Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Therapeutic Potentials of Aconite-like Alkaloids: Bioinformatics and Experimental Approaches

Author(s): Catalina Mares, Ana-Maria Udrea*, Catalin Buiu, Angela Staicu and Speranta Avram

Volume 24, Issue 2, 2024

Published on: 10 April, 2023

Page: [159 - 175] Pages: 17

DOI: 10.2174/1389557523666230328153417

Price: $65

Abstract

Compounds from plants that are used in traditional medicine may have medicinal properties. It is well known that plants belonging to the genus Aconitum are highly poisonous. Utilizing substances derived from Aconitum sp. has been linked to negative effects. In addition to their toxicity, the natural substances derived from Aconitum species may have a range of biological effects on humans, such as analgesic, anti-inflammatory, and anti-cancer characteristics. Multiple in silico, in vitro, and in vivo studies have demonstrated the effectiveness of their therapeutic effects. In this review, the clinical effects of natural compounds extracted from Aconitum sp., focusing on aconitelike alkaloids, are investigated particularly by bioinformatics tools, such as the quantitative structure- activity relationship method, molecular docking, and predicted pharmacokinetic and pharmacodynamic profiles. The experimental and bioinformatics aspects of aconitine’s pharmacogenomic profile are discussed. Our review could help shed light on the molecular mechanisms of Aconitum sp. compounds. The effects of several aconite-like alkaloids, such as aconitine, methyllycacintine, or hypaconitine, on specific molecular targets, including voltage-gated sodium channels, CAMK2A and CAMK2G during anesthesia, or BCL2, BCL-XP, and PARP-1 receptors during cancer therapy, are evaluated. According to the reviewed literature, aconite and aconite derivatives have a high affinity for the PARP-1 receptor. The toxicity estimations for aconitine indicate hepatotoxicity and hERG II inhibitor activity; however, this compound is not predicted to be AMES toxic or an hERG I inhibitor. The efficacy of aconitine and its derivatives in treating many illnesses has been proven experimentally. Toxicity occurs as a result of the high ingested dose; however, the usage of this drug in future research is based on the small quantity of an active compound that fulfills a therapeutic role.

Keywords: Aconite-like alkaloids, bioinformatics, molecular docking, QSAR, toxicity, analgesic, antitumoral, BCL2, PARP-1.

« Previous Next »
Graphical Abstract

[1]
Fokunang, C.N.; Ndikum, V.; Tabi, O.Y.; Jiofack, R.B.; Ngameni, B.; Guedje, N.M.; Tembe-Fokunang, E.A.; Tomkins, P.; Barkwan, S.; Kechia, F.; Asongalem, E.; Ngoupayou, J.; Torimiro, N.J.; Gonsu, K.H.; Sielinou, V.; Ngadjui, B.T.; Angwafor, I.I.I., III; Nkongmeneck, A.; Abena, O.M.; Ngogang, J.; Asonganyi, T.; Colizzi, V.; Lohoue, J. Kamsu-Kom, Traditional medicine: Past, present and future research and development prospects and integration in the national health system of cameroon. Afr. J. Tradit. Complement. Altern. Med., 2011, 8(3), 284-295.
[http://dx.doi.org/10.4314/ajtcam.v8i3.65276] [PMID: 22468007]
[2]
Udrea, A.M.; Mernea, M.; Buiu, C.; Avram, S. Scutellaria baicalensis flavones as potent drugs against acute respiratory injury during SARS-CoV-2 infection: Structural biology approaches. Processes, 2020, 8(11), 1468.
[http://dx.doi.org/10.3390/pr8111468]
[3]
Avram, S.; Mernea, M.; Bagci, E.; Hritcu, L.; Borcan, L.C.; Mihailescu, D.F. Advanced structure-activity relationships applied to mentha spicata l. subsp. spicata essential oil compounds as ache and nmda ligands, in comparison with donepezil, galantamine and memantine – new approach in brain disorders pharmacology. CNS Neurol. Disord. Drug Targets, 2017, 16(7), 800-811.
[http://dx.doi.org/10.2174/1871527316666170113115004] [PMID: 28088901]
[4]
Hao, D.C.; Gu, X-J.; Xiao, P.G. Chemical and biological studies of aconitum pharmaceutical resources. In: Medicinal Plants; Elsevier: Amsterdam, 2015; pp. 253-292.
[http://dx.doi.org/10.1016/B978-0-08-100085-4.00007-4]
[5]
Liu, Y.; Chen, T.; Chen, C.; Zou, D.; Li, Y. Isolation and preparation of an imidazole alkaloid from radix of Aconitum pendulum Busch by semi-preparative high-speed counter-current chromatography. Se Pu, 2014, 32(5), 543-546.
[http://dx.doi.org/10.3724/SP.J.1123.2013.12007] [PMID: 25185318]
[6]
Wang, C.F.; Gerner, P.; Wang, S.Y.; Wang, G.K.; Bulleyaconitine, A. Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic properties in vitro and in vivo. Anesthesiology, 2007, 107(1), 82-90.
[http://dx.doi.org/10.1097/01.anes.0000267502.18605.ad] [PMID: 17585219]
[7]
Yamei, C.; Yue, G.; Guangguo, T. Myocardial lipidomics profiling delineate the toxicity of traditional Chinese medicine Aconiti Lateralis radix praeparata. J. Ethnopharmacol., 2013, 147(2), 349-356.
[http://dx.doi.org/10.1016/j.jep.2013.03.017]
[8]
Zhang, L.; Siyiti, M.; Zhang, J.; Yao, M.; Zhao, F. Anti inflammatory and anti rheumatic activities in vitro of alkaloids separated from Aconitum soongoricum Stapf. Exp. Ther. Med., 2021, 21(5), 493.
[http://dx.doi.org/10.3892/etm.2021.9924] [PMID: 33791002]
[9]
Çankal, D.; Akkol, E.K.; Kılınç, Y.; İlhan, M.; Capasso, R. An effective phytoconstituent aconitine: A realistic approach for the treatment of trigeminal neuralgia. Mediat. Inflamm., 2021, 2021, 1-8.
[http://dx.doi.org/10.1155/2021/6676063] [PMID: 33935591]
[10]
Singhuber, J.; Zhu, M.; Prinz, S.; Kopp, B. Aconitum in traditional chinese medicine—a valuable drug or an unpredictable risk? J. Ethnopharmacol., 2009, 126(1), 18-30.
[http://dx.doi.org/10.1016/j.jep.2009.07.031] [PMID: 19651200]
[11]
Tak, S.; Lakhotia, M.; Gupta, A.; Sagar, A.; Bohra, G.; Bajari, R. Aconite poisoning with arrhythmia and shock. Indian Heart J., 2016, 68(S2), S207-S209.
[http://dx.doi.org/10.1016/j.ihj.2015.08.010] [PMID: 27751290]
[12]
El-Shazly, M.; Tai, C.J.; Wu, T.Y.; Csupor, D.; Hohmann, J.; Chang, F.R.; Wu, Y.C. Use, history, and liquid chromatography/mass spectrometry chemical analysis of Aconitum. J. Food Drug Anal, 2016, 24(1), 29-45.
[http://dx.doi.org/10.1016/j.jfda.2015.09.001] [PMID: 28911407]
[13]
Chan, T.Y.K. Aconite poisoning following the percutaneous absorption of Aconitum alkaloids. Forensic Sci. Int., 2012, 223(1-3), 25-27.
[http://dx.doi.org/10.1016/j.forsciint.2012.06.016] [PMID: 22766196]
[14]
Chen, X.; Wu, R.; Jin, H.; Gao, R.; Yang, B.; Wang, Q. Successful rescue of a patient with acute aconitine poisoning complicated by polycystic renal hemorrhage. J. Nippon Med. Sch., 2015, 82(5), 257-261.
[http://dx.doi.org/10.1272/jnms.82.257] [PMID: 26568394]
[15]
Ma, L.; Gu, R.; Tang, L.; Chen, Z.E.; Di, R.; Long, C. Important poisonous plants in tibetan ethnomedicine. Toxins, 2015, 7(1), 138-155.
[http://dx.doi.org/10.3390/toxins7010138] [PMID: 25594733]
[16]
Liu, X.X.; Jian, X.X.; Cai, X.F.; Chao, R.B.; Chen, Q.H.; Chen, D.L.; Wang, X.L.; Wang, F.P. Cardioactive C₁₉-diterpenoid alkaloids from the lateral roots of Aconitum carmichaeli “Fu Zi”. Chem. Pharm. Bull, 2012, 60(1), 144-149.
[http://dx.doi.org/10.1248/cpb.60.144] [PMID: 22223386]
[17]
Qasem, A.M.A.; Zeng, Z.; Rowan, M.G.; Blagbrough, I.S. Norditerpenoid alkaloids from Aconitum and Delphinium: Structural relevance in medicine, toxicology, and metabolism. Nat. Prod. Rep., 2022, 39(3), 460-473.
[http://dx.doi.org/10.1039/D1NP00029B] [PMID: 34636385]
[18]
Li, Y.; Li, Y.; Zhao, M.; Yuan, A.; Gong, X.; Zhao, M.; Peng, C. The effects of rheum palmatum l. on the pharmacokinetic of major diterpene alkaloids of aconitum carmichaelii debx. in rats. Eur. J. Drug Metab. Pharmacokinet., 2017, 42(3), 441-451.
[http://dx.doi.org/10.1007/s13318-016-0356-z] [PMID: 27357588]
[19]
Wang, F-P.; Chen, Q-H.; Liang, X-T. The C18-diterpenoid alkaloids. In: The Alkaloids: Chemistry and Biology; Elsevier: Amsterdam, 2009; Vol. 67, pp. 1-78.
[http://dx.doi.org/10.1016/S1099-4831(09)06701-7]
[20]
Pelletier, S.W.; Chokshi, H.P.; Desai, H.K. Separation of diterpenoid alkaloid mixtures using vacuum liquid chromatography. J. Nat. Prod., 1986, 49(5), 892-900.
[http://dx.doi.org/10.1021/np50047a021]
[21]
Bando, H.; Wada, K.; Watanabe, M.; Mori, T.; Amiya, T. Studies on the constituents of aconitum species. IV. On the components of Aconitum japonicum THUNB. Chem. Pharm. Bull, 1985, 33(11), 4717-4722.
[http://dx.doi.org/10.1248/cpb.33.4717]
[22]
Kitagawa, I.; Chen, Z.; Yoshihara, M.; Kobayashi, K.; Yoshikawa, M.; Ono, N.; Yoshimura, Y. [Chemical studies on crude drug processing. III. Aconiti tuber (2). On the constituents of “pao-fuzi”, the processed tuber of Aconitum carmichaeli Debx, and biological activities of lipo-alkaloids]. Yakugaku Zasshi, 1984, 104(8), 858-866.
[http://dx.doi.org/10.1248/yakushi1947.104.8_858] [PMID: 6520710]
[23]
Feng, F.; Liu, J.H.; Zhao, S.X. Diterpene alkaloids from Aconitum kirinense. Phytochemistry, 1998, 49(8), 2557-2559.
[http://dx.doi.org/10.1016/S0031-9422(98)00230-1]
[24]
Takayama, H.; Yokota, M.; Aimi, N.; Sakai, S.; Lu, S.T.; Chen, I.S. Two new diterpene alkaloids, 10-hydroxyneoline and 14-o-acetyl-10-hydroxyneoline, from aconitum fukutomei. J. Nat. Prod., 1990, 53(4), 936-939.
[http://dx.doi.org/10.1021/np50070a023]
[25]
Sun, Z.; Yang, L.; Zhao, L.; Cui, R.; Yang, W. Neuropharmacological effects of mesaconitine: Evidence from molecular and cellular basis of neural circuit. Neural Plast., 2020, 2020, 1-10.
[http://dx.doi.org/10.1155/2020/8814531] [PMID: 32904549]
[26]
Milgrom, E.G.; Sultankhodzhaev, M.N.; Chzhen’gui, C. Qualitative mass spectrometric analysis of the total diterpene bases from the roots of Aconitum kusnezoffi. Chem. Nat. Compd., 1996, 32(1), 71-73.
[http://dx.doi.org/10.1007/BF01373796]
[27]
Hsu, S.S.; Lin, Y.S.; Liang, W.Z. Mechanism of action of a diterpene alkaloid hypaconitine on cytotoxicity and inhibitory effect of BAPTA-AM in HCN‐2 neuronal cells. Clin. Exp. Pharmacol. Physiol., 2021, 48(5), 801-810.
[http://dx.doi.org/10.1111/1440-1681.13482] [PMID: 33609056]
[28]
Beshitaishvili, L.V.; Sultankhodzhaev, M.N. Alkaloids of aconitum orientale. Chem. Nat. Compd., 1989, 25(3), 379-379.
[http://dx.doi.org/10.1007/BF00597733]
[29]
Sirotenko, E.G.; Rashkes, Y.V.; Plugar’, V.N. GC-MS analysis of total diterpene alkaloids from roots of Aconitum septentrionale. Chem. Nat. Compd., 1989, 25(4), 460-464.
[http://dx.doi.org/10.1007/BF00597658]
[30]
Shamma, M.; Chinnasamy, P.; Miana, G.A.; Khan, A.; Bashir, M.; Salazar, M.; Patil, P.; Beal, J.L. The alkaloids of Delphinium cashmirianum. J. Nat. Prod., 1979, 42(6), 615-623.
[http://dx.doi.org/10.1021/np50006a006] [PMID: 541686]
[31]
Jacyno, J.M.; Harwood, J.S.; Lin, N.H.; Campbell, J.E.; Sullivan, J.P.; Holladay, M.W. Lycaconitine revisited: Partial synthesis and neuronal nicotinic acetylcholine receptor affinities. J. Nat. Prod., 1996, 59(7), 707-709.
[http://dx.doi.org/10.1021/np960352c] [PMID: 8759171]
[32]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[33]
Zhou, W.; Liu, H.; Qiu, L.Z.; Yue, L.X.; Zhang, G.J.; Deng, H.F.; Ni, Y.H.; Gao, Y. Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison. Med. Res. Rev., 2021, 41(3), 1798-1811.
[http://dx.doi.org/10.1002/med.21777] [PMID: 33512023]
[34]
Gao, Y.; Fan, H.; Nie, A.; Yang, K.; Xing, H.; Gao, Z.; Yang, L.; Wang, Z.; Zhang, L. Aconitine: A review of its pharmacokinetics, pharmacology, toxicology and detoxification. J. Ethnopharmacol., 2022, 293, 115270.
[http://dx.doi.org/10.1016/j.jep.2022.115270] [PMID: 35405250]
[35]
Liu, F.; Han, X.; Li, N.; Liu, K.; Kang, W. Aconitum alkaloids induce cardiotoxicity and apoptosis in embryonic zebrafish by influencing the expression of cardiovascular relative genes. Toxicol. Lett., 2019, 305, 10-18.
[http://dx.doi.org/10.1016/j.toxlet.2019.01.002] [PMID: 30639578]
[36]
Zhao, L.; Sun, Z.; Yang, L.; Cui, R.; Yang, W.; Li, B. Neuropharmacological effects of Aconiti Lateralis Radix Praeparata. Clin. Exp. Pharmacol. Physiol., 2020, 47(4), 531-542.
[http://dx.doi.org/10.1111/1440-1681.13228] [PMID: 31837236]
[37]
Xie, S.; Jia, Y.; Liu, A.; Dai, R.; Huang, L.; Hypaconitine-Induced, Q.T. Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs. J. Ethnopharmacol., 2015, 166, 375-379.
[http://dx.doi.org/10.1016/j.jep.2015.03.023] [PMID: 25800797]
[38]
Li, X.; Ou, X.; Luo, G.; Ou, X.; Xie, Y.; Ying, M.; Qu, W.; Zuo, H.; Qi, X.; Wang, Y.; Liu, Z.; Zhu, L. Mdr1a, Bcrp and Mrp2 regulate the efficacy and toxicity of mesaconitine and hypaconitine by altering their tissue accumulation and in vivo residence. Toxicol. Appl. Pharmacol., 2020, 409, 115332.
[http://dx.doi.org/10.1016/j.taap.2020.115332] [PMID: 33171190]
[39]
Wada, K.; Nihira, M.; Hayakawa, H.; Tomita, Y.; Hayashida, M.; Ohno, Y. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice. Forensic Sci. Int., 2005, 148(1), 21-29.
[http://dx.doi.org/10.1016/j.forsciint.2004.04.016] [PMID: 15607586]
[40]
Wang, Y.J.; Tao, P.; Wang, Y. Attenuated structural transformation of aconitine during sand frying process and antiarrhythmic effect of its converted products. Evid. Based Complement. Alternat. Med., 2021, 2021, 1-12.
[http://dx.doi.org/10.1155/2021/7243052] [PMID: 34733344]
[41]
Li, H.; Xu, J.; Gao, Y.; Jin, L.; Chen, J.; Chen, F. Supramolecular structure, in vivo biological activities and molecular-docking-based potential cardiotoxic exploration of aconine hydrochloride monohydrate as a novel salt form. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater., 2020, 76(2), 208-224.
[http://dx.doi.org/10.1107/S2052520620001250] [PMID: 32831223]
[42]
Tao, P.; Wang, Y.; Wang, Y. Attenuation and structural transformation of crassicauline a during sand frying process and antiarrhythmic effects of its transformed products. Front. Pharmacol., 2021, 12, 734671.
[http://dx.doi.org/10.3389/fphar.2021.734671] [PMID: 34795582]
[43]
Huang, Y.F.; He, F.; Cui, H.; Zhang, Y.Y.; Yang, H.Y.; Liang, Z.S.; Dai, W.; Cheng, C.S.; Xie, Y.; Liu, L.; Liu, Z.Q.; Zhou, H. Systematic investigation on the distribution of four hidden toxic Aconitum alkaloids in commonly used Aconitum herbs and their acute toxicity. J. Pharm. Biomed. Anal., 2022, 208, 114471.
[http://dx.doi.org/10.1016/j.jpba.2021.114471] [PMID: 34814080]
[44]
Komoda, Y.; Nosaka, S.; Takenoshita, M. Enhancement of lidocaine-induced epidural anesthesia by deoxyaconitine in the rabbit. J. Anesth., 2003, 17(4), 241-245.
[http://dx.doi.org/10.1007/s00540-003-0184-6] [PMID: 14625711]
[45]
Zhang, Y.; Zong, X.; Wu, J.L.; Liu, Y.; Liu, Z.; Zhou, H.; Liu, L.; Li, N. Pharmacokinetics and tissue distribution of eighteen major alkaloids of Aconitum carmichaelii in rats by UHPLC-QQQ-MS. J. Pharm. Biomed. Anal., 2020, 185, 113226.
[http://dx.doi.org/10.1016/j.jpba.2020.113226] [PMID: 32163851]
[46]
Ameri, A.; Metzmeier, P.; Peters, T. Frequency-dependent inhibition of neuronal activity by lappaconitine in normal and epileptic hippocampal slices. Br. J. Pharmacol., 1996, 118(3), 577-584.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15440.x] [PMID: 8762080]
[47]
Sun, M.L.; Ao, J.P.; Wang, Y.R.; Huang, Q.; Li, T.F.; Li, X.Y.; Wang, Y.X. Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression. Psychopharmacology, 2018, 235(9), 2559-2571.
[http://dx.doi.org/10.1007/s00213-018-4948-y] [PMID: 29926144]
[48]
Teng, G.; Zhang, F.; Li, Z.; Zhang, C.; Zhang, L.; Chen, L.; Zhou, T.; Yue, L.; Zhang, J. Quantitative electrophysiological evaluation of the analgesic efficacy of two lappaconitine derivatives: A window into antinociceptive drug mechanisms. Neurosci. Bull., 2021, 37(11), 1555-1569.
[http://dx.doi.org/10.1007/s12264-021-00774-w] [PMID: 34550562]
[49]
Bryzgalov, A.; Romanov, V.; Tolstikova, T.; Shults, E. Lappaconitine: Influence of halogen substituent on the antiarrhythmic activity. Cardiovasc. Hematol. Agents Med. Chem., 2014, 11(3), 211-217.
[http://dx.doi.org/10.2174/18715257113119990083] [PMID: 23763697]
[50]
Cheremnykh, K.P.; Savelyev, V.A.; Borisov, S.A.; Ivanov, I.D.; Baev, D.S.; Tolstikova, T.G.; Vavilin, V.A.; Shults, E.E. Hybrides of alkaloid lappaconitine with pyrimidine motif on the anthranilic acid moiety: Design, synthesis, and investigation of antinociceptive potency. Molecules, 2020, 25(23), 5578.
[http://dx.doi.org/10.3390/molecules25235578] [PMID: 33261161]
[51]
Heubach, J.; Schüle, A. Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species. Planta Med., 1998, 64(1), 22-26.
[http://dx.doi.org/10.1055/s-2006-957359] [PMID: 9491764]
[52]
Pfister, J.A.; Gardner, D.R.; Panter, K.E.; Manners, G.D.; Ralphs, M.H.; Stegelmeier, B.L.; Schoch, T.K. Larkspur (Delphinium spp.) poisoning in livestock. J. Nat. Toxins, 1999, 8(1), 81-94.
[PMID: 10091130]
[53]
Mohamed, R.A.; Abdallah, D.M.; El-brairy, A.I.; Ahmed, K.A.; El-Abhar, H.S. Palonosetron/methyllycaconitine deactivate hippocampal microglia 1, inflammasome assembly and pyroptosis to enhance cognition in a novel model of neuroinflammation. Molecules, 2021, 26(16), 5068.
[http://dx.doi.org/10.3390/molecules26165068] [PMID: 34443654]
[54]
Andriambeloson, E.; Huyard, B.; Poiraud, E.; Wagner, S. Methyllycaconitine‐ and scopolamine‐induced cognitive dysfunction: Differential reversal effect by cognition‐enhancing drugs. Pharmacol. Res. Perspect., 2014, 2(4), e00048.
[http://dx.doi.org/10.1002/prp2.48] [PMID: 25505596]
[55]
Ye, Q.; Hongmei, L.; Chengxin, F. Cardiotoxicity evaluation and comparison of diterpene alkaloids on zebrafish. Drug Chem. Toxicol., 2022, 44(3), 294-301.
[http://dx.doi.org/10.1080/01480545.2019.1586916] [PMID: 30895830]
[56]
Deng, J.; Han, J.; Chen, J.; Zhang, Y.; Huang, Q.; Wang, Y.; Qi, X.; Liu, Z.; Leung, E.L.H.; Wang, D.; Feng, Q.; Lu, L. Comparison of analgesic activities of aconitine in different mice pain models. PLoS One, 2021, 16(4), e0249276.
[http://dx.doi.org/10.1371/journal.pone.0249276] [PMID: 33793632]
[57]
Tong, P.; Wu, C.; Wang, X.; Hu, H.; Jin, H.; Li, C.; Zhu, Y.; Shan, L.; Xiao, L. Development and assessment of a complete-detoxication strategy for Fuzi (lateral root of Aconitum carmichaeli) and its application in rheumatoid arthritis therapy. J. Ethnopharmacol., 2013, 146(2), 562-571.
[http://dx.doi.org/10.1016/j.jep.2013.01.025] [PMID: 23376046]
[58]
Araya, E.I.; Claudino, R.F.; Piovesan, E.J.; Chichorro, J.G. Trigeminal neuralgia: Basic and clinical aspects. Curr. Neuropharmacol., 2020, 18(2), 109-119.
[http://dx.doi.org/10.2174/1570159X17666191010094350] [PMID: 31608834]
[59]
Zhu, L.; Wu, J.; Zhao, M.; Song, W.; Qi, X.; Wang, Y.; Lu, L.; Liu, Z. Mdr1a plays a crucial role in regulating the analgesic effect and toxicity of aconitine by altering its pharmacokinetic characteristics. Toxicol. Appl. Pharmacol., 2017, 320, 32-39.
[http://dx.doi.org/10.1016/j.taap.2017.02.008] [PMID: 28193520]
[60]
Zhou, M.T.; Chen, C.S.; Chen, B.C.; Zhang, Q.Y.; Andersson, R. Acute lung injury and ARDS in acute pancreatitis: Mechanisms and potential intervention. World J. Gastroenterol., 2010, 16(17), 2094-2099.
[http://dx.doi.org/10.3748/wjg.v16.i17.2094] [PMID: 20440849]
[61]
Man-Xiu, X.; He-Quan, Z.; Rui-Ping, P.; Bing-Ting, W.; Xian-Guo, L. Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain. Mol. Pain, 2018, 14, 1744806918797243.
[http://dx.doi.org/10.1177/1744806918797243] [PMID: 30180777]
[62]
Csupor, D.; Wenzig, E.M.; Zupkó, I.; Wölkart, K.; Hohmann, J.; Bauer, R. Qualitative and quantitative analysis of aconitine-type and lipo-alkaloids of Aconitum carmichaelii roots. J. Chromatogr. A, 2009, 1216(11), 2079-2086.
[http://dx.doi.org/10.1016/j.chroma.2008.10.082] [PMID: 19019379]
[63]
Cao, Y.; Chen, X.F.; Lü, D.Y.; Dong, X.; Zhang, G.Q.; Chai, Y.F. Using cell membrane chromatography and HPLC-TOF/MS method for in vivo study of active components from roots of Aconitum carmichaeli. J. Pharm. Anal., 2011, 1(2), 125-134.
[http://dx.doi.org/10.1016/S2095-1779(11)70022-3] [PMID: 29403691]
[64]
Ameri, A. The effects of Aconitum alkaloids on the central nervous system. Prog. Neurobiol., 1998, 56(2), 211-235.
[http://dx.doi.org/10.1016/S0301-0082(98)00037-9] [PMID: 9760702]
[65]
Jiali, G.; Lidao, B.; Aiwu, Z. The mechanism underlying hypaconitine-mediated alleviation of pancreatitis-associated lung injury through up-regulating aquaporin-1/TNF-α. Turk. J. Gastroenterol., 2020, 31(11), 790-798.
[http://dx.doi.org/10.5152/tjg.2020.19542] [PMID: 33361042]
[66]
Nistorescu, S.; Udrea, A.M.; Badea, M.A.; Lungu, I.; Boni, M.; Tozar, T.; Dumitrache, F.; Maraloiu, V.A.; Popescu, R.G.; Fleaca, C.; Andronescu, E.; Dinischiotu, A.; Staicu, A.; Balas, M. Low blue dose photodynamic therapy with porphyrin-iron oxide nanoparticles complexes: In vitro study on human melanoma cells. Pharmaceutics, 2021, 13(12), 2130.
[http://dx.doi.org/10.3390/pharmaceutics13122130] [PMID: 34959411]
[67]
Lungu, I.I.; Nistorescu, S.; Badea, M.A.; Petre, A.M.; Udrea, A.M.; Banici, A.M.; Fleacă, C.; Andronescu, E.; Dinischiotu, A.; Dumitrache, F.; Staicu, A.; Balaș, M. Doxorubicin-conjugated iron oxide nanoparticles synthesized by laser pyrolysis: In vitro study on human breast cancer cells. Polymers, 2020, 12(12), 2799.
[http://dx.doi.org/10.3390/polym12122799] [PMID: 33256060]
[68]
Song, N.; Ma, J.; Hu, W.; Guo, Y.; Hui, L.; Aamer, M.; Ma, J. Lappaconitine hydrochloride inhibits proliferation and induces apoptosis in human colon cancer HCT-116 cells via mitochondrial and MAPK pathway. Acta Histochem., 2021, 123(5), 151736.
[http://dx.doi.org/10.1016/j.acthis.2021.151736] [PMID: 34058516]
[69]
Li, Y.; Zheng, Y.; Yu, Y.; Gan, Y.; Gao, Z. Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels. Acta Pharmacol. Sin., 2019, 40(4), 451-459.
[http://dx.doi.org/10.1038/s41401-018-0067-x] [PMID: 29991710]
[70]
Luan, S.; Gao, Y.; Liang, X.; Zhang, L.; Yin, L.; He, C.; Liu, S.; Yin, Z.; Yue, G.; Zou, Y.; Li, L.; Song, X.; Lv, C.; Zhang, W.; Jing, B. Synthesis and structure-activity relationship of lipo-diterpenoid alkaloids with potential target of topoisomerase IIα for breast cancer treatment. Bioorg. Chem., 2021, 109, 104699.
[http://dx.doi.org/10.1016/j.bioorg.2021.104699] [PMID: 33611138]
[71]
Wada, K.; Yamashita, H. Cytotoxic effects of diterpenoid alkaloids against human cancer cells. Molecules, 2019, 24(12), 2317.
[http://dx.doi.org/10.3390/molecules24122317] [PMID: 31234546]
[72]
Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug–drug interactions. Scientific Reports., Available from: https://www.nature.com/articles/srep25343
[73]
Ji, B-L.; Xia, L-P.; Zhou, F-X.; Mao, G-Z.; Xu, L-X. Aconitine induces cell apoptosis in human pancreatic cancer via NF-κB signaling pathway. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(23), 4955-4964.
[PMID: 27981537]
[74]
Park, J.; Youn, D.H.; Um, J.Y. Aconiti lateralis radix preparata, the dried root of aconitum carmichaelii Debx., improves benign prostatic hyperplasia via suppressing 5-alpha reductase and inducing prostate cell apoptosis. Evid. Based Complement. Alternat. Med., 2019, 2019, 1-10.
[http://dx.doi.org/10.1155/2019/6369132] [PMID: 31467577]
[75]
Wang, X.; Lin, Y.; Zheng, Y. Antitumor effects of aconitine in A2780 cells via estrogen receptor β mediated apoptosis, DNA damage and migration. Mol. Med. Rep., 2020, 22(3), 2318-2328.
[http://dx.doi.org/10.3892/mmr.2020.11322] [PMID: 32705198]
[76]
Luan, S.; Gao, Y.; Liang, X.; Zhang, L.; Wu, Q.; Hu, Y.; Yin, L.; He, C.; Liu, S. Aconitine linoleate, a natural lipo-diterpenoid alkaloid, stimulates anti-proliferative activity reversing doxorubicin resistance in MCF-7/ADR breast cancer cells as a selective topoisomerase IIα inhibitor. Naunyn Schmiedebergs Arch. Pharmacol., 2022, 395(1), 65-76.
[http://dx.doi.org/10.1007/s00210-021-02172-5] [PMID: 34727218]
[77]
Qi, X.; Wang, L.; Wang, H.; Yang, L.; Li, X.; Wang, L. Aconitine inhibits the proliferation of hepatocellular carcinoma by inducing apoptosis. Int. J. Clin. Exp. Pathol., 2018, 11(11), 5278-5289.
[PMID: 31949608]
[78]
Yao, F.; Jiang, G-R.; Liang, G-Q.; Yuan, Q.; Zhu, Y.; Liu, M.; Zhang, L-R. The antitumor effect of the combination of aconitine and crude monkshood polysaccharide on hepatocellular carcinoma. Pak. J. Pharm. Sci., 2021, 34(3), 971-979.
[PMID: 34602421]
[79]
Wang, X.; Jia, Q.; Yu, Y.; Wang, H.; Guo, H.; Ma, X.; Liu, C.; Chen, X.; Miao, Q.; Guan, B.; Su, S.; Wei, H.; Wang, C. Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs. Acta Pharmacol. Sin., 2021, 42(2), 218-229.
[http://dx.doi.org/10.1038/s41401-020-0467-6] [PMID: 32747718]
[80]
Xing, B.N.; Jin, S.S.; Wang, H.; Tang, Q.F.; Liu, J.H.; Li, R.Y.; Liang, J.Y.; Tang, Y.Q.; Yang, C.H. New diterpenoid alkaloids from Aconitum coreanum and their anti-arrhythmic effects on cardiac sodium current. Fitoterapia, 2014, 94, 120-126.
[http://dx.doi.org/10.1016/j.fitote.2014.01.022] [PMID: 24508249]
[81]
Zhang, F.; Cai, L.; Zhang, J.; Qi, X.; Lu, C. Aconitine induced cardiac arrhythmia in human induced pluripotent stem cell derived cardiomyocytes. Exp. Ther. Med., 2018, 16(4), 3497-3503.
[http://dx.doi.org/10.3892/etm.2018.6644] [PMID: 30233701]
[82]
Peng, F.; Zhang, N.; Wang, C.; Wang, X.; Huang, W.; Peng, C.; He, G.; Han, B. Aconitine induces cardiomyocyte damage by mitigating BNIP3‐dependent mitophagy and the TNFα‐NLRP3 signalling axis. Cell Prolif., 2020, 53(1), e12701.
[http://dx.doi.org/10.1111/cpr.12701] [PMID: 31657084]
[83]
Udrea, A.M. Computational approaches of new perspectives in the treatment of depression during pregnancy. Farmacia, 2018, 66(4), 680-687.
[http://dx.doi.org/10.31925/farmacia.2018.4.18]
[84]
Avram, S.; Stan, M.S.; Udrea, A.M.; Buiu, C.; Boboc, A.A.; Mernea, M. 3D-ALMOND-QSAR models to predict the antidepressant effect of some natural compounds. Pharmaceutics, 2021, 13(9), 1449.
[http://dx.doi.org/10.3390/pharmaceutics13091449] [PMID: 34575524]
[85]
Yang, C.; Zhang, T.; Li, Z.; Xu, L.; Liu, F.; Ruan, J.; Liu, K.; Zhang, Z. P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies. Toxicol. Appl. Pharmacol., 2013, 273(3), 561-568.
[http://dx.doi.org/10.1016/j.taap.2013.09.030] [PMID: 24120885]
[86]
Douglas, E.V.P.; Tom, L.B.; David, B.A. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem., 2015, 58(9), 4066-4072.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00104]
[87]
Banerjee, P.; Eckert, A. O.; Schrey, A. K.; Preissner, R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res., 2018, 46(Web Server issue), W257-W263.
[http://dx.doi.org/10.1093/nar/gky318]
[88]
Ikezawa, N.; Iwasa, K.; Sato, F. Molecular cloning and characterization of CYP80G2, a cytochrome P450 that catalyzes an intramolecular C-C phenol coupling of (S)-reticuline in magnoflorine biosynthesis, from cultured Coptis japonica cells. J. Biol. Chem., 2008, 283(14), 8810-8821.
[http://dx.doi.org/10.1074/jbc.M705082200] [PMID: 18230623]
[89]
Fujita, Y.; Terui, K.; Fujita, M.; Kakizaki, A.; Sato, N.; Oikawa, K.; Aoki, H.; Takahashi, K.; Endo, S. Five cases of aconite poisoning: Toxicokinetics of aconitines. J. Anal. Toxicol., 2007, 31(3), 132-137.
[http://dx.doi.org/10.1093/jat/31.3.132] [PMID: 17579959]
[90]
Gao, X.; Hu, J.; Zhang, X.; Zuo, Y.; Wang, Y.; Zhu, S. Research progress of aconitine toxicity and forensic analysis of aconitine poisoning. Forensic Sci. Res., 2020, 5(1), 25-31.
[http://dx.doi.org/10.1080/20961790.2018.1452346] [PMID: 32490307]
[91]
Xingxing, X.; Xiaojing, Y.; Jian-Lin, W. Potentially cardiotoxic diterpenoid alkaloids from the roots of aconitum carmichaelii. J. Nat. Prod., 2019, 82(4), 980-989.
[http://dx.doi.org/10.1021/acs.jnatprod.8b01039]
[92]
Li, C.; Zou, R.; Zhang, H.; Wang, Y.; Qiu, B.; Qiu, S.; Wang, W.; Xu, Y. Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo. Arch. Toxicol., 2019, 93(6), 1697-1712.
[http://dx.doi.org/10.1007/s00204-019-02448-z] [PMID: 31025080]
[93]
Avram, S.; Buiu, C.; Duda-Seiman, D.; Duda-Seiman, C.; Borcan, F.; Mihailescu, D. Evaluation of the pharmacological descriptors related to the induction of antidepressant activity and its prediction by QSAR/QRAR methods. Mini Rev. Med. Chem., 2012, 12(6), 467-476.
[http://dx.doi.org/10.2174/138955712800493834] [PMID: 22587763]
[94]
Avram, S.; Milac, A.L.; Mihailescu, D. 3D-QSAR study indicates an enhancing effect of membrane ions on psychiatric drugs targeting serotonin receptor 5-HT1A. Mol. Biosyst., 2012, 8(5), 1418-1425.
[http://dx.doi.org/10.1039/c2mb00005a] [PMID: 22373544]
[95]
Muratov, E.N.; Bajorath, J.; Sheridan, R.P.; Tetko, I.V.; Filimonov, D.; Poroikov, V.; Oprea, T.I.; Baskin, I.I.; Varnek, A.; Roitberg, A.; Isayev, O.; Curtalolo, S.; Fourches, D.; Cohen, Y.; Aspuru-Guzik, A.; Winkler, D.A.; Agrafiotis, D.; Cherkasov, A.; Tropsha, A. QSAR without borders. Chem. Soc. Rev., 2020, 49(11), 3525-3564.
[http://dx.doi.org/10.1039/D0CS00098A] [PMID: 32356548]
[96]
Avram, S.; Svab, I.; Bologa, C.; Flonta, M.L. Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors. A 3D-QSAR-CoMFA method for new antiviral drug design. J. Cell. Mol. Med., 2003, 7(3), 287-296.
[http://dx.doi.org/10.1111/j.1582-4934.2003.tb00229.x] [PMID: 14594553]
[97]
Avram, S.; Duda-Seiman, D.; Borcan, F.; Wolschann, P. QSAR-CoMSIA applied to antipsychotic drugs with their dopamine D2 and serotonine 5HT2A membrane receptors. J. Serb. Chem. Soc., 2011, 76(2), 263-281.
[http://dx.doi.org/10.2298/JSC100806022A]
[98]
Turabekova, M.A.; Rasulev, B.F.; Dzhakhangirov, F.N.; Leszczynska, D.; Leszczynski, J. Aconitum and Delphinium alkaloids of curare-like activity. QSAR analysis and molecular docking of alkaloids into AChBP. Eur. J. Med. Chem., 2010, 45(9), 3885-3894.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.042] [PMID: 20594622]
[99]
Turabekova, M.A.; Rasulev, B.F.; Dzhakhangirov, F.N.; Toropov, A.A.; Leszczynska, D.; Leszczynski, J. Aconitum and delphinium diterpenoid alkaloids of local anesthetic activity: Comparative QSAR analysis based on GA-MLRA/PLS and optimal descriptors approach. J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev., 2014, 32(3), 213-238.
[http://dx.doi.org/10.1080/10590501.2014.938886] [PMID: 25226219]
[100]
Turabekova, M.A.; Rasulev, B.F.; Levkovich, M.G.; Abdullaev, N.D.; Leszczynski, J. Aconitum and Delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels. Comput. Biol. Chem., 2008, 32(2), 88-101.
[http://dx.doi.org/10.1016/j.compbiolchem.2007.10.003] [PMID: 18201930]
[101]
Wang, M.Y.; Liang, J.W.; Olounfeh, K.; Sun, Q.; Zhao, N.; Meng, F.H. A comprehensive in silico method to study the qstr of the aconitine alkaloids for designing novel drugs. Molecules, 2018, 23(9), 2385.
[http://dx.doi.org/10.3390/molecules23092385] [PMID: 30231506]
[102]
Bello-Ramírez, A.M.; Nava-Ocampo, A.A. A QSAR analysis of toxicity of Aconitum alkaloids. Fundam. Clin. Pharmacol., 2004, 18(6), 699-704.
[http://dx.doi.org/10.1111/j.1472-8206.2004.00280.x] [PMID: 15548242]
[103]
Tozar, T.; Santos Costa, S.; Udrea, A.M.; Nastasa, V.; Couto, I.; Viveiros, M.; Pascu, M.L.; Romanitan, M.O. Anti-staphylococcal activity and mode of action of thioridazine photoproducts. Sci. Rep., 2020, 10(1), 18043.
[http://dx.doi.org/10.1038/s41598-020-74752-z] [PMID: 33093568]
[104]
Udrea, A.M.; Dinache, A.; Pagès, J.M.; Pirvulescu, R.A. Quinazoline derivatives designed as efflux pump inhibitors: Molecular modeling and spectroscopic studies. Molecules, 2021, 26(8), 2374.
[http://dx.doi.org/10.3390/molecules26082374] [PMID: 33921798]
[105]
Liang, J.; Zhang, T.; Li, Z.; Chen, Z.; Yan, X.; Meng, F. Predicting potential antitumor targets of Aconitum alkaloids by molecular docking and protein–ligand interaction fingerprint. Med. Chem. Res., 2016, 25(6), 1115-1124.
[http://dx.doi.org/10.1007/s00044-016-1553-7]
[106]
Ko, H.L.; Ren, E.C. Functional aspects of PARP1 in DNA repair and transcription. Biomolecules, 2012, 2(4), 524-548.
[http://dx.doi.org/10.3390/biom2040524] [PMID: 24970148]
[107]
Youle, R.J.; Strasser, A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol., 2008, 9(1), 47-59.
[http://dx.doi.org/10.1038/nrm2308] [PMID: 18097445]
[108]
Gao, X.; Zhang, X.; Hu, J.; Xu, X.; Zuo, Y.; Wang, Y.; Ding, J.; Xu, H.; Zhu, S. Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria-mediated pathway. Mol. Med. Rep., 2017, 17(1), 284-292.
[http://dx.doi.org/10.3892/mmr.2017.7894] [PMID: 29115599]
[109]
Wang, H.; Liu, Y.; Guo, Z.; Wu, K.; Zhang, Y.; Tian, Y.; Zhao, B.; Lu, H. Aconitine induces cell apoptosis via mitochondria and death receptor signaling pathways in hippocampus cell line. Res. Vet. Sci., 2022, 143, 124-133.
[http://dx.doi.org/10.1016/j.rvsc.2022.01.001] [PMID: 35026629]
[110]
McClendon, A.K.; Osheroff, N. DNA topoisomerase II, genotoxicity, and cancer. Mutat. Res., 2007, 623(1-2), 83-97.
[http://dx.doi.org/10.1016/j.mrfmmm.2007.06.009] [PMID: 17681352]
[111]
Jin, B.; Robertson, K.D. DNA methyltransferases, DNA damage repair, and cancer. Adv. Exp. Med. Biol., 2013, 754, 3-29.
[http://dx.doi.org/10.1007/978-1-4419-9967-2_1] [PMID: 22956494]
[112]
Smit, A.B.; Celie, P.H.N.; Kasheverov, I.E.; Mordvintsev, D.Y.; van Nierop, P.; Bertrand, D.; Tsetlin, V.; Sixma, T.K. Acetylcholine-binding proteins: Functional and structural homologs of nicotinic acetylcholine receptors. J. Mol. Neurosci., 2006, 30(1-2), 9-10.
[http://dx.doi.org/10.1385/JMN:30:1:9] [PMID: 17192605]
[113]
Wei, J.; Fan, S.; Yu, H.; Shu, L.; Li, Y. A new strategy for the rapid identification and validation of the direct targets of aconitine-induced cardiotoxicity. Drug Des. Devel. Ther., 2021, 15, 4649-4664.
[http://dx.doi.org/10.2147/DDDT.S335461] [PMID: 34803375]
[114]
Fededa, J.P.; Gerlich, D.W. Molecular control of animal cell cytokinesis. Nat. Cell Biol., 2012, 14(5), 440-447.
[http://dx.doi.org/10.1038/ncb2482] [PMID: 22552143]
[115]
Wang, M.; Shi, Y.; Yao, L.; Li, Q.; Wang, Y.; Fu, D. Potential molecular mechanisms and drugs for aconitine-induced cardiotoxicity in zebrafish through RNA sequencing and bioinformatics analysis. Med. Sci. Monit., 2020, 26, e924092.
[http://dx.doi.org/10.12659/MSM.924092] [PMID: 32598336]
[116]
Udrea, A.M.; Avram, S.; Nistorescu, S.; Pascu, M.L.; Romanitan, M.O. Laser irradiated phenothiazines: New potential treatment for COVID-19 explored by molecular docking. J. Photochem. Photobiol. B, 2020, 211, 111997.
[http://dx.doi.org/10.1016/j.jphotobiol.2020.111997] [PMID: 32829256]
[117]
Yang, L.; Xie, X.; Cai, L.; Ran, X.; Li, Y.; Yin, T.; Zhao, H.; Li, C.P. p-sulfonated calix[8]arene functionalized graphene as a “turn on” fluorescent sensing platform for aconitine determination. Biosens. Bioelectron., 2016, 82, 146-154.
[http://dx.doi.org/10.1016/j.bios.2016.04.005] [PMID: 27085945]
[118]
Ono, T.; Hayashida, M.; Tezuka, A.; Hayakawa, H.; Ohno, Y. Antagonistic effects of tetrodotoxin on aconitine-induced cardiac toxicity. J. Nippon Med. Sch., 2013, 80(5), 350-361.
[http://dx.doi.org/10.1272/jnms.80.350] [PMID: 24189353]
[119]
Berman, H.; Henrick, K.; Nakamura, H. Announcing the worldwide protein data bank. Nat. Struct. Mol. Biol., 2003, 10(12), 980-980.
[http://dx.doi.org/10.1038/nsb1203-980] [PMID: 14634627]
[120]
McIntosh, J.M.; Absalom, N.; Chebib, M.; Elgoyhen, A.B.; Vincler, M. Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem. Pharmacol., 2009, 78(7), 693-702.
[http://dx.doi.org/10.1016/j.bcp.2009.05.020] [PMID: 19477168]
[121]
Zouridakis, M.; Giastas, P.; Zarkadas, E.; Chroni-Tzartou, D.; Bregestovski, P.; Tzartos, S.J. Crystal structures of free and antagonist-bound states of human α9 nicotinic receptor extracellular domain. Nat. Struct. Mol. Biol., 2014, 21(11), 976-980.
[http://dx.doi.org/10.1038/nsmb.2900] [PMID: 25282151]
[122]
BIOVIA, Dassault Systèmes, [Discovery Studio Visualizer], [V21.1.0.20298], San Diego: Dassault Systèmes, [2021].
[123]
Li, X.; Xu, F.; Xu, H.; Zhang, S.; Gao, Y.; Zhang, H.; Dong, Y.; Zheng, Y.; Yang, B.; Sun, J.; Zhang, X.C.; Zhao, Y.; Jiang, D. Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist. Nat. Commun., 2022, 13(1), 1286.
[http://dx.doi.org/10.1038/s41467-022-28808-5] [PMID: 35277491]

Rights & Permissions Print Cite
Article Metrics
22
2
© 2024 Bentham Science Publishers | Privacy Policy