Boldo, Its Secondary Metabolites and their Derivatives

Author(s): Bruce K. Cassels*, Gonzalo Fuentes-Barros, Sebastián Castro-Saavedra.

Journal Name: Current Traditional Medicine

Volume 5 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Boldo leaves (Boldo folium, from Peumus boldus Mol.) are very frequently used as a medicinal herb in Chile and are exported to many countries to be used in teas or as extracts included in herbal remedies, primarily as an aid to digestion and as a mild sedative. Scientific support for these uses is scanty, and boldine, an alkaloid viewed as characteristic of the tree and present in high concentration in the bark, is extracted by specialized companies and sold as the supposed main active constituent. Consequently, boldine has been the subject of a considerable number of research papers, while some of the other alkaloids present to a greater extent in the leaves have been relatively neglected except when found in large amounts in other species. These studies range from assays of antioxidant activity to anti-inflammatory, antineoplastic and other medical applications. The essential oil, usually containing a large percentage of the toxic ascaridole, was once used as a vermifuge and is now regarded with caution, but is still of interest as a possible natural insecticide, fungicide, antiparasitic and herbicide. The last decade has seen an explosive increase in papers pointing to possible uses of boldo and its constituents. This review attempts to bring these publications together in a comprehensive way with the purpose of stimulating and orienting further research into the useful properties of this Chilean endemic tree.

Keywords: Peumus boldus (boldo), pharmacological properties, secondary metabolites, hemisynthetic derivatives, herbal remedies, alkaloid.

[1]
Bourgoin E, Verne C. Sur l’existence d’un alcali organique dans le boldo. J Pharm Chim 1872; 16: 191-3.
[2]
Valdebenito G, Molina J, Benedetti S, Hormazábal M, Pavez C. Modelos de Negocios Sustentables de Recolección, Procesamiento y Comercialización de Productos Forestales No Madereros en Chile. Santiago, Chile: Fundación para la Innovación Agraria 2015.
[3]
Speisky H, Cassels BK. Boldo and boldine: An emerging case of natural drug development. Pharmacol Res 1994; 29: 1-12.
[4]
O’Brien P, Carrasco-Pozo C, Speisky H. Boldine and its antioxidant or health-promoting properties. Chem Biol Interact 2006; 159: 1-17.
[5]
Muthná D, Ćmielová J, Tomšik P, et al. Boldine and related aporphines: From antioxidant to antiproliferative properties. Nat Prod Commun 2013; 8: 1797-800.
[7]
Williams DH, Stone MJ, Hauck PR, Rahman SK. Why are secondary metabolites (natural products) biosynthesized? J Nat Prod 1989; 52: 1189-208.
[8]
Fuentes-Barros G, Castro-Saavedra S, Liberona L, Acevedo-Fuentes W, Tirapegui C, Cassels BK. Variation of the alkaloid content of Peumus boldus (boldo). Fitoterapia 2018; 127: 179-85.
[9]
Betts TJ. Cromatographic evaluation of boldine and associated alkaloids in boldo. J Chromatogr 1990; 511: 373-8.
[10]
Vogel H, Razmilic I, Muñoz M, Doll U, San Martín J. Studies of genetic variation of essential oil and alkaloid content in boldo (Peumus boldus). Planta Med 1999; 65: 90-1.
[11]
Falé PL, Amaral F, Madeira PJA, et al. Acetylcholinesterase inhibition, antioxidant activity and toxicity of Peumus boldus water extracts on HeLa and Caco-2 cell lines. Food Chem Toxicol 2012; 50: 2656-62.
[12]
Soto C, Caballero E, Pérez E, Zúñiga ME. Effect of extraction conditions on total phenolic content and antioxidant capacity of pretreated wild Peumus boldus leaves from Chile. Food Bioprod Process 2014; 92: 328-33.
[13]
Bakiri A, Hubert J, Reynaud R, et al. Computer-Aided 13C NMR chemical profiling of crude natural extract without fractionation. ‎. J Nat Prod 2017; 80: 1387-96.
[14]
Schmeda-Hirschmann G, Rodríguez JA, Theoduloz C, Astudillo SL, Feresin GE, Tapia A. Free-radical scavengers and antioxidants from Peumus boldus Mol. (“Boldo”). Free Radic Res 2003; 37: 447-52.
[15]
Quezada M, Asencio M, del Valle JM, Aguilera JM, Gómez B. Antioxidant activity of crude extract, alkaloid fraction, and flavonoid fraction from boldo (Peumus boldus Molina) leaves. J Food Sci 2004; 69: 371-6.
[16]
del Valle JM, Godoy C, Asencio M, Aguilera JM. Recovery of antioxidants from boldo (Peumus boldus Mol.) by conventional and supercritical CO2 extraction. Food Res Int 2004; 37: 695-702.
[17]
Simirgiotis MJ, Schmeda-Hirschmann G. Direct identification of phenolic constituents in Boldo Folium (Peumus boldus Mol.) infusions by high-performance liquid chromatography with diode array detection and electrospray ionization tandem mass spectroscopy. J Chromatogr A 2010; 1217: 443-9.
[18]
Tamura S, Hattori Y, Kaneko M, et al. Peumusolide A, unprecedented NES non-antagonistic inhibitor for nuclear export of MEK. Tetrahedron Lett 2010; 51: 1678-81.
[19]
Tamura S, Tonokawa M, Murakami N. Stereo-controlled synthesis of analogs of peumusolide A, NES non-antagonistic inhibitor for nuclear export of MEK. Tetrahedron Lett 2010; 51: 3134-7.
[20]
Tamura S, Doke S, Murakami N. Total synthesis of peumusolide A, NES non-antagonistic inhibitor for nuclear export of MEK. Tetrahedron 2010; 66: 8476-80.
[21]
Chou GX, Norio N, Ma CM, Wang ZT, Masao H. Isoquinoline alkaloids from Lindera aggregata. Chin J Nat Med 2005; 3: 272-5.
[22]
Wang C, Dai Y, Yang J, Chou G, Wang C, Wang Z. Treatment with total alkaloids from Radix Linderae reduces inflammation and joint destruction in type II collagen-induced model for rheumatoid arthritis. J Ethnopharmacol 2007; 111: 322-8.
[23]
Tomita M, Sawada T, Kozuka M, Hamano D, Yoshimura K. The alkaloids of Lindera strychnifolia (Sieb. et Zucc.) F. Vill. and Lindera umbellata Thunb. J Jpn Pharm Soc 1969; 89: 737-40. (Yakugaku Zasshi).
[24]
Kozuka M, Yoshikawa M, Sawada T. Alkaloids from Lindera strychnifolia. J Nat Prod 1984; 47: 1063.
[25]
Gan LS, Yao W, Mo JX, Zhou CX. Alkaloids from Lindera aggregata. Nat Prod Commun 2009; 4: 43-6.
[26]
Chen JZ, Chou GX, Wang CH, Yang L, Bligh SW, Wang ZT. Characterization of new metabolites from in vivo biotransformation of norisoboldine by liquid chromatography/mass spectrometry and NMR spectroscopy. J Pharm Biomed Anal 2010; 52: 687-93.
[27]
Marsaioli AJ, Reis FAM, Magalães AF, Rúveda EA. 13C NMR analysis of aporphine alkaloids. Phytochemistry 1979; 18: 165-9.
[28]
Basalo C, Mohn T, Hamburger M. Are extraction methods in quantitative assays of pharmacopoeia monographs exhaustive? A comparison with pressurized liquid extraction. Planta Med 2006; 72: 1157-62.
[29]
Lee SS, Lai YC, Chen CK, Tseng LH, Wang CY. Characterization of isoquinoline alkaloids from Neolitsea sericea var. aurata by HPLC-SPE-NMR. J Nat Prod 2007; 70: 637-42.
[30]
Han Z, Zheng Y, Chen N, et al. Simultaneous determination of four alkaloids in Lindera aggregata by ultra-high-pressure liquid chromatography-tandem mass spectrometry. J Chromatogr A 2008; 1212: 76-81.
[31]
Chen F, Li HL, Li YH, et al. Quantitative analysis of the major constituents in Chinese medicinal preparation SuoQuan formulae by ultra fast high performance liquid chromatography/quadrupole tandem mass spectrometry. Chem Cent J 2013; 7: 131.
[32]
Sun C, Li J, Wang D, Yu J, Wang X, Huang L. Preparative separation of alkaloids from Litsea cubeba using combined applications of pH-zone-refining and high-speed counter-current chromatography. RSC Advances 2015; 5: 75831-7.
[33]
Cámara CI, Bornancini CA, Cabrera JL, Ortega MG, Yudi LM. Quantitative analysis of boldine alkaloid in natural extracts by cyclic voltammetry at a liquid-liquid interface and validation of the method by comparison with high performance liquid chromatography. Talanta 2010; 83: 623-30.
[34]
Peralta CM, Henestrosa C, Gil RA, et al. Novel spectrofluorimetric method for boldine alkaloid determination in herbal drugs and phytopharmaceuticals. Spectrochim Acta A 2017; 184: 101-8.
[35]
Misra N, Siddiqui SA, Srivastava R, et al. Vibrational analysis of boldine hydrochloride using QM/MM approach. Spectroscopy 2010; 24: 483-99.
[36]
Srivastava A, Tandon P, Ayala AP, et al. Solid state characterization of an antioxidant alkaloid boldine using vibrational spectroscopy and quantum chemical calculations. Vib Spectrosc 2011; 56: 82-8.
[37]
Herrera MA, Jara GP, Villarroel R, et al. Surface enhanced Raman scattering study of the antioxidant alkaloid boldine using prismatic silver nanoparticles. Spectrochim Acta A Mol Biomol Spectrosc 2014; 133: 591-6.
[38]
Zahari A, Ablat A, Omer N, et al. Ultraviolet-visible study on acid-base equilibria of aporphine alkaloids with antiplasmodial and antioxidant activities from Alseodaphne corneri and Dehaasia longipedicellata. Scientif Rep 2016; 6: 21517.
[39]
Verdeguer M, García-Rellán D, Boira H, Pérez E, Gandolfo S, Blázquez MA. Herbicidal activity of Peumus boldus and Drimys winterii essential oils from Chile. Molecules 2011; 16: 403-11.
[40]
Blázquez MA, Carbó E. Control of Portulaca oleracea by boldo and lemon essential oils in different soils. Ind Crops Prod 2015; 76: 515-21.
[41]
Urzúa A, Santander R, Echeverría J, Villalobos C, Palacios SR, Rossi Y. Insecticidal properties of Peumus boldus Mol. essential oil on the house fly, Musca domestica L. BLACPMA 2010; 9: 465-9.
[42]
Rezende DACS, Souza RV, Magalhães ML, et al. Characterization of the biological potential of the essential oils from five species of medicinal plants. Am J Plant Sci 2017; 8: 154-70.
[43]
Vila R, Valenzuela L, Bello H, Cañigueral S, Montes M, Adzet T. Composition and antimicrobial activity of the essential oil of Peumus Boldus Leaves. Planta Med 1999; 65: 178-9.
[44]
Passone MA, Etcheverry M. Antifungal impact of volatile fractions of Peumus boldus and Lippia turbinata on Aspergillus section Flavi and residual levels of these oils in irradiated peanut. Int J Food Microbiol 2014; 168-169: 17-23.
[45]
Mazutti M, Mossi AJ, Cansian RL, Corazza ML, Dariva C, Oliveira JV. Chemical profile and antimicrobial activity of Boldo (Peumus boldus Molina) extracts obtained by compressed carbon dioxide extraction. Braz J Chem Eng 2008; 25: 427-34.
[46]
de Castro DS, da Silva DB, Tibúrcio JD, et al. Larvicidal activity of essential oil of Peumus boldus Molina and its ascaridole-enriched fraction against Culex quinquefasciatus. Exp Parasitol 2016; 171: 84-90.
[47]
Cavalli J-F, Tomi F, Bernardini A-F, Casanova J. Combined analysis of the essential oil of Chenopodium ambrosioides by GC, GC-MS and 13C-NMR spectroscopy: Quantitative determination of ascaridole, a heat-sensitive compound. Phytochem Anal 2004; 15: 275-9.
[48]
Rogalinski T, del Valle JM, Zetzl C, Brunner G. Extraction of boldo (Peumus boldus M.) leaves with hot pressurized water and supercritical CO2. 6th International Symposium on Supercritical Fluids - ISASF; 2003.April 28-30; Versailles, France..
[49]
Sargenti SR, Lanças FM. Supercritical fluid extraction of Peumus boldus (Molina). J Sep Sci 1997; 20: 511-5.
[50]
del Valle JM, Rogalinski T, Zetzl C, Brunner G. Extraction of boldo (Peumus boldus M.) leaves with supercritical CO2 and hot pressurized water. Food Res Int 2005; 38: 203-13.
[51]
Uquiche E, Huerta E, Sandoval A, del Valle JM. Effect of boldo (Peumus boldus M.) pretreatment on kinetics of supercritical CO2 extraction of essential oil. J Food Eng 2012; 109: 230-7.
[52]
Petigny L, Périno S, Minuti M, Visinoni F, Wajsman J, Chemat F. Simultaneous microwave extraction and separation of volatile and non-volatile organic compounds of boldo leaves. From Lab to Industrial Scale. Int J Mol Sci 2014; 15: 7183-98.
[53]
Pacheco N. Estudio de la composición fenólica de las especies nativas: Peumus boldus, Cryptocarya alba y Schinus latifolius. Thesis. Universidad de Chile, Santiago, Chile 2011.
[54]
Klimaczewski CV, Saraiva RA, Roos DH, et al. Antioxidant activity of Peumus boldus extract and alkaloid boldine against damage induced by Fe(II)-citrate in rat liver mitochondria in vitro. Ind Crops Prod 2014; 54: 240-7.
[55]
Zielinski AAF, Haminiuk CWI, Alberti A, Nogueira A, Demiate IM, Granato D. A comparative study of the phenolic compounds and the in vitro antioxidant activity of different Brazilian teas using multivariate statistical techniques. Food Res Int 2014; 60: 246-54.
[56]
Bianchini MC, Gularte CO, Escoto DF, et al. Peumus boldus (boldo) aqueous extract presents better protective effect than boldine against manganese-induced toxicity in D. melanogaster. Neurochem Res 2016; 41: 2699-707.
[57]
Hughes DW, Genest K, Skakum W. Alkaloids of Peumus boldus. Isolation of (+) reticuline and isoboldine. J Pharm Sci Exp Pharmacol 1968; 57: 1023-5.
[58]
Hughes DW, Genest K, Skakum W. Alkaloids of Peumus boldus. Isolation of laurotetanine and laurolitsine. J Pharm Sci 1968; 57: 1619-20.
[59]
de Orsi D, Gagliardi L, Manna F, Tonelli D. HPLC analysis of boldine in pharmaceuticals. Chromatographia 1997; 44: 619-22.
[60]
Pietta P, Mauri P, Manera E, Ceva P. Determination of isoquinoline alkaloids from Peumus boldus by high-performance liquid chromatography. J Chromatogr A 1988; 457: 442-5.
[61]
Schwanz M. Desenvolvimiento e validação de método para quantificação da boldina em Peumus boldus Mol. (Monimiaceae) e avaliação preliminar de sua estabilidade. MSc Thesis. Universidad Federal do Rio Grande do Sul Porto Alegre, Brasil 2006.
[62]
Espic M. Evaluación de la producción de biomasa áerea y del rendimiento en aceite esencial y boldina, de boldo (Peumus boldus Mol.) en la comuna de Papudo, V Región. Thesis. Universidad de Chile, Santiago, Chile 2007.
[63]
Russo A, Cardile V, Caggia S, et al. Boldo prevents UV light and nitric oxide-mediated plasmid DNA damage and reduces the expression of Hsp70 protein in melanoma cancer cells. J Pharm Pharmacol 2011; 63: 1219-29.
[64]
Petigny L, Périno-Issartier S, Wajsman J, Chemat F. Batch and continuous ultrasound assisted extraction of boldo leaves (Peumus boldus Mol.). Int J Mol Sci 2013; 14: 5750-64.
[65]
Hošt’álková A, Opletal L, Kuneš J, et al. Alkaloids from Peumus boldus and their acetylcholinesterase, butyrylcholinesterase and prolyl oligopeptidase inhibition activity. Nat Prod Commun 2015; 10: 577-80.
[66]
Carmona ER, Reyes-Díaz M, Parodi J, Inostroza-Blancheteau C. Antimutagenic evaluation of traditional medicinal plants from South America Peumus boldus and Cryptocarya alba using Drosophila melanogaster. J Toxicol Environ Health A 2017; 80: 208-17.
[67]
Palomino A. Constituyentes volátiles del aceite esencial de Peumus boldus (Boldo) del Perú. Rev Per Ing Quim 2007; 10: 18-21.
[68]
Bittner M, Aguilera MA, Hernández V, Arbert C, Becerra J, Casanueva ME. Fungistatic activity of essential oils extracted from Peumus boldus Mol., Laureliopsis philippiana (Looser) Schodde and Laurelia sempervirens (Ruiz & Pav.) Tul. (Chilean Monimiaceae). Chil J Agric Res 2009; 69: 30-7.
[69]
Herrera-Rodríguez C, Ramírez-Mendoza C, Becerra-Morales I, et al. Bioactivity of Peumus boldus Molina, Laurelia sempervirens (Ruiz & Pav.) Tul. and Laureliopsis philippiana (Looser) Schodde (Monimiacea) essential oils against Sitophilus zeamais Motschulsky. Chil J Agric Res 2015; 75: 334-40.
[70]
Alarcón E, Campos AM, Edwards AM, Lissi E, López-Alarcón C. Antioxidant capacity of herbal infusions and tea extracts: A comparison of ORAC-fluorescein and ORAC-pyrogallol red methodologies. Food Chem 2008; 107: 1114-9.
[71]
Atala E, Aspée A, Speisky H, Lissi E, López-Alarcón C. Antioxidant capacity of phenolic compounds in acidic medium: A pyrogallol red-based ORAC (oxygen radical absorbance capacity) assay. J Food Compos Anal 2013; 32: 116-25.
[72]
Vieitez I, Maceiras L, Jachmanián I, Alborés S. Antioxidant and antibacterial activity of different extracts from herbs obtained by maceration or supercritical technology. J Supercrit Fluids 2018; 133: 58-64.
[73]
Speisky H, Rocco C, Carrasco C, Lissi EA, López-Alarcón C. Antioxidant screening of medicinal herbal teas. Phytother Res 2006; 20: 462-7.
[74]
Pastene E, Parada V, Avello M, Ruiz A, García A. Catechin-based procyanidins from Peumus boldus Mol. aqueous extract inhibit Helicobacter pylori urease and adherence to adenocarcinoma gastric cells. Phytother Res 2014; 28: 1637-45.
[75]
Zhang H, Tsao R. Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects. Curr Opin Food Sci 2016; 8: 33-42.
[76]
Reiniger IW, Ribeiro da Silva C, Felzenszwalb I, et al. Boldine action against the stannous chloride effect. J Ethnopharmacol 1999; 68: 345-8.
[77]
Zhao Q, Zhao Y, Wang K. Antinociceptive and free radical scavenging activities of alkaloids isolated from Lindera angustifolia Chen. J Ethnopharmacol 2006; 106: 408-13.
[78]
Milián L, Estellés R, Abarca B, Ballesteros R, Sanz MJ, Blázquez MA. Reactive oxygen species (ROS) generation inhibited by aporphine and phenanthrene alkaloids semi-synthesized from natural boldine. Chem Pharm Bull 2004; 52: 696-9.
[79]
Milián L, Ballesteros R, Sanz MJ, Blázquez MA. Synthesis and reactive oxygen species scavenging activity of halogen alkaloids from boldine. Med Chem Res 2012; 21: 3133-9.
[80]
Cassels BK, Asencio M, Conget P, Speisky H, Videla LA, Lissi EA. Structure-antioxidative activity relationships in benzylisoquinoline alkaloids. Pharmacol Res 1995; 31: 103-7.
[81]
Lanhers MC, Joyeux M, Soulimani R, et al. Hepatoprotective and anti-inflammatory effects of a traditional medicinal plant of Chile, Peumus boldus. Planta Med 1991; 57: 110-5.
[82]
Heidari R, Moezi L, Asadi B, Ommati MM, Azarpira N. Hepatoprotective effect of boldine in a bile duct ligated rat model of cholestasis/cirrhosis. PharmaNutrition 2017; 5: 109-17.
[83]
Zagorová M, Prasnická A, Kadová Z, et al. Boldine attenuates cholestasis associated with nonalcoholic fatty liver disease in hereditary hypertriglyceridemic rats fed by high-sucrose diet. Physiol Res 2015; 64(Suppl. 4): S467-76.
[84]
Ochoa C, Granda C, Chapoñan M, et al. Efecto Protector de Peumus boldus en ratas con toxicidad hepática inducida por Paracetamol. CIMEL 2008; 13: 20-5.
[85]
Veloz D. Determinación de la actividad hepatoprotectora de boldo (Peumus boldus) en ratas (Rattus novergicus) con intoxicación hepática inducida por paracetamol. MSc Thesis Escuela Superior Politécnica de Chimborazo, Riobamba, Ecuador 2013.
[86]
Gutiérrez R, Jiménez J. Efecto protector del extracto acuoso de Peumus boldus (boldo) frente a la inducción de cirrosis hepática con paracetamol y fenobarbital en ratas, comparado con la silimarina. MSc Thesis. Universidad Nacional de San Agustín de Arequipa, Arequipa, Perú. 2015.
[87]
Olivares J. Efecto protector del extracto acuoso de las hojas de Peumus boldus “boldo” en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra. MSc Thesis. Universidad Nacional Mayor de San Marcos, Lima, Perú. 2015.
[88]
Yovera E. Efecto protector del extracto acuoso de las hojas de Peumus boldus “boldo” en la toxicidad hepática inducida por isoniazida en ratas Holtzman hembra. MSc Thesis. Universidad Nacional Mayor de San Marcos, Lima, Perú. 2015.
[89]
Cordero-Pérez P, Torres-González L, Aguirre-Garza M, et al. Efecto hepatoprotector de extractos de hierbas comerciales sobre el daño hepático inducido por tetracloruro de carbono en ratas Wistar. Pharmacognosy Res 2013; 5: 150-6.
[90]
Figueiredo MB, Santana VR, Nardelli MJ, et al. The effect of the aqueous extract Peumus boldus on the proliferation of hepatocytes and liver function in rats submitted to expanded hepatectomy. Acta Cir Bras 2016; 31: 608-14.
[91]
Gómez GI, Velarde V. Boldine treatment prevents kidney damage in rats with 5/6 nephrectomy. Indian J Med Res Pharm Sci 2016; 3: 80-90.
[92]
Gómez GI, Velarde V. Boldine improves kidney damage in the goldblatt 2K1C model avoiding the increase in TGF-β. J Mol Sci 2018; 19: 1864.
[93]
Sobeh M, Mahmoud MF, Abdelfattah MAO, El-Beshbishy HA, El-Shazly AM, Wink M. Hepatoprotective and hypoglycemic effects of a tannin rich extract from Ximenia americana var. caffra root. Phytomedicine 2017; 33: 36-42.
[94]
Konrath EL, Santin K, Nassif M, Latini A, Henriques A, Salbego C. Antioxidant and pro-oxidant properties of boldine on hippocampal slices exposed to oxygen-glucose deprivation in vitro. Neurotoxicology 2008; 29: 1136-40.
[95]
Klimaczewski CV, Ecker A, Piccoli B, Aschner M, Barbosa NV, Rocha JBT. Peumus boldus attenuates copper-induced toxicity in Drosophila melanogaster. Biomed Pharmacother 2018; 97: 1-8.
[96]
Fernández J, Lagos P, Rivera P, Zamorano-Ponce E. Effect of boldo (Peumus boldus Molina) infusion on lipoperoxidation induced by cisplatin in mice liver. Phytother Res 2009; 23: 1024-7.
[97]
Lau YS, Machha A, Achike FI, Murugan D, Mustafa MR. The aporphine alkaloid boldine improves endothelial function in spontaneously hypertensive rats. Exp Biol Med 2012; 237: 93-8.
[98]
Lau YS, Tian XY, Huang Y, Murugan D, Achike FI, Mustafa MR. Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism. Biochem Pharmacol 2013; 85: 367-75.
[99]
Lau YS, Tian XY, Mustafa MR, et al. Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin II-mediated BMP4-oxidative stress cascade. Br J Pharmacol 2013; 170: 1190-8.
[100]
Lau YS, Ling WC, Murugan D, Mustafa MR. Boldine ameliorates vascular oxidative stress and endothelial dysfunction: Therapeutic implication for hypertension and diabetes. J Cardiovasc Pharmacol 2015; 65: 522-31.
[101]
de Lima NM, Ferreira EO, Fernandes MY, et al. Neuroinflammatory response to experimental stroke is inhibited by boldine. Behav Pharmacol 2017; 28: 223-37.
[102]
Qiu X, Shi L, Zhuang H, et al. Cerebrovascular protective effect of boldine against neural apoptosis via inhibition of mitochondrial Bax translocation and cytochrome C release. Med Sci Monit 2017; 23: 4106-16.
[103]
Hu J, Speisky J, Cotgreave IA. The inhibitory effects of boldine, glaucine and probucol on TPA-induced down regulation of gap junction function: Relationships to intracellular peroxides, protein kinase C translocation, and connexin 43 phosphorylation. Biochem Pharmacol 1995; 50: 1635-43.
[104]
López R, Arismendi M, Sáez JC, Godoy I, Ocaranza MP. Boldine decreases post ischemia/reperfusion myocardial apoptosis in rats. Rev Chil Cardiol 2011; 31: 146-54.
[105]
Hernández-Salinas R, Vielma AZ, Arismendi MN, Boric MP, Sáez JC, Velarde V. Boldine prevents renal alterations in diabetic rats. J Diabetes Res 2013; 2013: 593672.
[106]
Yi C, Ezan P, Fernández P, et al. Inhibition of glial hemichannels by boldine treatment reduces neural suffering in a murine model of Alzheimer’s disease. Glia 2017; 65: 1607-25.
[107]
Speisky H, Cassels BK, Lissi EA, Videla LA. Antioxidant properties of the alkaloid boldine in systems undergoing lipid peroxidation and enzyme inactivation. Biochem Pharmacol 1991; 41: 1575-81.
[108]
Valenzuela A, Sanhueza J, Alonso P, Corbari A, Nieto S. Inhibitory action of conventional food-grade natural antioxidants and of natural antioxidants of new development on the thermal-induced oxidation of cholesterol. Int J Food Sci Nutr 2004; 55: 155-62.
[109]
Morales MA, Bustamante SE, Brito G, Paz D, Cassels BK. Cardiovascular effects of plant secondary metabolites norarmepavine, coclaurine and norcoclaurine. Phytother Res 1998; 12: 103-9.
[110]
Ivorra MD, Chuliá S, Lugnier C, D’Ocón MP. Selective action of two aporphines at α1-adrenoceptors and potential-operated Ca2+ channels. Eur J Pharmacol 1993; 231: 165-74.
[111]
Ivorra MD, Martínez F, Serrano A, D’Ocón P. Different mechanism of relaxation induced by aporphine alkaloids in rat uterus. J Pharm Pharmacol 1993; 45: 439-43.
[112]
Chuliá S, Moreau J, Naline E, et al. The effect of S-(+)-boldine on the α1-adrenoceptor of the guinea-pig aorta. Br J Pharmacol 1996; 119: 1305-12.
[113]
Madrero Y, Elorriaga M, Martínez S, et al. A possible structural determinant of selectivity of boldine and derivatives for the α1A-adrenoceptor subtype. Br J Pharmacol 1996; 119: 1563-8.
[114]
Ivorra MD, Valiente M, Martínez S, et al. 8-NH2-Boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structural requirements for aporphines at alpha1-adrenoceptor subtypes. Planta Med 2005; 71: 897-903.
[115]
Schramm A, Saxena P, Chlebek L, et al. Natural products as potential ether-a-go-go-related gene channel inhibitors – screening of plant-derived alkaloids. Planta Med 2014; 80: 740-6.
[116]
Chen KS, Ko FN, Teng CM, Wu YC. Antiplatelet and vasorelaxing actions of some aporphinoids. Planta Med 1996; 62: 133-6.
[117]
Teng CM, Hsueh CM, Chang YL, Ko FN, Lee SS, Liu KCS. Antiplatelet effect of some aporphine and phenanthrene alkaloids in rabbits and man. J Pharm Pharmacol 1997; 49: 706-11.
[118]
Santanam N, Penumetcha M, Speisky H, Parthasarathy S. A novel alkaloid antioxidant, boldine and synthetic antioxidant, reduced form of RU486, inhibit the oxidation of LDL in vitro and atherosclerosis in vivo in LDLR (-/-) mice. Atherosclerosis 2004; 173: 203-10.
[119]
Luo Y, Liu M, Xia Y, Dai Y, Chou G, Wang Z. Therapeutic effect of norisoboldine, an alkaloid isolated from Radix Linderae, on collagen-induced arthritis in mice. Phytomedicine 2010; 17: 726-31.
[120]
Luo Y, Liu M, Dai Y, et al. Norisoboldine inhibits the production of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 cells by down-regulating the activation of MAPKs but not N-F-κB. Inflammation 2010; 33: 389-97.
[121]
Lu Q, Lu S, Gao X, et al. Norisoboldine, an alkaloid compound isolated from Radix Linderae, inhibits synovial angiogenesis in adjuvant-induced arthritis rats by moderating Notch1 pathway-related endothelial tip cell phenotype. Exp Biol Med 2012; 237: 919-32.
[122]
Wei Z, Wang F, Song J, et al. Norisoboldine inhibits the production of interleukin-6 in fibroblast-like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF-κB-p65/CREB pathways. J Cell Biochem 2012; 113: 2785-95.
[123]
Wei ZF, Jiao XL, Wang T, et al. Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2), and MMP-13 expression. Acta Pharmacol Sin 2013; 34: 403-13.
[124]
Wei ZF, Tong B, Xia YF, et al. Norisoboldine suppresses osteoclast differentiation through preventing the accumulation of TRAF6-TAK1 complexes and activation of MAPKs/NF-κB/c-Fos/NFATc1 Pathways. PLoS One 2013; 8: e59171.
[125]
Lu Q, Tong B, Luo Y, et al. Norisoboldine suppresses VEGF-induced endothelial cell migration via the cAMP-PKA-NF-κB/Notch1 pathway. PLoS One 2013; 8: e81220.
[126]
Luo Y, Wei Z, Chou G, Wang Z, Xia Y, Dai Y. Norisoboldine induces apoptosis of fibroblast-like synoviocytes from adjuvant-induced arthritis rats. Int Immunopharmacol 2014; 20: 110-6.
[127]
Gao X, Lu Q, Chou G, et al. Norisoboldine attenuates inflammatory pain via the adenosine A1 receptor. Eur J Pain 2014; 18: 939-48.
[128]
Tong B, Dou Y, Wang T, et al. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues. Toxicol Appl Pharmacol 2015; 282: 90-9.
[129]
Duan C, Guo J-M, Dai Y, et al. The absorption enhancement of norisoboldine in the duodenum of adjuvant-induced arthritis rats involves the impairment of P-glycoprotein. Biopharm Drug Dispos 2017; 38: 75-83.
[130]
Qiao S, Zhao H, Xu H, et al. Effects of boldine on bone microstructure in collagen induced arthritis rats. J China-Jpn Frienship Hosp 2015; 29: 99-102.
[131]
Zhao H, Xu H, Qiao S, et al. Boldine isolated from Litsea cubeba inhibits bone resorption by suppressing the osteoclast differentiation in collagen-induced arthritis. Int Immunopharmacol 2017; 51: 114-23.
[132]
Wei ZF, Lv Q, Xia Y, et al. Norisoboldine, an anti-arthritis alkaloid isolated from Radix Linderae, attenuates osteoclast differentiation and inflammatory bone erosion in an aryl hydrocarbon receptor-dependent manner. Int J Biol Sci 2015; 11: 1113-26.
[133]
Tong B, Yuan X, Dou Y, et al. Norisoboldine, an isoquinoline alkaloid, acts as an aryl hydrocarbon receptor ligand to induce intestinal Treg cells and thereby attenuate arthritis. Int J Biochem Cell Biol 2016; 75: 63-73.
[134]
Gyurkovska V, Philipov S, Kostova N, Ivanovska N. Acetylated derivative of glaucine inhibits joint inflammation in collagenase-induced arthritis. Immunopharmacol Immunotoxicol 2015; 37: 56-62.
[135]
Lv Q, Qiao SM, Xia Y, et al. Norisoboldine ameliorates DSS-induced ulcerative colitis in mice through induction of regulatory T cells in colons. Int Immunopharmacol 2015; 29: 787-97.
[136]
Pandurangan AK, Mohebali N, Hasanpourghadi M, Looi CY, Mustafa MR, Mohd EN. Boldine suppresses dextran sulfate sodium-induced mouse experimental colitis: NF-κB and IL-6/STAT3 as potential targets. Biofactors 2016; 42: 247-58.
[137]
Gao S, Li W, Lin G, et al. Norisoboldine, an alkaloid from Radix linderae, inhibits NFAT activation and attenuates 2,4-dinitrofluorobenzene-induced dermatitis in mice. Immunopharmacol Immunotoxicol 2016; 38: 327-33.
[138]
Backhouse N, Delporte C, Guivernau M, Cassels BK, Speisky H. Anti-inflammatory and antipyretic effects of boldine. Agents Actions 1994; 42: 114-7.
[139]
Gotteland M, Jiménez I, Brunser O, et al. Protective effect of boldine in experimental colitis. Planta Med 1997; 63: 311-5.
[140]
Lv Q, Wang K, Qiao S, et al. Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway. Cell Death Dis 2018; 9: 258.
[141]
Lv Q, Wang K, Qiao S-M, Dai Y, Wei Z-F. Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome. Chin J Integr Med 2018; 16: 161-74.
[142]
Yang X, Gao X, Cao Y, et al. Anti-Inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways. Planta Med 2018; 84: 20-5.
[143]
Kondo Y, Imai Y, Hojo H, Endo T, Nozoe S. Suppression of tumor cell growth and mitogen response by aporphine alkaloids, dicentrine, glaucine, corydine and apomorphine. J Pharmacobiodyn 1990; 13: 426-31.
[144]
Hoet S, Stévigny C, Block S, et al. Alkaloids from Cassytha filiformis and related aporphines: Antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases. Planta Med 2004; 70: 407-13.
[145]
Lei Y, Tan J, Wink M, Ma Y, Li N, Su G. An isoquinoline alkaloid from the Chinese herbal plant Corydalis yanhusuo W.T. Wang inhibits P-glycoprotein and multidrug resistance-associate protein 1. Food Chem 2013; 136: 1117-21.
[146]
Kang H, Jang SW, Pak JH, Shim S. Glaucine inhibits breast cancer cell migration and invasion by inhibiting MMP-9 gene expression through the suppression of NF-κB activation. Mol Cell Biochem 2015; 403: 85-94.
[147]
Chen I-S, Chen J-J, Duh C-Y, Tsai I-L, Chang C-T. New aporphine alkaloids and cytotoxic constituents of Hernandia nymphaeifolia. Planta Med 1997; 63: 154-7.
[148]
Kim HK, Piao CJ, Choi SU, Son MW, Lee KR. New cytotoxic tetrahydroprotoberberine-aporphine dimeric and aporphine alkaloids from Corydalis turtschaninovii. Planta Med 2010; 76: 1733-8.
[149]
Zahari A, Cheah FK, Mohamad J, et al. Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata. Planta Med 2014; 80: 599-603.
[150]
Suwandri EHH, Syah YM, Juliaway LD. Cytotoxic activity of alkaloids isolated from Cryptocarya archboldiana Allen Pharmacy (ISSN 1693-3591) 2015; 12: 94-100.
[151]
Suárez-Rozas C, Castro-Castillo V, Salas-Norambuena J, et al. Synthesis of boldine derivatives with potential antineoplastic activity. Fifth Iberoamerican Congress on Natural Products. 2016 April 25-29; Bogotá, Colombia.
[152]
Zhong M, Liu Y, Liu J, et al. Isocorydine derivatives and their anticancer activities. Molecules 2014; 19: 12099-115.
[153]
Ito C, Itoigawa M, Tokuda H, Kuchide M, Nishino H, Furukawa H. Chemopreventive activity of isoquinoline alkaloids from Corydalis plants. Planta Med 2001; 67: 473-5.
[154]
Gerhardt D, Horn AP, Gaelzer MM, et al. Boldine: A potential new antiproliferative drug against glioma cell lines. Invest New Drugs 2009; 27: 517-25.
[155]
Gerhardt D, Bertola G, Bernardi A, et al. Boldine attenuates cancer cell growth in an experimental model of glioma in vivo. J Cancer Sci Ther 2013; 5: 195-9.
[156]
Gerhardt D, Bertola G, Dietrich F, et al. Boldine induces cell cycle arrest and apoptosis in T24 human bladder cancer cell line via regulation of ERK, AKT, and GSK-3β. Urol Oncol 2014; 32: 36.e1-9.
[157]
Paydar M, Kamalidehghan B, Wong YL, Wong WF, Looi CY, Mustafa MR. Evaluation of cytotoxic and chemotherapeutic properties of boldine in breast cancer using in vitro and in vivo models. Drug Des Devel Ther 2014; 8: 719-33.
[158]
Tomšík P, Mičuda S, Muthná D, et al. Boldine inhibits mouse mammary carcinoma in vivo and human MCF-7 breast cancer cells in vitro. Planta Med 2016; 82: 1416-24.
[159]
Kuck AM, Frydman B. A Synthesis of (±)-Isocorydine. J Org Chem 1961; 26: 5253-4.
[160]
Zhong M, Jiang Y, Chen Y, Yan Q, Liu J, Di D. Asymmetric total synthesis of (S)-isocorydine. Tetrahedron Asymmetry 2015; 26: 1145-9.
[161]
Sun H, Hou H, Lu P, et al. Isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/m cell cycle arrest and apoptosis. PLoS One 2012; 7: e36808.
[162]
Lu P, Sun H, Zhang L, et al. Isocorydine targets the drug-resistant cellular side population through PDCD4-related apoptosis in hepatocellular carcinoma. Mol Med 2012; 18: 1136-46.
[163]
Pan J-X, Chen G, Li J-J, et al. Isocorydine suppresses doxorubicin-induced epithelial-mesenchymal transition via inhibition of ERK signaling pathways in hepatocellular carcinoma. Am J Cancer Res 2018; 8: 154-64.
[164]
Li M, Zhang L, Ge C, et al. An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma. Oncotarget 2015; 6: 25149-60.
[165]
Chen L, Tian H, Li M, et al. Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis. Tumour Biol 2016; 37: 5951-61.
[166]
Liu X, Tian H, Li H, et al. Derivate isocorydine (d-ICD) suppresses migration and invasion of hepatocellular carcinoma cell by downregulating ITGA1 expression. Int J Mol Sci 2017; 18: 514.
[167]
Yan Q, Li R, Xin A, et al. Design, synthesis, and anticancer properties of isocorydine derivatives. Bioorg Med Chem 2017; 25: 6542-53.
[168]
Pérez EG, Cassels BK. Alkaloids from the genus Duguetia. In Cordell GA, Ed. The Alkaloids, Chemistry and Biology, Chennai: Academic Press 2010; 68: 83-156.
[169]
Pessoa CÓ, Cassels BK. Antiproliferative activity of some isoquinoline alkaloids and derivatives. Unpublished 2009.
[170]
Lin HF, Huang HL, Liao JF, Shen CC, Huang RL. Dicentrine analogue-induced G2/M arrest and apoptosis through inhibition of topoisomerase II activity in human cancer cells. Planta Med 2015; 81: 830-7.
[171]
Huang RL, Chen CC, Huang YL, et al. Anti-tumor effects of d-dicentrine from the root of Lindera megaphylla. Planta Med 1998; 64: 212-5.
[172]
Garbarino J, Troncoso N, Frasca G, et al. Potential anticancer activity against human epithelial cancer cells of Peumus boldus leaf extract. Nat Prod Commun 2008; 3: 2095-8.
[173]
Bourgou S, Pichette A, Marzouk B, Legault J. Bioactivities of black cumin essential oil and its main terpenes from Tunisia. S Afr J Bot 2010; 76: 210-6.
[174]
Sobral MV, Xavier AL, Lima TC, de Sousa DP. Antitumor activity of monoterpenes found in essential oils. Scientif World J 2014; 2014: 953451.
[175]
Efferth T, Olbrich A, Sauerbrey A, Ross DD, Gebhart E, Neugebauer M. Activity of ascaridol from the anthelmintic herb Chenopodium anthelminticum L. against sensitive and multidrug-resistant tumor cells. Anticancer Res 2002; 22: 4221-4.
[176]
Bezerra DP, Marinho Filho JD, Alves AP, et al. Antitumor activity of the essential oil from the leaves of Croton regelianus and its component ascaridole. Chem Biodivers 2009; 6: 1224-31.
[177]
Abbasi R, Efferth T, Kuhmann C, et al. The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells. Toxicol Appl Pharmacol 2012; 259: 302-10.
[178]
Woo SH, Sun NJ, Cassady JM, Snapka RM. Topoisomerase II inhibition by aporphine alkaloids. Biochem Pharmacol 1999; 57: 1141-5.
[179]
García MT, Blázquez MA, Ferrándiz MJ, et al. New alkaloid antibiotics that target the DNA topoisomerase I of Streptococcus pneumoniae. J Biol Chem 2011; 286: 6402-13.
[180]
Noureini SK, Tanavar F. Boldine, a natural aporphine alkaloid, inhibits telomerase at non-toxic concentrations. Chem Biol Interact 2015; 231: 27-34.
[181]
Noureini SK, Wink M. Dose-dependent cytotoxic effects of boldine in HepG-2 cells - telomerase inhibition and apoptosis induction. Molecules 2015; 20: 3730-43.
[182]
Noureini SK, Kheirabadi M, Zarei Y, et al. Telomerase inhibition by a new synthetic derivative of the aporphine alkaloid boldine. Int J Mol Sci 2018; 19: 1239.
[183]
Mondal J, Bishayee K, Panigrahi AK, Khuda-Bukhsh AR. Low doses of ethanolic extract of Boldo (Peumus boldus) can ameliorate toxicity generated by cisplatin in normal liver cells of mice in vivo and in WRL-68 cells in vitro, but not in cancer cells in vivo or in vitro. J Integr Med 2014; 12: 425-38.
[184]
Mondal J, Panigrahi AK, Khuda-Bukhsh AR. Physico-chemical and ultra-structural characterizations of PLGA-loaded nanoparticles of boldine and their efficay in ameliorating cisplatin induced hepatotoxicity in normal liver cells in vitro. J Innov Pharmaceut Biol Sci 2015; 2: 506-21.
[185]
Thomet FA, Pinyol P, Villena J, Espinoza LJ, Reveco PG. Cytotoxic thiocarbamate derivatives of boldine. Nat Prod Commun 2010; 5: 1587-90.
[186]
Thomet FA, Piñol P, Villena J, Reveco PG. In vitro cytotoxic evaluation of a novel phosphinyl derivative of boldine. Molecules 2011; 16: 2253-8.
[187]
Thomet FA, Pinyol P, Villena J, Reveco PG. Towards a more selective analogue of oxaliplatin: Synthesis of [Pt((1R,2R)diaminocyclohexane 3-carboxypredicentrinato)]. Inorg Chim Acta 2012; 384: 255-9.
[188]
Mellado M, Jara C, Astudillo D, Villena J, Reveco PG, Thomet FA. Oxaliplatin analogues with carboxy derivatives of boldine with enhanced antioxidant activity. Bioinorg Chem Appl 2015; 2015: 920143.
[189]
Morello A, Lipchenca I, Cassels BK, Speisky H, Aldunate J, Repetto Y. Trypanocidal effect of boldine and related alkaloids upon several strains of Trypanosoma cruzi. Comp Biochem Physiol Pharmacol Toxicol Endocrinol 1994; 107C: 367-71.
[190]
Neal RA, van Bueren J. Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro. Trans R Soc Trop Med Hyg 1988; 82: 709-14.
[191]
Jiménez G, Dagger F, Hasegawa M, et al. Antiproliferative effect of aporfine alkaloid Boldine on Leishmania mexicana. International Congress on Leishmania and Leishmaniasis. World Leish II Crete, Greece 20-24 May, 2001..
[192]
Hung J, Castillo J, Jiménez G, Hasegawa M, Rodriguez M. Spectroscopic study of antileishmanial drug incubated in the promastigotes of Leishmania mexicana. Spectrochim Acta A Mol Biomol Spectrosc 2003; 59: 3177-83.
[193]
Mollataghi A, Coudiere E, Hadi AH, et al. Anti-acetylcholinesterase, anti-α-glucosidase, anti-leishmanial and anti-fungal activities of chemical constituents of Beilschmiedia species. Fitoterapia 2012; 83: 298-02.
[194]
Salama IC, Arrais-Lima C, Arrais-Silva WW. Evaluation of boldine activity against intracellular amastigotes of Leishmania amazonensis. Korean J Parasitol 2017; 55: 337-40.
[195]
Jenett-Siems K, Kraft C, Siems K, et al. Sipaucins A-C, sesquiterpenoids from Siparuna pauciflora. Phytochemistry 2003; 63: 377-81.
[196]
Zahari A, Ablat A, Sivasothy Y, Mohamad J, Choudhary MI, Awang K. In vitro antiplasmodial and antioxidant activities of bisbenzylisoquinoline alkaloids from Alseodaphne corneri Kosterm. Asian Pac J Trop Med 2016; 9: 328-32.
[197]
Nasrullah AA, Zahari A, Mohamad J, Awang K. Antiplasmodial alkaloids from the bark of Cryptocarya nigra (Lauraceae). Molecules 2013; 18: 8009-617.
[198]
Geroldinger G, Tonner M, Hettegger H, et al. Mechanism of ascaridole activation in Leishmania. Biochem Pharmacol 2017; 132: 48-62.
[199]
Jiménez I, Speisky H. Biological disposition of boldine: In vitro and in vivo studies. Phytother Res 2000; 14: 254-60.
[200]
Hroch M, Mičuda S, Cermanová J, Chládek J, Tomšik P. Development of an HPLC fluorescence method for determination of boldine in plasma, bile and urine of rats and identification of its major metabolites by LC-MS/MS. J Chromatog B 2013; 936: 48-56.
[201]
Zeng RJ, Li Y, Chen JZ, et al. A novel UPLC-MS/ MS method for sensitive quantitation of boldine in plasma, a potential anti-inflammatory agent: Application to a pharmacokinetic study in rats. Biomed Chromatogr 2015; 29: 459-64.
[202]
Cermanová J, Prašnická A, Doleželová E, et al. Pharmacokinetics of boldine in control and Mrp2-deficient rats. Physiol Res 2016; 65(Suppl. 4): S489-97.
[203]
Chen JZ, Xu Y, Chou GX, Wang CH, Yang L, Wang ZT. Simultaneous determination of norisoboldine and its major metabolite in rat plasma by ultraperformance liquid chromatography-mass spectrometry and its application in a pharmacokinetic study. Biomed Chromatogr 2011; 25: 367-72.
[204]
Guo CC, Yu CH, Li L, et al. Rapid determination of isocorydine in rat plasma and tissues using liquid chromatography – tandem mass spectrometry and its applications to pharmacokinetics and tissue distribution. Xenobiotica 2012; 42: 466-76.
[205]
Liu YQ, Li HL, He JC, Feng EF, Rao GX, Xu GL. Development and validation of a high-performance liquid chromatography coupled with ultraviolet detection method for the determination of isocorydine in rat plasma and its application in pharmacokinetics. Drug Res (Stuttg) 2013; 63: 558-63.
[206]
Chen Y, Yan Q, Zhong M, et al. Study on pharmacokinetics and tissue distribution of the isocorydine derivative (AICD) in rats by HPLC-DAD method. Acta Pharm Sin B 2015; 5: 238-45.
[207]
Li Y, Zeng RJ. Pharmacokinetics and metabolism study of isoboldine, a major bioactive component from Radix linderae in male rats by UPLC-MS/MS. J Ethnopharmacol 2015; 171: 154-60.
[208]
Meyer GMJ, Meyer MR, Wissenbach DK, Maurer HH. Studies on the metabolism and toxicologicaldetection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC-MS, LC-MSn and LC-high-resolution MSn. J Mass Spectrom 2013; 48: 24-41.
[209]
Silva-Aguayo G, Hepp-Gallo R, Tapia-Vargas M, Casals-Bustos P, Bustos-Figueroa G, Osses-Ruiz F. Evaluation of boldo (Peumus boldus Molina) and lime for the control of Sitophilus zeamais Motschulsky. Agrociencia 2006; 40: 219-28.
[210]
Betancur J, Silva G, Rodríguez C, Fischer S, Zapata N. Insecticidal activity of Peumus boldus Molina essential oil against Sitophilus zeamais Motschulsky. Chil J Agric Res 2010; 70: 399-407.
[211]
Santos CZ, Bobek VB, Pietruchinski E. Evaluation of the activity of essential oil antifungal Peumus boldus (Monimiaceae) facing the yeast species Candida albicans. Visão Acadêmica (Curitiba) 2014; 15: 43-50.
[212]
Souza EL, Lima EO, Freire KRL, Sousa CP. Inhibitory action of some essential oils and phytochemicals on the growth of moulds isolated from foods. Braz Arch Biol Technol 2005; 48: 245-50.
[213]
Passone MA, Girardi NS, Etcheverry M. Antifungal and antiaflatoxigenic activity by vapor contact of three essential oils, and effects of environmental factors on their efficacy. Food Sci Technol 2013; 53: 434-44.
[214]
Girardi NS, García D, Robledo SN, Passone MA, Nesci A, Etcheverry M. Microencapsulation of Peumus boldus oil by complex coacervation to provide peanut seeds protection against fungal pathogens. Ind Crops Prod 2016; 92: 93-101.
[215]
Rezende DACS, Cardoso MG, Souza RV, et al. Essential oils from Mentha piperita, Cymbopogon citratus, Rosmarinus officinalis, Peumus boldus and Foeniculum vulgare: Inhibition of phospholipase A2 and cytotoxicity to human erythrocytes. Am J Plant Sci 2017b; 8: 2196-207.
[216]
Martínez S, Madrero Y, Elorriaga M, et al. Halogenated derivatives of boldine with high selectivity for α1A-adrenoceptors in rat cerebral cortex. Life Sci 1999; 64: 1205-14.
[217]
Sobarzo-Sánchez EM, Arbaoui J, Protais P, Cassels BK. Halogenated boldine derivatives with enhanced monoamine selectivity. J Nat Prod 2000; 63: 480-4.
[218]
Asencio M, Hurtado-Guzmán C, López JJ, Cassels BK, Protais P, Chagraoui A. Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors: halogenation and D1 receptor selectivity. Bioorg Med Chem 2005; 13: 3699-704.
[219]
Moreno L, Cabedo N, Ivorra MD, et al. 3,4-Dihydroxy- and 3,4-methylenedioxyphenanthrene-type alkaloids with high selectivity for D2 dopamine receptor. Bioorg Med Chem Lett 2013; 23: 4824-7.
[220]
Gafner S, Dietz BM, McPhail KL, et al. Alkaloids from Eschscholzia californica and their capacity to inhibit binding of [3H]8-hydroxy-2-(di-N-propyl-amino) tetralin to 5-HT1A receptors in vitro. J Nat Prod 2006; 68: 432-5.
[221]
Madapa S, Harding WW. Semisynthetic studies on and biological evaluation of N-methyllaurotetanine analogues as ligands for 5-HT receptors. J Nat Prod 2015; 78: 722-9.
[222]
Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: Rationale and current status of research. CNS Drugs 2013; 27: 703-16.
[223]
Walstab J, Wohlfarth C, Hovius R, et al. Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: Implications for treating gastrointestinal disorders. Neurogastroenterol Motil 2014; 26: 810-20.
[224]
Gotteland M, Espinoza J, Cassels BK, Speisky H. Effect of a dry boldo extract on oro-cecal intestinal transit in healthy volunteers. Rev Med Chil 1995; 123: 955-60.
[225]
Chung LY, Lo MW, Mustafa MR, Goh SH, Imiyabir Z. 5-Hydroxytryptamine2A receptor binding activity of compounds from Litsea sessilis. Phytother Res 2009; 23: 330-4.
[226]
Zetler G. Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: Bulbocapnine, corytuberine, boldine and glaucine. Arch Int Pharmacodyn 1988; 296: 255-81.
[227]
Asencio M, Delaquerrière B, Cassels BK, Speisky H, Comoy E, Protais P. Biochemical and behavioral effects of boldine and glaucine on dopamine systems. Pharmacol Biochem Behav 1999; 62: 7-13.
[228]
Loghin F, Chagraoui A, Asencio M, et al. Effects of some antioxidative aporphine derivatives on striatal dopaminergic transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice. Eur J Pharm Sci 2003; 18: 133-40.
[229]
Othman WNN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K. Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae). Bioorg Med Chem 2016; 24: 4464-9.
[230]
Exley P, Iturriaga-Vásquez P, Lukas RJ, Sher E, Cassels BK, Bermúdez I. Evaluation of benzyltetrahydroisoquinolines as ligands for neural nicotinic acetylcholine receptors. Br J Pharmacol 2005; 146: 15-24.
[231]
Iturriaga-Vásquez P, Pérez EG, Slater EY, Bermúdez I, Cassels BK. Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem 2007; 15: 3368-72.
[232]
Dhingra D, Soni K. Behavioral and biochemical evidences for nootropic activity of boldine in young and aged mice. Biomed Pharmacother 2018; 97: 895-904.
[233]
Moezi L, Yahosseini S, Jamshidzadeh A, Dastgheib M, Pirsalami F. Sub-chronic boldine treatment exerts anticonvulsant effects in mice. Neurol Res 2018; 40: 146-52.
[234]
García-Alcover I, Colonques-Bellmunt J, Garijo R, et al. Development of a Drosophila melanogaster spliceosensor system for in vivo high-throughput screening in myotonic dystropyhy type 1. Dis Model Mech 2014; 7: 1297-306.
[235]
García-Alcover I, López-Castel A, Álvarez-Abril MC, et al. Phenanthrene derivatives for use as medicaments. WO Patent 2014091020, 2014.
[236]
Álvarez-Abril MC. Caracterización de la actividad biológica y farmacológica del alcaloide boldina en la distrofia miotónica de tipo 1. PhD Thesis. Valencia (Spain): Universidad de Valencia 2015.
[237]
Ranilla LG, Kwon Y, Apostolidis E, Shetty K. Phenolic compounds, antioxidant activity and in vitro inhibitory potential against key enzymes relevant for hyperglycemia and hypertension of commonly used medicinal plants, herbs and spices in Latin America. Bioresour Technol 2010; 101: 4676-89.
[238]
Villiger A, Sala F, Suter A, Butterweck V. In vitro inhibitory potential of Cynara scolymus, Silybum marianum, Taraxacum officinale, and Peumus boldus on key enzymes relevant to metabolic syndrome. Phytomedicine 2014; 22: 138-44.
[239]
Buchholz T, Melzig MF. 2016. Medicinal plants traditionally used for treatment of obesity and diabetes mellitus – screening for pancreatic lipase and α-amylase inhibition. Phytother Res 2016; 30: 260-6.
[240]
Herrera T, Aguilera Y, Rebollo Hernanz, et al. Teas and herbal infusions as sources of melatonin and other bioactive non-nutrient components. LWT 2018; 89: 65-73.
[241]
Falé P, Ferreira C, Rodrigues A, Frazão F, Serralheiro M. Studies on the molecular mechanism of cholesterol reduction by Fraxinus angustifolia, Peumus boldus, Cynara cardunculus and Pterospartum tridentatum infusions. J Med Plants Res 2014; 8: 9-17.
[242]
Makishi GLA. Propriedades de soluções filmogênicas e de filmes de gelatina ou colágeno com extrato de boldo-do-Chile. PhD Thesis Faculdade de Zootecnia e Engenharia de Alimentos, Universidad de São Paulo, Pirassununga 2016.
[243]
Sánchez GR, Castilla CL, Gómez NB, et al. Leaf extract from the endemic plant Peumus boldus as an effective bioproduct for the green synthesis of silver nanoparticles. Mater Lett 2016; 183: 255-60.
[244]
Santoro D, Ahrens K, Vesny R, Navarro C, Gatto H, Marsella R. Evaluation of the in vitro effect of Boldo and Meadowsweet plant extracts on the expression of antimicrobial peptides and inflammatory markers in canine keratinocytes. Res Vet Sci 2017; 115: 255-62.
[245]
Kaziyama VM, Fernandes MJB, Simoni IC. Atividade antiviral de extratos de plantas medicinais disponíveis comercialmente frente aos herpesvírus suíno e bovino. Rev Bras Plantas Med 2012; 14: 522-8.
[246]
Chen JJ, Chang YL, Teng CM, Chen IS. Anti-platelet aggregation alkaloids and lignans from Hernandia nymphaeifolia. Planta Med 2000; 66: 251-6.
[247]
Zhang CF, Nakamura N, Tewtrakul S, et al. Sesquiterpenes and alkaloids from Lindera chunii and their inhibitory activities against hiv-1 integrase. Chem Pharm Bull 2002; 50: 1195-200.
[248]
Kashiwada Y, Aoshima A, Ikeshiro Y, et al. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids. Bioorg Med Chem 2005; 13: 443-8.
[249]
Tietjen I, Ntie-Kang F, Mwimanzi P, et al. Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors. PLoS One 2015; 10: e0121099.
[250]
Yu B, Cook C, Santanam N. The aporphine alkaloid boldine induces adiponectin expression and regulation in 3T3-L1 cells. J Med Food 2009; 12: 1074-83.
[251]
D’souza SL, Deshmukh B, Bhamore JR, Rawat KA, Lenka N, Kailasa SK. Synthesis of fluorescent nitrogen-doped carbon dots from dried shrimps for cell imaging and boldine drug delivery system. RSC Advances 2016; 6: 12169-79.
[252]
Si YX, Ji S, Wang W, et al. Effects of boldine on tyrosinase: Inhibition kinetics and computational simulation. Process Biochem 2013; 48: 152-61.
[253]
Sobarzo-Sánchez E, Soto PG, Valdés Rivera C, Sánchez G, Hidalgo ME. Applied biological and physicochemical activity of isoquinoline alkaloids: oxoisoaporphine and boldine. Molecules 2012; 17: 10958-70.
[254]
López D, Márquez A, Gutiérrez-Cutiño M, Venegas-Yazigi D, Bustos R, Matiacevich S. Edible film with antioxidant capacity based on salmon gelatin and boldine. Food Sci Technol 2017; 160-9.
[255]
Feng T, Xu Y, Cai XH, Du ZZ, Luo XD. Antimicrobially active isoquinoline alkaloids from Litsea cubeba. Planta Med 2009; 75: 76-9.
[256]
Chiou CM, Lin CT, Huang WJ, et al. Semisynthesis and myocardial activity of thaliporphine N-homologues. J Nat Prod 2013; 76: 405-12.
[257]
Ku HC, Lee SY, Lee SS, Su MJ. Thaliporphine, an alkaloid from Neolitsea konishii, exerts antioxidant, anti-inflammatory, and anti-apoptotic responses in guinea pig during cardiovascular collapse in inflammatory disease. J Funct Foods 2016; 26: 57-64.
[258]
Ku HC, Lee SY, Chen CH, et al. TM-1-1DP exerts protective effect against myocardial ischemia reperfusion injury via AKT-eNOS pathway. Naunyn Schmiedebergs Arch Pharmacol 2015; 388: 539-48.
[259]
Chen GS, Huang KH, Huang CC, Wang JY. Thaliporphine derivative improves acute lung injury after traumatic brain injury. BioMed Res Int 2015; 729831.
[260]
European Union herbal monograph on Peumus boldus Molina, folium EMA/HMPC/453725/2016. Available from http://www.ema.europa.eu/docs/en_ GB/document_library/Herbal-Herbal_monograph/ 2017/01/WC500219581.pdf.
[261]
Monzote L, Stamberg W, Staniek K, Gille L. Toxic effects of carvacrol, caryophyllene oxide, and ascaridole from essential oil of Chenopodium ambrosioides on mitochondria. Toxicol Appl Pharmacol 2009; 240: 337-47.
[262]
Geroldinger G, Tonner M, Hettegger H, et al. Mechanism of ascaridole activation in Leishmania. Biochem Pharmacol 2017; 132: 48-62.
[263]
Christoffers WA, Blömeke B, Coenraads PJ, Schuttelaar ML. The optimal patch test concentration for ascaridole as a sensitizing component of tea tree oil. Contact Dermat 2014; 71: 129-37.
[264]
Gielen K, Goossens A. Occupational allergic contact dermatitis from drugs in healthcare workers. Contact Dermat 2001; 45: 273-9.
[265]
Lambert JP, Cormier A. Potential interaction between warfarin and boldo-fenugreek. Pharmacotherapy 2001; 21: 509-12.
[266]
Carbajal R, Yisfalem A, Pradhan N, Baumstein D, Chaudhari A. Case report: Boldo (Peumus boldus) and tacrolimus interaction in a renal transplant patient. Transplant Proc 2014; 46: 2400-2.
[267]
Piscaglia F, Leoni S, Venturi A, Graziella F, Donati G, Bolondi L. Caution in the use of boldo in herbal laxatives: A case of hepatotoxicity. Scand J Gastroenterol 2005; 40: 236-9.
[268]
Ribeiro RJ, Silvestre C, Duarte C. Hidden risks of alternative medicines: A case of boldo-induced hepatotoxicity. J Diet Suppl 2017; 14: 186-90.
[269]
Agarwal SC, Crook JR, Pepper CB. Herbal remedies-how safe are they? A case report of polymorphic ventricular tachycardia/ventricular fibrillation induced by herbal medication used for obesity. Int J Cardiol 2006; 106: 260-1.
[270]
Monzón S, Lezaun A, Sáenz D, et al. Anaphylaxis to boldo infusion, a herbal remedy. Allergy 2004; 59: 1019-20.
[271]
Chaboussant PJ, Gagez AL, Graber M, et al. Behavioural impairments and hallucinations after consumption of boldo leaf infusions. Therapie 2014; 69: 465-7.
[272]
Mejía-Dolores JW, Mendoza-Quispe DE, Moreno-Rumay EL, et al. Neurotoxic effect of aqueous extract of boldo (Peumus boldus) in an animal model. Rev Peru Med Exp Salud Publica 2014; 31: 62-8.
[273]
Almeida ER, Melo AM, Xavier H. Toxicological evaluation of the hydro-alcohol extract of the dry leaves of Peumus boldus and boldine in rats. Phytother Res 2000; 14: 99-102.
[274]
Monagas M, Urpi-Sarda M, Sanchez-Patan F, et al. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food Funct 2010; 1: 233-53.
[275]
Ottaviani JI, Borges G, Momma TY, et al. The metabolome of [2-14C](−)-epicatechin in humans: Implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci Rep 2016; 6: 29034.
[276]
Feng X, Li Y, Brobbey Oppong M, Qiu F. Insights into the intestinal bacterial metabolism of flavonoids and the bioactivities of their microbe-derived ring cleavage metabolites. Drug Metab Rev 2018.
[http://dx.doi.org/10.1080/03602532.2018.1485691]
[277]
Álvarez-Cilleros D, Martín MÁ, Ramos S. (-)-Epicatechin and the colonic 2,3-dihydroxybenzoic acid metabolite regulate glucose uptake, glucose production, and improve insulin signaling in renal NRK-52E cells. Mol Nutr Food Res 2018.
[http://dx.doi.org/10.1002/ mnfr.201700470]
[278]
Álvarez-Cilleros D, Martín MÁ, Goya L, Ramos S. (−)-Epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid protect renal proximal tubular cell against high glucose-induced oxidative stress by modulating NOX-4/SIRT-1 signalling. J Funct Foods 2018; 46: 19-28.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 5
ISSUE: 1
Year: 2019
Page: [31 - 65]
Pages: 35
DOI: 10.2174/2215083804666181113112928

Article Metrics

PDF: 12
HTML: 4
EPUB: 1