonist, it also has a stimulating effect on Tregs [58].


2.4. Essential oils & Natural Killer (NK) cells 

Publications reporting an effect of essential oils or their aromatic components are almost nonexistent. However, there is a study reporting a stimulating effect of α-phellandrene on NK cells [42] as well as a study reporting a similar effect of limonene [59]. 

3. TWO UNRECOGNIZED ASPECTS

3.1. Essential oils & microbiota

The growing body of data linking the microbiota and immunity, combined with growing public interest in the beneficial effects of pre- and probiotics, make the gut microbiota trail a path that is difficult to ignore.

Due to their antibacterial properties, essential oils are rarely associated with the balance of the microbiota. For some health professionals, they are even not recommended during a course of probiotics. However, several studies show a beneficial influence of certain aromatic molecules on the microbiota.
Two hypotheses could explain this phenomenon:

  • essential oils could more effectively kill micro-organisms that upset this balance than beneficial bacterial populations
  • essential oils could influence the immune actors that impact the microbiota, for example by promoting Treg populations or by influencing Tγδ-lymphocytes.

It has been reported that geraniol, a molecule found in abundance in the essential oil of Palmarosa (Cymbopogon martinii) or Bee balm (Monarda fistulosa), has a positive impact on intestinal dysbiosis [60-61].

At the same time, limonene, linalool and citral are also identified to have a positive impact on the microbiota. Citral in particular favors the production of butyrate, an important short-chain fatty acid that supports digestive health and helps to control inflammation [62]. Note that in this very specific context, gastro-resistant formulation takes on a meaning.

3.2. The mysterious role of TRP channels

Transient Receptor Potential (TRP) type channels are a family of channel receptors considered to be "molecular sensors". They perceive changes in our environment like temperature, mechanical deformation, osmotic disturbance, etc. and influence our physiological mechanisms accordingly. In other words, it is a form of "sixth molecular sense". However, many molecules from plants are able to modulate the activity of TRPs. What we eat is a good indicator of the quality of our environment.

In phyto- and aromatherapy, they are at the origin of the cold and analgesic effect of menthol. The latter stimulates the TRPM8 receptors, usually activated by low temperatures [63].

The "hot" effect of chili via capsaicin also happens via this type of receptor, just like the allyl isothiocyanate of wasabi. But the action of these channels is far from limited to a feeling of cold or hot.

In fact, TRP receptors are expressed by many immune cells [64-65] and their effect on inflammatory mechanisms suggests that they could represent a central mechanism in the immunomodulating effects of essential oils [66-69]. This innovative aspect of aromatherapy will probably be the subject of a dedicated article in the future.
4. TOMORROW'S TRACKS

4.1. For which products?


Based on the above data, essential oils can intervene punctually on many aspects of immunity. However, an integrative approach based exclusively on these would require a complex mixture with an uncertain result.

Furthermore, their primary interest could be based on their powerful anti-inflammatory properties and less on direct immunostimulation. This regulatory effect on inflammatory activity makes it possible to limit certain symptoms and an "inflammatory runaway". Note that many essential oils also have particularly interesting properties in the infectious context:

  • antibacterial activity, notably oils rich in thymol and carvacrol [70-71] such as the essential oil of Common oregano (Origanum vulgare), Common thyme (Thymus vulgaris CT thymol) or even Mountain savory (Satureja montana).
  • antiviral activity, in particular of the essential oil of Tea tree (Melaleuca alternifolia) [72-73] which is explained in particular by the abundance of terpinen-4-ol [74] therefore, one could consider the oil or Marjoram (Origanum majorana). Essential oils rich in 1,8-cineole can also be considered in this context such as the essential oil of eucalyptus (Eucalyptus globulus) [75].

Therefore, it seems preferable to consider essential oils at the core of a "first-line" product in the event of a cold or in a risky context such as repeated colds. We can also consider preventive formulas, but we would prefer to combine these with other active ingredients to reinforce specific dimensions.
We will also avoid multiplying the number of essential oils in a formula in order to avoid possible physiological "interference" between the different molecular profiles.

4.2. What to associate them with?

4.2.1. For a product in winter

For a product intended to lessen the symptoms and recurrence of winter ailments, 1,8-cineole oils appear obvious, with a preference for eucalyptus essential oil. This one seems to have additional properties to those that share all cineole oils. Ravintsara is interesting because it contains 1,8-cineole but scientific data does not give it any advantage compared to other cineol oils.

Add to this eucalyptus an essential oil rich in thymol and / or carvacrol, an essential oil rich in terpinen-4-ol and an essential oil of turmeric roots. Then you will get a particularly interesting aromatic quartet. It will be then possible to strengthen it with an extract such as echinacea, ginseng or skullcap from Lake Baikal.

4.2.2. For a global approach to daily immune health

A holistic approach to immune health will require the use of essential oils that are less focused on inflammation and antibiotic properties just like ibuprofen is not taken daily because of occasional headaches.

We can associate essential oils with "microbiotic properties" such as a duo Palmarosa (rich in geraniol) and Lemongrass (rich in citral) which will be combined with ginseng (Panax ginseng) rich in rare / bioactive ginsenosides and ginsan (Read about unequaled properties of this type of ginseng on immunity). The more daring could integrate a source of β-caryophyllene in order to strengthen the stimulating action of Tregs: crucial immune cells in microbiotic balance.
It is difficult to grasp the immunomodulating action of essential oils as their effects are diverse and specific. If the data attest to an undeniable health potential [76], their very targeted and sometimes opposite actions make achieving a very delicate synergy. However, a careful selection allows to associate certain essential oils to boost a more "generalist" extract (immunostimulating fungus, bioactive ginseng or even echinacea).

In opposition, their powerful modulating activity on inflammatory reactions as well as their anti-infectious capacities, quite naturally make them suitable to accompany winter ailments. It makes them a preferred solution for the management of the first symptoms.

In daily prevention, two paths seem particularly promising: intervention at the level of the intestinal microbiota and fine immune modulation through channel receptors of the TRP-type.
REFERENCES

[1] Huo M, Cui X, Xue J, Chi G, Gao R, Deng X, Guan S, Wei J, Soromou LW, Feng H, Wang D (2013) – “Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model.” J Surg Res. 2013 Mar;180(1):e47-54. doi: 10.1016/j.jss.2012.10.050. Epub 2012 Dec 4.
[2] Ma J, Xu H, Wu J, Qu C, Sun F, Xu S (2015) – “Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation.” Int Immunopharmacol. 2015 Dec;29(2):708-713. doi: 10.1016/j.intimp.2015.09.005. Epub 2015 Oct 1.
[3] Kim MG, Kim SM, Min JH, Kwon OK, Park MH, Park JW, Ahn HI, Hwang JY, Oh SR, Lee JW, Ahn KS (2019) – “Anti-inflammatory effects of linalool on ovalbumin-induced pulmonary inflammation.” Int Immunopharmacol. 2019 Sep;74:105706. doi: 10.1016/j.intimp.2019.105706. Epub 2019 Jun 26.
[4] Yadav N, Chandra H (2017) – “Suppression of inflammatory and infection responses in lung macrophages by eucalyptus oil and its constituent 1,8-cineole: Role of pattern recognition receptors TREM-1 and NLRP3, the MAP kinase regulator MKP-1, and NFκB.” PLoS One. 2017 Nov 15;12(11):e0188232. doi: 10.1371/journal.pone.0188232. eCollection 2017.
[5] Zhao C, Sun J, Fang C, Tang F (2014) – “1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice.” Inflammation. 2014 Apr;37(2):566-72. doi: 10.1007/s10753-013-9770-4.
[6] Kennedy-Feitosa E, Okuro RT, Pinho Ribeiro V, Lanzetti M, Barroso MV, Zin WA, Porto LC, Brito-Gitirana L, Valenca SS (2016) – “Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse.” Pulm Pharmacol Ther. 2016 Dec;41:11-18. doi: 10.1016/j.pupt.2016.09.004. Epub 2016 Sep 4.
[7] Sadlon AE, Lamson DW (2010) – “Immune-modifying and antimicrobial effects of Eucalyptus oil and simple inhalation devices.” Altern Med Rev. 2010 Apr;15(1):33-47.
[8] Nogueira MN, Aquino SG, Rossa Junior C, Spolidorio DM (2014) – “Terpinen-4-ol and alpha-terpineol (tea tree oil components) inhibit the production of IL-1β, IL-6 and IL-10 on human macrophages.” Inflamm Res. 2014 Sep;63(9):769-78. doi: 10.1007/s00011-014-0749-x. Epub 2014 Jun 20.
[9] Ninomiya K, Hayama K, Ishijima SA, Maruyama N, Irie H, Kurihara J, Abe S (2013) – “Suppression of inflammatory reactions by terpinen-4-ol, a main constituent of tea tree oil, in a murine model of oral candidiasis and its suppressive activity to cytokine production of macrophages in vitro.” Biol Pharm Bull. 2013;36(5):838-44.
[10] Su YW, Chao SH, Lee MH, Ou TY, Tsai YC (2010) – “Inhibitory effects of citronellol and geraniol on nitric oxide and prostaglandin E₂production in macrophages.” Planta Med. 2010 Oct;76(15):1666-71. doi: 10.1055/s-0030-1249947. Epub 2010 May 26.
[11] Shen Y, Sun Z, Guo X (2015) – “Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.” Eur J Pharmacol. 2015 Jan 15;747:45-51. doi: 10.1016/j.ejphar.2014.09.040. Epub 2014 Oct 2.
[12] Porto Mde P, da Silva GN, Luperini BC, Bachiega TF, de Castro Marcondes JP, Sforcin JM, Salvadori DM (2014) – “Citral and eugenol modulate DNA damage and pro-inflammatory mediator genes in murine peritoneal macrophages.” Mol Biol Rep. 2014 Nov;41(11):7043-51. doi: 10.1007/s11033-014-3657-9.
[13] Bachiega TF, Sforcin JM (2011) – “Lemongrass and citral effect on cytokines production by murine macrophages.” J Ethnopharmacol. 2011 Sep 1;137(1):909-13. doi: 10.1016/j.jep.2011.07.021. Epub 2011 Jul 18.
[14] Katsukawa M, Nakata R, Takizawa Y, Hori K, Takahashi S, Inoue H (2010) – “Citral, a component of lemongrass oil, activates PPARα and γ and suppresses COX-2 expression.” Biochim Biophys Acta. 2010 Nov;1801(11):1214-20. doi: 10.1016/j.bbalip.2010.07.004. Epub 2010 Jul 23.
[15] Lee HJ, Jeong HS, Kim DJ, Noh YH, Yuk DY, Hong JT (2008) – “Inhibitory effect of citral on NO production by suppression of iNOS expression and NF-kappa B activation in RAW264.7 cells.” Arch Pharm Res. 2008 Mar;31(3):342-9. doi: 10.1007/s12272-001-1162-0. Epub 2008 Apr 13.
[16] Magalhães CB, Casquilho NV, Machado MN, Riva DR, Travassos LH, Leal-Cardoso JH, Fortunato RS, Faffe DS, Zin WA (2019) – “The anti-inflammatory and anti-oxidative actions of eugenol improve lipopolysaccharide-induced lung injury.” Respir Physiol Neurobiol. 2019 Jan;259:30-36. doi: 10.1016/j.resp.2018.07.001. Epub 2018 Jul 8.
[17] Lee YY, Hung SL, Pai SF, Lee YH, Yang SF (2007) – “Eugenol suppressed the expression of lipopolysaccharide-induced proinflammatory mediators in human macrophages.” J Endod. 2007 Jun;33(6):698-702. Epub 2007 Apr 2.
[18] Li W, Tsubouchi R, Qiao S, Haneda M, Murakami K, Yoshino M (2006) – “Inhibitory action of eugenol compounds on the production of nitric oxide in RAW264.7 macrophages.” Biomed Res. 2006 Apr;27(2):69-74.
[19] Bachiega TF, de Sousa JP, Bastos JK, Sforcin JM (2012) – “Clove and eugenol in noncytotoxic concentrations exert immunomodulatory/anti-inflammatory action on cytokine production by murine macrophages.” J Pharm Pharmacol. 2012 Apr;64(4):610-6. doi: 10.1111/j.2042-7158.2011.01440.x. Epub 2012 Feb 7.
[20] Kim SS, Oh OJ, Min HY, Park EJ, Kim Y, Park HJ, Nam Han Y, Lee SK (2003) – “Eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells.” Life Sci. 2003 Jun 6;73(3):337-48.
[21] Rodrigues TG, Fernandes A Jr, Sousa JP, Bastos JK, Sforcin JM (2009) – “In vitro and in vivo effects of clove on pro-inflammatory cytokines production by macrophages.” Nat Prod Res. 2009;23(4):319-26. doi: 10.1080/14786410802242679.
[22] Kim ME, Na JY, Lee JS (2018) – “Anti-inflammatory effects of trans-cinnamaldehyde on lipopolysaccharide-stimulated macrophage activation via MAPKs pathway regulation.” Immunopharmacol Immunotoxicol. 2018 Jun;40(3):219-224. doi: 10.1080/08923973.2018.1424902. Epub 2018 Jan 22.
[23] Chao LK, Hua KF, Hsu HY, Cheng SS, Lin IF, Chen CJ, Chen ST, Chang ST (2008) – “Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling.” Food Chem Toxicol. 2008 Jan;46(1):220-31. Epub 2007 Aug 8.
[24] Huang H, Wang Y (2017) – “The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice.” Cell Mol Biol (Noisy-le-grand). 2017 Aug 30;63(8):58-63. doi: 10.14715/cmb/2017.63.8.13.
[25] Lee SK, Hong CH, Huh SK, Kim SS, Oh OJ, Min HY, Park KK, Chung WY, Hwang JK (2002) – “Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) activity in mouse macrophage cells.” J Environ Pathol Toxicol Oncol. 2002;21(2):141-8.
[26] Hong CH, Noh MS, Lee WY, Lee SK (2002) – “Inhibitory effects of natural sesquiterpenoids isolated from the rhizomes of Curcuma zedoaria on prostaglandin E2 and nitric oxide production.” Planta Med. 2002 Jun;68(6):545-7.
[27] Kim DS, Lee HJ, Jeon YD, Han YH, Kee JY, Kim HJ, Shin HJ, Kang J, Lee BS, Kim SH, Kim SJ, Park SH, Choi BM, Park SJ, Um JY, Hong SH (2015) – “Alpha-Pinene Exhibits Anti-Inflammatory Activity Through the Suppression of MAPKs and the NF-κB Pathway in Mouse Peritoneal Macrophages.” Am J Chin Med. 2015;43(4):731-42. doi: 10.1142/S0192415X15500457. Epub 2015 Jun 28.
[28] Yoon WJ, Lee NH, Hyun CG (2010) – “Limonene suppresses lipopolysaccharide-induced production of nitric oxide, prostaglandin E2, and pro-inflammatory cytokines in RAW 264.7 macrophages.” J Oleo Sci. 2010;59(8):415-21.
[29] Shen Y, Sun Z, Guo X (2015) – “Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.” Eur J Pharmacol. 2015 Jan 15;747:45-51. doi: 10.1016/j.ejphar.2014.09.040. Epub 2014 Oct 2.
[30] Shen Y, Sun Z, Guo X (2015) – “Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ.” Eur J Pharmacol. 2015 Jan 15;747:45-51. doi: 10.1016/j.ejphar.2014.09.040. Epub 2014 Oct 2.
[31] Katsukawa M, Nakata R, Koeji S, Hori K, Takahashi S, Inoue H (2011) – “Citronellol and geraniol, components of rose oil, activate peroxisome proliferator-activated receptor α and γ and suppress cyclooxygenase-2 expression.” Biosci Biotechnol Biochem. 2011;75(5):1010-2. Epub 2011 May 20.
[32] Ning J, Xu L, Zhao Q, Zhang YY, Shen CQ (2018) – “The Protective Effects of Terpinen-4-ol on LPS-Induced Acute Lung Injury via Activating PPAR-γ.” Inflammation. 2018 Dec;41(6):2012-2017. doi: 10.1007/s10753-018-0844-1.
[33] Cheng Y, Dong Z, Liu S (2014) – “β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology. 2014;94(1-2):1-12. doi: 10.1159/000362689. Epub 2014 Aug 26.
[34] Gonçalves ECD, Assis PM, Junqueira LA, Cola M, Santos ARS, Raposo NRB, Dutra RC. (2020) – “Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways.” J Nat Prod. 2020 Apr 24;83(4):1190-1200. doi: 10.1021/acs.jnatprod.9b01134. Epub 2020 Mar 9.
[35] Serafino A, Sinibaldi Vallebona P, Andreola F, Zonfrillo M, Mercuri L, Federici M, Rasi G, Garaci E, Pierimarchi P (2008) – “Stimulatory effect of Eucalyptus essential oil on innate cell-mediated immune response.” BMC Immunol. 2008 Apr 18;9:17. doi: 10.1186/1471-2172-9-17.
[36] Del Toro-Arreola S, Flores-Torales E, Torres-Lozano C, Del Toro-Arreola A, Tostado-Pelayo K, Guadalupe Ramirez-Dueñas M, Daneri-Navarro A (2005) – “Effect of D-limonene on immune response in BALB/c mice with lymphoma.” Int Immunopharmacol. 2005 May;5(5):829-38. Epub 2005 Jan 25.
[37] Hamada M, Uezu K, Matsushita J, Yamamoto S, Kishino Y (2002) – “Distribution and immune responses resulting from oral administration of D-limonene in rats.” J Nutr Sci Vitaminol (Tokyo). 2002 Apr;48(2):155-60.
[38] D'Alincourt Salazar M, da Silva RF, Da Fonseca CO, Lagrota-Candido J, Quirico-Santos T (2014) – “Intranasal administration of perillyl alcohol activates peripheral and bronchus-associated immune system in vivo.” Arch Immunol Ther Exp (Warsz). 2014 Feb;62(1):59-66. doi: 10.1007/s00005-013-0262-x. Epub 2013 Nov 21.
[39] Pérez-Rosés R, Risco E, Vila R, Peñalver P, Cañigueral S (2015) – “Effect of some essential oils on phagocytosis and complement system activity.” J Agric Food Chem. 2015 Feb 11;63(5):1496-504. doi: 10.1021/jf504761m. Epub 2015 Feb 2.
[40] Miliani M, Nouar M, Paris O, Lefranc G, Mennechet F, Aribi M (2018) – « Thymoquinone Potently Enhances the Activities of Classically Activated Macrophages Pulsed with Necrotic Jurkat Cell Lysates and the Production of Antitumor Th1-/M1-Related Cytokines.” J Interferon Cytokine Res. 2018 Nov 13. doi: 10.1089/jir.2018.0010.
[41] Barnawi J, Tran HB, Roscioli E, Hodge G, Jersmann H, Haberberger R, Hodge S (2016) – “Pro-phagocytic Effects of Thymoquinone on Cigarette Smoke-exposed Macrophages Occur by Modulation of the Sphingosine-1-phosphate Signalling System.” COPD. 2016 Oct;13(5):653-61. doi: 10.3109/15412555.2016.1153614. Epub 2016 May 4.
[42] Lin JJ, Lin JH, Hsu SC, Weng SW, Huang YP, Tang NY, Lin JG, Chung JG (2013) – “Alpha-phellandrene promotes immune responses in normal mice through enhancing macrophage phagocytosis and natural killer cell activities.” In Vivo. 2013 Nov-Dec;27(6):809-14. PMID: 24292586
[43] Lang M, Ferron PJ, Bursztyka J, Montjarret A, Duteil E, Bazire A, Bedoux G (2019) – “Evaluation of immunomodulatory activities of essential oils by high content analysis.” J Biotechnol. 2019 Sep 10;303:65-71. doi: 10.1016/j.jbiotec.2019.07.010. Epub 2019 Jul 29.
[44] Somensi N, Rabelo TK, Guimarães AG, Quintans-Junior LJ, de Souza Araújo AA, Moreira JCF, Gelain DP (2019) – “Carvacrol suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway.” Int Immunopharmacol. 2019 Oct;75:105743. doi: 10.1016/j.intimp.2019.105743. Epub 2019 Jul 26.
[45] Chauhan AK, Jakhar R, Paul S, Kang SC (2014) – “Potentiation of macrophage activity by thymol through augmenting phagocytosis.” Int Immunopharmacol. 2014 Feb;18(2):340-6. doi: 10.1016/j.intimp.2013.11.025. Epub 2013 Dec 5.
[46] Tian X, Liu H, Xiang F, Xu L, Dong Z (2019) – “β-Caryophyllene protects against ischemic stroke by promoting polarization of microglia toward M2 phenotype via the TLR4 pathway.” Life Sci. 2019 Nov 15;237:116915. doi: 10.1016/j.lfs.2019.116915. Epub 2019 Oct 11.
[47] Yu X, Xu M, Li N, Li Z, Li H, Shao S, Zou K, Zou L (2017) – “β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.” Biochem Biophys Res Commun. 2017 Aug 19;490(2):514-520. doi: 10.1016/j.bbrc.2017.06.071. Epub 2017 Jun 15.
[48] Wilson AJ, Saskowski J, Barham W, Khabele D, Yull F (2015) – “Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer.” Mol Cancer. 2015 Nov 9;14:192. doi: 10.1186/s12943-015-0463-5.
[49] Yonggang T, Yiming M, Heying Z, Cheng S, Qiushi W, Xianghong Y, Wei Z, Huawei Z, Shan F (2012) – “Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified aromatic-turmerone (AR).” Hum Vaccin Immunother. 2012 Oct;8(10):1416-24. doi: 10.4161/hv.21526. Epub 2012 Oct 1.
[50] Takei M, Umeyama A, Arihara S (2006) – “T-cadinol and calamenene induce dendritic cells from human monocytes and drive Th1 polarization.” Eur J Pharmacol. 2006 May 10;537(1-3):190-9. Epub 2006 Mar 3.
[51] Takei M, Tachikawa E, Umeyama A (2008) – “Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization.” Biomark Insights. 2008 Apr 18;3:269-286.
[52] Amirghofran Z, Ahmadi H, Karimi MH, Kalantar F, Gholijani N, Malek-Hosseini Z (2016) – “In vitro inhibitory effects of thymol and carvacrol on dendritic cell activation and function.” Pharm Biol. 2016 Jul;54(7):1125-32. doi: 10.3109/13880209.2015.1055579. Epub 2015 Jun 12.
[53] Chen HC, Chang WT, Hseu YC, Chen HY, Chuang CH, Lin CC, Lee MS, Lin MK (2016) – “Immunosuppressive Effect of Litsea cubeba L. Essential Oil on Dendritic Cell and Contact Hypersensitivity Responses.” Int J Mol Sci. 2016 Aug 12;17(8). pii: E1319. doi: 10.3390/ijms17081319.
[54] Khorrami S, Daneshmandi S, Mosayeb G (2018) – “Sesame seeds essential oil and Sesamol modulate the pro-inflammatory function of macrophages and dendritic cells and promote Th2 response.” Med J Islam Repub Iran. 2018 Oct 10;32:98. doi: 10.14196/mjiri.32.98. eCollection 2018.
[55] Carrasco FR, Schmidt G, Romero AL, Sartoretto JL, Caparroz-Assef SM, Bersani-Amado CA, Cuman RK (2009) – “Immunomodulatory activity of Zingiber officinale Roscoe, Salvia officinalis L. and Syzygium aromaticum L. essential oils: evidence for humor- and cell-mediated responses.” J Pharm Pharmacol. 2009 Jul;61(7):961-7. doi: 10.1211/jpp/61.07.0017.
[56] Mikhaeil BR, Maatooq GT, Badria FA, Amer MM (2003) – “Chemistry and immunomodulatory activity of frankincense oil.” Z Naturforsch C J Biosci. 2003 Mar-Apr;58(3-4):230-8.
[57] Nam SY, Chang MH, Do JS, Seo HJ, Oh HK (2008) – “Essential oil of niaouli preferentially potentiates antigen-specific cellular immunity and cytokine production by macrophages.” Immunopharmacol Immunotoxicol. 2008;30(3):459-74. doi: 10.1080/08923970802135187.
[58] Alberti TB, Barbosa WL, Vieira JL, Raposo NR, Dutra RC (2017) – “(-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.” Int J Mol Sci. 2017 Apr 1;18(4). pii: E691. doi: 10.3390/ijms18040691.
[59] Terao R, Murata A , Sugamoto K , Watanabe T , Nagahama K , Nakahara K , Kondo T , Murakami N , Fukui K , Hattori H , Eto N (2019) – “Immunostimulatory effect of kumquat (Fortunella crassifolia) and its constituents, β-cryptoxanthin and R-limonene.” Food Funct. 2019 Jan 22;10(1):38-48. doi: 10.1039/c8fo01971a.
[60] De Fazio L, Spisni E, Cavazza E, Strillacci A, Candela M, Centanni M, Ricci C, Rizzello F, Campieri M, Valerii MC. (2016) - "Dietary Geraniol by Oral or Enema Administration Strongly Reduces Dysbiosis and Systemic Inflammation in Dextran Sulfate Sodium-Treated Mice." Front Pharmacol. 2016 Mar 3;7:38. doi: 10.3389/fphar.2016.00038. eCollection 2016.
[61] Rizzello F, Ricci C, Scandella M, Cavazza E, Giovanardi E, Valerii MC, Campieri M, Comparone A, De Fazio L, Candela M, Turroni S, Spisni E. (2018) - "Dietary geraniol ameliorates intestinal dysbiosis and relieves symptoms in irritable bowel syndrome patients: a pilot study." BMC Complement Altern Med. 2018 Dec 19;18(1):338. doi: 10.1186/s12906-018-2403-6.
[62] Wang L, Zhang Y, Fan G, Ren JN, Zhang LL, Pan SY (2019) – “Effects of orange essential oil on intestinal microflora in mice.” J Sci Food Agric. 2019 Jun;99(8):4019-4028. doi: 10.1002/jsfa.9629. Epub 2019 Mar 12.
[63] Liu B, Fan L, Balakrishna S, Sui A, Morris JB, Jordt SE (2013) – “TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.” Pain. 2013 Oct;154(10):2169-77. doi: 10.1016/j.pain.2013.06.043. Epub 2013 Jun 29.
[64] Parenti A, De Logu F, Geppetti P, Benemei S (2016) – “What is the evidence for the role of TRP channels in inflammatory and immune cells?” Br J Pharmacol. 2016 Mar;173(6):953-69. doi: 10.1111/bph.13392. Epub 2016 Feb 18. Review.
[65] Khalil M, Alliger K, Weidinger C, Yerinde C, Wirtz S, Becker C, Engel MA (2018) – “Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia.” Front Immunol. 2018 Feb 7;9:174. doi: 10.3389/fimmu.2018.00174. eCollection 2018. Review.
[66] Khalil M, Babes A, Lakra R, Försch S, Reeh PW, Wirtz S, Becker C, Neurath MF, Engel MA (2016) – “Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production.” Mucosal Immunol. 2016 Nov;9(6):1500-1513. doi: 10.1038/mi.2016.16. Epub 2016 Mar 16.
[67] Yadav N, Chandra H (2018) – “Modulation of alveolar macrophage innate response in proinflammatory-, pro-oxidant-, and infection- models by mint extract and chemical constituents: Role of MAPKs.” Immunobiology. 2018 Jan;223(1):49-56. doi: 10.1016/j.imbio.2017.10.015. Epub 2017 Oct 8.
[68] Sabnis AS, Reilly CA, Veranth JM, Yost GS (2008) – “Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperatures.” Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L194-200. doi: 10.1152/ajplung.00072.2008. Epub 2008 Apr 25.
[69] Mendes SJF, Sousa FIAB, Pereira DMS, Ferro TAF, Pereira ICP, Silva BLR, Pinheiro AJMCR, Mouchrek AQS, Monteiro-Neto V, Costa SKP, Nascimento JLM, Grisotto MAG, da Costa R, Fernandes ES (2016) – “Cinnamaldehyde modulates LPS-induced systemic inflammatory response syndrome through TRPA1-dependent and independent mechanisms.” Int Immunopharmacol. 2016 May;34:60-70. doi: 10.1016/j.intimp.2016.02.012. Epub 2016 Feb 26.
[70] Salehi B, Mishra AP, Shukla I, Sharifi-Rad M, Contreras MDM, Segura-Carretero A, Fathi H, Nasrabadi NN, Kobarfard F, Sharifi-Rad J (2018) – “Thymol, thyme, and other plant sources: Health and potential uses.” Phytother Res. 2018 Sep;32(9):1688-1706. doi: 10.1002/ptr.6109. Epub 2018 May 22. Review.
[71] Sharifi-Rad M, Varoni EM, Iriti M, Martorell M, Setzer WN, Del Mar Contreras M, Salehi B, Soltani-Nejad A, Rajabi S, Tajbakhsh M, Sharifi-Rad J (2018) – “Carvacrol and human health: A comprehensive review.” Phytother Res. 2018 Sep;32(9):1675-1687. doi: 10.1002/ptr.6103. Epub 2018 May 9. Review.
[72] Garozzo A, Timpanaro R, Stivala A, Bisignano G, Castro A (2011) – “Activity of Melaleuca alternifolia (tea tree) oil on Influenza virus A/PR/8: study on the mechanism of action.” Antiviral Res. 2011 Jan;89(1):83-8. doi: 10.1016/j.antiviral.2010.11.010. Epub 2010 Nov 21.
[73] Garozzo A, Timpanaro R, Bisignano B, Furneri PM, Bisignano G, Castro A (2009) – “In vitro antiviral activity of Melaleuca alternifolia essential oil.” Lett Appl Microbiol. 2009 Dec;49(6):806-8. doi: 10.1111/j.1472-765X.2009.02740.x. Epub 2009 Sep 18.
[74] Li X, Duan S, Chu C, Xu J, Zeng G, Lam AK, Zhou J, Yin Y, Fang D, Reynolds MJ, Gu H, Jiang L (2013) – “Melaleuca alternifolia concentrate inhibits in vitro entry of influenza virus into host cells.” Molecules. 2013 Aug 9;18(8):9550-66. doi: 10.3390/molecules18089550.
[75] Yang Z, Wu N, Fu Y, Yang G, Wang W, Zu Y, Efferth T (2010) – “Anti-infectious bronchitis virus (IBV) activity of 1,8-cineole: effect on nucleocapsid (N) protein.” J Biomol Struct Dyn. 2010 Dec;28(3):323-30.
[76] Peterfalvi A, Miko E, Nagy T, Reger B, Simon D, Miseta A, Czéh B, Szereday L (2019) – “Much More Than a Pleasant Scent: A Review on Essential Oils Supporting the Immune System.” Molecules. 2019 Dec 11;24(24). pii: E4530. doi: 10.3390/molecules24244530.