Pharmacological properties and molecular mechanisms of thymol: Prospects for its therapeutic potential and pharmaceutical development

Frontiers in Pharmacology

Volumn 8, Issue JUN, 2017, Pages

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

^a UNITED ARAB EMIRATES UNIVERSITY   (United Arab Emirates)

Author keywords

Animals; Antioxidant; Cancer; Drug discovery; Free radical scavenger; Natural compounds; Phytochemicals; Thymol

Indexed keywords

ACETYLSALICYLIC ACID; ARSENIC; CARVACROL; CHOLINESTERASE INHIBITOR; CHROMIUM; DIACEREIN; ESSENTIAL OIL; MERCURY; PARA CYMENE; TERPINENE; THYMOL;

ALZHEIMER DISEASE; ANTIANGIOGENIC ACTIVITY; ANTIBACTERIAL ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; ANXIETY; AREA UNDER THE CURVE; ARSENIC POISONING; ASTHMA; ATHEROSCLEROSIS; BREAST CANCER; CARDIOTOXICITY; CERVICAL CANCER CELL LINE; CHAGAS DISEASE; COLITIS; DEMENTIA; DEPRESSION; DIABETES MELLITUS; DIET SUPPLEMENTATION; DIETARY SUPPLEMENT; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DEGRADATION; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG FORMULATION; DRUG HALF LIFE; DRUG LIVER LEVEL; DRUG MECHANISM; DRUG POTENCY; DRUG RELEASE; EAR EDEMA; EC50; EPILEPSY; GENOTOXICITY; GLIOBLASTOMA; GLIOMA; HEART ARRHYTHMIA; HEART INFARCTION; HEPATOCELLULAR CARCINOMA CELL LINE; HUMAN; HYPERTENSION; IC50; LARYNX CARCINOMA; LD50; LEUKEMIA CELL; LIVER TOXICITY; MALE INFERTILITY; MASTOCYTOMA; MAXIMUM PLASMA CONCENTRATION; MEAN ABSORPTION TIME; MEAN RESIDENCE TIME; MERCURIALISM; MICROENCAPSULATION; NEPHROTOXICITY; NEUROBLASTOMA; NEUROMUSCULAR BLOCKING; NONHUMAN; OBESITY; OSTEOARTHRITIS; OSTEOSARCOMA CELL LINE; PAW EDEMA; PHYSICAL CHEMISTRY; PLEURISY; RADIATION PROTECTION; RADIATION SICKNESS; RADIOSENSITIZATION; REVIEW; RHEUMATOID ARTHRITIS; SINGLE DRUG DOSE; STOMACH CARCINOMA; TIME TO MAXIMUM PLASMA CONCENTRATION; ULCER;

EID: 85021671331     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2017.00380     Document Type: Review

References (294)

1. Abd-Elhakim, Y. M., and 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. doi: 10.1080/02772248.2015.1121490
2. Aboelwafa, H. R., and 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. doi: 10.1139/bcb-2014-0154
3. 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. doi: 10.1016/0278-6915(84)90033-4
4. Aftab, K., Atta-Ur-Rahman, and Usmanghani, K. (1995). Blood pressure lowering action of active principle from Trachyspermum ammi (L.) Sprague. Phytomedicine 2, 35-40. doi: 10.1016/S0944-7113(11)80046-2
5. Aghamohammadi, A., Hosseinimehr, S. J., Ghasemi, A., Azadbakht, M., and Pourfallah, T. A. (2015). Radiosensitization effects of a Zataria multiflora extract on human glioblastoma cells. Asian Pac. J. Cancer Prev. 16, 7285-7290. doi: 10.7314/APJCP.2015.16.16.7285
6. Ahmadifar, E., Falahatkar, B., and 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. doi: 10.1111/j.1439-0426.2011.01763.x
7. Alam, K., Nagi, M. N., Badary, O. A., Al-shabanah, O. A., Al-Rikabi, A. C., and Al-Bekairi, A. M. (1999). The protective action of thymol against carbon tetrachloride hepatotoxicity in mice. Pharmacol. Res. 40, 159-163. doi: 10.1006/phrs.1999.0472
8. Aliabadi, A., Izadi, M., and 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
9. 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. doi: 10.1080/10942912.2011.578319
10. Al-Khalaf, M. I. (2013). Thyme and thymol effects on induced bronchial asthma in mice. Life Sci. J. 10, 693-699
11. Al-Malki, A. L. (2010). Antioxidant properties of thymol and butylated hydroxytoluene in carbon tetrachloride-induced mice liver injury. JKAU 22, 239-248. doi: 10.4197/Sci.22-1.16
12. Aman, S., Moin, S., Owais, M., and 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
13. Amandi, R., Hyde, J. R., Ross, S. K., Lotz, T. J., and Poliakoff, M. (2005). Continuous reactions in supercritical fluids; a cleaner, more selective synthesis of thymol in supercritical CO2. Green Chem. 7, 288-293. doi: 10.1039/b418983c
14. Amirghofran, Z., Ahmadi, H., Karimi, M. H., Kalantar, F., Gholijani, N., and Malek-Hosseini, Z. (2016). In vitro inhibitory effects of thymol and carvacrol on dendritic cell activation and function. Pharm. Biol. 54, 125-132. doi: 10.3109/13880209.2015.1055579
15. Amirghofran, Z., Hashemzadeh, R., Javidnia, K., Golmoghaddam, H., and 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. doi: 10.3109/1547691X.2011.590828
16. Amiri, H. (2012). Essential oils composition and antioxidant properties of three Thymus species. Evid. Based Complement. Alternat. Med. 2012:728065. doi: 10.1155/2012/728065
17. 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
18. 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. doi: 10.4315/0362-028X.JFP-11-390
19. Arab, H. A., Fathi, M., Mortezai, E., and Hosseinimehr, S. J. (2015). Chemoprotective effect of thymol against genotoxicity induced by bleomycin in human lymphocytes. Pharm. Biomed. Res. 1, 26-31. doi: 10.18869/acadpub.pbr.1.1.26
20. Arai, T. (1988). Cytotoxicity of thymol on cultured mammalian cells. Shigaku 76, 24-35
21. 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. doi: 10.1007/s00436-015-4547-3
22. Archana, P. R., Nageshwar Rao, B., and Satish Rao, B. S. (2011a). In vivo radioprotective potential of thymol, a monoterpene phenol derivative of cymene. Mutat. Res. 726, 136-145. doi: 10.1016/j.mrgentox.2011.08.007
23. Archana, P. R., Nageshwar Rao, B., and 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. doi: 10.1177/1534735410387421
24. Astudillo, A., Hong, E., Bye, R., and Navarrete, A. (2014). Antispasmodic activity of extracts and compounds of Acalypha phleoides Cav. Phytother. Res. 18, 102-106. doi: 10.1002/ptr.1414
25. Austgulen, L. T., Solheim, E., and Scheline, R. R. (1987). Metabolism in rats of p-cymene derivatives: carvacrol and thymol. Pharmacol. Toxicol. 61, 98-102. doi: 10.1111/j.1600-0773.1987.tb01783.x
26. Aydin, E., Tasdemir, S., Hacimuftuoglu, F., and Turkez, H. (2016). Anticancer, antioxidant and cytotoxic potential of thymol in vitro brain tumor cell model. Cent. Nerv. Syst. Agents Med. Chem. doi: 10.2174/1871524916666160823121854 [Epub ahead of print]
27. Aydin, S., Basaran, A. A., and Basaran, 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. doi: 10.1016/j.mrgentox.2004.10.017
28. Azirak, S., and Rencuzogullari, E. (2008). The in vivo genotoxic effects of carvacrol and thymol in rat bone marrow cells. Environ. Toxicol. 23, 728-735. doi: 10.1002/tox.20380
29. Azizi, Z., Ebrahimi, S., Saadatfar, E., Kamalinejad, M., and Majlessi, N. (2012). Cognitive-enhancing activity of thymol and carvacrol in two rat models of dementia. Behav. Pharmacol. 23, 241-249. doi: 10.1097/FBP.0b013e3283534301
30. Bairwa, R., Sodha, R. S., and Rajawat, B. S. (2012). Trachyspermum ammi. Pharmacogn. Rev. 6, 56-60. doi: 10.4103/0973-7847.95871
31. Beer, A. M., Lukanov, J., and Sagorchev, P. (2007). Effect of thymol on the spontaneous contractile activity of the smooth muscles. Phytomedicine 14, 65-69. doi: 10.1016/j.phymed.2006.11.010
32. Begrow, F., Engelbertz, J., Feistel, B., Lehnfeld, R., Bauer, K., and Verspohl, E. J. (2010). Impact of thymol in thyme extracts on their antispasmodic action and ciliary clearance. Planta Med. 76, 311-318. doi: 10.1055/s-0029-1186179
33. 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. doi: 10.1590/S1807-59322005000400004
34. Bhandari, S. S., and Kabra, M. P. (2014). To evaluate anti-anxiety activity of thymol. J. Acute Dis. 3, 136-140. doi: 10.1016/S2221-6189(14)60030-5
35. Bhatia, K. S., and 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. doi: 10.1023/A:1011906022903
36. Bhutada, P., Mundhada, Y., Bansod, K., Dixit, P., Umathe, S., and Mundhada, D. (2010). Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behav. 18, 207-210. doi: 10.1016/j.yebeh.2010.03.007
37. Boudry, G., and Perrier, C. (2008). Thyme and cinnamon extracts induce anion secretion in piglet small intestine via cholinergic pathways. J. Physiol. Pharmacol. 59, 543-552
38. Braga, P. C., Dal Sasso, M., Culici, M., Bianchi, T., Bordoni, L., and Marabini, L. (2006). Anti-inflammatory activity of thymol: inhibitory effect on the release of human neutrophil elastase. Pharmacology 77, 130-136. doi: 10.1159/000093790
39. Bukovska, A., Cikos, S., Juhas, S., Ilkova, G., Rehak, P., and Koppel, J. (2007). Effects of a combination of Thyme and Oregano essential oils on TNBS-induced colitis in mice. Mediators Inflamm. 2007:23296. doi: 10.1155/2007/23296
40. Cabello, M. L. R., Praena, D. G., Puerto, M., Silvia Pichardo, S., Jos, A., and 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. doi: 10.1016/j.tiv.2015.02.006
41. Calo, R., Visone, C. M., and 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. doi: 10.1016/j.mrgentox.2015.07.009
42. Cardoso, E. S., Santana, T. A., Diniz, P. B., Montalvao, M. M., Bani, C. C., and Thomazzi, S. M. (2016). Thymol ameliorates inflammatory response and accelerates regeneration in cardiotoxin-induced muscle injury. J. Pharm. Pharmacol. 68, 352-360. doi: 10.1111/jphp.12520
43. Chambin, O., Champion, D., Debray, C., Rochat-Gonthier, M. H., Le Meste, M., and Pourcelot, Y. (2004). Effects of different cellulose derivatives on drug release mechanism studied at a preformulation stage. J. Control. Release 95, 101-108. doi: 10.1016/j.jconrel.2003.11.009
44. 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. doi: 10.4077/CJP.2014.BAB192
45. 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. doi: 10.1159/000331864
46. Chang, Y. C., Tai, K. W., Huang, F. M., and Huang, M. F. (2000). Cytotoxic and nongenotoxic effects of phenolic compounds in human pulp cell cultures. J. Endod. 26, 440-443. doi: 10.1097/00004770-200008000-00002
47. Chauhan, A. K., Jakhar, R., Paul, S., and Kang, S. C. (2014). Potentiation of macrophage activity by thymol through augmenting phagocytosis. Int. Immunopharmacol. 18, 340-346. doi: 10.1016/j.intimp.2013.11.025
48. Chauhan, A. K., and Kang, S. C. (2015). Therapeutic potential and mechanism of thymol action against ethanol induced gastric mucosal injury in rat model. Alcohol 49, 739-745. doi: 10.1016/j.alcohol.2015.08.004
49. Chauhan, P. S., Satti, N. K., Suri, K. A., Amina, M., and 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. doi: 10.1016/j.cbi.2010.02.016
50. 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. doi: 10.1016/j.rbmo.2015.06.011
51. Choi, J. H., Kim, S. W., Yu, R., and Yun, J. W. (2016). Monoterpene phenolic compound thymol promotes browning of 3T3-L1 adipocytes. Eur. J. Nutr. doi: 10.1007/s00394-016-1273-2 [Epub ahead of print]
52. Choi, Y., Arron, J. R., and Townsend, M. J. (2009). Promising bone related therapeutic targets for rheumatoid arthritis therapy. Nat. Rev. Rheumatol. 5, 543-548. doi: 10.1038/nrrheum.2009.175
53. 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. doi: 10.1017/S1751731114000172
54. 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. doi: 10.1093/humupd/dmp048
55. 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. doi: 10.1159/000444361
56. 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. doi: 10.1016/j.bmc.2014.08.020
57. Demirci, F., Paper, D. H., Franz, G., and 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. doi: 10.1021/jf034850k
58. 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. doi: 10.1016/j.bbr.2015.04.052
59. Dhaneshwar, S., Patel, V., Patil, D., and Meena, G. (2013). Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug. Bioorg. Med. Chem. Lett. 23, 55-61. doi: 10.1016/j.bmcl.2012.11.016
60. 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. doi: 10.5713/ajas.14.0704
61. Didri, N., Dubreuil, L., and Pinkas, M. (1994). Activity of thymol, carvacrol, cinnamaldehyde and eugenol on oral bacteria. Pharm. Acta Helv. 69, 25-28. doi: 10.1016/0031-6865(94)90027-2
62. Dutta, D. D., Parimala, G., Devi, S. S., and 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. doi: 10.1016/j.cbi.2011.05.009
63. Duyckaerts, C., Delatour, B., and Potier, M. C. (2009). Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 5-36. doi: 10.1007/s00401-009-0532-1
64. Ebashi, S. (1965). "The sarcoplasmic reticulum and excitation-contraction coupling". in Molecular Biology of Muscular Contraction, eds S. Ebashi, F. Oosawa, T. Sekine, and Y. Tonomula (Amsterdam: Igaku-shoin, Tokyo and Elsevier Publishing Co), 197-206
65. El-Nekeety, A. A., Mohamed, S. R., Hathout, A. S., Hassan, N. S., Aly, S. E., and Abdel-Wahhab, M. A. (2011). Antioxidant properties of Thymus vulgaris oil against aflatoxin-induce oxidative stress in male rats. Toxicon 57, 984-991. doi: 10.1016/j.toxicon.2011.03.021
66. El-Sayed, E. M., Abd-Allah, A. R., Mansour, A. M., and 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. doi: 10.1002/jbt.21681
67. El-Sayed, E. S. M., Mansour, A. M., and 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. doi: 10.1002/jbt.21740
68. Engelbertz, J., Lechtenberg, M., Studt, L., Hensel, A., and Verspohl, E. J. (2012). Bioassay-guided fractionation of a thymol-deprived hydrophilic thyme extract and its antispasmodic effect. J. Ethnopharmacol. 141, 848-853. doi: 10.1016/j.jep.2012.03.025
69. 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. doi: 10.1248/bpb.24.307
70. 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. doi: 10.1155/2012/657026
71. Farinacci, M., Colitti, M., Sqorlon, S., and Stefanon, B. (2008). Immunomodulatory activity of plant residues on ovine neutrophils. Vet. Immunol. Immunopathol. 126, 54-63. doi: 10.1016/j.vetimm.2008.06.006
72. Feldmann, M. (2002). Development of anti-TNF therapy for rheumatoid arthritis. Nat. Rev. Immunol. 2, 364-371. doi: 10.1038/nri802
73. Feldmann, M., Brennan, F. M., and Maini, R. N. (1996). Rheumatoid arthritis. Cell 85, 307-310. doi: 10.1016/S0092-8674(00)81109-5
74. Gao, S., and Singh, J. (1998). In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes. J. Control. Release 51, 193-199. doi: 10.1016/S0168-3659(97)00168-5
75. Garcia, D. A., Bujons, J., Vale, C., and Sunol, C. (2006). Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons. Neuropharmacology 50, 25-35. doi: 10.1016/j.neuropharm.2005.07.009
76. 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. doi: 10.1016/j.resp.2013.02.011
77. Gholijani, N., and 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. doi: 10.3109/1547691X.2016.1173134
78. Gholijani, N., Gharagozloo, M., Farjadian, S., and Amirghofran, Z. (2016). Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. J. Immunotoxicol. 13, 157-164. doi: 10.3109/1547691X.2015.1029145
79. Gholijani, N., Gharagozloo, M., Kalantar, F., Ramezani, A., and 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. doi: 10.15171/apb.2015.089
80. Ghosheh, O. A., Houdi, A. A., and 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. doi: 10.1016/S0731-7085(98)00300-8
81. 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. doi: 10.1016/j.aquaculture.2012.04.027
82. 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. doi: 10.1017/S0265021502000923
83. Haque, M. R., Ansari, S. H., Najmi, A. K., and Ahmad, M. A. (2014). Monoterpene phenolic compound thymol prevents high fat diet induced obesity in murine model. Toxicol. Mech. Methods 24, 116-123. doi: 10.3109/15376516.2013.861888
84. Hasegawa, R., Nakaji, Y., Kurokawa, Y., and Tobe, M. (1989). Acute toxicity tests on 113 environmental chemicals. Sci. Rep. Res. Inst. Tohoku Univ. Med. 36, 10-16
85. Hashemipour, H., Kermanshahi, H., Golian, A., and 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. doi: 10.3382/ps.2012-02685
86. He, L., Mo, H., Hadisusilo, S., Qureshi, A. A., and Elson, C. E. (1997). Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J. Nutr. 127, 668-674
87. Hejazian, S. H. (2006). Analgesic Effect of essential oil (EO) from Carum copticum in mice. World J. Med. Sci. 1, 95-99
88. Hejazian, S. H., Bagheri, S. M., and 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. doi: 10.4103/1947-2714.147982
89. Hernandez, F., Madrid, J., Garcia, V., Orengo, J., and Megias, M. D. (2004). Influence of two plant extracts on broiler performance, digestibility, and digestive organ size. Poult. Sci. 83, 169-174. doi: 10.1093/ps/83.2.169
90. Hirobe, C., Qiao, Z. S., Takeya, K., and Itokawa, H. (1998). Cytotoxic principles from Majorana syriaca. Nat. Med. 52, 74-77
91. Hisayama, T., and 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. doi: 10.1254/jjp.40.69
92. Holmberg, K., and Hansen, B. (1979). Ester synthesis with dicyclohexylcarbodiimide improved by acid catalysts. Acta Chem. Scand. B 33, 410-412. doi: 10.3891/acta.chem.scand.33b-0410
93. 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. doi: 10.1021/jf501006y
94. Horvathova, E., Turcaniova, V., and 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
95. 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. doi: 10.3109/0886022X.2014.991998
96. Hsu, S. S., Lin, K. L., Chou, C. T., Chiang, A. J., Liang, W. Z., and Chang, H. T. (2011). Effect of thymol on Ca2+ homeostasis and viability in human glioblastoma cells. Eur. J. Pharmacol. 670, 85-91. doi: 10.1016/j.ejphar.2011.08.017
97. Hyun, T. K., Kim, H. C., and Kim, J. S. (2014). Antioxidant and antidiabetic activity of Thymus quinquecostatus Celak. Ind. Crops Prod. 52, 611-616. doi: 10.1016/j.indcrop.2013.11.039
98. 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
99. Ito, Y., and Kuriyama, H. (1974). Effects of thymol on the electrical and mechanical properties of the guinea-pig taenia coli. J. Physiol. 236, 143-157. doi: 10.1113/jphysiol.1974.sp010427
100. 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. doi: 10.1590/s0102-695x2012005000021
101. Janbaz, K. H., Saeed, S. A., and Gilani, A. H. (2003). Hepatoprotective effect of thymol on chemical-induced hepatotoxicity in rodents. Pak. J. Biol. Sci. 2003, 448-451
102. Jang, I. S., Ko, Y. H., Kang, S. Y., and 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. doi: 10.1016/j.anifeedsci.2006.06.009
103. 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. doi: 10.1016/S0015-6264(64)80192-9
104. Jeusette, I. C., Lhoest, E. T., Istasse, L. P., and Diez, M. O. (2005). Influence of obesity on plasma lipid and lipoprotein concentrations in dogs. Am. J. Vet. Res. 66, 81-86. doi: 10.2460/ajvr.2005.66.81
105. Jimenez, J., Navarro, M. C., Montilla, M. P., and Martin, A. (1993). Thymus zygis oil: Its effects on CCl4 induced hepatotoxicity and free radical scavenger activity. J. Essent. Oil Res. 5, 153-158
106. Jordan, W., Van Barneveld, H., Gerlich, O., Kleine-Boymann, M., and Ullrich, J. (1991). "Phenol". in Ullmanns Encyclopedia of Industrial Chemistry, 5th Edn, Vol. A 19, eds B. Elvers, S. Hawkins, and G. Schulz (Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA), 299-312
107. Juan, R. A., Olga, P. A., and 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
108. Jukic, M., Politeo, O., Maksimovic, M., and Milos, M. (2007). In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone. Phytother Res. 21, 259-261. doi: 10.1002/ptr.2063
109. Kabouche, A., Ghannadi, A., and Kabouche, Z. (2009). Thymus ciliates-the highest thymol containing essential oil of the genus. Nat. Prod. Commun. 4, 1251-1252
110. Kamataki, T., Sugita, O., Naminohira, S., and 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. doi: 10.1254/jjp.28.837
111. 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. doi: 10.4014/jmb.1506.06073
112. Karpanen, T. J., Worthington, T., Hendry, E. R., Conway, B. R., and 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. doi: 10.1093/jac/dkn325
113. Kavoosi, G., Dadfar, S. M. M., and 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. doi: 10.1111/1750-3841.12015
114. Kavoosi, G., and 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. doi: 10.1016/j.fct.2012.06.002
115. Kavoosi, G., Teixeira da Silva, J. A., and 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. doi: 10.1111/j.2042-7158.2012.01510.x
116. Kawasaki, H., Mizuta, K., Fujita, T., and Kumamoto, E. (2013). Inhibition by menthol and its related chemicals of compound action potentials in frog sciatic nerves. Life Sci. 92, 359-367. doi: 10.1016/j.lfs.2013.01.012
117. 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. doi: 10.1515/znc-2016-0005
118. Khajeali, Y., Kheiri, F., Rahimian, Y., Faghani, M., and 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
119. Khajeh, M., Yamini, Y., Sefidkon, F., and 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. doi: 10.1016/j.foodchem.2003.09.041
120. 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. doi: 10.1186/s13568-017-0344-y
121. Khosravi, A. R., and Erle, D. J. (2016). Chitin-induced airway epithelial cell innate immune responses are inhibited by carvacrol/thymol. PLoS ONE 11:e0159459. doi: 10.1371/journal.pone.0159459
122. 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. doi: 10.1007/s11418-013-0786-8
123. Kishwar, F., Mahmood, I., Mahmood, T., and 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
124. 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. doi: 10.1177/009127002401102678
125. Kostyuk, P. G., Belan, P. V., and Tepikin, A. V. (1991). Free calcium transients and oscillations in nerve cells. Exp. Brain Res. 83, 459-464. doi: 10.1007/BF00231173
126. Kruk, I., Michalska, T., Lichszteld, K., Koadna, A., and Aboul-Enein, H. Y. (2000). The effect of thymol and its derivatives on reactions generating reactive oxygen species. Chemosphere 41, 1059-1064. doi: 10.1016/S0045-6535(99)00454-3
127. Ku, C. M., and 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. doi: 10.1016/j.foodchem.2013.04.044
128. Kundu, S., Shabir, H., Basir, S. F., and 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
129. Lazar, M. A. (2005). How obesity causes diabetes: not a tall tale. Science 307, 373-375. doi: 10.1126/science.1104342
130. 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. doi: 10.1007/s10068-015-0093-0
131. Lee, K. P., Kim, J. E., Park, W. H., and Hong, H. (2016). Regulation of C6 glioma cell migration by thymol. Oncol. Lett. 11, 2619-2624. doi: 10.3892/ol.2016.4237
132. 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. doi: 10.1038/bjp.2008.85
133. Li, S., Ru, Y., Liu, M., Xu, B., Peron, A., and Shi, X. (2012). The effect of essential oils on performance, immunity and gut microbial population in weaner pigs. Livest. Sci. 145, 119-123. doi: 10.1016/j.livsci.2012.01.005
134. 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. doi: 10.1007/s10753-013-9732-x
135. 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. doi: 10.3390/12081606
136. Lide, D. R., and Frederikse, H. P. R. (1996). CRC Handbook of Chemistry and Physics. Boca Raton, NY: CRC Press, 3-258
137. Lorente, I., Ocete, M. A., Zarzuelo, A., Cabo, M. M., and Jimenez, J. (1989). Bioactivity of the essential oil of Bupleurum fruticosum. J. Nat. Prod. 52, 267-272. doi: 10.1021/np50062a008
138. Magyar, J., Szentandrassy, N., Banyasz, T., Fulop, L., Varro, A., and Nanasi, P. P. (2002). Effects of thymol on calcium and potassium currents in canine and human ventricular cardiomyocytes. Br. J. Pharmacol. 136, 330-338. doi: 10.1038/sj.bjp.0704718
139. Magyar, J., Szentandrassy, N., Banyasz, T., Fulop, L., Varro, A., and Nanasi, P. P. (2004). Effects of terpenoid phenol derivatives on calcium current in canine and human ventricular cardiomyocytes. Eur. J. Pharmacol. 487, 29-36. doi: 10.1016/j.ejphar.2004.01.011
140. Mahmoud, A. L. (1994). Antifungal action and antiaflatoxigenic properties of some essential oil constituents. Lett. Appl. Microbiol. 19, 110-113. doi: 10.1111/j.1472-765X.1994.tb00918.x
141. 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. doi: 10.1016/j.mrgentox.2015.05.005
142. Manabe, A., Nakayama, S., and Sakamoto, K. (1987). Effects of essential oils on erythrocytes and hepatocytes from rats and dipalmitoyl phosphatidylcholine-liposomes. Jpn. J. Pharmacol. 44, 77-84. doi: 10.1254/jjp.44.77
143. Manou, I., Bouillard, L., Devleeschouwer, M. J., and 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. doi: 10.1046/j.1365-2672.1998.00353.x
144. Marchese, A., Orhan, I. E., Daglia, M., Barbieri, R., Di Lorenzo, A., and Nabavi, S. F. (2016). Antibacterial and antifungal activities of thymol: A brief review of the literature. Food Chem. 210, 402-414. doi: 10.1016/j.foodchem.2016.04.111
145. Marin, L. D., Sanchez-Borzone, M., and 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. doi: 10.2174/157340611796150969
146. Marino, M., Bersani, C., and Comi, G. (1999). Antimicrobial activity of the essential oils of Thymus vulgaris L. measured using a bioimpedometric method. J. Food Prot. 62, 1017-1023. doi: 10.4315/0362-028X-62.9.1017
147. 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. doi: 10.2298/ABS1102457M
148. Marsik, P., Kokoska, L., Landa, P., Nepovim, A., Soudek, P., and 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. doi: 10.1055/s-2005-871288
149. Martins, I. M., Barreiro, M. F., Coelho, M., and Rodrigues, A. E. (2014). Microencapsulation ofessential oils with biodegradable polymeric carriers for cosmetic applications. Chem. Eng. J. 245, 191-200. doi: 10.1016/j.cej.2014.02.024
150. 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. doi: 10.1111/j.1600-051X.1992.tb01143.x
151. 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. doi: 10.1021/jf073272v
152. Mathela, C. S., Singh, K. K., and Gupta, V. K. (2010). Synthesis and in vitro antibacterial activity of thymol and carvacrol derivatives. Acta Pol. Pharm. 67, 375-380
153. Meister, A., Bernhardt, G., Christoffel, V., and 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. doi: 10.1055/s-1999-14006
154. 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. doi: 10.4238/2014.April.8.12
155. 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. doi: 10.1016/j.jep.2010.04.005
156. 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. doi: 10.1016/j.mrgentox.2007.01.011
157. Michiels, J., Missotten, J., Dierick, N., Fremaut, D., Maene, P., and 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. doi: 10.1002/jsfa.3358
158. 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. doi: 10.1155/2015/851721
159. Miller, A. H., and Timmie, W. P. (2009). Mechanisms of cytokine induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav. Immun. 23, 149-158. doi: 10.1016/j.bbi.2008.08.006
160. Mishra, R. K., and 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. doi: 10.1016/j.bmcl.2014.10.028
161. Mohammadi, B., Haeseler, G., Leuwer, M., Dengler, R., Krampfl, K., and Bufler, J. (2001). Structural requirements of phenol derivatives for direct activation of chloride currents via GABA(A) receptors. Eur. J. Pharmacol. 421, 85-91. doi: 10.1016/S0014-2999(01)01033-0
162. Moller, H. (1939). Effect of thymol on thyroid gland. Arch. Exp. Pathol. Pharmak. 191, 615-620
163. Monteiro, M. V., de Melo Leite, A. K., Bertini, L. M., de Morais, S. M., and 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. doi: 10.1016/j.jep.2006.11.036
164. Mottawie, H., Ibrahiem, A., and Amer, H. (2011). Role of some phytochemicals in the treatment of bronchial asthma. Med. J. Cairo Univ. 79, 75-80
165. Nagle, P. S., Pawar, Y. A., Sonawane, A. E., Nikum, A. P., and Patil, U. D. (2013). Thymol: synthesis, reactions & its spectrum of pharmacological and chemical applications. Indo. Am. J. Pharm. Res. 3, 7549-7561
166. Nagoor Meeran, M. F., Jagadeesh, G. S., and 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. doi: 10.1002/jbt.21431
167. Nagoor Meeran, M. F., Jagadeesh, G. S., and Selvaraj, P. (2015a). Catecholamine toxicity triggers myocardial membrane destabilization in rats: thymol and its counter action. RSC Adv. 5, 43338-43344. doi: 10.1016/j.ejphar.2016.02.063
168. Nagoor Meeran, M. F., Jagadeesh, G. S., and 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. doi: 10.1016/j.jff.2015.01.013
169. Nagoor Meeran, M. F., Jagadeesh, G. S., and 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. doi: 10.1016/j.ejphar.2015.02.028
170. Nagoor Meeran, M. F., Jagadeesh, G. S., and 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. doi: 10.1016/j.cbi.2016.03.017
171. Nagoor Meeran, M. F., Jagadeesh, G. S., and 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. doi: 10.1016/j.cbi.2015.12.006
172. Nagoor Meeran, M. F., and 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. doi: 10.1002/jbt.21431
173. Nayak, B. S., Ghosh, S. K., and 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
174. 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. doi: 10.1016/j.carbpol.2013.10.084
175. Norwitz, G., Nataro, N., and Keliher, P. N. (1986). Study of the steam distillation of phenolic compounds using ultraviolet spectrometry. Anal. Chem. 58, 639-641. doi: 10.1021/ac00294a034
176. O'Brien, T. J., Ceryak, S., and Patierno, S. R. (2003). Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms. Mutat. Res. 533, 3-36. doi: 10.1016/j.mrfmmm.2003.09.006
177. Ocana, A., and 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. doi: 10.1155/2012/104706
178. Ocana-Fuentes, A., Arranz-Gutierrez, E., Senorans, F. J., and 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. doi: 10.1016/j.fct.2010.03.026
179. Ogaard, B., Larsson, E., Glans, R., Henriksson, T., and 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
180. Ogata, N., Matsushima, N., and Shibata, T. (1995). Pharmacokinetics of wood creosote: glucuronic acid and sulfate conjugation of phenolic compounds. Pharmacology 51, 195-204. doi: 10.1159/000139335
181. Oguri, A., Suda, M., Totsuka, Y., Sugimura, T., and Wakabayashi, K. (1998). Inhibitory effects of antioxidants on formation of heterocyclic amines. Mutat. Res. 402, 237-245. doi: 10.1016/S0027-5107(97)00303-5
182. Olasupo, N., Fitzgerald, D., Gasson, M., and Narbad, A. (2003). Activity of natural antimicrobial compounds against Escherichia coli and Salmonella enterica sero var. typhimurium. Lett. Appl. Microbiol. 37, 448-451. doi: 10.1046/j.1472-765X.2003.01427.x
183. Ozen, T., Demirtas, I., and 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. doi: 10.1016/j.foodchem.2010.05.103
184. Ozkan, A., and 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
185. Ozkan, A., and 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
186. Ozolua, R. I., Umuso, D. I., Uwaya, D. O., Modugu, A. A., Oghuvwu, S. O., and 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
187. 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. doi: 10.1177/0960327115627688
188. Palaniappan, K., and Holley, R. A. (2010). Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria. Int. J. Food Microbiol. 140, 164-168. doi: 10.1016/j.ijfoodmicro.2010.04.001
189. Pan, K., Chen, H., Davidson, P. M., and Zhong, Q. (2014). Thymol nanoencapsulated by sodium caseinate: physical and antilisterial properties. J. Agric. Food Chem. 62, 1649-1657. doi: 10.1021/jf4055402
190. Pandey, A. K., Singh, P., and Tripathi, N. N. (2014). Chemistry and bioactivities of essential oils of some Ocimum species: an overview. Asian Pac. J. Trop. Biomed. 4, 682-694. doi: 10.12980/APJTB.4.2014C77
191. Parasei, P., Bahmani, M., Naghdi, N., Asadi-Samani, M., and Rafieian-Kopaei, M. (2016). A review of therapeutic and pharmacological effects of thymol. Pharm. Lett. 8, 150-154
192. Parker, D. A., Marino, V., and Ong, J. (2014). Pharmacological actions of thymol and an analogue at GABAB autoreceptors. Clin. Exp. Pharmacol. Physiol. 41, 623-627. doi: 10.1111/1440-1681.12278
193. 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. doi: 10.1016/j.fct.2013.08.037
194. Pavela, R. (2009). Larvicidal property of essential oils against Culex quinquefasciatus Say (Diptera: Culicidae). Ind. Crops Prod. 30, 311-315. doi: 10.1016/j.indcrop.2009.06.005
195. Pearson, D. A., Frankel, E. N., Aeschbach, R., and 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. doi: 10.1021/jf9603893
196. 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. doi: 10.1111/j.1472-8206.2009.00768.x
197. Pemmaraju, S. C., Pruthi, P. A., Prasad, R., and Pruthi, V. (2013). Candida albicans biofilm inhibition by synergistic action of terpenes and fluconazole. Indian J. Exp. Biol. 51, 1032-1037
198. Perez-Roses, R., Risco, E., Vila, R., Penalver, P., and Canigueral, S. (2016). Biological and non-biological antioxidant activity of some essential oils. J. Agric. Food Chem. 64, 4716-4724. doi: 10.1021/acs.jafc.6b00986
199. Platel, K., and Srinivasan, K. (2004). Digestive stimulant action of spices: a myth or reality? Indian J. Med. Res. 2004, 167-179
200. Poulose, A. J., and 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. doi: 10.1016/0003-9861(78)90039-5
201. Priestley, C. M., Williamson, E. M., Wafford, K. A., and 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. doi: 10.1038/sj.bjp.0705542
202. Raddatz, D., Bockemuhl, M., and 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. doi: 10.1097/00042737-200505000-00012
203. Rahmani, A. H., Al Zohairy, M. A., Aly, S. M., and Khan, M. A. (2014). Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Biomed. Res. Int. 2014:761608. doi: 10.1155/2014/761608
204. Raoof, A. A., van Obbergh, L. J., de Ville de Goyet, J., and Veerbeeck, R. K. (1996). Extrahepatic glucuronidation of propofol in man: possible contribution of gut wall and kidney. Eur. J. Clin. Pharmacol. 50, 91-96. doi: 10.1007/s002280050074
205. 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. doi: 10.1186/s12906-015-0966-z
206. 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. doi: 10.1016/j.phymed.2014.07.017
207. 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
208. Ribeiro, A. R., Diniz, P. B., Pinheiro, M. S., Albuquerque-Junior, R. L., and 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. doi: 10.1016/j.cbi.2015.12.004
209. 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. doi: 10.1016/j.jep.2012.07.028
210. 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. doi: 10.1016/j.ijfoodmicro.2010.01.029
211. 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
212. 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. doi: 10.1128/AAC.49.4.1652-1655.2005
213. 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. doi: 10.1016/j.phrs.2009.10.005
214. Rogler, G., and Andus, T. (1998). Cytokines in inflammatory bowel disease. World J. Surg. 22, 382-389. doi: 10.1007/s002689900401
215. Roost, M., Ghaedi, M., Daneshfar, A., and 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. doi: 10.1016/j.jchromb.2014.10.035
216. Rota, M. C., Herrera, A., Martinez, R. M., Sotomayor, J. A., and Jordàn, M. J. (2008). Antimicrobial activity and chemical composition of Thymus vulgaris, Thymus zygis and Thymus hyemalis essential oils. Food Control 19, 681-687. doi: 10.1016/j.foodcont.2007.07.007
217. 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. doi: 10.1055/s-0029-1243136
218. 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. doi: 10.1007/s12035-016-0083-0 [Epub ahead of print]
219. 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. doi: 10.1007/s00210-013-0917-5
220. Sanchez, M. E., Turina, A. V., Garcia, D. A., Nolan, M. V., and Perillo, M. A. (2004). Surface activity of thymol: implications for an eventual pharmacological activity. Colloids Surf. B Biointerfaces 34, 77-86. doi: 10.1016/j.colsurfb.2003.11.007
221. 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. doi: 10.1079/PHN2005659
222. Saravanan, S., and 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. doi: 10.1016/j.ejphar.2015.05.034
223. Saravanan, S., and Pari, L. (2016). Protective effect of thymol on high fat diet induced diabetic nephropathy in C57BL/6J mice. Chem. Biol. Interact. 245, 1-11. doi: 10.1016/j.cbi.2015.11.033
224. Sarkozi, S., Almassy, J., Lukacs, B., Dobrosi, N., Nagy, G., and 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. doi: 10.1007/s10974-007-9113-x
225. Sasaki, K., Wada, K., Tanaka, Y., Yoshimura, T., Matuoka, K., and 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. doi: 10.1089/jmf.2005.8.184
226. Satooka, H., and Kubo, I. (2012). Effects of thymol on B16-F10 melanoma cells. J. Agric. Food Chem. 60, 2746-2752. doi: 10.1021/jf204525b
227. Schroder, V., and 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
228. 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. doi: 10.1038/oby.2004.245
229. Seeman, P., Chen, S. S., Chau-Wong, M., and Staiman, A. (1974). Calcium reversal of nerve blockade by alcohols, anesthetics, tranquilizers, and barbiturates. Can. J. Physiol. Pharmacol. 52, 526-534. doi: 10.1139/y74-070
230. Shapiro, S., and Guggenheim, B. (1995). The action of thymol on oral bacteria. Oral Microbiol. Immunol. 10, 241-246. doi: 10.1111/j.1399-302X.1995.tb00149.x
231. Shapiro, S., Meier, A., and Guggenheim, B. (1994). The antimicrobiol activity of essential oils and essential oil components toward oral bacteria. Oral Microbiol. Immunol. 9, 202-208. doi: 10.1111/j.1399-302X.1994.tb00059.x
232. Shen, A. Y., Huang, M. H., Liao, L. F., and Wang, T. S. (2005). Thymol analogues with antioxidant and L-type calcium current inhibitory activity. Drug Dev. Res. 64, 195-202. doi: 10.1002/ddr.10436
233. Shettigar, N. B., Das, S., Rao, N. B., and 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. doi: 10.1002/tox.21971
234. 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. doi: 10.1038/sj.bjp.0703898
235. Singh, M. (1980). Amylase release from dissociated mouse pancreatic acinar cells stimulated by glucagon: effect of membrane stabilizers. J. Physiol. 309, 81-91. doi: 10.1113/jphysiol.1980.sp013495
236. Skold, K., Twetman, S., Hallgren, A., Yucel-Lindberg, T., and 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. doi: 10.1046/j.0909-8836.1998.eos106106.x
237. Slamenova, D., Horvathova, E., Sramkova, M., and 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
238. Sofowora, A., Ogunbodede, E., and 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
239. Soliman, K. M., and Badeaa, R. I. (2002). Effect of oil extracted from some medicinal plants on different mycotoxigenic fungi. Food Chem. Toxicol. 40, 1669-1675. doi: 10.1016/S0278-6915(02)00120-5
240. Soran, M. L., and Lung, I. (2010). HPTLC analysis of thymol in extracts of Satureja hortensis L. obtained by different techniques. J. Plan. Chromatogr. 23, 320-322. doi: 10.1556/JPC.23.2010.5.2
241. Stammati, A., Bonsi, P., Zucco, F., Moezelaar, R., Alakomi, H. L., and von Wright, A. (1999). Toxicity of selected plant volatiles in microbial and mammalian short-term assays. Food Chem. Toxicol. 37, 813-823. doi: 10.1016/S0278-6915(99)00075-7
242. Stunkard, A. J., and Allison, K. C. (2003a). Binge eating disorder: disorder or marker. Int. J. Eat. Disord. 34, S107-S116
243. Stunkard, A. J., and Allison, K. C. (2003b). Two forms of disordered eating inobesity: binge eating and night eating. Int. J. Obes. Relat. Metab. Disord. 27, 1-12
244. Stunkard, A. J., Faith, M. S., and Allison, K. C. (2003). Depression and obesity. Biol. Psychiatry 54, 330-335. doi: 10.1016/S0006-3223(03)00608-5
245. Surendra Kumar, M., Reddy, R., Manasa, G., Vanaja, P., Sirisha, G., and Astalakshmi, N. (2011). Antifertility effect of Trachyspermum ammi (Linn) sprague fruits on male rats. Int. J. Pharm. Biol. Arch. 2, 705-709
246. Suzuki, Y., and Furuta, H. (1988). Stimulation of guinea pig neutrophil superoxide anion-producing system with thymol. Inflammation 12, 575-584. doi: 10.1007/BF00914319
247. Suzuki, Y., Nakamura, S., Sugiyama, K., and Furuta, H. (1987). Differences of Superoxide production in blood leukocytes stimulated with thymol between human and non-human primates. Life Sci. 41, 1659-1664. doi: 10.1016/0024-3205(87)90735-1
248. Szentandrassy, N., Szentesi, P., Magyar, J., Nanasi, P. P., and Csernoch, L. (2003). Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle. BMC Pharmacol. 3:9. doi: 10.1186/1471-2210-3-9
249. 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. doi: 10.1016/j.lfs.2003.09.034
250. 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. doi: 10.1016/S0006-3495(04)74213-7
251. Takada, M., Agata, I., Sakamoto, M., Yagi, N., and Hayashi, N. (1979). On the metabolic detoxication to thymol in rabbit and man. J. Toxicol. Sci. 4, 341-350. doi: 10.2131/jts.4.341
252. Takishima, K., Setaka, M., and Shimizu, H. (1979). On the overshoot of calcium accumulation in fragmented sarcoplasmic reticulum induced by thymol. J. Biochem. 86, 347-353. doi: 10.1093/oxfordjournals.jbchem.a132532
253. Tamura, T., and 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. doi: 10.1016/j.bbrc.2004.04.085
254. 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
255. Torres de Pinedo, A., Penalver, P., and Morales, J. C. (2007). Synthesis and evaluation of new phenolic-based antioxidants: structure-activity relationship. Food Chem. 103, 55-61. doi: 10.1016/j.foodchem.2006.07.026
256. 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. doi: 10.4081/ijas.2007.1s.374
257. 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. doi: 10.1128/AAC.49.6.2474-2478.2005
258. Tsai, M. L., Lin, C., Lin, W. C., and Yang, C. H. (2011). Antimicrobial, antioxidant and anti-inflammatory activities of essential oils from five selected herbs. Biosci. Biotechnol. Biochem. 75, 1977-1983. doi: 10.1271/bbb.110377
259. Turrin, N. P., and Rivest, S. (2004). Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol. Dis. 16, 321-324. doi: 10.1016/j.nbd.2004.03.010
260. Twetman, S., Hallgren, A., and Petersson, L. G. (1995). Effect of antibacterial varnish on mutant streptococci in plaque form enamel adjacent to orthodontic appliances. Caries Res. 29, 188-191. doi: 10.1159/000262067
261. 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
262. Undeger, U., Basaran, A., Degen, G. H., and 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. doi: 10.1016/j.fct.2009.05.020
263. Van den Broucke, C. O., and Lemli, J. A. (1980). Antispasmodic activity of Origanum compactum. Planta Med. 38, 317-331. doi: 10.1055/s-2008-1074884
264. Van den Broucke, C. O., and Lemli, J. A. (1982). Antispasmodic activity of Origanum compactum. Part 2: antagonistic effect of thymol and carvacrol. Planta Med. 45, 188-190. doi: 10.1055/s-2007-971371
265. Van den Hoven, R., Zappe, H., Zitterl-Eglseer, K., Jugl, M., and 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. doi: 10.1136/vr.152.18.555
266. 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. doi: 10.1021/jf025753e
267. 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. doi: 10.1021/jp3082358
268. 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. doi: 10.1002/ptr.4695
269. Viana, G. S. B., Matos, F. F., Araujo, W. L., Matos, F. J. A., and Craveiro, A. A. (1981). Essential oil of Lippia grata: pharmacological effects and main constituents. Quart. J. Crude Drug Res. 19, 1-10. doi: 10.3109/13880208109065203
270. Vigo, E., Cepeda, A., Gualillo, O., and 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. doi: 10.1211/0022357022665
271. Vila, R. (2002). "Flavonoids and further polyphenols in the genus Thymus". in Thyme: The Genus Thymus. Medicinal and Aromatic Plants-Industrial Profiles, eds E. Stahl-Biskup and F. Saez (New York, NY: Taylor and Francis), 75
272. Wade, A., and Reynolds, J. E. F. (1997). Martindale-the Extra Pharmacopoeia. London: The Pharmaceutical Press, 536-537
273. Wechsler, J. B., Hsu, C. L., and 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. doi: 10.1016/j.jaci.2013.12.024
274. Wei, H. K., Xue, H. X., Zhou, Z. X., and 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. doi: 10.1017/S1751731116001397
275. Williams, R. T. (1959). Detoxication Mechanisms, 2nd Edn. London: Chapman and Hall, 300-301
276. Wirtz, S., and 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. doi: 10.1007/s003840000227
277. Wojdylo, A., Oszmianski, J., and Czemerys, R. (2007). Antioxidant activity and phenolic compounds in 32 selected herbs. Food Chem. 105, 940-949. doi: 10.1016/j.foodchem.2007.04.038
278. Xu, J., Zhou, F., Ji, B. P., Pei, R. S., and Xu, N. (2008). The antibacterial mechanism of carvacrol and thymol against Escherichia coli. Lett. Appl. Microbiol. 47, 174-179. doi: 10.1111/j.1472-765X.2008.02407.x
279. Xu, Z. H., Wang, C., Fujita, T., Jiang, C. Y., and Kumamoto, E. (2015). Action of thymol on spontaneous excitatory transmission in adult rat spinal substantia gelatinosa neurons. Neurosci. Lett. 606, 94-99. doi: 10.1016/j.neulet.2015.08.042
280. Yanishlieva, N. V., Marinovaa, E. M., Gordon, M. H., and Raneva, V. G. (1999). Antioxidant activity and mechanism of action of thymol and carvacrol in two lipid systems. Food Chem. 64, 59-66. doi: 10.1016/S0308-8146(98)00086-7
281. Yin, Q. H., Zhuang, Y. Z., and Yan, X. F. (2010). Antitumor efficacy of thymol. Prog. Mod. Biomed. 10, 2073-2075
282. Youdim, K. A., and 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. doi: 10.1016/S1388-1981(99)00045-1
283. Youdim, K. A., and 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
284. Yousefzadi, M., Riahi-Madvar, A., Hadian, J., Rezaee, F., and Rafiee, R. (2012). In vitro cytotoxic and antimicrobial activity of essential oil from Satureja sahendica. Toxicol. Environ. Chem. 94, 1735-1745. doi: 10.5812/ircmj.4989
285. Yu, Y. M., Chao, T. Y., Chang, W. C., Chang, M. J., and 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. doi: 10.1016/j.jfda.2016.02.004
286. Yucel-Lindberg, T., Twetman, S., Skold-Larsson, K., and 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. doi: 10.1080/000163599429066
287. Zahin, M., Ahmad, I., and Aqil, F. (2010). Antioxidant and antimutagenic activity of Carum copticum fruit extracts. Toxicol. In Vitro. 24, 1243-1249. doi: 10.1016/j.tiv.2010.02.004
288. Zamani, Z., Alipour, D., Moghimi, H. R., Mortazavi, S. A., and Saffary, M. (2015). Development and evaluation of thymol microparticles using cellulose derivatives as controlled release dosage form. Iran J. Pharm. Res. 14, 1031-1040
289. Zarzuelo, A., and Crespo, E. (2002). "The medicinal and non-medicinal uses of thyme". in Thyme: The Genus Thymus. Medicinal and Aromatic Plants-Industrial Profiles, eds E. Stahl-Biskup and F. Saez (New York, NY: Taylor & Francis), 263-292
290. 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
291. 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. doi: 10.1016/j.foodchem.2013.07.058
292. Zheng, Z. L., Tan, J. Y. W., Liu, H. Y., Zhou, X. H., Xiang, X., and 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. doi: 10.1016/j.aquaculture.2009.04.025
293. Zhou, E., Fu, Y., Wei, Z., Yu, Y., Zhang, X., and Yang, Z. (2014). Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma. Fitoterapia 96, 131-137. doi: 10.1016/j.fitote.2014.04.016
294. Zidan, D. E., Kahilo, K. A., El-Far, A., and 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