Pharmacological Properties and Molecular Mechanisms of Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development

Mohamed Fizur Nagoor Meeran, Hayate Javed, Hasan Al Taee, Sheikh Azimullah, Shreesh K Ojha, Mohamed Fizur Nagoor Meeran, Hayate Javed, Hasan Al Taee, Sheikh Azimullah, Shreesh K Ojha

Abstract

Thymol, chemically known as 2-isopropyl-5-methylphenol is a colorless crystalline monoterpene phenol. It is one of the most important dietary constituents in thyme species. For centuries, it has been used in traditional medicine and has been shown to possess various pharmacological properties including antioxidant, free radical scavenging, anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal, antiseptic and antitumor activities. The present article presents a detailed review of the scientific literature which reveals the pharmacological properties of thymol and its multiple therapeutic actions against various cardiovascular, neurological, rheumatological, gastrointestinal, metabolic and malignant diseases at both biochemical and molecular levels. The noteworthy effects of thymol are largely attributed to its anti-inflammatory (via inhibiting recruitment of cytokines and chemokines), antioxidant (via scavenging of free radicals, enhancing the endogenous enzymatic and non-enzymatic antioxidants and chelation of metal ions), antihyperlipidemic (via increasing the levels of high density lipoprotein cholesterol and decreasing the levels of low density lipoprotein cholesterol and low density lipoprotein cholesterol in the circulation and membrane stabilization) (via maintaining ionic homeostasis) effects. This review presents an overview of the current in vitro and in vivo data supporting thymol's therapeutic activity and the challenges concerning its use for prevention and its therapeutic value as a dietary supplement or as a pharmacological agent or as an adjuvant along with current therapeutic agents for the treatment of various diseases. It is one of the potential candidates of natural origin that has shown promising therapeutic potential, pharmacological properties and molecular mechanisms as well as pharmacokinetic properties for the pharmaceutical development of thymol.

Keywords: animals; antioxidant; cancer; drug discovery; free radical scavenger; natural compounds; phytochemicals; thymol.

Figures

FIGURE 1
FIGURE 1
Schematic representation on the effects of thymol in different experimental models of cancer.
FIGURE 2
FIGURE 2
Effect of thymol on ISO and doxorubicin induced cardiotoxicity.
FIGURE 3
FIGURE 3
Effect of thymol on ISO induced altered ionic homeostasis and mitochondrial dysfunction.
FIGURE 4
FIGURE 4
Effect of thymol on metabolic and kidney disorders.

References

    1. Abd-Elhakim Y. M., Mohamed W. A. M. (2016). Assessment of the role of thymol in combating chromium (VI)-induced oxidative stress in isolated rat erythrocytes in vitro. Toxicol. Environ. Chem. 98 1227–1240. 10.1080/02772248.2015.1121490
    1. Aboelwafa H. R., Yousef H. N. (2015). The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats. Biochem. Cell Biol. 93 282–289. 10.1139/bcb-2014-0154
    1. Aeschbach R., Loliger J., Scott B. C., Murcia A., Butler J., Halliwell M., et al. (1994). Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem. Toxicol. 32 31–36. 10.1016/0278-6915(84)90033-4
    1. Aftab K., Atta-Ur-Rahman, Usmanghani K. (1995). Blood pressure lowering action of active principle from Trachyspermum ammi (L.) Sprague. Phytomedicine 2 35–40. 10.1016/S0944-7113(11)80046-2
    1. Aghamohammadi A., Hosseinimehr S. J., Ghasemi A., Azadbakht M., Pourfallah T. A. (2015). Radiosensitization effects of a Zataria multiflora extract on human glioblastoma cells. Asian Pac. J. Cancer Prev. 16 7285–7290. 10.7314/APJCP.2015.16.16.7285
    1. Ahmadifar E., Falahatkar B., Akrami R. (2011). Effects of dietary thymol-carvacrol on growth performance, hematological parameters and tissue composition of juvenile rainbow trout, Oncorhynchus mykiss. J. Appl. Ichthyol. 27 1057–1060. 10.1111/j.1439-0426.2011.01763.x
    1. Alam K., Nagi M. N., Badary O. A., Al-shabanah O. A., Al-Rikabi A. C., Al-Bekairi A. M. (1999). The protective action of thymol against carbon tetrachloride hepatotoxicity in mice. Pharmacol. Res. 40 159–163. 10.1006/phrs.1999.0472
    1. Aliabadi A., Izadi M., Rezvani M. E. (2016). Esmaeili-dehaj, M. Effects of thymol on serum biochemical and antioxidant indices in kindled rats. Int. J. Med. Lab. 2016 43–49.
    1. Alinezhad H., Azimi R., Zare M., Ebrahimzadeh M. A., Eslami S., Nabavi S. F., et al. (2013). Antioxidant and antihemolytic activities of ethanolic extract of flowers, leaves, and stems of Hyssopus officinalis L. var. angustifolius. Int. J. Food Prop. 16 1169–1178. 10.1080/10942912.2011.578319
    1. Al-Khalaf M. I. (2013). Thyme and thymol effects on induced bronchial asthma in mice. Life Sci. J. 10 693–699.
    1. Al-Malki A. L. (2010). Antioxidant properties of thymol and butylated hydroxytoluene in carbon tetrachloride -induced mice liver injury. JKAU 22 239–248. 10.4197/Sci.22-1.16
    1. Aman S., Moin S., Owais M., Siddiqui M. U. (2013). Antioxidant activity of thymol: protective role in AAPH-induced hemolysis in diabetic erythrocytes. Int. J. Pharm. Sci. Invent. 2 55–60.
    1. Amandi R., Hyde J. R., Ross S. K., Lotz T. J., Poliakoff M. (2005). Continuous reactions in supercritical fluids; a cleaner, more selective synthesis of thymol in supercritical CO2. Green Chem. 7 288–293. 10.1039/b418983c
    1. Amirghofran Z., Ahmadi H., Karimi M. H., Kalantar F., Gholijani N., Malek-Hosseini Z. (2016). In vitro inhibitory effects of thymol and carvacrol on dendritic cell activation and function. Pharm. Biol. 54 125–132. 10.3109/13880209.2015.1055579
    1. Amirghofran Z., Hashemzadeh R., Javidnia K., Golmoghaddam H., Esmaeilbeig A. (2011). In vitro immunomodulatory effects of extracts from three plants of the Labiatae family and isolation of the active compound(s). J. Immunotoxicol. 8 265–273. 10.3109/1547691X.2011.590828
    1. Amiri H. (2012). Essential oils composition and antioxidant properties of three Thymus species. Evid. Based Complement. Alternat. Med. 2012:728065 10.1155/2012/728065
    1. Anamura S. I. (1989). Effects of phenolic dental medicaments on arachidonic arachidonic acid metabolism and their antiinflammatory action. Hiroshima Daigaku Shigaku Zasshi. 21 147–162.
    1. Anderson R. C., Krueger N. A., Genovese K. J., Stanton T. B., Mackinnon K. M., Harvey R. B., et al. (2012). Effect of thymol or diphenyliodonium chloride on performance, gut fermentation characteristics, and Campylobacter colonization in growing swine. J. Food Prot. 75 758–761. 10.4315/0362-028X.JFP-11-390
    1. Arab H. A., Fathi M., Mortezai E., Hosseinimehr S. J. (2015). Chemoprotective effect of thymol against genotoxicity induced by bleomycin in human lymphocytes. Pharm. Biomed. Res. 1 26–31. 10.18869/acadpub.pbr.1.1.26
    1. Arai T. (1988). Cytotoxicity of thymol on cultured mammalian cells. Shigaku 76 24–35.
    1. Araujo L. X., Novato T. P., Zeringota V., Matos R. S., Senra T. O., Maturano R., et al. (2015). Acaricidal activity of thymol against larvae of Rhipicephalus microplus (Acari: Ixodidae) under semi-natural conditions. Parasitol. Res. 114 3271–3276. 10.1007/s00436-015-4547-3
    1. Archana P. R., Nageshwar Rao B., Satish Rao B. S. (2011a). In vivo radioprotective potential of thymol, a monoterpene phenol derivative of cymene. Mutat. Res. 726 136–145. 10.1016/j.mrgentox.2011.08.007
    1. Archana P. R., Nageshwar Rao B., Satish Rao B. S. (2011b). Modulation of gamma ray-induced genotoxic effect by thymol, a monoterpene phenol derivative of cymene. Integr. Cancer Ther. 10 374–383. 10.1177/1534735410387421
    1. Astudillo A., Hong E., Bye R., Navarrete A. (2014). Antispasmodic activity of extracts and compounds of Acalypha phleoides Cav. Phytother. Res. 18 102–106. 10.1002/ptr.1414
    1. Austgulen L. T., Solheim E., Scheline R. R. (1987). Metabolism in rats of p-cymene derivatives: carvacrol and thymol. Pharmacol. Toxicol. 61 98–102. 10.1111/j.1600-0773.1987.tb01783.x
    1. Aydin E., Taşdemir S., Hacimuftuoglu F., Turkez H. (2016). Anticancer, antioxidant and cytotoxic potential of thymol in vitro brain tumor cell model. Cent. Nerv. Syst. Agents Med. Chem. 10.2174/1871524916666160823121854 [Epub ahead of print].
    1. Aydin S., Başaran A. A., Başaran N. (2005). The effects of thyme volatiles on the induction of DNA damage by the heterocyclic amine IQ and mitomycin C. Mutat. Res. 2005 43–53. 10.1016/j.mrgentox.2004.10.017
    1. Azirak S., Rencuzogullari E. (2008). The in vivo genotoxic effects of carvacrol and thymol in rat bone marrow cells. Environ. Toxicol. 23 728–735. 10.1002/tox.20380
    1. Azizi Z., Ebrahimi S., Saadatfar E., Kamalinejad M., Majlessi N. (2012). Cognitive- enhancing activity of thymol and carvacrol in two rat models of dementia. Behav. Pharmacol. 23 241–249. 10.1097/FBP.0b013e3283534301
    1. Bairwa R., Sodha R. S., Rajawat B. S. (2012). Trachyspermum ammi. Pharmacogn. Rev. 6 56–60. 10.4103/0973-7847.95871
    1. Beer A. M., Lukanov J., Sagorchev P. (2007). Effect of thymol on the spontaneous contractile activity of the smooth muscles. Phytomedicine 14 65–69. 10.1016/j.phymed.2006.11.010
    1. Begrow F., Engelbertz J., Feistel B., Lehnfeld R., Bauer K., Verspohl E. J. (2010). Impact of thymol in thyme extracts on their antispasmodic action and ciliary clearance. Planta Med. 76 311–318. 10.1055/s-0029-1186179
    1. Bertevello P. L., Logullo A. F., Nonogaki S., Campos F. M., Chiferi V., Alves C. C., et al. (2005). Immunohistochemical assessment of mucosal cytokine profile in acetic acid experimental colitis. Clinics 60 277–286. 10.1590/S1807-59322005000400004
    1. Bhandari S. S., Kabra M. P. (2014). To evaluate anti-anxiety activity of thymol. J. Acute Dis. 3 136–140. 10.1016/S2221-6189(14)60030-5
    1. Bhatia K. S., Singh J. (1998). Mechanism of transport enhancement of LHRH through porcine epidermis by terpenes and iontophoresis: permeability and lipid extraction studies. Pharm. Res. 15 1857–1862. 10.1023/A:1011906022903
    1. Bhutada P., Mundhada Y., Bansod K., Dixit P., Umathe S., Mundhada D. (2010). Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behav. 18 207–210. 10.1016/j.yebeh.2010.03.007
    1. Boudry G., Perrier C. (2008). Thyme and cinnamon extracts induce anion secretion in piglet small intestine via cholinergic pathways. J. Physiol. Pharmacol. 59 543–552.
    1. Braga P. C., Dal Sasso M., Culici M., Bianchi T., Bordoni L., Marabini L. (2006). Anti- inflammatory activity of thymol: inhibitory effect on the release of human neutrophil elastase. Pharmacology 77 130–136. 10.1159/000093790
    1. Bukovska A., Cikos S., Juhas S., Ilkova G., Rehak P., Koppel J. (2007). Effects of a combination of Thyme and Oregano essential oils on TNBS-induced colitis in mice. Mediators Inflamm. 2007:23296 10.1155/2007/23296
    1. Cabello M. L. R., Praena D. G., Puerto M., Silvia Pichardo S., Jos A., Camean A. M. (2015). In vitro pro-oxidant/antioxidant role of carvacrol, thymol and their mixture in the intestinal Caco-2 cell line. Toxicol. In Vitro 29 647–656. 10.1016/j.tiv.2015.02.006
    1. Calo R., Visone C. M., Marabini L. (2015). Thymol and Thymus vulgaris L. activity against UVA- and UVB-induced damage in NCTC 2544 cell line. Mutat. Res. 791 30–37. 10.1016/j.mrgentox.2015.07.009
    1. Cardoso E. S., Santana T. A., Diniz P. B., Montalvao M. M., Bani C. C., Thomazzi S. M. (2016). Thymol ameliorates inflammatory response and accelerates regeneration in cardiotoxin-induced muscle injury. J. Pharm. Pharmacol. 68 352–360. 10.1111/jphp.12520
    1. Chambin O., Champion D., Debray C., Rochat-Gonthier M. H., Le Meste M., Pourcelot Y. (2004). Effects of different cellulose derivatives on drug release mechanism studied at a preformulation stage. J. Control. Release 95 101–108. 10.1016/j.jconrel.2003.11.009
    1. Chang H. T., Chou C. T., Liang W. Z., Lu T., Kuo D. H., Shieh P., et al. (2014). Effects of thymol on Ca2+ homeostasis and apoptosis in MDCK renal tubular cells. Chin. J. Physiol. 57 90–98. 10.4077/CJP.2014.BAB192
    1. Chang H. T., Hsu S. S., Chou C. T., Cheng J. S., Wang J. L., Lin K. L., et al. (2011). Effect of thymol on Ca2+ homeostasis and viability in MG63 human osteosarcoma cells. Pharmacology 88 201–212. 10.1159/000331864
    1. Chang Y. C., Tai K. W., Huang F. M., Huang M. F. (2000). Cytotoxic and nongenotoxic effects of phenolic compounds in human pulp cell cultures. J. Endod. 26 440–443. 10.1097/00004770-200008000-00002
    1. Chauhan A. K., Jakhar R., Paul S., Kang S. C. (2014). Potentiation of macrophage activity by thymol through augmenting phagocytosis. Int. Immunopharmacol. 18 340–346. 10.1016/j.intimp.2013.11.025
    1. Chauhan A. K., Kang S. C. (2015). Therapeutic potential and mechanism of thymol action against ethanol induced gastric mucosal injury in rat model. Alcohol 49 739–745. 10.1016/j.alcohol.2015.08.004
    1. Chauhan P. S., Satti N. K., Suri K. A., Amina M., Bani S. (2010). Stimulatory effects of Cuminum cyminum and flavonoid glycoside on Cyclosporine-A and restraint stress induced immune-suppression in Swiss albino mice. Chem. Biol. Interact. 185 66–72. 10.1016/j.cbi.2010.02.016
    1. Chikhoune A., Stouvenel L., Iguer-Ouada M., Hazzit M., Schmitt A., Lores P., et al. (2015). In vitro effects of Thymus munbyanus essential oil and thymol on human sperm motility and function. Reprod. Biomed. Online 31 411–420. 10.1016/j.rbmo.2015.06.011
    1. Choi J. H., Kim S. W., Yu R., Yun J. W. (2016). Monoterpene phenolic compound thymol promotes browning of 3T3-L1 adipocytes. Eur. J. Nutr. 10.1007/s00394-016-1273-2 [Epub ahead of print]
    1. Choi Y., Arron J. R., Townsend M. J. (2009). Promising bone related therapeutic targets for rheumatoid arthritis therapy. Nat. Rev. Rheumatol. 5 543–548. 10.1038/nrrheum.2009.175
    1. Colombo M., Priori D., Gandolfi G., Boatto G., Nieddu M., Bosi P., et al. (2014). Effect of free thymol on differential gene expression in gastric mucosa of the young pig. Animal 8 786–791. 10.1017/S1751731114000172
    1. Cooper T. G., Noonan E., Von Eckardstein S., Auger J., Baker H. W., Behre H. M., et al. (2009). World Health Organization reference values for human semen characteristics. Hum. Reprod. Update 16 231–245. 10.1093/humupd/dmp048
    1. Cornaghi L., Arnaboldi F., Calo R., Landoni F., Preis W. F. B., Marabini L., et al. (2016). Effects of UV rays and thymol/ Thymus vulgaris L. Extract in an ex vivo human skin model: morphological and genotoxicological assessment. Cells Tissues Organs 201 180–192. 10.1159/000444361
    1. de Morais S. M., Vila-Nova N. S., Bevilaqua C. M., Rondon F. C., Lobo C. H., de Alencar Araripe Noronha Moura A., et al. (2014). Thymol and eugenol derivatives as potential antileishmanial agents. Thymol and eugenol derivatives as potential antileishmanial agents. Bioorg. Med. Chem. 22 6250–6255. 10.1016/j.bmc.2014.08.020
    1. Demirci F., Paper D. H., Franz G., Baser K. H. (2004). Investigation of the Origanum onites L. essential oil using the chorioallantoic membrane (CAM) assay. J. Agric. Food Chem. 52 251–254. 10.1021/jf034850k
    1. Deng X. Y., Li H. Y., Chen J. J., Li R. P., Qu R., Fu Q., et al. (2015). Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice. Behav. Brain Res. 291 12–19. 10.1016/j.bbr.2015.04.052
    1. Dhaneshwar S., Patel V., Patil D., Meena G. (2013). Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug. Bioorg. Med. Chem. Lett. 23 55–61. 10.1016/j.bmcl.2012.11.016
    1. Diao H., Zheng P., Yu B., He J., Mao X., Yu J., et al. (2015). Effects of benzoic acid and thymol on growth performance and gut characteristics of weaned piglets. Asian Australas. J. Anim. Sci. 28 827–839. 10.5713/ajas.14.0704
    1. Didri N., Dubreuil L., Pinkas M. (1994). Activity of thymol, carvacrol, cinnamaldehyde and eugenol on oral bacteria. Pharm. Acta Helv. 69 25–28. 10.1016/0031-6865(94)90027-2
    1. Dutta D. D., Parimala G., Devi S. S., Chakraborty T. (2011). Effect of thymol on peripheral blood mononuclear cell PBMC and acute promyelotic cancer cell line HL-60. Chem. Biol. Interact. 193 97–106. 10.1016/j.cbi.2011.05.009
    1. Duyckaerts C., Delatour B., Potier M. C. (2009). Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118 5–36. 10.1007/s00401-009-0532-1
    1. Ebashi S. (1965). “The sarcoplasmic reticulum and excitation-contraction coupling,” in Molecular Biology of Muscular Contraction eds Ebashi S., Oosawa F., Sekine T., Tonomula Y. (Amsterdam: Igaku-shoin, Tokyo and Elsevier Publishing Co; ) 197–206.
    1. El-Nekeety A. A., Mohamed S. R., Hathout A. S., Hassan N. S., Aly S. E., Abdel-Wahhab M. A. (2011). Antioxidant properties of Thymus vulgaris oil against aflatoxin-induce oxidative stress in male rats. Toxicon 57 984–991. 10.1016/j.toxicon.2011.03.021
    1. El-Sayed E. M., Abd-Allah A. R., Mansour A. M., El-Arabey A. A. (2014). Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J. Biochem. Mol. Toxicol. 29 165–172. 10.1002/jbt.21681
    1. El-Sayed E. S. M., Mansour A. M., Abdul-Hameed M. S. (2016). Thymol and carvacrol prevent doxorubicin- induced cardiotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J. Biochem. Mol. Toxicol. 30 37–44. 10.1002/jbt.21740
    1. Engelbertz J., Lechtenberg M., Studt L., Hensel A., Verspohl E. J. (2012). Bioassay-guided fractionation of a thymol-deprived hydrophilic thyme extract and its antispasmodic effect. J. Ethnopharmacol. 141 848–853. 10.1016/j.jep.2012.03.025
    1. Enomoto S., Asano R., Iwahori Y., Narui T., Okada Y., Singab B., et al. (2001). Hematological studies on black cumin oil from the seeds of Nigella sativa L. Biol. Pharm. Bull. 24 307–310. 10.1248/bpb.24.307
    1. Fachini-Queiroz F. C., Kummer R., Estevao-Silva C. F., Carvalho M. D., Cunha J. M., Grespan R., et al. (2012). Effects of thymol and carvacrol, constituents of Thymus vulgaris L. essential oil, on the inflammatory response. Evid. Based Complement. Alternat. Med. 2012:657026 10.1155/2012/657026
    1. Farinacci M., Colitti M., Sqorlon S., Stefanon B. (2008). Immunomodulatory activity of plant residues on ovine neutrophils. Vet. Immunol. Immunopathol. 126 54–63. 10.1016/j.vetimm.2008.06.006
    1. Feldmann M. (2002). Development of anti-TNF therapy for rheumatoid arthritis. Nat. Rev. Immunol. 2 364–371. 10.1038/nri802
    1. Feldmann M., Brennan F. M., Maini R. N. (1996). Rheumatoid arthritis. Cell 85 307–310. 10.1016/S0092-8674(00)81109-5
    1. Gao S., Singh J. (1998). In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes. J. Control. Release 51 193–199. 10.1016/S0168-3659(97)00168-5
    1. Garcia D. A., Bujons J., Vale C., Sunol C. (2006). Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons. Neuropharmacology 50 25–35. 10.1016/j.neuropharm.2005.07.009
    1. Gavliakova S., Biringerova Z., Buday T., Brozmanova M., Calkovsky V., Poliacek I., et al. (2013). Antitussive effects of nasal thymol challenges in healthy volunteers. Respir. Physiol. Neurobiol. 187 104–107. 10.1016/j.resp.2013.02.011
    1. Gholijani N., Amirghofran Z. (2016). Effects of thymol and carvacrol on T-helper cell subset cytokines and their main transcription factors in ovalbumin-immunized mice. J. Immunotoxicol. 13 729–737. 10.3109/1547691X.2016.1173134
    1. Gholijani N., Gharagozloo M., Farjadian S., Amirghofran Z. (2016). Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. J. Immunotoxicol. 13 157–164. 10.3109/1547691X.2015.1029145
    1. Gholijani N., Gharagozloo M., Kalantar F., Ramezani A., Amirghofran Z. (2015). Modulation of cytokine production and transcription factor activities in human Jurkat T-cells by thymol and carvacrol. Adv. Pharm. Bull. 5 635–660. 10.15171/apb.2015.089
    1. Ghosheh O. A., Houdi A. A., Crooks P. A. (1999). High performance liquid chromatographic analysis of the pharmacologically active quinones and related compounds in the oil of the black seed (Nigella sativa L). J. Pharm. Biomed. Anal. 19 757–762. 10.1016/S0731-7085(98)00300-8
    1. Giannenas I., Triantafillou E., Stavrakakis S., Margaroni M., Mavridis S., Steiner T., et al. (2012). Assessment of dietary supplementation with carvacrol or thymol containing feed additives on performance, intestinal microbiota and antioxidant status of rainbow trout (Oncorhynchus mykiss). Aquaculture 350 26–32. 10.1016/j.aquaculture.2012.04.027
    1. Haeseler G., Maue D., Grosskreutz J., Bufler J., Nentwig B., Piepenbrock S., et al. (2002). Voltage dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. Eur. J. Anaesthesiol. 19 571–579. 10.1017/S0265021502000923
    1. Haque M. R., Ansari S. H., Najmi A. K., Ahmad M. A. (2014). Monoterpene phenolic compound thymol prevents high fat diet induced obesity in murine model. Toxicol. Mech. Methods 24 116–123. 10.3109/15376516.2013.861888
    1. Hasegawa R., Nakaji Y., Kurokawa Y., Tobe M. (1989). Acute toxicity tests on 113 environmental chemicals. Sci. Rep. Res. Inst. Tohoku Univ. Med. 36 10–16.
    1. Hashemipour H., Kermanshahi H., Golian A., Veldkamp T. (2013). Effect of thymol and carvacrol feed supplementation on performance, antioxidant enzyme activities, fatty acid composition, digestive enzyme activities, and immune response in broiler chickens. Poult. Sci. 92 2059–2069. 10.3382/ps.2012-02685
    1. He L., Mo H., Hadisusilo S., Qureshi A. A., Elson C. E. (1997). Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J. Nutr. 127 668–674.
    1. Hejazian S. H. (2006). Analgesic Effect of essential oil (EO) from Carum copticum in mice. World J. Med. Sci. 1 95–99.
    1. Hejazian S. H., Bagheri S. M., Safari F. (2014). Spasmolytic and anti-spasmodic action of Trachyspermum ammi essence on rat’s ileum contraction. N. Am. J. Med. Sci. 6 643–647. 10.4103/1947-2714.147982
    1. Hernandez F., Madrid J., Garcia V., Orengo J., Megias M. D. (2004). Influence of two plant extracts on broiler performance, digestibility, and digestive organ size. Poult. Sci. 83 169–174. 10.1093/ps/83.2.169
    1. Hirobe C., Qiao Z. S., Takeya K., Itokawa H. (1998). Cytotoxic principles from Majorana syriaca. Nat. Med. 52 74–77.
    1. Hisayama T., Takayanagi I. (1986). Some properties and mechanisms of thymol-induced release of calcium from the calcium-store in guineapig taenia caecum. Jpn. J. Pharmacol. 40 69–82. 10.1254/jjp.40.69
    1. Holmberg K., Hansen B. (1979). Ester synthesis with dicyclohexylcarbodiimide improved by acid catalysts. Acta Chem. Scand. B 33 410–412. 10.3891/acta.chem.scand.33b-0410
    1. Horvathova E., Navarova J., Galova E., Sevcovicova A., Chodakova L., Snahnicanova Z., et al. (2014). Assessment of antioxidative, chelating, and DNA-protective effects of selected essential oil components (eugenol, carvacrol, thymol, borneol, eucalyptol) of plants and intact Rosmarinus officinalis oil. J. Agric. Food Chem. 62 6632–6639. 10.1021/jf501006y
    1. Horvathova E., Turcaniova V., Slamenova D. (2007). Comparative study of DNA-damaging and DNA protective effects of selected components of essential plant oils in human leukemic cells K562. Neoplasma 54 478–483.
    1. Hosseinimehr S. J., Asadian R., Naghshvar F., Azizi S., Jafarinejad M., Noaparast Z., et al. (2015). Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice. Ren. Fail. 37 280–284. 10.3109/0886022X.2014.991998
    1. Hsu S. S., Lin K. L., Chou C. T., Chiang A. J., Liang W. Z., Chang H. T. (2011). Effect of thymol on Ca2+ homeostasis and viability in human glioblastoma cells. Eur. J. Pharmacol. 670 85–91. 10.1016/j.ejphar.2011.08.017
    1. Hyun T. K., Kim H. C., Kim J. S. (2014). Antioxidant and antidiabetic activity of Thymus quinquecostatus Celak. Ind. Crops Prod. 52 611–616. 10.1016/j.indcrop.2013.11.039
    1. Instituto Superiore di Sanita (1999). Up to Date Review of Toxicological Data of Some Plant Volatiles with Antifungal Activity. NTIS Report No PB2000106327 Rome: Instituto Superiore di Sanita.
    1. Ito Y., Kuriyama H. (1974). Effects of thymol on the electrical and mechanical properties of the guinea-pig taenia coli. J. Physiol. 236 143–157. 10.1113/jphysiol.1974.sp010427
    1. Jaafari A., Tilaoui M., Mouse H. A., Ait M’bark L., Aboufatima R., Chait A., et al. (2012). Comparative study of the antitumor effect of natural monoterpenes: relationship to cell cycle analysis. Braz. J. Pharmacog. 22 534–540. 10.1590/s0102-695x2012005000021
    1. Janbaz K. H., Saeed S. A., Gilani A. H. (2003). Hepatoprotective effect of thymol on chemical- induced hepatotoxicity in rodents. Pak. J. Biol. Sci. 2003 448–451.
    1. Jang I. S., Ko Y. H., Kang S. Y., Lee C. Y. (2007). Effect of commercial essential oils on growth performance, digestive enzyme activity and intestinal microflora population in broiler chickens. Anim. Feed Sci. Technol. 134 304–315. 10.1016/j.anifeedsci.2006.06.009
    1. Jenner P. M., Hagan E. C., Taylor J. M., Cook E. L., Fitzhugh O. G., Jenner P., et al. (1964). Food flavourings and compounds of related structure I. Acute oral toxicity. Food Cosmet. Toxicol. 2 327–343. 10.1016/S0015-6264(64)80192-9
    1. Jeusette I. C., Lhoest E. T., Istasse L. P., Diez M. O. (2005). Influence of obesity on plasma lipid and lipoprotein concentrations in dogs. Am. J. Vet. Res. 66 81–86. 10.2460/ajvr.2005.66.81
    1. Jimenez J., Navarro M. C., Montilla M. P., Martin A. (1993). Thymus zygis oil: Its effects on CCl4 induced hepatotoxicity and free radical scavenger activity. J. Essent. Oil Res. 5 153–158.
    1. Jordan W., Van Barneveld H., Gerlich O., Kleine-Boymann M., Ullrich J. (1991). “Phenol,” in Ullmanns Encyclopedia of Industrial Chemistry 5th Edn Vol. A 19 eds Elvers B., Hawkins S., Schulz G. (Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; ) 299–312.
    1. Juan R. A., Olga P. A., Mirian P. P. (2015). Chemical composition and anti-trypanosoma cruzi effect of Thymus vulgaris L. (thyme) essential oil and its main component, thymol, in mice. Am. J. Pharm. Pharmacol. 2 21–27.
    1. Jukic M., Politeo O., Maksimovic M., Milos M. (2007). In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone. Phytother Res. 21 259–261. 10.1002/ptr.2063
    1. Kabouche A., Ghannadi A., Kabouche Z. (2009). Thymus ciliates-the highest thymol containing essential oil of the genus. Nat. Prod. Commun. 4 1251–1252.
    1. Kamataki T., Sugita O., Naminohira S., Kitagawa H. (1978). Effects of various compounds on lipid peroxidation mediated by detergent-solubilized rat liver NADPH-cytochrome C reductase. Jpn. J. Pharmacol. 28 837–845. 10.1254/jjp.28.837
    1. Kang S. H., Kim Y. S., Kim E. K., Hwang J. W., Jeong J. H., Dong X., et al. (2016). Anticancer effect of thymol on AGS human gastric carcinoma cells. J. Microbiol. Biotechnol. 26 28–37. 10.4014/jmb.1506.06073
    1. Karpanen T. J., Worthington T., Hendry E. R., Conway B. R., Lambert P. A. (2008). Antimicrobial efficacy of chlorhexidine digluconate alone and in combination with eucalyptus oil, tea tree oil and thymol against planktonic and biofilm cultures of Staphylococcus epidermidis. J. Antimicrob. Chemother. 62 1031–1036. 10.1093/jac/dkn325
    1. Kavoosi G., Dadfar S. M. M., Purfard A. M. (2013). Mechanical, physical, antioxidant, and antimicrobial properties of gelatin films incorporated with thymol for potential use as nano wound dressing. J. Food Sci. 78 E244–E250. 10.1111/1750-3841.12015
    1. Kavoosi G., Teixeira da Silva J. A. (2012). Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in glucose- stimulated human monocyte. Food Chem. Toxicol. 50 3079–3085. 10.1016/j.fct.2012.06.002
    1. Kavoosi G., Teixeira da Silva J. A., Saharkhiz M. J. (2012). Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in lipopolysaccharide stimulated macrophages. J. Pharm. Pharmacol. 64 1491–1500. 10.1111/j.2042-7158.2012.01510.x
    1. Kawasaki H., Mizuta K., Fujita T., Kumamoto E. (2013). Inhibition by menthol and its related chemicals of compound action potentials in frog sciatic nerves. Life Sci. 92 359–367. 10.1016/j.lfs.2013.01.012
    1. Khadir A., Sobeh M., Gad H. A., Benbelaid F., Bendahou M., Peixoto H., et al. (2016). Chemical composition and biological activity of the essential oil from Thymus lanceolatus. Z. Naturforsch. 71 155–163. 10.1515/znc-2016-0005
    1. Khajeali Y., Kheiri F., Rahimian Y., Faghani M., Namjo A. (2012). Effect of use different levels of caraway (Carum carvi L.) powder on performance, some blood parameters and intestinal morphology on broiler chickens. World Appl. Sci. J. 19 1202–1207.
    1. Khajeh M., Yamini Y., Sefidkon F., Bahramifar N. (2004). Comparison of essential oil composition of Carum copticum obtained by supercritical carbon dioxide extraction and hydrodistillation methods. Food Chem. 86 587–591. 10.1016/j.foodchem.2003.09.041
    1. Khan S. T., Khan M., Ahmad J., Wahab R., Abd-Elkader O. H., Musarrat J., et al. (2017). Thymol and carvacrol induce autolysis, stress, growth inhibition and reduce the biofilm formation by Streptococcus mutans. AMB Express 7 49 10.1186/s13568-017-0344-y
    1. Khosravi A. R., Erle D. J. (2016). Chitin-induced airway epithelial cell innate immune responses are inhibited by carvacrol/thymol. PLoS ONE 11:e0159459 10.1371/journal.pone.0159459
    1. Kim Y. S., Hwang J. W., Kang S. H., Kim E. H., Jeon Y. J., Jeong J. H., et al. (2014). Thymol from Thymus quinquecostatus Celak. protects against tert-butyl hydroperoxide- induced oxidative stress in Chang cells. J. Nat. Med. 68 154–162. 10.1007/s11418-013-0786-8
    1. Kishwar F., Mahmood I., Mahmood T., Ul-Haq Q. (2013). Thymol, an active constituent of Nigella sativa, could reduce toxicity of some trace metals (Fe(III),Cr(VI),Cu(II),V(IV) and Co(II)). Eur. Academ. Res. 1 1110–1125.
    1. Kohlert C., Schindler G., Marz R. W., Abel G., Brinkhaus B., Derendorf H., et al. (2002). Systemic availability and pharmacokinetics of thymol in humans. J. Clin. Pharmacol. 42 731–737. 10.1177/009127002401102678
    1. Kostyuk P. G., Belan P. V., Tepikin A. V. (1991). Free calcium transients and oscillations in nerve cells. Exp. Brain Res. 83 459–464. 10.1007/BF00231173
    1. Kruk I., Michalska T., Lichszteld K., Koadna A., Aboul-Enein H. Y. (2000). The effect of thymol and its derivatives on reactions generating reactive oxygen species. Chemosphere 41 1059–1064. 10.1016/S0045-6535(99)00454-3
    1. Ku C. M., Lin J. Y. (2013). Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food Chem. 141 1104–1113. 10.1016/j.foodchem.2013.04.044
    1. Kundu S., Shabir H., Basir S. F., Khan L. A. (2016). Thymol tempers As (III) and Hg (II) caused hypercontractility by similar pathways in isolated aortic and tracheal rings. Int. J. Pharm. Pharmaceut. Sci. 8 404–407.
    1. Lazar M. A. (2005). How obesity causes diabetes: not a tall tale. Science 307 373–375. 10.1126/science.1104342
    1. Lee B. H., Nam T. G., Park W. J., Kang H., Heo H. J., Chung D. K., et al. (2015). Antioxidative and neuroprotective effects of volatile components in essential oils from Chrysanthemum indicum Linne flowers. Food Sci. Biotechnol. 24 717–723. 10.1007/s10068-015-0093-0
    1. Lee K. P., Kim J. E., Park W. H., Hong H. (2016). Regulation of C6 glioma cell migration by thymol. Oncol. Lett. 11 2619–2624. 10.3892/ol.2016.4237
    1. Lee S. P., Buber M. T., Yang Q., Cerne R., Cortes R. T., Sprous D. G., et al. (2008). Thymol and related alkyl phenols activate the hTRPA1 channel. Brit. J. Pharmacol. 153 1739–1749. 10.1038/bjp.2008.85
    1. Li S., Ru Y., Liu M., Xu B., Peron A., Shi X. (2012). The effect of essential oils on performance, immunity and gut microbial population in weaner pigs. Livest. Sci. 145 119–123. 10.1016/j.livsci.2012.01.005
    1. Liang D., Li F., Fu Y., Cao Y., Song X., Wang T., et al. (2014). Thymol inhibits LPS- Stimulated inflammatory response via down-regulation of NF-κB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation 37 214–222. 10.1007/s10753-013-9732-x
    1. Liang H., Bao F., Dong X., Tan R., Zhang C., Lu Q., et al. (2007). Antibacterial thymol derivatives isolated from Centipeda minima. Molecules 12 1606–1613. 10.3390/12081606
    1. Lide D. R., Frederikse H. P. R. (1996). CRC Handbook of Chemistry and Physics. Boca Raton, NY: CRC Press; 3–258.
    1. Lorente I., Ocete M. A., Zarzuelo A., Cabo M. M., Jimenez J. (1989). Bioactivity of the essential oil of Bupleurum fruticosum. J. Nat. Prod. 52 267–272. 10.1021/np50062a008
    1. Magyar J., Szentandrassy N., Banyasz T., Fulop L., Varro A., Nanasi P. P. (2002). Effects of thymol on calcium and potassium currents in canine and human ventricular cardiomyocytes. Br. J. Pharmacol. 136 330–338. 10.1038/sj.bjp.0704718
    1. Magyar J., Szentandrassy N., Banyasz T., Fulop L., Varro A., Nanasi P. P. (2004). Effects of terpenoid phenol derivatives on calcium current in canine and human ventricular cardiomyocytes. Eur. J. Pharmacol. 487 29–36. 10.1016/j.ejphar.2004.01.011
    1. Mahmoud A. L. (1994). Antifungal action and antiaflatoxigenic properties of some essential oil constituents. Lett. Appl. Microbiol. 19 110–113. 10.1111/j.1472-765X.1994.tb00918.x
    1. Maisanaba S., Prieto A. I., Puerto M., Gutierrez-Praena D., Demir E., Marcos R., et al. (2015). In vitro genotoxicity testing of carvacrol and thymol using the micronucleus and mouse lymphoma assays. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 784 37–44. 10.1016/j.mrgentox.2015.05.005
    1. Manabe A., Nakayama S., Sakamoto K. (1987). Effects of essential oils on erythrocytes and hepatocytes from rats and dipalmitoyl phosphatidylcholine-liposomes. Jpn. J. Pharmacol. 44 77–84. 10.1254/jjp.44.77
    1. Manou I., Bouillard L., Devleeschouwer M. J., Barel A. O. (1998). Evaluation of the preservation properties of Thymus vulgaris essential oil in applied formulations under a challenge test. J. Appl. Microbiol. 84 368–376. 10.1046/j.1365-2672.1998.00353.x
    1. Marchese A., Orhan I. E., Daglia M., Barbieri R., Di Lorenzo A., Nabavi S. F. (2016). Antibacterial and antifungal activities of thymol: A brief review of the literature. Food Chem. 210 402–414. 10.1016/j.foodchem.2016.04.111
    1. Marin L. D., Sanchez-Borzone M., Garcia D. A. (2011). Comparative antioxidant properties of some gabaergic phenols and related compounds, determined for homogeneous and membrane systems. Med. Chem. 7 317–324. 10.2174/157340611796150969
    1. Marino M., Bersani C., Comi G. (1999). Antimicrobial activity of the essential oils of Thymus vulgaris L. measured using a bioimpedometric method. J. Food Prot. 62 1017–1023. 10.4315/0362-028X-62.9.1017
    1. Markovic P., Chatzopoulou P., Siljegovic J., Nikolic M., Glamoclija J., Ciric A., et al. (2011). Chemical analysis and antimicrobial activities of the essential oils of Satureja thymbra L. and Thymbra spicata L. and their main components. Arch. Biol. Sci. 63 457–464. 10.2298/ABS1102457M
    1. Marsik P., Kokoska L., Landa P., Nepovim A., Soudek P., Vanek T. (2005). In vitro inhibitory effects of thymol and quinones of Nigella sativa seeds on cyclooxygenase-1- and -2-catalyzed prostaglandin E2 biosyntheses. Planta Med. 71 739–742. 10.1055/s-2005-871288
    1. Martins I. M., Barreiro M. F., Coelho M., Rodrigues A. E. (2014). Microencapsulation ofessential oils with biodegradable polymeric carriers for cosmetic applications. Chem. Eng. J. 245 191–200. 10.1016/j.cej.2014.02.024
    1. Maruniak J., Clark W. B., Walker C. B., Magnusson I., Marks R. G., Taylor M., et al. (1992). The effect of 3 mouthrinses on plaque and gingivitis development. J. Clin. Periodontol. 19 19–23. 10.1111/j.1600-051X.1992.tb01143.x
    1. Mastelic J., Jerkovic I., Blazevic I., Poljak-Blazi M., Borovic S., Ivancic Bace I., et al. (2008). Comparative study on the antioxidant and biological activities of carvacrol, thymol, and eugenol derivatives. J. Agric. Food Chem. 56 3989–3996. 10.1021/jf073272v
    1. Mathela C. S., Singh K. K., Gupta V. K. (2010). Synthesis and in vitro antibacterial activity of thymol and carvacrol derivatives. Acta Pol. Pharm. 67 375–380.
    1. Meister A., Bernhardt G., Christoffel V., Buschauer A. (1999). Antispasmodic activity of Thymus vulgaris extract on the isolated guinea-pig trachea: discrimination between drug and ethanol effects. Planta Med. 65 512–516. 10.1055/s-1999-14006
    1. Melo J. O., Fachin A. L., Rizo W. F., Jesus H. C., Arrigoni-Blank M. F., Alves P. B., et al. (2014). Cytotoxic effects of essential oils from three Lippia gracilis Schauer genotypes on HeLa, B16 and MCF-7 cells and normal human fibroblasts. Gen. Mol. Res. 13 2691–2697. 10.4238/2014.April.8.12
    1. Mendes S. S., Bomfim R. R., Jesus H. C., Alves P. B., Blank A. F., Estevam C. S., et al. (2010). Evaluation of the analgesic and anti-inflammatory effects of the essential oil of Lippia gracilis leaves. J. Ethnopharmacol. 129 391–397. 10.1016/j.jep.2010.04.005
    1. Mezzoug N., Elhadri A., Dallouh A., Amkiss S., Skali N. S., Abrini J., et al. (2007). Investigation of the mutagenic and antimutagenic effects of Origanum compactum essential oil and some of its constituents. Mutat. Res. 629 100–110. 10.1016/j.mrgentox.2007.01.011
    1. Michiels J., Missotten J., Dierick N., Fremaut D., Maene P., De Smet S. (2008). In vitro degradation and in vivo passage kinetics of carvacrol, thymol, eugenol and trans- cinnamaldehyde along the gastrointestinal tract of piglets. J. Sci. Food Agric. 88 2371–2381. 10.1002/jsfa.3358
    1. Miguel M. G., Gago C., Antunes M. D., Megias C., Cortes-Giraldo I., Vioque J., et al. (2015). Antioxidant and antiproliferative activities of the essential oils from Thymbra capitata and thymus species grown in portugal. Evid. Based Complement. Alternat. Med. 2015:851721 10.1155/2015/851721
    1. Miller A. H., Timmie W. P. (2009). Mechanisms of cytokine induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav. Immun. 23 149–158. 10.1016/j.bbi.2008.08.006
    1. Mishra R. K., Baker M. T. (2014). Seizure prevention by the naturally occurring phenols, carvacrol and thymol in a partial seizure-psychomotor model. Bioorg. Med. Chem. Lett. 24 5446–5449. 10.1016/j.bmcl.2014.10.028
    1. Mohammadi B., Haeseler G., Leuwer M., Dengler R., Krampfl K., Bufler J. (2001). Structural requirements of phenol derivatives for direct activation of chloride currents via GABA(A) receptors. Eur. J. Pharmacol. 421 85–91. 10.1016/S0014-2999(01)01033-0
    1. Moller H. (1939). Effect of thymol on thyroid gland. Arch. Exp. Pathol. Pharmak. 191 615–620.
    1. Monteiro M. V., de Melo Leite A. K., Bertini L. M., de Morais S. M., Nunes-Pinheiro D. C. (2007). Topical anti-inflammatory, gastroprotective and antioxidants effects of the essential oil of Lippia sidoides Cham. leaves. J. Ethnopharmacol. 111 378–382. 10.1016/j.jep.2006.11.036
    1. Mottawie H., Ibrahiem A., Amer H. (2011). Role of some phytochemicals in the treatment of bronchial asthma. Med. J. Cairo Univ. 79 75–80.
    1. Nagle P. S., Pawar Y. A., Sonawane A. E., Nikum A. P., Patil U. D. (2013). Thymol: synthesis, reactions & its spectrum of pharmacological and chemical applications. Indo. Am. J. Pharm. Res. 3 7549–7561.
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2014). Protective efficacy of thymol on glycoproteins in isoproterenol induced myocardial infarcted rats: an in vivo and in vitro study. Int. J. Pharmaceut. Biol. Arch. 5 168–173. 10.1002/jbt.21431
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2015a). Catecholamine toxicity triggers myocardial membrane destabilization in rats: thymol and its counter action. RSC Adv. 5 43338–43344. 10.1016/j.ejphar.2016.02.063
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2015b). Thymol attenuates altered lipid metabolism in β adrenergic agonist induced myocardial infarcted rats by inhibiting tachycardia, altered electrocardiogram, apoptosis and cardiac hypertrophy. J. Funct. Foods 14 51–62. 10.1016/j.jff.2015.01.013
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2015c). Thymol attenuates inflammation in isoproterenol induced myocardial infarcted rats by inhibiting the release of lysosome enzymes and downregulating the expressions of proinflammatory cytokines. Eur. J. Pharmacol. 753 153–161. 10.1016/j.ejphar.2015.02.028
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2016a). Synthetic catecholamine triggers β1-adrenergic receptor activation and stimulates cardiotoxicity via oxidative stress mediated apoptotic cell death in rats: abrogating action of thymol. Chem. Biol. Interact. 251 17–25. 10.1016/j.cbi.2016.03.017
    1. Nagoor Meeran M. F., Jagadeesh G. S., Selvaraj P. (2016b). Thymol, a dietary monoterpene phenol abrogates mitochondrial dysfunction in β-adrenergic agonist induced myocardial infarcted rats by inhibiting oxidative stress. Chem. Biol. Interact. 244 159–168. 10.1016/j.cbi.2015.12.006
    1. Nagoor Meeran M. F., Prince P. S. (2012). Protective effects of thymol on altered plasma lipid peroxidation and nonenzymic antioxidants in isoproterenol- induced myocardial infarcted rats. J. Biochem. Mol. Toxicol. 26 368–373. 10.1002/jbt.21431
    1. Nayak B. S., Ghosh S. K., Patro K. T. B. (2009). Preparation and characterization of famotidine microcapsule employing mucoadhesive polymers combination to enhance gastero retention for oral delivery. Int. J. Pharm. Pharm. Sci. 1 112–120.
    1. Nieddu M., Rassu G., Boatto G., Bosi P., Trevisi P., Giunchedi P., et al. (2014). Improvement of thymol properties by complexation with cyclodextrins: In vitro and in vivo studies. Carbohyd. Polym. 102 393–399. 10.1016/j.carbpol.2013.10.084
    1. Norwitz G., Nataro N., Keliher P. N. (1986). Study of the steam distillation of phenolic compounds using ultraviolet spectrometry. Anal. Chem. 58 639–641. 10.1021/ac00294a034
    1. O’Brien T. J., Ceryak S., Patierno S. R. (2003). Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms. Mutat. Res. 533 3–36. 10.1016/j.mrfmmm.2003.09.006
    1. Ocana A., Reglero G. (2012). Effects of thyme extract oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis) on Cytokine production and gene expression of ox LDL- stimulated THP-1-macrophages. J. Obes. 11:104706 10.1155/2012/104706
    1. Ocana-Fuentes A., Arranz-Gutierrez E., Senorans F. J., Reglero G. (2010). Supercritical fluid extraction of oregano (Origanum vulgare) essentials oils: anti-inflammatory properties based on cytokine response on THP-1 macrophages. Food Chem. Toxicol. 48 1568–1575. 10.1016/j.fct.2010.03.026
    1. Ogaard B., Larsson E., Glans R., Henriksson T., Birkhed D. (1997). Antimicrobial effect of a chlorhexidine-thymol varnish (Cervitec) in orthodontic patients. A prospective, randomized clinical trial. J. Orofac. Orthop. 58 206–213.
    1. Ogata N., Matsushima N., Shibata T. (1995). Pharmacokinetics of wood creosote: glucuronic acid and sulfate conjugation of phenolic compounds. Pharmacology 51 195–204. 10.1159/000139335
    1. Oguri A., Suda M., Totsuka Y., Sugimura T., Wakabayashi K. (1998). Inhibitory effects of antioxidants on formation of heterocyclic amines. Mutat. Res. 402 237–245. 10.1016/S0027-5107(97)00303-5
    1. Olasupo N., Fitzgerald D., Gasson M., Narbad A. (2003). Activity of natural antimicrobial compounds against Escherichia coli and Salmonella enterica sero var. typhimurium. Lett. Appl. Microbiol. 37 448–451. 10.1046/j.1472-765X.2003.01427.x
    1. Ozen T., Demirtas I., Aksit H. (2011). Determination of antioxidant activities of various extracts and essential oil compositions of Thymus praecox subsp. skorpilii var. skorpilii. Food Chem. 124 58–64. 10.1016/j.foodchem.2010.05.103
    1. Ozkan A., Erdogan A. A. (2011). Comparative evaluation of antioxidant and anticancer activity of essential oil from Origanum onites (Lamiaceae) and its two major phenolic components. Turk. J. Biol. 35 735–742.
    1. Ozkan A., Erdogan A. A. (2012). Comparative study of the antioxidant/ prooxidant effects of carvacrol and thymol at various concentrations on membrane and DNA of parental and drug resistant H1299 cells. Nat. Prod. Commun. 7 1557–1560.
    1. Ozolua R. I., Umuso D. I., Uwaya D. O., Modugu A. A., Oghuvwu S. O., Olomu J. M. (2016). Evaluation of the anti-asthmatic and antitussive effects of aqueous leaf extract of Ocimum gratissimum in rodents. Med. Aromat. Plants 5 2.
    1. Palabiyik S. S., Karakus E., Halici Z., Cadirci E., Bayir Y., Ayaz G., et al. (2016). The protective effects of carvacrol and thymol against paracetamol– induced toxicity on human hepatocellular carcinoma cell lines (HepG2). Hum. Exp. Toxicol. 35 1252–1263. 10.1177/0960327115627688
    1. Palaniappan K., Holley R. A. (2010). Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria. Int. J. Food Microbiol. 140 164–168. 10.1016/j.ijfoodmicro.2010.04.001
    1. Pan K., Chen H., Davidson P. M., Zhong Q. (2014). Thymol nanoencapsulated by sodium caseinate: physical and antilisterial properties. J. Agric. Food Chem. 62 1649–1657. 10.1021/jf4055402
    1. Pandey A. K., Singh P., Tripathi N. N. (2014). Chemistry and bioactivities of essential oils of some Ocimum species: an overview. Asian Pac. J. Trop. Biomed. 4 682–694. 10.12980/APJTB.4.2014C77
    1. Parasei P., Bahmani M., Naghdi N., Asadi-Samani M., Rafieian-Kopaei M. (2016). A review of therapeutic and pharmacological effects of thymol. Pharm. Lett. 8 150–154.
    1. Parker D. A., Marino V., Ong J. (2014). Pharmacological actions of thymol and an analogue at GABAB autoreceptors. Clin. Exp. Pharmacol. Physiol. 41 623–627. 10.1111/1440-1681.12278
    1. Pathania A. S., Guru S. K., Verma M. K., Sharma C., Abdullah S. T., Malik F., et al. (2013). Disruption of the PI3K/AKT/mTOR signaling cascade and induction of apoptosis in HL-60 cells by an essential oil from Monarda citriodora. Food Chem. Toxicol. 62 246–254. 10.1016/j.fct.2013.08.037
    1. Pavela R. (2009). Larvicidal property of essential oils against Culex quinquefasciatus Say (Diptera: Culicidae). Ind. Crops Prod. 30 311–315. 10.1016/j.indcrop.2009.06.005
    1. Pearson D. A., Frankel E. N., Aeschbach R., German J. B. (1997). Inhibition of endothelial cell- mediated oxidation of low-density lipoprotein by rosemary and plant phenolics. J. Agric. Food Chem. 45 578–582. 10.1021/jf9603893
    1. Peixoto-Neves D., Silva-Alves K. S., Gomes M. D., Lima F. C., Lahlou S., Magalhaes P. J., et al. (2010). Vasorelaxant effects of the monoterpenic phenol isomers, carvacrol and thymol, on rat isolated aorta. Fund. Clin. Pharmacol. 24 341–350. 10.1111/j.1472-8206.2009.00768.x
    1. Pemmaraju S. C., Pruthi P. A., Prasad R., Pruthi V. (2013). Candida albicans biofilm inhibition by synergistic action of terpenes and fluconazole. Indian J. Exp. Biol. 51 1032–1037.
    1. Perez-Roses R., Risco E., Vila R., Penalver P., Canigueral S. (2016). Biological and non- biological antioxidant activity of some essential oils. J. Agric. Food Chem. 64 4716–4724. 10.1021/acs.jafc.6b00986
    1. Platel K., Srinivasan K. (2004). Digestive stimulant action of spices: a myth or reality? Indian J. Med. Res. 2004 167–179.
    1. Poulose A. J., Croteau R. (1978). Biosynthesis of aromatic monoterpenes: conversion of γ- terpinene to p- cymene and thymol in Thymus vulgaris L. Arch. Biochem. Biophys. 187 307–314. 10.1016/0003-9861(78)90039-5
    1. Priestley C. M., Williamson E. M., Wafford K. A., Sattelle D. B. (2003). Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABA(A) receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster. Br. J. Pharmacol. 140 1363–1372. 10.1038/sj.bjp.0705542
    1. Raddatz D., Bockemuhl M., Ramadori G. (2005). Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome. Eur. J. Gastroenterol. Hepatol. 17 547–557. 10.1097/00042737-200505000-00012
    1. Rahmani A. H., Al Zohairy M. A., Aly S. M., Khan M. A. (2014). Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Biomed. Res. Int. 2014:761608 10.1155/2014/761608
    1. Raoof A. A., van Obbergh L. J., de Ville de Goyet J., Veerbeeck R. K. (1996). Extrahepatic glucuronidation of propofol in man: possible contribution of gut wall and kidney. Eur. J. Clin. Pharmacol. 50 91–96. 10.1007/s002280050074
    1. Raskovic A., Pavlovic N., Kvrgic M., Sudji J., Mitic G., Capo I., et al. (2015). Effects of pharmaceutical formulations containing thyme on carbon tetrachloride-induced liver injury in rats. BMC Complement. Altern. Med. 15:442 10.1186/s12906-015-0966-z
    1. Rassu G., Nieddu M., Bosi P., Trevisi P., Colombo M., Priori D., et al. (2014). Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications. Phytomedicine 21 1627–1632. 10.1016/j.phymed.2014.07.017
    1. Reema M. A. (2011). Cytotoxic, cytogenetics and immunomodulatory effects of thymol from Thymus vulgaris on cancer and normal cell lines in vitro and in vivo. Al-Mustansiriyah J. Sci. 22 41–53.
    1. Ribeiro A. R., Diniz P. B., Pinheiro M. S., Albuquerque-Junior R. L., Thomazzi S. M. (2016). Gastroprotective effects of thymol on acute and chronic ulcers in rats: the role of prostaglandins, ATP- sensitive K+ channels, and gastric mucus secretion. Chem. Biol. Interact. 244 121–128. 10.1016/j.cbi.2015.12.004
    1. Riella K. R., Marinho R. R., Santos J. S., Pereira-Filho R. N., Cardoso J. C., Albuquerque-Junior R. L., et al. (2012). Anti-inflammatory and cicatrizing activities of thymol, a monoterpene of the essential oil from Lippia gracilis, in rodents. J. Ethnopharmacol. 143 656–663. 10.1016/j.jep.2012.07.028
    1. Rivas L., McDonnell M. J., Burgess C. M., O’Brien M., Navarro-Villa A., Fanning S., et al. (2010). Inhibition of verocytotoxigenic Escherichia coli in model broth and rumen systems by carvacrol and thymol. Int. J. Food Microbiol. 139 70–78. 10.1016/j.ijfoodmicro.2010.01.029
    1. Robbins B. H. (1934). Quantitative studies on the absorption and excretion of certain resorcinols and cresols in dogs and man. J. Pharmacol. Exp. Therapeut. 52 54–60.
    1. Robledo S., Osorio E., Munoz D., Jaramillo L. M., Restrepo A., Arango G., et al. (2005). In vitro and in vivo cytotoxicities and antileishmanial activities of thymol and hemisynthetic derivatives. Antimicrob. Agents Chemother. 49 1652–1655. 10.1128/AAC.49.4.1652-1655.2005
    1. Rogerio A. P., Dora C. L., Andrade E. L., Chaves J. S., Silva L. F., Lemos-Senna E., et al. (2010). Anti- inflammatory effect of quercetin-loaded microemulsion in the airways allergic inflammatory model in mice. Pharmacol. Res. 61 288–297. 10.1016/j.phrs.2009.10.005
    1. Rogler G., Andus T. (1998). Cytokines in inflammatory bowel disease. World J. Surg. 22 382–389. 10.1007/s002689900401
    1. Roost M., Ghaedi M., Daneshfar A., Sahraei R. (2015). Ultrasound assisted microextraction- nano material solid phase dispersion for extraction and determination of thymol and carvacrolin pharmaceutical samples: experimental design methodology. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 975 34–39. 10.1016/j.jchromb.2014.10.035
    1. Rota M. C., Herrera A., Martinez R. M., Sotomayor J. A., Jordàn M. J. (2008). Antimicrobial activity and chemical composition of Thymus vulgaris, Thymus zygis and Thymus hyemalis essential oils. Food Control 19 681–687. 10.1016/j.foodcont.2007.07.007
    1. Rustaiyan A., Masoudi S., Monfared A., Kamalinejad M., Lajevardi T., Sedaghat S., et al. (2000). Volatile constituents of three Thymus species grown wild in Iran. Planta Med. 66 197–198. 10.1055/s-0029-1243136
    1. Sammi S. R., Trivedi S., Rath S. K., Nagar A., Tandon S., Kalra A., et al. (2016). 1-Methyl-4- propan-2-ylbenzene from Thymus vulgaris attenuates cholinergic dysfunction. Mol. Neurobiol. 10.1007/s12035-016-0083-0 [Epub ahead of print].
    1. Sancheti J., Shaikh M. F., Chaudhari R., Somani G., Patil S., Jain P., et al. (2014). Characterization of anticonvulsant and antiepileptogenic potential of thymol in various experimental models. Naunyn-Schmiedebergs Arch. Pharmacol. 387 59–66. 10.1007/s00210-013-0917-5
    1. Sanchez M. E., Turina A. V., Garcia D. A., Nolan M. V., Perillo M. A. (2004). Surface activity of thymol: implications for an eventual pharmacological activity. Colloids Surf. B Biointerfaces 34 77–86. 10.1016/j.colsurfb.2003.11.007
    1. Sanchez-Castillo C. P., Velasquez-Monroy O., Lara-Esqueda A., Berber A., Sepulveda J., Tapia-Conyer R., et al. (2005). Diabetes and hypertension increases in a society with abdominal obesity: results of the Mexican National Health Survey. Public Health Nutr. 8 53–60. 10.1079/PHN2005659
    1. Saravanan S., Pari L. (2015). Role of thymol on hyperglycaemia and hyperlipidemia in high fat diet-induced type 2 diabetic C57BL/6J mice. Eur. J. Pharmacol. 761 279–287. 10.1016/j.ejphar.2015.05.034
    1. Saravanan S., Pari L. (2016). Protective effect of thymol on high fat diet induced diabetic nephropathy in C57BL/6J mice. Chem. Biol. Interact. 245 1–11. 10.1016/j.cbi.2015.11.033
    1. Sarkozi S., Almassy J., Lukacs B., Dobrosi N., Nagy G., Jona I. (2007). Effect of natural phenol derivatives on skeletal type sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. J. Muscle Res. Cell Motil. 28 167–174. 10.1007/s10974-007-9113-x
    1. Sasaki K., Wada K., Tanaka Y., Yoshimura T., Matuoka K., Anno T. (2005). Thyme (Thymus vulgaris L.) leaves and its constituents increase the activities of xenobiotic- metabolizing enzymes in mouse liver. J. Med. Food. 8 184–189. 10.1089/jmf.2005.8.184
    1. Satooka H., Kubo I. (2012). Effects of thymol on B16-F10 melanoma cells. J. Agric. Food Chem. 60 2746–2752. 10.1021/jf204525b
    1. Schroder V., Vollmer H. (1932). The excretion of thymol, carvacrol, eugenol and guiacoland the distribution of these substances in the organism. Arch. Exp. Pathol. Pharmak. 168 331–353.
    1. Sedova L., Berube J., Gaudet D., Dumont M., Tremblay J., Hamet P., et al. (2004). Diet- induced obesity delays cardiovascular recovery from stress in spontaneously hypertensive rats. Obes. Res. 12 1951–1958. 10.1038/oby.2004.245
    1. Seeman P., Chen S. S., Chau-Wong M., Staiman A. (1974). Calcium reversal of nerve blockade by alcohols, anesthetics, tranquilizers, and barbiturates. Can. J. Physiol. Pharmacol. 52 526–534. 10.1139/y74-070
    1. Shapiro S., Guggenheim B. (1995). The action of thymol on oral bacteria. Oral Microbiol. Immunol. 10 241–246. 10.1111/j.1399-302X.1995.tb00149.x
    1. Shapiro S., Meier A., Guggenheim B. (1994). The antimicrobiol activity of essential oils and essential oil components toward oral bacteria. Oral Microbiol. Immunol. 9 202–208. 10.1111/j.1399-302X.1994.tb00059.x
    1. Shen A. Y., Huang M. H., Liao L. F., Wang T. S. (2005). Thymol analogues with antioxidant and L-type calcium current inhibitory activity. Drug Dev. Res. 64 195–202. 10.1002/ddr.10436
    1. Shettigar N. B., Das S., Rao N. B., Rao S. B. (2015). Thymol, a monoterpene phenolic derivative of cymene, abrogates mercury-induced oxidative stress resultant cytotoxicity and genotoxicity in hepatocarcinoma cells. Environ. Toxicol. 30 968–980. 10.1002/tox.21971
    1. Shipkova M., Strassburg C. P., Braun F., Streit F., Grone H. J., Armstrong V. W., et al. (2001). Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes. Brit. J. Clin. Pharmacol. 132 1027–1034. 10.1038/sj.bjp.0703898
    1. Singh M. (1980). Amylase release from dissociated mouse pancreatic acinar cells stimulated by glucagon: effect of membrane stabilizers. J. Physiol. 309 81–91. 10.1113/jphysiol.1980.sp013495
    1. Skold K., Twetman S., Hallgren A., Yucel-Lindberg T., Modeer T. (1998). Effect of a chlorhexidine/thymol- containing varnish on prostaglandin E2 levels in gingival crevicular fluid. Eur. J. Oral Sci. 106 571–575. 10.1046/j.0909-8836.1998.eos106106.x
    1. Slamenova D., Horvathova E., Sramkova M., Marsalkova L. (2007). DNA-protective effects of two components of essential plant oils carvacrol and thymol on mammalian cells cultured in vitro. Neoplasma 54 108–112.
    1. Sofowora A., Ogunbodede E., Onayade A. (2013). The role and place of medicinal plants in the strategies for disease prevention. Afr. J. Tradit. Complement. Altern. Med. 10 210–229.
    1. Soliman K. M., Badeaa R. I. (2002). Effect of oil extracted from some medicinal plants on different mycotoxigenic fungi. Food Chem. Toxicol. 40 1669–1675. 10.1016/S0278-6915(02)00120-5
    1. Soran M. L., Lung I. (2010). HPTLC analysis of thymol in extracts of Satureja hortensis L. obtained by different techniques. J. Plan. Chromatogr. 23 320–322. 10.1556/JPC.23.2010.5.2
    1. Stammati A., Bonsi P., Zucco F., Moezelaar R., Alakomi H. L., von Wright A. (1999). Toxicity of selected plant volatiles in microbial and mammalian short-term assays. Food Chem. Toxicol. 37 813–823. 10.1016/S0278-6915(99)00075-7
    1. Stunkard A. J., Allison K. C. (2003a). Binge eating disorder: disorder or marker. Int. J. Eat. Disord. 34 S107–S116.
    1. Stunkard A. J., Allison K. C. (2003b). Two forms of disordered eating inobesity: binge eating and night eating. Int. J. Obes. Relat. Metab. Disord. 27 1–12.
    1. Stunkard A. J., Faith M. S., Allison K. C. (2003). Depression and obesity. Biol. Psychiatry 54 330–335. 10.1016/S0006-3223(03)00608-5
    1. Surendra Kumar M., Reddy R., Manasa G., Vanaja P., Sirisha G., Astalakshmi N. (2011). Antifertility effect of Trachyspermum ammi (Linn) sprague fruits on male rats. Int. J. Pharm. Biol. Arch. 2 705–709.
    1. Suzuki Y., Furuta H. (1988). Stimulation of guinea pig neutrophil superoxide anion-producing system with thymol. Inflammation 12 575–584. 10.1007/BF00914319
    1. Suzuki Y., Nakamura S., Sugiyama K., Furuta H. (1987). Differences of Superoxide production in blood leukocytes stimulated with thymol between human and non-human primates. Life Sci. 41 1659–1664. 10.1016/0024-3205(87)90735-1
    1. Szentandrassy N., Szentesi P., Magyar J., Nanasi P. P., Csernoch L. (2003). Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle. BMC Pharmacol. 3:9 10.1186/1471-2210-3-9
    1. Szentandrassy N., Szigeti G., Szegedi C., Sarkozi S., Magyar J., Banyasz T., et al. (2004). Effect of thymol on calcium handling in mammalian ventricular myocardium. Life Sci. 74 909–921. 10.1016/j.lfs.2003.09.034
    1. Szentesi P., Szappanos H., Szegedi C., Gonczi M., Jona I., Cseri J., et al. (2004). Altered elementary calcium release events and enhanced calcium release by thymol in rat skeletal muscle. Biophys. J. 86 1436–1453. 10.1016/S0006-3495(04)74213-7
    1. Takada M., Agata I., Sakamoto M., Yagi N., Hayashi N. (1979). On the metabolic detoxication to thymol in rabbit and man. J. Toxicol. Sci. 4 341–350. 10.2131/jts.4.341
    1. Takishima K., Setaka M., Shimizu H. (1979). On the overshoot of calcium accumulation in fragmented sarcoplasmic reticulum induced by thymol. J. Biochem. 86 347–353. 10.1093/oxfordjournals.jbchem.a132532
    1. Tamura T., Iwamoto H. (2004). Thymol: a classical small-molecule compound that has a dual effect (potentiating and inhibitory) on myosin. Biochem. Biophys. Res. Commun. 318 786–791. 10.1016/j.bbrc.2004.04.085
    1. Taranu I., Marin D. E., Untea A., Janczyk P., Motiu M., Criste R. D., et al. (2012). Effect of dietary natural supplements on immune response and mineral bioavailability in piglets after weaning. Czech. J. Anim. Sci. 57 332–343.
    1. Torres de Pinedo A., Penalver P., Morales J. C. (2007). Synthesis and evaluation of new phenolic-based antioxidants: structure-activity relationship. Food Chem. 103 55–61. 10.1016/j.foodchem.2006.07.026
    1. Trevisi P., Merialdi G., Mazzoni M., Casini L., Tittarelli C., De Filippi S., et al. (2010). Effect of dietary addition of thymol on growth, salivary and gastric function immune response, and excretion of Salmonella enteric serovar Typhimurium, in weaning pigs challenged with this microbe strain. Ital. J. Anim. Sci. 6 374–376. 10.4081/ijas.2007.1s.374
    1. Trombetta D., Castelli F., Sarpietro M. G., Venuti V., Cristani M., Daniele C., et al. (2005). Mechanisms of antibacterial action of three monoterpenes. Antimicrob. Agents Chemother. 49 2474–2478. 10.1128/AAC.49.6.2474-2478.2005
    1. Tsai M. L., Lin C., Lin W. C., Yang C. H. (2011). Antimicrobial, antioxidant and anti- inflammatory activities of essential oils from five selected herbs. Biosci. Biotechnol. Biochem. 75 1977–1983. 10.1271/bbb.110377
    1. Turrin N. P., Rivest S. (2004). Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol. Dis. 16 321–324. 10.1016/j.nbd.2004.03.010
    1. Twetman S., Hallgren A., Petersson L. G. (1995). Effect of antibacterial varnish on mutant streptococci in plaque form enamel adjacent to orthodontic appliances. Caries Res. 29 188–191. 10.1159/000262067
    1. Umar S., Asif M., Sajad M., Ansari M., Hussain U., Ahmad W., et al. (2012). Anti- inflammatory and antioxidant activity of Trachyspermum ammi seeds in collagen induced arthritis in rats. Int. J. Drug Dev. Res. 4 210–219.
    1. Undeger U., Basaran A., Degen G. H., Basaran N. (2009). Antioxidant activities of major thyme ingredients and lack of (oxidative) DNA damage in V79 Chinese hamster lung fibroblast cells at low levels of carvacrol and thymol. Food Chem. Toxicol. 47 2037–2043. 10.1016/j.fct.2009.05.020
    1. Van den Broucke C. O., Lemli J. A. (1980). Antispasmodic activity of Origanum compactum. Planta Med. 38 317–331. 10.1055/s-2008-1074884
    1. Van den Broucke C. O., Lemli J. A. (1982). Antispasmodic activity of Origanum compactum. Part 2: antagonistic effect of thymol and carvacrol. Planta Med. 45 188–190. 10.1055/s-2007-971371
    1. Van den Hoven R., Zappe H., Zitterl-Eglseer K., Jugl M., Franz C. (2003). Study of the effect of Bronchipret on the lung function of five Austrian saddle horses suffering recurrent airway obstruction (heaves). Vet. Rec. 152 555–557. 10.1136/vr.152.18.555
    1. Vardar-Unlu G. V., Candan F., Sokmen A., Daferera D., Pollissiou M., Sokmen M., et al. (2003). Antimicrobial and antioxidant activity of the essential oil and methanol extracts of Thymus pectinatus Fisch. et Mey. Var. pectinatus (Lamiaceae). J. Agric. Food Chem. 51 63–67. 10.1021/jf025753e
    1. Venu S., Naik D. B., Sarkar S. K., Usha K., Aravind U. K., Nijamudheen A., et al. (2013). Oxidation reactions of thymol: a pulse radiolysis and theoretical study. J. Phys. Chem. A 117 291–299. 10.1021/jp3082358
    1. Veras H. N., Araruna M. K., Costa J. G., Coutinho H. D., Kerntopf M. R., Botelho M. A., et al. (2013). Topical antiinflammatory activity of essential oil of Lippia sidoides Cham: possible mechanism of action. Phytother. Res. 27 179–185. 10.1002/ptr.4695
    1. Viana G. S. B., Matos F. F., Araujo W. L., Matos F. J. A., Craveiro A. A. (1981). Essential oil of Lippia grata: pharmacological effects and main constituents. Quart. J. Crude Drug Res. 19 1–10. 10.3109/13880208109065203
    1. Vigo E., Cepeda A., Gualillo O., Perez-Fernandez R. (2004). In-vitro anti-inflammatory effect of Eucalyptus globulus and Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophages. J. Pharm. Pharmacol. 56 257–263. 10.1211/0022357022665
    1. Vila R. (2002). “Flavonoids and further polyphenols in the genus Thymus,” in Thyme: The Genus Thymus. Medicinal and Aromatic Plants-Industrial Profiles eds Stahl-Biskup E., Saez F. (New York, NY: Taylor and Francis; ) 75.
    1. Wade A., Reynolds J. E. F. (1997). Martindale-the Extra Pharmacopoeia. London: The Pharmaceutical Press; 536–537.
    1. Wechsler J. B., Hsu C. L., Bryce P. J. (2014). IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation. J. Allergy Clin. Immunol. 133 1735–1743. 10.1016/j.jaci.2013.12.024
    1. Wei H. K., Xue H. X., Zhou Z. X., Peng J. (2016). A carvacrol-thymol blend decreased intestinal oxidative stress and influenced selected microbes without changing the messenger RNA levels of tight junction proteins in jejunal mucosa of weaning piglets. Animal 15 1–9. 10.1017/S1751731116001397
    1. Williams R. T. (1959). Detoxication Mechanisms 2nd Edn. London: Chapman and Hall; 300–301.
    1. Wirtz S., Neurath M. F. (2000). Animal models of intestinal inflammation: new insights into the molecular pathogenesis and immunotherapy of inflammatory bowel disease. Int. J. Colorectal. Dis. 15 144–160. 10.1007/s003840000227
    1. Wojdylo A., Oszmianski J., Czemerys R. (2007). Antioxidant activity and phenolic compounds in 32 selected herbs. Food Chem. 105 940–949. 10.1016/j.foodchem.2007.04.038
    1. Xu J., Zhou F., Ji B. P., Pei R. S., Xu N. (2008). The antibacterial mechanism of carvacrol and thymol against Escherichia coli. Lett. Appl. Microbiol. 47 174–179. 10.1111/j.1472-765X.2008.02407.x
    1. Xu Z. H., Wang C., Fujita T., Jiang C. Y., Kumamoto E. (2015). Action of thymol on spontaneous excitatory transmission in adult rat spinal substantia gelatinosa neurons. Neurosci. Lett. 606 94–99. 10.1016/j.neulet.2015.08.042
    1. Yanishlieva N. V., Marinovaa E. M., Gordon M. H., Raneva V. G. (1999). Antioxidant activity and mechanism of action of thymol and carvacrol in two lipid systems. Food Chem. 64 59–66. 10.1016/S0308-8146(98)00086-7
    1. Yin Q. H., Zhuang Y. Z., Yan X. F. (2010). Antitumor efficacy of thymol. Prog. Mod. Biomed. 10 2073–2075.
    1. Youdim K. A., Deans S. G. (1999). Beneficial effects of thyme oil on age-related changes in the phospholipid C20 and C22 polyunsaturated fatty acid composition of various rat tissues. Biochim. Biophys. Acta 1438 140–146. 10.1016/S1388-1981(99)00045-1
    1. Youdim K. A., Deans S. G. (2000). Effect of thyme oil and thymol dietary supplementation on the antioxidant status and fatty acid composition of the ageing rat brain. Br. J. Nutr. 83 87–93.
    1. Yousefzadi M., Riahi-Madvar A., Hadian J., Rezaee F., Rafiee R. (2012). In vitro cytotoxic and antimicrobial activity of essential oil from Satureja sahendica. Toxicol. Environ. Chem. 94 1735–1745. 10.5812/ircmj.4989
    1. Yu Y. M., Chao T. Y., Chang W. C., Chang M. J., Lee M. F. (2016). Thymol reduces oxidative stress, aortic intimal thickening, and inflammation-related gene expression in hyperlipidemic rabbits. J. Food Drug Anal. 24 556–563. 10.1016/j.jfda.2016.02.004
    1. Yucel-Lindberg T., Twetman S., Skold-Larsson K., Modeer T. (1999). Effect of an antibacterial dental varnish on the levels of prostanoids, leukotriene B4 and interleukin-1 beta in gingival crevicular fluid. Acta Odontol. Scand. 57 23–27. 10.1080/000163599429066
    1. Zahin M., Ahmad I., Aqil F. (2010). Antioxidant and antimutagenic activity of Carum copticum fruit extracts. Toxicol. In Vitro. 24 1243–1249. 10.1016/j.tiv.2010.02.004
    1. Zamani Z., Alipour D., Moghimi H. R., Mortazavi S. A., Saffary M. (2015). Development and evaluation of thymol microparticles using cellulose derivatives as controlled release dosage form. Iran J. Pharm. Res. 14 1031–1040.
    1. Zarzuelo A., Crespo E. (2002). “The medicinal and non-medicinal uses of thyme,” in Thyme: The Genus Thymus. Medicinal and Aromatic Plants—Industrial Profiles eds Stahl- Biskup E., Saez F. (New York, NY: Taylor & Francis; ) 263–292.
    1. Zee O. P., Jung Y. H., Lee K. R., Moon H. I., Baek H. G., Lee M. J., et al. (2001). Thymol derivatives Having Anti Tumor Activity, and Anti-Cancer Agent Comprising the same. U. S. 6255517. Washington, DC: Patent and Trademark Office.
    1. Zhang Y., Niu Y., Luo Y., Ge M., Yang T., Yu L. L., et al. (2014). Fabrication, characterization and antimicrobial activities of thymol-loaded zein nanoparticles stabilized by sodium caseinate–chitosan hydrochloride double layers. Food Chem. 142 269–275. 10.1016/j.foodchem.2013.07.058
    1. Zheng Z. L., Tan J. Y. W., Liu H. Y., Zhou X. H., Xiang X., Wang K. Y. (2009). Evaluation of oregano essential oil (Origanum heracleoticum L.) on growth, antioxidant effect and resistance against Aeromonas hydrophila in channel catfish (Ictalurus punctatus). Aquaculture 292 214–218. 10.1016/j.aquaculture.2009.04.025
    1. Zhou E., Fu Y., Wei Z., Yu Y., Zhang X., Yang Z. (2014). Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma. Fitoterapia 96 131–137. 10.1016/j.fitote.2014.04.016
    1. Zidan D. E., Kahilo K. A., El-Far A., Sadek K. M. (2016). Ginger (Zingiber officinale) and thymol dietary supplementation improve the growth performance, immunity and antioxidant status in broilers. Glob. Vet. 16 530–538.

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