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Research Article

Phenolic Profile, Acute Toxicity, and Hepatoprotective and Antiproliferative Activities of Algerian Ruta tuberculata Forssk

Author(s): Asma Saidi*, Leila Hambaba, Burak Kucuk, Ercan Cacan and Ramazan Erenler

Volume 18, Issue 3, 2022

Published on: 19 January, 2022

Article ID: e191121198118 Pages: 12

DOI: 10.2174/1573407217666211119092552

Price: $65

Abstract

Objectives: Ruta tuberculata forssk. (Rutaceae) is an aromatic plant widely used in traditional Algerian medicine due to its pharmaceutical virtues against various disorders. This study aims to determine the phenolic profile of aqueous (RAE) and methanol (RME) extracts of R. tuberculata aerial parts and to investigate their acute oral toxicity, as well as their possible antiproliferative and hepatoprotective effects.

Methods: Polyphenols were identified by quantitative LC-MS/MS analysis. Oral acute toxicity was performed according to OCDE guidelines. The hepatoprotective activity was evaluated by paracetamol-induced hepatotoxicity and supported by biochemical and histological analysis of liver and kidneys. The antiproliferative activity against human colorectal HT-29 and ovarian OV2008 cancer cell lines was determined using SRB assay.

Results: LC-MS/MS analysis revealed that RME has higher phenols and flavonoids content than RAE; however, its major identified flavonoids are Kaempferol, rutin, and naringenin. R. tuberculata seems mildly toxic at several doses, with oral LD50 greater than 5000 mg/kg. The significant increase in hepatic markers enzymes activities as well as cholesterol, triglycerides, and glycemic levels, caused by PCM-administration, was potentially reduced following the co-treatments with vitamin C and RME, respectively, compared to RAE. Moreover, RME-treatment markedly prevented all histological changes. Compared to RAE, RME (100 μg/mL) exhibited excellent antiproliferative activity against both tested cancer lines (% inhibition ≥ 80%).

Conclusion: Both R. tuberculata extracts (200 mg/kg/daily) were non-toxic and exerted a potential hepatoprotective effect against PCM-induced hepatotoxicity. Accordingly, RME may be considered a good candidate for the development of new therapies against colorectal and ovarian cancers.

Keywords: R. tuberculata, acute oral toxicity, hepatoprotective activity, antiproliferative activity, flavonoids, LC-MS/MS analysis.

Graphical Abstract

[1]
Marzouk, B.; Marzouk, Z.; Haloui, E.; Fenina, N.; Bouraoui, A.; Aouni, M. Screening of analgesic and anti-inflammatory activities of Citrullus colocynthis from southern Tunisia. J. Ethnopharmacol., 2010, 125, 344-349.
[http://dx.doi.org/10.1016/j.jep.2009.04.025]
[2]
Kacem, M.; Simon, G.; Leschiera, R.; Misery, L.; Elfekil, A.; Lebonvallet, N. Antioxidant and anti-inflammatory effects of Ruta chalepensis L. extracts on LPS-stimulated raw 264.7 Cells. In Vitro Cell. Dev. Biol. Anim., 2014, 51, 128-141.
[http://dx.doi.org/10.1007/s11626-014-9813-7]
[3]
Richardson, J.S.; Sethi, G.; Lee, G.S.; Malek, S.N. Chalepin: isolated from Ruta angustifolia L. Pers induces mitochondrial mediated apoptosis in lung carcinoma cells. BMC Complement. Altern. Med., 2016, 16, E389.
[http://dx.doi.org/10.1186/s12906-016-1368-6]
[4]
Aouachria, S.; Boumerfeg, S.; Benslama, A.; Benbacha, F.; Guemmez, T.; Khennouf, S.; Arrar, L.; Baghiani, A. Acute, sub-acute toxicity and antioxidant activities (in vitro and in vivo) of Reichardia picroide crude extract. J. Ethnopharmacol., 2017, 208, 105-116.
[http://dx.doi.org/10.1016/j.jep.2017.06.028]
[5]
Erenler, R.; Meral, B.; Sen, O.; Elmastas, M.; Aydin, A.; Eminagaoglu, O.; Topcu, G. Bioassay-guided isolation, identification of compounds from Origanum rotundifolium and investigation of their antiproliferative and antioxidant activities. Pharm. Biol., 2017, 55, 1646-1653.
[http://dx.doi.org/10.1080/13880209.2017.1310906]
[6]
Rha, C.S.; Jeong, H.W.; Park, S.; Lee, S.; Jung, Y.S.; Kim, D.O. Antioxidative, anti-inflammatory, and anticancer effects of purified flavonol glycosides and aglycones in green tea. Antioxidants, 2019, 8, E278.
[http://dx.doi.org/10.3390/antiox8080278]
[7]
Lv, Y.; Zhang, B.; Xing, G.; Wangb, F.; Hu, Z. Protective effect of naringenin against acetaminopheninduced acute liver injury in metallothionein (MT)-null mice. Food Funct., 2013, 4, 297-302.
[http://dx.doi.org/10.1039/C2FO30213F]
[8]
Hernández-Aquino, E.; Muriel, P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J. Gastroenterol., 2018, 24, 1679-1707.
[http://dx.doi.org/10.3748/wjg.v24.i16.1679]
[9]
Pushpa, H.D.; Shree, R.; Shibani, P.; Shetty Ramesh, D.H. Screening of antimicrobial, antioxidant and anticancer activity of Ruta graveolens. Adv. Biol. Res. (Faisalabad), 2015, 9, 257-264.
[http://dx.doi.org/10.5829/idosi.abr.2015.9.94234]
[10]
Zengin, G.; Senkardes, I.; Mollica, A.; Picot-Allain, C.M.N.; Bulut, G.; Dogan, A.; Mahomoodally, M.F. New insights into the in vitro biological effects, in silico docking and chemical profile of clary sage - Salvia sclarea L. Comput. Biol. Chem., 2018, 75, 111-119.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.05.005]
[11]
Yagi, S.; Mohammed, A.B.A.; Tzanova, T.; Schohn, H.; Abdelgadir, H.; Stefanucci, A.; Zengin, G. Chemical profile, antiproliferative, antioxidant, and enzyme inhibition activities and docking studies of Cymbopogon schoenanthus (L.) Spreng. and Cymbopogon nervatus (Hochst.) Chiov. from Sudan. J. Food Biochem., 2020, 44, e13107.
[http://dx.doi.org/10.1111/jfbc.13107]
[12]
Mohammed, A.B.A.; Yagi, S.; Tzanova, T.; Schohn, H.; Abdelgadir, H.; Stefanucci, A.; Zengin, G. Chemical profile, antiproliferative, antioxidant and enzyme inhibition activities of Ocimum basilicum L. and Pulicaria undulata (L.) C.A. Mey. grown in Sudan. S. Afr. J. Bot., 2020, 132, 403-409.
[http://dx.doi.org/10.1016/j.sajb.2020.06.006]
[13]
Khlifi, D.; Sghaier, R.M.; Amouri, S.; Laouini, D.; Hamdi, M.; Bouajila, J. Composition and anti-oxidant, anti-cancer and anti-inflammatory activities of Artemisia herba-alba, Ruta chalepensis L. and Peganum harmala L. Food Chem. Toxicol., 2013, 55, 202-208.
[http://dx.doi.org/10.1016/j.fct.2013.01.004]
[14]
Pollio, A.; De Natale, A.; Appetiti, E.; Aliotta, G.; Touwaide, A. Continuity and change in the Mediterranean medical tradition: Ruta spp. (rutaceae) in Hippocratic medicine and present practices. J. Ethnopharmacol., 2008, 116, 469-482.
[http://dx.doi.org/10.1016/j.jep.2007.12.013]
[15]
Aguila, L.; Ruedlinger, J.; Mansilla, K.; Ordenes, J.; Salvatici, R.; de Campos, R.R.; Romero, F. Relaxant effects of a hydroalcoholic extract of Ruta graveolens on isolated rat tracheal rings. Biol. Res., 2015, 48, 28.
[http://dx.doi.org/10.1186/s40659-015-0017-8]
[16]
Eissa, T.F.; González-Burgos, E.; Carretero, M.E.; Gómez-Serranillos, M.P. Biological activity of HPLC-characterized ethanol extract from the aerial parts of Haplophyllum tuberculatum. Pharm. Biol., 2014, 52, 151-156.
[http://dx.doi.org/10.3109/13880209.2013.819517]
[17]
Eissa, T.F.; González-Burgos, E.; Carretero, M.E.; Gómez-Serranillos, M.P. Compositional analysis and in vitro protective activity against oxidative stress of essential oils from Egyptian plants used in traditional medicine. Nat. Prod. Commun., 2014, 9, 1377-1382.
[http://dx.doi.org/10.1177/1934578X1400900939]
[18]
Al-Brashdi, A.S.; Al-Ariymi, H.A.; Al Hashmi, M.; Khan, S.A. Evaluation of antioxidant potential, total phenolic content and phytochemical screening of aerial parts of a folkloric medicine, Haplophyllum tuberculatum (Forssk) A. Juss. J. Coast. Life Med., 2016, 4, 315-319.
[http://dx.doi.org/10.12980/jclm.4.2016J6-4]
[19]
Ratheesh, M.; Shyni, G.L.; Sindhu, G.; Helen, A. Protective effects of isolated polyphenolic and alkaloid fractions of Ruta graveolens L. on acute and chronic models of inflammation. Inflammation, 2009, 33, 18-24.
[http://dx.doi.org/10.1007/s10753-009-9154-y]
[20]
Hamdi, A.; Majouli, K.; Abdelhamid, A.; Marzouk, B.; Belghith, H.; Chraief, I.; Bouraoui, A.; Marzouk, Z.; Heyden, Y.V. Pharmacological activities of the organic extracts and fatty acid composition of the petroleum ether extract from Haplophyllum tuberculatum leaves. J. Ethnopharmacol., 2018, 216, 97-103.
[http://dx.doi.org/10.1016/j.jep.2018.01.012]
[21]
Haddouchi, F.; Chaouche, T.M.; Zaouali, Y.; Ksouri, R.; Attou, A.; Benmansour, A. Chemical composition and antimicrobial activity of the essential oils from four Ruta species growing in Algeria. Food Chem., 2013, 141, 253-258.
[http://dx.doi.org/10.1016/j.foodchem.2013.03.007]
[22]
Fadlalla, F.K.; Watson, A.; Yehualaeshet, T.; Turner, T.; Samuel, T. Ruta graveolens extract induces DNA damage pathways and blocks Akt activation to inhibit cancer cell proliferation and survival. Anticancer Res., 2011, 31, 233-241.
[23]
Nayki, C.; Nayki, U.; Keskin Cimen, F.; Kulhan, M.; Yapca, O.E.; Kurt, N.; Bilgin Ozbek, A. The effect of rutin on ovarian ischemia-reperfusion injury in a rat model. Gynecol. Endocrinol., 2018, 34, 809-814.
[http://dx.doi.org/10.1080/09513590.2018.1450378]
[24]
Wu, P.; Meng, X.; Zheng, H.; Zeng, Q.; Chen, T.; Wang, W.; Zhang, X.; Su, J. Kaempferol attenuates ROS-induced hemolysis and the molecular mechanism of its induction of apoptosis on Bladder cancer. Molecules, 2018, 23, E2592.
[http://dx.doi.org/10.3390/molecules23102592]
[25]
Imran, I.M.; Salehi, B.; Sharifi-Rad, J.; Aslam Gondal, T.; Saeed, F.; Imran, A.; Shahbaz, M.; Tsouh Fokou, P.V.; Umair Arshad, M.; Khan, H.; Guerreiro, S.G.; Martins, N.; Estevinho, L.M. Kaempferol: a key emphasis to its anticancer potential. Molecules, 2019, 24, E2277.
[http://dx.doi.org/10.3390/molecules24122277]
[26]
Hadjadj, S.; Bayoussef, Z.; El Hadj-Khelil, A.O.; Beggat, H.; Bouhafs, Z.; Boukak, Y.; Khaldi, I.A.; Mimouni, S.; Sayah, F.; Meriem, T. Ethnobotanical study and phytochemical screening of six medicinal plants used in traditional medicine in the Northeastern Sahara of Algeria (area of Ouargla). J. Med. Plants Res., 2015, 8, 1049-1059.
[http://dx.doi.org/10.5897/JMPR2015.5932]
[27]
Slinkard, K.; Singleton, V.L. Total phenol analyse: automation and comparison with manual methods. Am. J. Enol. Vitic., 1977, 28, 49-55.
[28]
Bahorun, T.; Grinier, B.; Trotin, F.; Brunet, G.; Pin, T.; Luncky, M.; Vasseur, J.; Cazin, M.; Cazin, C.; Pinkas, M. Oxygen species scavenging activity of phenolic extracts from hawthorn fresh plant organs and pharmaceutical preparations, Arzneimitt. Forsch., 1996, 46, 1086-1089.
[29]
OECD. Guidelines for the testing of chemicals. Acute Oral. Toxic. Proced., 2008, 425, 29.
[30]
Hussain, L.; Ikram, J.; Rehman, K.; Tariq, M.; Ibrahim, M.; Akash, M.S.H. Hepatoprotective effects of malvasylvestrisl. against paracetamol-induced hepatotoxicity. Turk. J. Biol., 2014, 38, 396-402.
[http://dx.doi.org/10.3906/biy-1312-32]
[31]
Wu, H.; Zhang, G.; Huang, L.; Pang, H.; Zhang, N.; Chen, Y.; Wang, G. Hepatoprotective effect of polyphenol-enriched fraction from Folium microcos on oxidative stress and apoptosis in acetaminophen-induced liver injury in mice. Oxid. Med. Cell. Longev., 2017, 4, 1-14.
[http://dx.doi.org/10.1155/2017/3631565]
[32]
Al-Rehaily, A.J.; Al-Howiriny, T.A.; Ahmad, M.S.; Al-Yahya, M.A.; El-Feraly, F.S.; Hufford, C.D.; McPhail, A.T. Alkaloids from Haplophyllum tuberculatum. Phytochemistry, 2001, 57, 597-602.
[http://dx.doi.org/10.1016/S0031-9422(01)00041-3]
[33]
Lee, J.; Rennaker, C. Influence of extraction methodology on grape composition values. Food Chem., 2011, 126, 295-300.
[http://dx.doi.org/10.1016/j.foodchem.2010.11.006]
[34]
Saad, B.; Azaizeh, H.; Abu-Hijleh, G.; Said, O. Safety of traditional Arab herbal medicine. Evid. Based Complement. Alternat. Med., 2006, 3, 433-439.
[http://dx.doi.org/10.1093/ecam/nel058]
[35]
Den Hartogh, D.J.; Tsiani, E. Antidiabetic properties of naringenin: a Citrus fruit polyphenol. Biomolecules, 2019, 9, E99.
[http://dx.doi.org/10.3390/biom9030099]
[36]
Adam, S.I.Y.; Ahmed, N.N.A.; Eltayeb, A.M.; Saad, H.; Taha, K.A. toxicity of Ruta graveolens seeds’ extracts on male wistar rats. Int. J. Anim. Vet. Adv., 2014, 6, 92-96.
[http://dx.doi.org/10.19026/ijava.6.5624]
[37]
Ali, B.H.; Bashir, A.K.; Rasheed, R.A. Effect of the traditional medicinal plants Rhazya stricta, Balanitis aegyptiaca and Haplophylum tuberculatum on paracetamol-induced hepatotoxicity in mice. Phytother. Res., 2001, 15, 598-603.
[http://dx.doi.org/10.1002/ptr.818]
[38]
Farkhondeh, T.; Kianmehr, M.; Kazemi, T.; Samarghandian, S.; Khazdair, M.R. Toxicity effects of Nerium oleander, basic and clinical evidence: A comprehensive review. Hum. Exp. Toxicol., 2020, 39(6), 773-784.
[http://dx.doi.org/10.1177/0960327120901571]
[39]
Lee, J.; Kim, J.H. Kaempferol inhibits pancreatic cancer cell growth and migration through the blockade of EGFR-related pathway in vitro. PLoS One, 2016, 11, 1-14.
[http://dx.doi.org/10.1371/journal.pone.0155264]
[40]
Abdulkhaleq, F.M.; Alhussainy, T.M.; Badr, M.M.; Khalil, A.A.A.; Gammoh, O.; Ghanim, B.Y.; Qinna, N.A. Antioxidative stress effects of vitamins C, E, and B12, and their combination can protect the liver against acetaminophen-induced hepatotoxicity in rats. Drug Des. Devel. Ther., 2018, 12, 3525-3533.
[http://dx.doi.org/10.2147/DDDT.S172487]
[41]
Hassanin, K.M.A.; Hashem, K.S.; Abdel-Kawi, S.H. Hepatoprotective effects of vitamin C and micronized vitamin C against paracetamol induced hepatotoxicity in rats: a comparative study. Int. J. Biochem. Biotechnol., 2013, 2, 474-483.
[http://dx.doi.org/10.21608/jvmr.2013.77678]
[42]
Zang, L.Y.; Cosma, G.; Gardner, H.; Shi, X.; Castranova, V.; Vallyathan, V. Effect of antioxidant protection by p-coumaric acid on low-density lipoprotein cholesterol oxidation. Am. J. Physiol. Cell Physiol., 2000, 279, 954-960.
[http://dx.doi.org/10.1152/ajpcell.2000.279.4.C954]
[43]
Liu, Y.; Cao, Y.; Fang, S.; Wang, T.; Yin, Z.; Shang, X. Antidiabetic effect of Cyclocarya paliurus leaves depends on the contents of zntihyperglycemic flavonoids and antihyperlipidemic triterpenoids. Molecules, 2018, 23, E1042.
[http://dx.doi.org/10.3390/molecules23051042]
[44]
Toserkani, A.; Razi Jalali, M.; Najafzaheh, H. Changes of lipid profiles, glucose, and hemogram after administration of Ruta graveolens extract in diabetic rats. Comp. Clin. Pathol., 2012, 21, 1587-1592.
[http://dx.doi.org/10.1007/s00580-011-1331-3]
[45]
Merghem, M.; Dahamna, S.; Rezzagui, A.; Boussahel, S.; Belgue, A.; Dehimi, K.; Harzallah, D. Acute and chronic toxicity of aqueous extract of Ruta montana L. in rodents. Pharmacogn. Commun., 2013, 3, 50-57.
[http://dx.doi.org/10.5530/pc.2013.2.11]
[46]
Ghorbani, A. Mechanisms of antidiabetic effects of flavonoid rutin. Biomed. Pharmacother., 2017, 96, 305-312.
[http://dx.doi.org/10.1016/j.biopha.2017.10.001]
[47]
Kamisan, F.H.; Yahya, F.; Aisyah Ismail, N.; Shamsahal Din, S.; Mamat, S.S.; Zabidi, Z.; Zainulddin, W.N.W.; Mohtarrudin, N.; Husain, H.; Ahmad, Z.; Zakaria, Z.A. Hepatoprotective activity of methanol extract of Melastoma malabathricum leaf in rats. J. Acupunct. Meridian Stud., 2013, 6, 52-55.
[http://dx.doi.org/10.1016/j.jams.2012.08.002]
[48]
Aseervatham, G.S.; Sivasudha, T.; Sasikumar, J.M.; Christabel, P.H.; Jeyadevi, R.; Ananth, D.A. Antioxidant and hepatoprotective potential of Pouteria campechiana on acetaminophen-induced hepatic toxicity in rats. J. Physiol. Biochem., 2014, 70, 1-14.
[http://dx.doi.org/10.1007/s13105-013-0274-3]
[49]
Rasekh, H.R.; Khoshnood-Mansourkhani, M.J.; Kamalinejad, M. Hypolipidemic effects of Teucrium polium in rats. Fitoterapia, 2001, 72, 937-939.
[http://dx.doi.org/10.1016/S0367-326X(01)00348-3]
[50]
National Instituez of health guide, 25, No 28.Guide for the care and use of laboratory animals, 8th ed; National Academies Press: Washington, D.C, 1996, pp. 1-246.

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