Anti-inflammatory, anti-oxidant, and immunomodulatory activities of the genus Ferula and their constituents: A review

Document Type : Review Article

Authors

1 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Clinical Research Unit, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Physiology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

Abstract

Objective(s): Ferula is a genus of the family Apiaceae and it includes around 170 species of flowering plants mostly native to the Mediterranean region and eastern to central Asia. In Iran, Ferula spp. are widely used in cuisine and traditional medicine. This review discusses the anti-inflammatory, anti-oxidant, and immunomodulatory activities of different species of Ferula. 
Materials and Methods: To prepare the present review, Scopus, Google Scholar, PubMed, and Web of Science scientific databases were searched to retrieve relevant articles published from 1985 until December 2020. 
Results: Based on our literature review, Ferula plants and their derivatives decrease the levels of inflammatory mediators and exert anti-apoptotic effects. Under oxidative stress conditions, these plants and their constituents were shown to decrease oxidative markers such as malondialdehyde, reactive oxygen species, and nitric oxide but increase superoxide dismutase, glutathione peroxidase, catalase activity, and glutathione level. Ferula plants and their constituents also showed immunomodulatory effects by affecting various cytokines. Besides, in vivo and in vitro studies showed hypotensive, neuroprotective, memory-enhancing, anti-oxidant, hepatoprotective, antimicrobial, anticarcinogenic, anticytotoxic, antiobesity, and anthelmintic effects for various species of Ferula and their constituents. These plants also showed a healing effect on gynecological issues such as miscarriage, unusual pain, difficult menstruation, and leukorrhea.  All these beneficial effects could have resulted from the anti-inflammatory, anti-oxidant, and immunomodulatory effects of these plants and their constituents.
Conclusion: Based on the available literature, members of the genus Ferula can be regarded as potential therapeutics against inflammatory conditions, oxidative stress, and immune dysregulation.

Keywords


1. Moradi M-T, Karimi A, Lorigooini Z, Pourgheysari B, Alidadi S, Hashemi L. In vitro anti influenza virus activity, anti-oxidant potential and total phenolic content of twelve Iranian medicinal plants. Marmara Pharm J 2017; 21:843-851.
2. Nazari ZE, Iranshahi M. Biologically active sesquiterpene coumarins from Ferula species. Phytother Res 2011; 25:315-323.
3. Gholamnejad Z, Byrami G, Boskabady MH, Iranshahi M. Possible mechanism (s) of the relaxant effect of asafoetida (Ferula assafoetida) oleo-gum-resin extract on guinea-pig tracheal smooth muscle. Avicenna J Phytomed 2012; 2:10-16.
4. Bayrami G, Boskabady MH, Iranshahi M, Gholamnezhad Z. Relaxant effects of asafoetida extract and its constituent umbelliprenin on guinea-pig tracheal smooth muscle. Chin J Integr Med 2013; 1-6.
5. Kiyanmehr M, Boskabady MH, Khazdair MR, Hashemzehi M. Possible mechanisms for functional antagonistic effect of Ferula assafoetida on muscarinic receptors in tracheal smooth muscle. Malays J Med Sci 2016; 23:35-43.
6. Khazdair MR, Boskabady MH, Kiyanmehr M, Hashemzehi M, Iranshahi M. The inhibitory effects of Ferula assafoetida on muscarinic receptors of Guinea-Pig tracheal smooth muscle. Jundishapur J Nat Pharm Prod 2015; 10:e20008.
7. Khazdair MR, Boskabady MH. The relaxant effect of Ferula assafoetida on smooth muscles and the possible mechanisms. J Herb Med Pharmacol 2015; 4: 40-44.
8. Mohammadhosseini M, Venditti A, Sarker SD, Nahar L, Akbarzadeh A. The genus Ferula: Ethnobotany, phytochemistry and bioactivities–A review. Ind Crops Prod 2019; 129:350-394.
9. Mala K, Thomas J, Syam DS, Maliakel B, Krishnakumar I. Safety and efficacy of ferula asafoetida in functional dyspepsia: A randomized, double-blinded, placebo-controlled study. Evid Based Complement Alternat Med 2018; Article ID 4813601, 11 pages.
10. Amalraj A, Gopi S. Biological activities and medicinal properties of Asafoetida: A review. J Tradit Complement Med 2017; 7:347-359.
11. Moosavi SJ, Habibian M, Peeri M, Azarbayjani MA, Nabavi SM, Nabavi SF, et al. Protective effect of Ferula gummosa hydroalcoholic extract against nitric oxide deficiency-induced oxidative stress and inflammation in rats renal tissues. Clin Exp Hypertens 2015; 37:136-141.
12. Vijayasteltar L, Jismy I, Joseph A, Maliakel B, Kuttan R, Krishnakumar I. Beyond the flavor: a green formulation of Ferula asafoetida oleo-gum-resin with fenugreek dietary fibre and its gut health potential. Toxicol Rep 2017; 4:382-390.
13. Bouratoua A, Khalfallah A, Bensouici C, Kabouche Z, Alabdul Magid A, Harakat D, et al. Chemical composition and anti-oxidant activity of aerial parts of Ferula longipes Coss. ex Bonnier and Maury. Nat Prod Res 2018; 32:1873-1880.
14. Wang Z-Q, Huang C, Huang J, Han H-Y, Li G-Y, Wang J-H, et al. The stereochemistry of two monoterpenoid diastereomers from Ferula dissecta. RSC Adv 2014; 4:14373-14377.
15. Sattar Z, Iranshahi M. Phytochemistry and pharmacology of Ferula persica Boiss.: A review. Iran J Basic Med Sci 2017; 20:1-8.
16. Tabrizian K, Yaghoobi NS, Iranshahi M, Shahraki J, Rezaee R, Hashemzaei M. Auraptene consolidates memory, reverses scopolamine-disrupted memory in passive avoidance task, and ameliorates retention deficits in mice. Iran J Basic Med Sci 2015; 18: 1014-1019.
17. Tabrizian K, Musavi SS, Rigi M, Hosseindadi F, Kordi S, Shamshirgaran F, et al. Behavioral and molecular effects of intrahippocampal infusion of auraptene, resveratrol, and curcumin on H-89-induced deficits on spatial memory acquisition and retention in Morris water maze. Human & Exp Tox 2019; 38: 775-784.
18. Hashemzaei M, Sadeghibonjar MA, Tabrizian K, Iranshahi M, Iranshahy M, Rezaee R. Evaluation of the analgesic effect of Umbelliprenin and Umbelliprenin-morphine co-administration on the acute, chronic and neuropathic pain. Ind J Pharmac Education Res 2015; 49: 121-125.
19. Shahraki J, Rezaee R, Mohammadzehi Kenar S, Setoodeh Nezhad S, Bagheri Gh, Jahantigh HA. Konstantinos Tsarouhas 6, Mahmoud Hashemzaei, et al. Umbelliprenin relieves paclitaxel-induced neuropathy. J Pharm Pharmacol 2020; 12: 1822-1829.
20. Hashemzaei M, Dousti T, Tsarouhas K, Bagheri GH, Konstantinos nikolouzakis T, Rezaee R, et al. Effect of umbelliprenin on blood pressure in high-fat diet hypertensive rats. Farmacia 2020; 68:447-452.
21. Zarei H, Rezaee R, Behravan E, Soltani F, Mosaffa F, Iranshahi M, et al. Diversin, from Ferula diversivittata protects human lymphocytes against oxidative stress induced by H2O2. Nat Prod Res 2013; 27:1016-1019.
22. Sahebkar A, Iranshahi M. Biological activities of essential oils from the genus Ferula (Apiaceae). Asian Biomed 2010; 4:835-847.
23. Bagheri SM, Hedesh ST, Mirjalili A, Dashti-R MH. Evaluation of anti-inflammatory and some possible mechanisms of antinociceptive effect of Ferula assafoetida oleo gum resin. Evid Based Complement Alternat Med 2016; 21:271-276.
24. Bagheri SM, Mohamadsadeghi H, Hejazian ES. Antinociceptive effect of seed’s essential oil of Ferula assa‑foetida in mice. Int J Clin Exp Physiol 2017; 4:34-37.
25. Bagheri SM, Sahebkar A, Gohari AR, Saeidnia S, Malmir M, Iranshahi M. Evaluation of cytotoxicity and anticonvulsant activity of some Iranian medicinal Ferula species. Pharm Biol 2010; 48:242-246.
26. Moghadam FH, Mesbah-Ardakani M, Nasr-Esfahani MH. Effects of oleo gum resin of Ferula assafoetida L. on senescence in human dermal fibroblasts:-Asafoetida reverses senescence in fibroblasts. J Pharmacopuncture 2017; 20:213-219.
27. Saghravanian SJ, Fereidoni M, Asadollahi A. Effect of hydroalcoholic extract of Ferula szowitsiana DC. on paw edema in rat. KAUMS J (FEYZ) 2016; 20:125-132.
28. Askari VR, Baradaran Rahimi V, Assaran A, Iranshahi M, Boskabady MH. Evaluation of the anti-oxidant and anti-inflammatory effects of the methanolic extract of Ferula szowitsiana root on PHA-induced inflammation in human lymphocytes. Drug Chem Toxicol 2020; 43:353-360.
29. Mandegary A, Sayyah M, Heidari MR. Antinociceptive and anti-inflammatory activity of the seed and root extracts of Ferula gummosa Boiss in mice and rats. DARU J Pharm Sci 2004; 12:58-62.
30. Ghareeb DA, ElAhwany AM, El-mallawany SM, Saif AA. In vitro screening for anti-acetylcholiesterase, anti-oxidant, anti-glucosidase, anti-inflammatory and anti-bacterial effect of three traditional medicinal plants. Biotech and Biotechnological Equip 2014; 28:1155-1164.
31. Xing Y, Li N, Zhou D, Chen G, Jiao K, Wang W, et al. Sesquiterpene coumarins from Ferula sinkiangensis act as neuroinflammation inhibitors. Planta Med 2017; 83:135-142.
32. Zamani Taghizadeh Rabe S, Iranshahi M, Mahmoudi M. In vitro anti-inflammatory and immunomodulatory properties of umbelliprenin and methyl galbanate. J Immunotoxicol 2016; 13:209-216.
33. IRANSHAHI M, Askari M, Sahebkar A, Hadjipavlou LD. Evaluation of anti-oxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. DARU J Pharm Sci 2009; 17:99-103.
34. Barthomeuf C, Lim S, Iranshahi M, Chollet P. Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine 2008; 15:103-111.
35. Geroushi A, Auzi AA, Elhwuegi AS, Elzawam F, Elsherif A, Nahar L, et al. Antiinflammatory sesquiterpenes from the root oil of Ferula hermonis. Phytother Res 2011; 25:774-777.
36. Safi R, Rodriguez F, Hilal G, Diab‐Assaf M, Diab Y, El‐Sabban M, et al. Hemisynthesis, antitumoral effect, and molecular docking studies of ferutinin and its analogues. Chem Bio & Drug Design 2016; 87:382-397.
37. Hoult J, Payá M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacol 1996; 27:713-722.
38. Murakami A, Nakamura Y, Tanaka T, Kawabata K, Takahashi D, Koshimizu K, et al. Suppression by citrus auraptene of phorbol ester-and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation. Carcinogenesis 2000; 21:1843-1850.
39. Iranshahi M, Arfa P, Ramezani M, Jaafari MR, Sadeghian H, Bassarello C, et al. Sesquiterpene coumarins from Ferula szowitsiana and in vitro antileishmanial activity of 7-prenyloxycoumarins against promastigotes. Phytochemistry 2007; 68:554-5561.
40. Curini M, Epifano F, Maltese F, Marcotullio MC, Tubaro A, Altinier G, et al. Synthesis and anti-inflammatory activity of natural and semisynthetic geranyloxycoumarins. Bioorg Med Chem Lett 2004; 14:2241-2243.
41. Sahebkar A. Citrus auraptene: a potential multifunctional therapeutic agent for nonalcoholic fatty liver disease. Ann Hepatol 2016; 10:575-577.
42. Rezaee R, Behravan E, Behravan J, Soltani F, Naderi Y, Emami B, et al. Antigenotoxic activities of the natural dietary coumarins umbelliferone, herniarin and 7-isopentenyloxy coumarin on human lymphocytes exposed to oxidative stress. Drug Chem Toxicol 2014; 2:144-148.
43. Kavoosi G, Tafsiry A, Ebdam AA, Rowshan V. Evaluation of anti-oxidant and antimicrobial activities of essential oils from Carum copticum seed and Ferula assafoetida latex. J Food Sci 2013; 78:T356-T361.
44. Lahazi V, Taheri G, Jafarisani M. Anti-oxidant enzymes activity of Ferula flabelliloba and Ferula diversivitata extracts/Ferula flabelliloba ve Ferula diversivitata ekstraktlarının antioksidan enzim aktiviteleri. Turkish J Biochem 2015; 40:310-315.
45. Dehghan G, Shafiee A, Ghahremani MH, Ardestani SK, Abdollahi M. Anti-oxidant potential of various extracts from Ferula szovitsiana. in relation to their phenolic content. Pharm Biol 2007; 45:691-699.
46. Askari VR, Baradaran Rahimi V, Assaran A, Iranshahi M, Boskabady MH. Evaluation of the anti-oxidant and anti-inflammatory effects of the methanolic extract of Ferula szowitsiana root on PHA-induced inflammation in human lymphocytes. Drug Chem Toxicol 2019; 1-8.
47. Yusufoglu H, Soliman G, Abdel-Rahman R, Abdel-Kader M, Genaie M, Bedir E, et al. Anti-oxidant and antihyperglycemic effects of Ferula drudeana and Ferula huber-morathii in experimental diabetic rats. Int J Pharmacol 2015; 11:738-748.
48. Upadhyay PK. Pharmacological activities and therapeutic uses of resins obtained from Ferula asafoetida Linn: A Review. Int J Green Pharmacy (IJGP) 2017; 11:240-247.
49. Saleem M, Alam A, Sultana S. Asafoetida inhibits early events of carcinogenesis: a chemopreventive study. Life Sci 2001; 68:1913-1921.
50. Safaeian L, Ghannadi A, Javanmard SH, Vahidian MH. The effect of hydroalcoholic extract of Ferula foetida stems on blood pressure and oxidative stress in dexamethasone-induced hypertensive rats. Res Pharm Sci 2015; 10:326-334.
51. Javaid R, Aslam M, Javaid R, Nizami Q, Javed K, Azhar M. Extract of Ferula foetida Regel reverses gentamicin-induced nephrotoxicity in rats. EXCLI J 2012; 11:760-766.
52. Mallikarjuna G, Dhanalakshmi S, Raisuddin S, Rao AR. Chemomodulatory influence of Ferula asafoetida on mammary epithelial differentiation, hepatic drug metabolizing enzymes, anti-oxidant profiles and N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. Breast Cancer Res Treat 2003; 81:1-10.
53. Torabi F, Dadkhah A, Fatemi F, Dini S, Taghizadeh M, Malayeri MRM. Prevention and therapy of 1, 2-dimethyl hydrazine induced colon carcinogenesis by Ferula assafoetida hydroalcoholic extract/1, 2-dimetilhidrazin ile indüklenmiş kalın bağırsak kanserlerinin Ferula assafoetida ekstraktı kullanılarak önlenmesi ve tedavisi. Turk Biyokim Derg 2015; 40:390-400.
54. Safari R, Hoseinifar SH, Nejadmoghadam S, Jafar A. Transciptomic study of mucosal immune, anti-oxidant and growth related genes and non-specific immune response of common carp (Cyprinus carpio) fed dietary Ferula (Ferula assafoetida). Fish Shellfish Immunol 2016; 55:242-248.
55. Zhang H, Lu J, Zhou L, Jiang L, Zhou M. Anti-oxidant and antitumor effects of Ferula sinkiangensis KM Shen. Int J Clin Exp Med  2015; 8:20845-20852.
56. Ghorbani A, Mogharrabi M, Mohebbati R, Mousavi SM, HASAN ZS, Emamian M, et al. Effect of long-term administration of Ferula gummosa root extract on serum oxidant-anti-oxidant status.  Iran J Pharm Sci 2016; 12:85-96.
57. Deniz G, Laloglu E, Koc K, Geyikoglu F. Hepatoprotective potential of Ferula communis extract for carbon tetrachloride induced hepatotoxicity and oxidative damage in rats. Biotech Histochem 2019; 94:334-340.
58. Mahaki H, Tanzadehpanah H, Abou-Zied OK, Moghadam NH, Bahmani A, Salehzadeh S, et al. Cytotoxicity and anti-oxidant activity of kamolonol acetate from Ferula pseudalliacea, and studying its interactions with calf thymus DNA (ct-DNA) and human serum albumin (HSA) by spectroscopic and molecular docking techniques. Process Biochem 2019; 79:203-213.
59. Ibraheim ZZ, Abdel‐Mageed WM, Dai H, Guo H, Zhang L, Jaspars M. Antimicrobial anti-oxidant daucane sesquiterpenes from Ferula hermonis Boiss. Phytother Res 2012; 26:579-586.
60. Miski M, Jakupovic J. Daucane esters from Ferula rigidula. Phytochem 1990; 29:173-178.
61. Benchabane O, Hazzit M, Baaliouamer A, Mouhouche F. Analysis and anti-oxidant activity of the essential oils of Ferula vesceritensis Coss. et Dur. and Thymus munbyanus Desf. J Essential Oil Bearing Plants 2012; 15:774-781.
62. Pavlović I, Petrović S, Radenković M, Milenković M, Couladis M, Branković S, et al. Composition, antimicrobial, antiradical and spasmolytic activity of Ferula heuffelii Griseb. ex Heuffel (Apiaceae) essential oil. Food Chem 2012; 130:310-315.
63. Elghwaji W, El-Sayed AM, El-Deeb KS, ElSayed AM. Chemical composition, antimicrobial and antitumor potentiality of essential oil of Ferula tingitana L. Apiaceae grow in Libya. Pharmacogn Mag 2017; 13(Suppl 3):S446.
64. Kahraman C, Topcu G, Bedir E, Tatli II, Ekizoglu M, Akdemir ZS. Phytochemical screening and evaluation of the antimicrobial and anti-oxidant activities of Ferula caspica M. Bieb. extracts. Saudi Pharm J 2019 ;27:525-531.
65. Nahvinejad MR, Mansourabadi AH, Jamehbozorg S, Moogooei M, ZARE ZH, Nahvinejad M. Metabolic regulation and anti-oxidative effect of Ferula asafoetida ethanolic extract on children with leukemia. Iran J Pharm Sci 2016; 6:70-83.
66. Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F, et al. Auraptene from Ferula szowitsiana protects human peripheral lymphocytes against oxidative stress. Phytother Res: 2010; 24:85-89.
67. Etemad L, Zamani M, Iranshahi M, Roohbakhsh A. The protective effect of auraptene against oxidative stress and pentylenetetrazol-induced chemical kindling in mice. Iran J Pharm Res 2019; 18:1395.
68. Ghanbarabadi M, Iranshahi M, Amoueian S, Mehri S, Motamedshariaty VS, Mohajeri SA. Neuroprotective and memory enhancing effects of auraptene in a rat model of vascular dementia: Experimental study and histopathological evaluation. Neurosci Lett 2016; 623:13-21.
69. Bibak B, Shakeri F, Barreto GE, Keshavarzi Z, Sathyapalan T, Sahebkar A. A review of the pharmacological and therapeutic effects of auraptene. Biofactors 2019; 45:867-879.
70.  Askari VR,  Baradara Rahimi V,  Rezaee SA,  Boskabady MH. Auraptene regulates Th1/Th2/TReg balances, NF-κB nuclear localization and nitric oxide production in normal and Th2 provoked situations in human isolated lymphocytes. Phytomedicine 2018; 43:1-10.
71. Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F, et al. Evaluation of antigenotoxicity effects of umbelliprenin on human peripheral lymphocytes exposed to oxidative stress. Cell Biol Toxicol 2009; 25:291-296.
72. Motai T, Kitanaka S. Sesquiterpene chromones from Ferula fukanensis and their nitric oxide production inhibitory effects. J Nat Prod 2005; 68:1732-5.
73. Oüzek G, Schepetkin IA, Utegenova GA, Kirpotina LN, Andrei SR, Oüzek T, et al. Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils. J Leukoc Biol 2017; 101:1361-1371.
74. Askari VR, Alavinezhad A, Rahimi VB, Rezaee SA, Boskabady MH. Immuno-modulatory effects of methanolic extract of Ferula szowitsiana on isolated human Th1/Th2/Treg cytokines levels, and their genes expression and nitric oxide production. Cytokine 2020; 138:155387.
75. Grigore A. Plant phenolic compounds as immunomodulatory agents. Phenolic compounds–Biological activity London, UK: IntechOpen 2017; 75-98.
76. Nishimoto S, Muranaka A, Nishi K, Kadota A, Sugahara T. Immunomodulatory effects of citrus fruit auraptene in vitro and in vivo. J Funct Foods 2012; 4:883-890.
77. Askari VR, Rahimi VB, Rezaee SA, Boskabady MH. Auraptene regulates Th1/Th2/TReg balances, NF-κB nuclear localization and nitric oxide production in normal and Th2 provoked situations in human isolated lymphocytes. Phytomedicine 2018; 43:1-10.
78. Yan H, Ma Z, Deng X. Anti-inflammatory effect of auraptene extracted from trifoliate orange (Poncirus trifoliate) on LPS-stimulated RAW 264.7 cells. Inflammation 2013; 36:1525-32.
79. Kohno S, Murata T, Sugiura A, Ito C, Iranshahi M, Hikita K, et al. Methyl galbanate, a novel inhibitor of nitric oxide production in mouse macrophage RAW264. 7 cells. J Nat Med 2011; 65:353-359.
80. Schepetkin IA, Kushnarenko SV, Özek G, Kirpotina LN, Sinharoy P, Utegenova GA, et al. Modulation of human neutrophil responses by the essential oils from Ferula akitschkensis and their constituents. J Agric Food Chem 2016; 64:7156-7170.