Download PDF
Planta Med 2019; 85(11/12): 815-824
DOI: 10.1055/a-0873-8622
Biological and Pharmacological Activity
Reviews
Georg Thieme Verlag KG Stuttgart · New York

The Nonvolatile and Volatile Metabolites of Prangos ferulacea and Their Biological Properties[*]

Maurizio Bruno
1   Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Parco dʼOrleans II, Palermo, Italy
,
Vincenzo Ilardi
2   Department of Earth and Marine Sciences (DISTeM), University of Palermo, Palermo, Italy
,
Giulio Lupidi
2   Department of Earth and Marine Sciences (DISTeM), University of Palermo, Palermo, Italy
,
Luana Quassinti
3   School of Pharmacy, University of Camerino, Camerino, Italy
,
Massimo Bramucci
3   School of Pharmacy, University of Camerino, Camerino, Italy
,
Dennis Fiorini
4   School of Science and Technologies, University of Camerino, Camerino, Italy
,
Alessandro Venditti
5   Department of Chemistry, University of Rome “La Sapienza”, Rome, Italy
,
Filippo Maggi
3   School of Pharmacy, University of Camerino, Camerino, Italy
› Author Affiliations
Further Information

Publication History

received 18 December 2018
revised 01 March 2019

accepted 05 March 2019

Publication Date:
20 March 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Prangos ferulacea (L.) Lindl. (Fam. Apiaceae), an orophilous species of eastern Mediterranean and western Asia, possesses a number of biological properties that are worthy of exploitation in different fields. Phytochemical investigations revealed the presence of coumarins, prenyl-coumarins, and furano-coumarins as the main constituents of this species, as well as several flavonoids. Among prenyl-coumarins, osthol is a promising apoptotic agent quite selective toward cancer cells. In addition, the essential oils have been extensively investigated, and several chemotypes have been identified. This work reviews the literature on this species published between 1965 and 2018, describes its volatile and nonvolatile metabolites, and outlines its pharmacological effects.

Key words

Prangos ferulacea - Apiaceae - coumarins - prenyl-coumarins - furano-coumarins - essential oil

* Dedicated to Professor Dr. Cosimo Pizza in recognition of his important contributions to natural product research on the occasion of his 70th birthday in 2019.


 

  • References

  • 1 Maggi F, Papa F, Giuliani C, Maleci Bini L, Venditti A, Bianco A, Nicoletti M, Iannarelli R, Caprioli G, Sagratini G, Cortese M, Ricciutelli M, Vittori S. Essential oil chemotypification and secretory structures of the neglected vegetable Smyrnium olusatrum L. (Apiaceae) growing in central Italy. Flavour Fragr J 2015; 30: 139-159
    CrossrefPubMedGoogle Scholar
  • 2 Ekiert H. Medicinal plant biotechnology: the Apiaceae family as the example of rapid development. Pharmazie 2000; 55: 561-567
    PubMedGoogle Scholar
  • 3 Sayed-Ahmad B, Talou T, Saad Z, Hijazi A, Merah O. The Apiaceae: ethnomedicinal family as source for industrial uses. Ind Crops Prod 2017; 109: 661-671
    CrossrefPubMedGoogle Scholar
  • 4 Benelli G, Pavela R, Petrelli R, Cappellacci L, Canale A, Senthil-Nathan S, Maggi F. Not just popular spices! Essential oils from Cuminum cyminum and Pimpinella anisum are toxic to insect pests and vectors without affecting non-target invertebrates. Ind Crops Prod 2018; 124: 236-243
    CrossrefPubMedGoogle Scholar
  • 5 Ajani Y, Ajani A, Cordes JM, Watson MF, Downie SR. Phylogenetic analysis of nrDNA ITS reveals relationships within five groups of Iranian Apiaceae sub family Apioideae. Taxon 2008; 57: 383-401
    PubMedGoogle Scholar
  • 6 Kew Royal Botanic Gardens. The Plant List. Available at: http://www.theplantlist.org Accessed March 12, 2019
    PubMedGoogle Scholar
  • 7 Euro+Med PlantBase. The Euro+Med PlantBase – The information resource for Euro-Mediterranean plant diversity. Available at: http://ww2.bgbm.org/EuroPlusMed/query.asp Accessed March 12, 2019
    PubMedGoogle Scholar
  • 8 Lindley J. Some account of the Prangos Hay Plant of Northern India. Quart J Sc Lit Arts 1825; 19: 7
    PubMedGoogle Scholar
  • 9 Jury SL. Cachrys L. e Prangos Lindl. In: Castroviejo Vol. 10, Iberian Flora: Vascular plants of the Iberian Peninsula and Balearic Islands. 1986: 151-155
    Google Scholar
  • 10 Di Martino A, Raimondo FA. Distribuzione es ecologia di Cachrys ferulacea (L.) Calestani interessante foraggera dei pascoli alto montani della Sicilia. Boll Stud Inform Bot Giardin Colon 1974; 26: 116-129
    PubMedGoogle Scholar
  • 11 Dagdelen S, Bilenler T, Durmaz G, Gokbulut I, Hayaloglu AA, Karabulut I. Volatile composition, antioxidant and antimicrobial activities of herbal plants used in the manufacture of Van Herby (OTLU) cheese. J Food Process Pres 2014; 38: 1716-1725
    CrossrefPubMedGoogle Scholar
  • 12 Özcan MM, Dursun N, Arslan D. Some nutritional properties of Prangos ferulacea (L.) Lindl and Rheum ribes L. stems growing wild in Turkey. Int J Food Sci Nutr 2007; 58: 162-167
    CrossrefPubMedGoogle Scholar
  • 13 Kafash-Farkhad N, Asadi-Samani M, Khaledifar B. A review on secondary metabolites and pharmacological effects of Prangos ferulacea (L.) Lindl. Life Sci J 2013; 10: 360-367
    PubMedGoogle Scholar
  • 14 Sadraei H, Shokoohinia Y, Sajjadi SE, Mozafari M. 2013. Antispasmodic effects of Prangos ferulacea acetone extract and its main component osthole on ileum contraction. Res Pharm Sci 2012; 8: 137-144
    PubMedGoogle Scholar
  • 15 Abyshev AZ. Pranferol from the roots of Prangos ferulacea . Khim Prir Soedin 1969; 5: 3-5
    PubMedGoogle Scholar
  • 16 Abyshev AZ. Coumarins and furocoumarins from the stems and roots of Prangos ferulacea indigenous to Armenia. Rastitelʼnye Resursy 1969; 5: 269-271
    PubMedGoogle Scholar
  • 17 Abyshev AZ, Denisenko PP. The structure of prangeferol. Khim Prir Soedin 1972; 8: 114
    PubMedGoogle Scholar
  • 18 Abyshev AZ. Structure of some components from of the roots of Prangos ferulacea . Khim Prir Soedin 1974; 10: 568-574
    PubMedGoogle Scholar
  • 19 Razavi SM. Phenolic compounds from the aerial parts of Prangos ferulaceae, with antioxidant activity. Eurasia J Biosci 2012; 91-96
    CrossrefPubMedGoogle Scholar
  • 20 Bubeva-Ivanova L, Zheleva A, Mitrev A, Mincheva V, Savchev P. Natural coumarins. VI. Coumarin contents of Prangos ferulacea . Farmatsiia (Sofia) 1973; 23: 36-42
    PubMedGoogle Scholar
  • 21 Tawaha K, Al-Montaseb S, Al-Kalil S. Coumarins from the aerial parts of Prangos ferulacea . Alex J Pharm Sci 2001; 15: 89-91
    PubMedGoogle Scholar
  • 22 Abbas-Mohammadi M, Moridi Farimani M, Salehi P, Nejad Ebrahimi S, Sonboli A, Kelso C, Skropeta D. Acetylcholinesterase-inhibitory activity of Iranian plants: combined HPLC/bioassay-guided fractionation, molecular networking and docking strategies for the dereplication of active compounds. J Pharm Biomed Anal 2018; 158: 471-479
    CrossrefPubMedGoogle Scholar
  • 23 Delnavazi MR, Soleimani M, Hadjiakhoondi A, Yassa N. Isolation of phenolic derivatives and essential oil analysis of Prangos ferulacea (L.) Lindl. aerial parts. Iran J Pharm Res 2017; 16: 207-215
    PubMedGoogle Scholar
  • 24 Shokoohinia Y, Hosseinzadeh L, Alipour M, Mostafaie A, Mohammadi-Motlagh HR. Comparative evaluation of cytotoxic and apoptogenic effects of several coumarins on human cancer cell lines: osthole induces apoptosis in p53-deficient H1299 cells. Adv Pharmacol Sci 2014; 2014: 847574
    PubMedGoogle Scholar
  • 25 Gholivand MB, Yamini Y, Dayeni M, Shokoohinia Y. The influence of the extraction mode on three coumarin compounds yield from Prangos ferulacea (L.) Lindl roots. J Iran Chem Soc 2015; 12: 707-714
    CrossrefPubMedGoogle Scholar
  • 26 Shokoohinia Y, Sajjadi SE, Gholamzadeh S, Fattahi A, Behbahani M. Antiviral and cytotoxic evaluation of coumarins from Prangos ferulacea . Pharm Biol 2014; 52: 1543-1549
    CrossrefPubMedGoogle Scholar
  • 27 Sajjadi SE, Shokoohinia Y, Gholamzadeh S, Behbahani M, Fattahi A. Antiviral evaluation of coumarins from Prangos ferulacea L. (Lindl). Res Pharm Sci 2012; 7: S783
    PubMedGoogle Scholar
  • 28 Mouri C, Mozaffarian V, Zhang X, Laursen R. Characterization of flavonols in plants used for textile dyeing and the significance of flavonol conjugates. Dyes Pigm 2014; 100: 135-141
    CrossrefPubMedGoogle Scholar
  • 29 Pistelli L, Catalano S, Manunta A, Marsili A. Coumarins from Cachrys ferulacea collected in Sardinia. Planta Med 1989; 55: 203
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Pistelli L, Marsili A, Morelli I, Barili PL, Pizza C. Umbelliferose from Cachrys ferulacea seeds: determination of the sugar sequence by NMR 2D-COLOC technique. Planta Med 1990; 56: 230-231
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Camarda L, Mazzola P, Sprio V. Coumarins from the fruits of Cachrys ferulacea . J Nat Prod 1987; 50: 310
    CrossrefPubMedGoogle Scholar
  • 32 Kuznetsova GA, Abyshev AZ. Natural (−)-7-methoxy-8-(β,γ-dihydroxyisopentyl)coumarin. Khim Prir Soedin 1965; 1: 283-288
    PubMedGoogle Scholar
  • 33 Kuznetsova GA, Abyshev AZ, Perelʼson ME, Sheinker YN, Pek GY. New coumarin, pranferol, from the roots of Prangos ferulacea . Khim Prir Soedin 1966; 2: 310-315
    PubMedGoogle Scholar
  • 34 Abyshev AZ. Coumarins from the fruits of Prangos ferulacea . Khim Prir Soedin 1968; 4: 130-131
    PubMedGoogle Scholar
  • 35 Abyshev AZ, Denisenko PP, Kostyuchenko NP, Anisimova OS, Ermakov AI, Sheinker YN. Pranferin, a new coumarin from the roots of Prangos ferulaceae . Khim Prir Soedin 1970; 6: 675-680
    PubMedGoogle Scholar
  • 36 Nikonov GK, Saidkhodzhaev AI. Structure of pranferin, a new coumarin from the roots of Prangos ferulaceae . Khim Prir Soedin 1971; 7: 255-257
    PubMedGoogle Scholar
  • 37 Abyshev AZ, Denisenko PP, Kostyuchenko NP, Ermakov AI, Sheinker YN. Gosferol, a new furocoumarin from the roots of Prangos ferulacea . Khim Prir Soedin 1972; 8: 49-54
    PubMedGoogle Scholar
  • 38 Abyshev AZ, Denisenko PP, Kostyuchenko NP, Ermakov AI, Sheinker YN. Natural acetate of meranzin hydrate, a new component of the roots of Prangos ferulacea . Khim Prir Soedin 1972; 8: 608-612
    PubMedGoogle Scholar
  • 39 Eshbakova KA, Saidkhodzhaev AI, Baser KHB, Duman H, Vdovin AD, Abdullaev ND. Furocoumarins from Prangos ferulacea . Chem Nat Comp 2006; 42: 102-103
    CrossrefPubMedGoogle Scholar
  • 40 Melough MM, Cho E, Chun OK. Furocoumarins: a review of biochemical activities, dietary sources and intake, and potential health risks. Food Chem Toxicol 2018; 113: 99-107
    CrossrefPubMedGoogle Scholar
  • 41 You L, An R, Wang X, Li Y. Discovery of novel osthole derivatives as potential anti-breast cancer treatment. Bioorg Med Chem Lett 2010; 20: 7426-7428
    CrossrefPubMedGoogle Scholar
  • 42 Shokoohinia Y, Hosseinzadeh L, Moieni-Arya M, Mostafaie A, Mohammadi-Motlagh HR. Osthole attenuates doxorubicin-induced apoptosis in PC12 cells through inhibition of mitochondrial dysfunction and ROS production. Biomed Res Int 2014; 2014: 156848
    PubMedGoogle Scholar
  • 43 Shokoohinia Y, Bazargan S, Miraghaee S, Javadirad E, Hosseinzadeh L. Safety assessment of osthole isolated from Prangos ferulacea: acute and subchronic toxicities and modulation of cytochrome P450. Jundishapur J Nat Pharm Prod 2017; 12: e63764
    PubMedGoogle Scholar
  • 44 Mavi A, Terzi Z, Ozgen U, Yildirim A, Coskun M. Antioxidant properties of some medicinal plants: Prangos ferulacea (Apiaceae), Sedum sempervivoides (Crassulaceae), Malva neglecta (Malvaceae), Cruciata taurica (Rubiaceae), Rosa pimpinellifolia (Rosaceae), Galium verum subsp. verum (Rubiaceae), Urtica dioica (Urticaceae). Biol Pharm Bull 2004; 27: 702-705
    CrossrefPubMedGoogle Scholar
  • 45 Coruh N, Sagdicoglu CAG, Oezgoekce F. Antioxidant properties of Prangos ferulacea (L.) Lindl., Chaerophyllum macropodum Boiss. and Heracleum persicum Desf. from Apiaceae family used as food in Eastern Anatolia and their inhibitory effects on glutathione-S-transferase. Food Chem 2007; 100: 1237-1242
    CrossrefPubMedGoogle Scholar
  • 46 Razavi SM, Zahri S, Zarrini G, Nazemiyeh H, Mohammadi S. Biological activity of quercetin-3-O-glucoside, a known plant flavonoid. Russ J Bioorg Chem 2009; 35: 376-378
    CrossrefPubMedGoogle Scholar
  • 47 Durmaz H, Sagun E, Tarakci Z, Ozgokce F. Antibacterial activities of Allium vineale, Chaerophyllum macropodum and Prangos ferulacea Afr. J Biotechnol 2006; 5: 11795-11798
    PubMedGoogle Scholar
  • 48 Azadpour Motlagh A, Dolatian M, Mojab F, Nasiri M, Ezatpour B, Sahranavard Y, Shakiba H, Rahimy B, Ghanati K. The effect of Prangos ferulacea vaginal cream on accelerating the recovery of bacterial vaginosis: a randomized controlled clinical trial. Int J Community Based Nurs Midwifery 2018; 6: 101-110
    PubMedGoogle Scholar
  • 49 Kaffash Farkhad N, Farokhi F, Soltani Band K, Tukmacki A. Hydro-alcoholic extract of the root of Prangos ferulacea (L.) Lindl can improve serum glucose and lipids in alloxan-induced diabetic rats. Avicenna J Phytomed 2012; 2: 179-187
    PubMedGoogle Scholar
  • 50 Farokhi F, Kaffash Farkhad N, Soltani Band K, Togmechi A. Preventive effects of Prangos ferulacea (L.) Lindle on liver damage of diabetic rats induced by alloxan. Avicenna J Phytomed 2012; 2: 63-71
    PubMedGoogle Scholar
  • 51 Mokhtari M, Mohammadi J. The effect of hydroalcoholic extracts of Prangos ferulacea on blood factors of kidney and liver functions in diabetic male wistar rats. Galen Med J 2012; 2: 174-180
    PubMedGoogle Scholar
  • 52 Ramesh B, Pugalendi K. Antihyperlipidemic and antidiabetic effects of umbelliferone in streptozotocin diabetic rats. Yale J Biol Med 2005; 78: 189-196
    PubMedGoogle Scholar
  • 53 Emamghoreishi M, Taghavi A, Javidnia K. The effect of aqueous and methanolic extracts of Prangos ferulacea on formalin-induced pain in mice. Journal of Jahrom University of Medical Sciences 2012; 9: 1-6
    PubMedGoogle Scholar
  • 54 Sadraei H, Shokoohinia Y, Sajjadi SE, Ghadirian B. Antispasmodic effect of osthole and Prangos ferulacea extract on rat uterus smooth muscle motility. Res Pharm Sci 2012; 7: 141-149
    PubMedGoogle Scholar
  • 55 Kazerooni T, Mousavizadeh K. Effect of Prangos ferulacea on abortion on pregnant rats. Fertil Steril 2005; 84: 168-169
    PubMedGoogle Scholar
  • 56 Kazerooni T, Mousavizadeh K, Abdollahee A, Sarkarian M, Sattar A. Abortifacient effect of Prangos ferulacea on pregnant rats. Contraception 2006; 73: 554-556
    CrossrefPubMedGoogle Scholar
  • 57 Safaeian R, Amin G, Azarnivand H. Study of chemical compositions of the essential oils of aerial parts of Prangos ferulacea (L.) lindly in growing stage in the north of Fars province. Acta Hortic 2012; 964: 71-76
    PubMedGoogle Scholar
  • 58 Safaeian R, Amin G, Azarnivand H. Phytochemistry of Prangos ferulacea (L.) Lindl. in one of the habitats of Zagros Mountain. Ecopersia 2013; 1: 63-74
    PubMedGoogle Scholar
  • 59 Amiri H. Essential oil variation of Prangos ferulacea Lindl. in different stage of plant growth. Iran J Med Arom Plants 2007; 23: 121-127
    PubMedGoogle Scholar
  • 60 Mohebi Z, Heshmati GA, Sefidkon F, Zare Chahouki MA. The influence of plant growth stage, individuals of species, and extraction methods on the essential oil content and the chemical composition of Prangos ferulacea (L.) Lindl. Appl Ecol Env Res 2017; 15: 1765-1776
    PubMedGoogle Scholar
  • 61 Akbari MT, Esmaeili A, Zarea AH, Saad N, Bagheri F. Chemical composition and antibacterial activity of essential oil from leaves, stems and flowers of Prangos ferulacea (L.) Lindl. grown in Iran. Bulg Chem Commun 2010; 42: 36-39
    PubMedGoogle Scholar
  • 62 Seidi Damyeh M, Niakousari M. Impact of ohmic-assisted hydrodistillation on kinetics data, physicochemical and biological properties of Prangos ferulacea Lindle. essential oil: comparison with conventional hydrodistillation. Innov Food Sci Emerg Technol 2016; 33: 387-396
    CrossrefPubMedGoogle Scholar
  • 63 Seidi Damyeh M, Niakousari M, Saharkhiz MJ. Ultrasound pretreatment impact on Prangos ferulacea Lindl. and Satureja macrosiphonia Bornm. essential oil extraction and comparing their physicochemical and biological properties. Ind Crops Prod 2016; 87: 105-115
    CrossrefPubMedGoogle Scholar
  • 64 Taherkhani M, Rustaiyan A, Masoudi S. Volatile constituents of the aerial parts of Ferulago subvelutina Rech. f., Ferulago stellata Boiss., leaves and flowers of Prangos ferulacea (L.) Lindle. and leaves of Ferula ovina (Boiss.) Boiss.: four Umbelliferae herbs from Iran. Asian J Chem 2012; 24: 1601-1606
    PubMedGoogle Scholar
  • 65 Razavi SM. Chemical composition and some allelopathic aspects of essential oils of (Prangos ferulacea L.) Lindl at different stages of growth. J Agr Sci Tech 2012; 14: 349-356
    PubMedGoogle Scholar
  • 66 Razavi SM, Nazemiyeh H, Zarrini G, Asna-Asharii S, Dehghan G. Chemical composition and antimicrobial activity of essential oil of Prangos ferulaceae (L.) Lindl from Iran. Nat Prod Res 2010; 24: 530-533
    CrossrefPubMedGoogle Scholar
  • 67 Masoudi S, Eghbali H, Abadi VK. Volatile constituents of the aerial parts of Ferulago subvelutina Rech. f., Ferulago stellata Boiss., leaves and flowers of Prangos ferulacea (L.) Lindle. and leaves of Ferula ovina (Boiss.) Boiss. Four Umbelliferae herbs from Iran. J Ess Oil-Bearing Plants 2016; 19: 592-605
    PubMedGoogle Scholar
  • 68 Bertoli A, Pistelli L, Morelli I, Spinelli G, Manunta A. Constituents of Cachrys ferulacea oils. J Ess Oil Res 1998; 10: 533-536
    CrossrefPubMedGoogle Scholar
  • 69 Ali Massumi M, Fazeli MR, Alavi SHR, Ajani Y. Chemical constituents and antibacterial activity of essential oil of Prangos ferulacea (L.) Lindl. fruits. Iran J Pharm Sci 2007; 3: 171-176
    PubMedGoogle Scholar
  • 70 Menghini A, Cagiotti MR, Montanarella L, Fischer FC, Bos R. The essential oil of the fruit of Prangos ferulacea Lindley. Essenze. Derivati Agrumari 1987; 57: 34-40
    PubMedGoogle Scholar
  • 71 Başer KHC, Ermin N, Adiguzel N, Aytac Z. Composition of the essential oil of Prangos ferulacea (L.) Lindl. J Ess Oil Res 1996; 8: 297-298
    CrossrefPubMedGoogle Scholar
  • 72 Yousefi K, Hamedeyazdan S, Hodaei D, Lotfipour F, Baradaran B, Orangi M, Fathiazad F. An in vitro ethnopharmacological study on Prangos ferulacea: a wound healing agent. Bioimpacts 2017; 7: 75-82
    CrossrefPubMedGoogle Scholar
  • 73 Sajjadi SE, Shokoohinia Y, Gholamzadeh S. Chemical composition of essential oil of Prangos ferulacea (L.) Lindl. roots. Chemija 2011; 22: 178-180
    PubMedGoogle Scholar
  • 74 Doković DD, Bulatović VM, Božić BD, Kataranovski MV, Zrakić TM, Kovacević NN. 3, 5-Nonadiyne isolated from the rhizome of Cachrys ferulacea inhibits endogenous nitric oxide release by rat peritoneal macrophages. Chem Pharm Bull 2004; 52: 853-854
    CrossrefPubMedGoogle Scholar
  • 75 Evergetis E, Michaelakis A, Haroutounian SA. Exploitation of Apiaceae family essential oils as potent biopesticides and rich source of phellandrenes. Ind Crops Prod 2013; 41: 365-370
    CrossrefPubMedGoogle Scholar
  • 76 Amiri H. Chemical constituents and antibacterial activity of essential oil of Prangos ferulacea (L.) Lindl. J Med Plants 2007; 6: 36-41
    PubMedGoogle Scholar
  • 77 Sefidkon F, Khajavi MS, Malackpour B. Analysis of the oil of Prangos ferulacea (L.) Lindl. J Ess Oil Res 1998; 10: 81-82
    CrossrefPubMedGoogle Scholar
  • 78 Mohammadhosseini M. Chemical profile and antibacterial activity in hydrodistilled oil from aerial parts of Prangos ferulacea (L.) Lindl. and prediction of gas chromatographic retention indices by using genetic algorithm multiple linear regressions. Asian J Chem 2012; 24: 3814-3820
    PubMedGoogle Scholar
  • 79 Sümer Ercan F, Bas H, Koc M, Pandir D, Oztemiz S. Insecticidal activity of essential oil of Prangos ferulacea (Umbelliferae) against Ephestia kuehniella (Lepidoptera: Pyralidae) and Trichogramma embryophagum (Hymenoptera: Trichogrammatidae). Turk J Agric For 2013; 37: 719-725
    CrossrefPubMedGoogle Scholar
  • 80 Razavi SM, Nazemiyeh H, Zarrini G, Asna-Asharii S, Dehghan G. Chemical composition and antimicrobial activity of essential oil of Prangos ferulaceae (L.) Lindl from Iran. Nat Prod Res 2010; 24: 530-533
    CrossrefPubMedGoogle Scholar