Review

References__________________________________________________________________________

Thiyagarajan V, Lee KW, Leong MK, Weng CF. Potential natural mTOR inhibitors screened by in silico approach and suppress hepatic stellate cells activation. J Biomol Struct Dyn. 2018 Dec;36(16):4220-4234. doi: 10.1080/07391102.2017.1411295. 

Abstract. The mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase, plays a central role in the regulation of cell proliferation, growth, differentiation, migration, and survival. In this study, the 3-D structure of the mTOR (PDB ID: 2FAP) was used for the docking of 47 natural compounds and compared with pharmacophore model of 14 known mTOR inhibitors to identify the novel and specific natural inhibitor. The top four compounds, rutin, curcumin, antroquinonol, and benzyl cinnamate, have been selected based on their PLP score and further validated with hepatic stellate cells NHSC and THSC. Curcumin and antroquinonol significantly inhibited NHSC and THSC cells proliferation in a dose-dependent manner, whereas rutin and benzyl cinnamate showed less alteration of cell viability. Rutin inhibited the phosphorylation of mTOR (p-mTOR) and p-p70 S6 K in NHSC and THSC cells by Western blotting. Additionally, p-p70 S6 K protein was significantly decreased by incubation with benzyl cinnamate and curcumin in THSC cells. Taken together, this result suggests that rutin is a potential mTOR inhibitor in screen hits of molecular docking to hamper the activation of HSC and further applications in the treatment of liver fibrosis.

Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Nishimura T, Jinno H. Activation of the human transient receptor potential vanilloid subtype 1 by essential oils. Biol Pharm Bull. 2010;33(8):1434-7. doi: 10.1248/bpb.33.1434. 

Abstract. Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel activated by capsaicin. TRPV1 is expressed not only on human sensory neurons but also on human epidermal and hair follicle keratinocytes. Therefore, TRPV1 could have the potential to be a therapeutic target for skin disorders. To search for novel TRPV1 agonists, we screened 31 essential oils by using human TRPV1-expressing HEK293 cells. TRPV1 was activated by 4 essential oils: rose, thyme geraniol, palmarosa, and tolu balsam. The dose-response curves for TRPV1 activation by the essential oils revealed a rank order potency [the half-maximal effective concentration (EC(50))] of rose>palmarosa>thyme geraniol>tolu balsam, and rank order efficiency (% activity in response to 1 microM capsaicin) of tolu balsam>rose>palmarosa>thyme geraniol. Moreover, the dose-response curves for TRPV1 activation by citronellol (main constituent of rose oil) and geraniol (main constituent of thyme geraniol and palmarosa oils) were consistent with the potency and efficiency of each essential oil. In contrast, benzyl cinnamate and benzyl benzoate (main constituent of tolu balsam oil) and geranyl acetate (main constituent of thyme geraniol oil) did not show TRPV1 activity. In this first-of-its-kind study, we successfully investigated the role of some essential oils in promoting human TRPV1 activation, and also identified two monoterpenes, citronellol and geraniol, as new human TRPV1 agonists.

EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Bampidis V, Azimonti G, Bastos ML, Christensen H, Dusemund B, Fašmon Durjava M, Kouba M, López-Alonso M, López Puente S, Marcon F, Mayo B, Pechová A, Petkova M, Ramos F, Sanz Y, Villa RE, Woutersen R, Galobart J, Manini P. Safety of 37 feed additives consisting of flavouring compounds belonging to different chemical groups for use in all animal species (FEFANA asbl). EFSA J. 2022 Apr 19;20(4):e07249. doi: 10.2903/j.efsa.2022.7249. 

Abstract. Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the supplementary information submitted on the safety of 37 compounds belonging to different chemical groups, when used as sensory additives (flavourings) in feed for all animal species formerly assessed by the Panel in the context of the re-evaluation of these feed additives. The FEEDAP Panel concludes that ethyl oleate [09.192] and benzyl cinnamate [09.738] are safe at the proposed use level of 5 mg/kg complete feed for all animal species, the consumer and the environment; ethyl salicylate [09.748] is safe up to the maximum proposed use level of 5 mg/kg complete feed for all animal species and the consumer. No new data were submitted on the safety for the user that would allow the FEEDAP Panel to change its previous conclusion for 26 out of the 37 compounds under assessment. The use of 4-terpinenol [02.072], linalyl butyrate [09.050], linalyl formate [09.080], linalyl propionate [09.130], linalyl isobutyrate [09.423], isopulegol [02.167] and 1,2-dimethoxy-4-(prop-1-enyl)-benzene [04.013] as flavouring additives at the proposed use level of 5 mg/kg in feed for all animal species is considered safe for the environment. The use of 3-methyl-2-cyclopenten-1-one [07.112] at 0.5 mg/kg and methyl dihydrojasmonate [09.520] at 5 mg/kg in feed for all animal species except marine animals is considered safe for the environment. © 2022 Wiley‐VCH Verlag GmbH & Co. KgaA on behalf of the European Food Safety Authority.

ELLIS HL, JACOBSON J. Benzyl cinnamate (Jacobson's solution) with vitamin A. A one-year experience in the treatment of cerebrovascular lesions. Harlem Hosp Bull (N Y). 1960 Mar;1:97-102. PMID: 13820044.

Bhatia SP, Wellington GA, Cocchiara J, Lalko J, Letizia CS, Api AM. Fragrance material review on benzyl cinnamate. Food Chem Toxicol. 2007;45 Suppl 1:S40-8. doi: 10.1016/j.fct.2007.09.027. 

Abstract. A toxicologic and dermatologic review of benzyl cinnamate when used as a fragrance ingredient is presented.

SCAL JC. Benzyl cinnamate in treatment of Ménière's syndrome and tinnitus aurum; a clinical report. Eye Ear Nose Throat Mon. 1946 Mar;25:150. PMID: 21027078.