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Understanding the Physicochemical Properties of Mitragynine, a Principal Alkaloid of Mitragyna speciosa, for Preclinical Evaluation

by Surash Ramanathan, Suhanya Parthasarathy, Vikneswaran Murugaiyah, Enrico Magosso, Soo Choon Tan and Sharif Mahsufi Mansor

Molecules 2015, 20(3), 4915-4927; https://doi.org/10.3390/molecules20034915 - 18 Mar 2015

Cited by 40 | Viewed by 15828

Abstract

Varied pharmacological responses have been reported for mitragynine in the literature, but no supportive scientific explanations have been given for this. These studies have been undertaken without a sufficient understanding of the physicochemical properties of mitragynine. In this work a UV spectrophotometer approach [...] Read more.

Varied pharmacological responses have been reported for mitragynine in the literature, but no supportive scientific explanations have been given for this. These studies have been undertaken without a sufficient understanding of the physicochemical properties of mitragynine. In this work a UV spectrophotometer approach and HPLC-UV method were employed to ascertain the physicochemical properties of mitragynine. The pK_a of mitragynine measured by conventional UV (8.11 ± 0.11) was in agreement with the microplate reader determination (8.08 ± 0.04). Mitragynine is a lipophilic alkaloid, as indicated by a logP value of 1.73. Mitragynine had poor solubility in water and basic media, and conversely in acidic environments, but it is acid labile. In an in vitro dissolution the total drug release was higher for the simulated gastric fluid but was prolonged and incomplete for the simulated intestinal fluid. The hydrophobicity, poor water solubility, high variability of drug release in simulated biological fluids and acid degradable characteristics of mitragynine probably explain the large variability of its pharmacological responses reported in the literature. The determined physicochemical properties of mitragynine will provide a basis for developing a suitable formulation to further improve its solubility, stability and oral absorption for better assessment of this compound in preclinical studies. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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3574 KiB

Open AccessArticle

Scopoletin Protects against Methylglyoxal-Induced Hyperglycemia and Insulin Resistance Mediated by Suppression of Advanced Glycation Endproducts (AGEs) Generation and Anti-Glycation

by Wen-Chang Chang, Shinn-Chih Wu, Kun-Di Xu, Bo-Chieh Liao, Jia-Feng Wu and An-Sheng Cheng

Molecules 2015, 20(2), 2786-2801; https://doi.org/10.3390/molecules20022786 - 09 Feb 2015

Cited by 46 | Viewed by 9272

Abstract

Recently, several types of foods and drinks, including coffee, cream, and cake, have been found to result in high methylglyoxal (MG) levels in the plasma, thus causing both nutritional and health concerns. MG can be metabolized by phase-II enzymes in liver through the [...] Read more.

Recently, several types of foods and drinks, including coffee, cream, and cake, have been found to result in high methylglyoxal (MG) levels in the plasma, thus causing both nutritional and health concerns. MG can be metabolized by phase-II enzymes in liver through the positive regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). In this study, we investigated the ability of scopoletin (SP) to protect against MG-induced hyperglycemia and insulin resistance. Recently, SP was shown to be a peroxisome proliferator-activated receptor-γ activator to elevate insulin sensitivity. We investigated the effects of oral administration of SP on the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats to understand the potential mechanism of scopoletin for diabetes protection. Our results suggested that SP activated Nrf2 by Ser40 phosphorylation, resulting in the metabolism of MG into d-lactic acid and the inhibition of AGEs generation, which reduced the accumulation of AGEs in the livers of MG-induced rats. In this manner, SP improved the results of the oral glucose tolerance test and dyslipidemia. Moreover, SP also increased the plasma translocation of glucose transporter-2 and promoted Akt phosphorylation caused by insulin treatment in MG-treated FL83B hepatocytes. In contrast, SP effectively suppressed protein tyrosine phosphatase 1B (PTP1B) expression, thereby alleviating insulin resistance. These findings suggest that SP acts as an anti-glycation and anti-diabetic agent, and thus has therapeutic potential for the prevention of diabetes. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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2183 KiB

Open AccessArticle

Structure-Based Virtual Screening of Novel Natural Alkaloid Derivatives as Potential Binders of h-telo and c-myc DNA G-Quadruplex Conformations

by Roberta Rocca, Federica Moraca, Giosuè Costa, Stefano Alcaro, Simona Distinto, Elias Maccioni, Francesco Ortuso, Anna Artese and Lucia Parrotta

Molecules 2015, 20(1), 206-223; https://doi.org/10.3390/molecules20010206 - 24 Dec 2014

Cited by 26 | Viewed by 9466

Abstract

Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex [...] Read more.

Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in π-π stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG₃(T₂AG₃)₃] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Toxicity of Evodiae fructus on Rat Liver Mitochondria: The Role of Oxidative Stress and Mitochondrial Permeability Transition

by Qingyan Cai, Jingjing Wei, Wei Zhao, Si Shi, Yu Zhang, Renrong Wei, Yue Zhang, Weirong Li and Qi Wang

Molecules 2014, 19(12), 21168-21182; https://doi.org/10.3390/molecules191221168 - 16 Dec 2014

Cited by 49 | Viewed by 7874

Abstract

Evodiae fructus (EF) has been used in China for thousands of years as an analgesic, antiemetic, anti-inflammatory and antidiarrheal drug. EF is a toxic drug and causes hepatotoxicity in humans. Although recent chronic toxicity studies performed on aqueous extract of EF has revealed [...] Read more.

Evodiae fructus (EF) has been used in China for thousands of years as an analgesic, antiemetic, anti-inflammatory and antidiarrheal drug. EF is a toxic drug and causes hepatotoxicity in humans. Although recent chronic toxicity studies performed on aqueous extract of EF has revealed that it can produce obvious cumulative hepatotoxicity, the mechanism behind this toxicity is still uncertain. In the present study, we investigated the influence of EF on oxidative stress, mitochondrial permeability transition, adenosine triphosphate (ATP), and cytochrome C release of hepatic mitochondria. Rats were divided into four groups and fed distilled water, 6, 12, 24 g/kg of aqueous extract of EF daily for 15 days. Evodiamine, rutaecarpine and evodine were quantified in the aqueous extract by high performance liquid chromatography with ultraviolet detection (HPLC/UV). The results showed that aqueous extract of EF could significantly (p < 0.05) decrease MnSOD levels to 56.50%, 46.77% and 19.67% of control group, GSH level was decreased to 74.24%, 53.97% and 47.91% of control group and MDA level was increased to 131.55%, 134.34% and 150.81% of control group in the 6, 12 and 24 g/kg groups, respectively; extract also induced mitochondria swelling, vacuolation, MPT pore opening and a significant decrease (p < 0.05) in mitochondrial potential, while ATP levels were significant decreased (p < 0.05) to 65.24%, 38.08% and 34.59% of control group in the 6, 12 and 24 g/kg groups, respectively, resulting in ATP depletion and CytC release, finally trigger cell death signaling, which are the partial hepatotoxicity mechanisms of EF. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Antioxidant and Anticancer Aporphine Alkaloids from the Leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena

by Chi-Ming Liu, Chiu-Li Kao, Hui-Ming Wu, Wei-Jen Li, Cheng-Tsung Huang, Hsing-Tan Li and Chung-Yi Chen

Molecules 2014, 19(11), 17829-17838; https://doi.org/10.3390/molecules191117829 - 03 Nov 2014

Cited by 111 | Viewed by 11187

Abstract

Fifteen compounds were extracted and purified from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena. These compounds include liriodenine (1), lysicamine (2), (−)-anonaine (3), (−)-asimilobine (4), (−)-caaverine (5), (−)-N-methylasimilobine ( [...] Read more.

Fifteen compounds were extracted and purified from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena. These compounds include liriodenine (1), lysicamine (2), (−)-anonaine (3), (−)-asimilobine (4), (−)-caaverine (5), (−)-N-methylasimilobine (6), (−)-nuciferine (7), (−)-nornuciferine (8), (−)-roemerine (9), 7-hydroxydehydronuciferine (10) cepharadione B (11), β-sitostenone (12), stigmasta-4,22-dien-3-one (13) and two chlorophylls: pheophytin-a (14) and aristophyll-C (15). The anti-oxidation activity of the compounds was examined by antiradical scavenging, metal chelating and ferric reducing power assays. The results have shown that these compounds have antioxidative activity. The study has also examined the antiproliferation activity of the isolated compounds against human melanoma, prostate and gastric cancer cells. The results shown that 7-hydroxydehydronuciferine (10) significantly inhibited the proliferation of melanoma, prostate and gastric cancer cells. Together, these findings suggest that leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena are a good resource for obtaining the biologically active substances with antioxidant properties. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Assessment of Mechanisms Involved in Antinociception Produced by the Alkaloid Caulerpine

by Luiz Henrique Agra Cavalcante-Silva, Maria Alice Pimentel Falcão, Ana Carolina Santana Vieira, Max Denisson Maurício Viana, João Xavier De Araújo-Júnior, Jéssica Celestino Ferreira Sousa, Tania Maria Sarmento da Silva, José Maria Barbosa-Filho, François Noël, George Emmanuel C. De Miranda, Bárbara Viviana de Oliveira Santos and Magna Suzana Alexandre-Moreira

Molecules 2014, 19(9), 14699-14709; https://doi.org/10.3390/molecules190914699 - 16 Sep 2014

Cited by 17 | Viewed by 6196

Abstract

In previous works we showed that oral administration of caulerpine, a bisindole alkaloid isolated from algae of the genus Caulerpa, produced antinociception when assessed in chemical and thermal models of nociception. In this study, we evaluated the possible mechanism of action of [...] Read more.

In previous works we showed that oral administration of caulerpine, a bisindole alkaloid isolated from algae of the genus Caulerpa, produced antinociception when assessed in chemical and thermal models of nociception. In this study, we evaluated the possible mechanism of action of this alkaloid in mice, using the writhing test. The antinociceptive effect of caulerpine was not affected by intraperitoneal (i.p.) pretreatment of mice with naloxone, flumazenil, l-arginine or atropine, thus discounting the involvement of the opioid, GABAergic, l-arginine-nitric oxide and (muscarinic) cholinergic pathways, respectively. In contrast, i.p. pretreatment with yohimbine, an α₂-adrenoceptor antagonist, or tropisetron, a 5-HT₃ antagonist, significantly blocked caulerpine-induced antinociception. These results suggest that caulerpine exerts its antinociceptive effect in the writhing test via pathways involving α₂-adrenoceptors and 5-HT₃ receptors. In summary, this alkaloid could be of interest in the development of new dual-action analgesic drugs. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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985 KiB

Open AccessArticle

Preparative Isolation of Seven Diterpenoid Alkaloids from Aconitum coreanum by pH-Zone-Refining Counter-Current Chromatography

by Xueyong Wang, Xikai Shu, Xiao Wang, Jinqian Yu and Feng Jing

Molecules 2014, 19(8), 12619-12629; https://doi.org/10.3390/molecules190812619 - 19 Aug 2014

Cited by 9 | Viewed by 6875

Abstract

The aim of this paper was to seek an efficient method to preparative separation of alkaloid compounds from Aconitum coreanum (Guanbaifu), a well-known traditional Chinese medicinal plant for heart disease. Seven alkaloid compounds were successfully purified by pH-zone-refining counter-current chromatography with two-phase solvent [...] Read more.

The aim of this paper was to seek an efficient method to preparative separation of alkaloid compounds from Aconitum coreanum (Guanbaifu), a well-known traditional Chinese medicinal plant for heart disease. Seven alkaloid compounds were successfully purified by pH-zone-refining counter-current chromatography with two-phase solvent system of petroleum ether–ethyl acetate–methanol–water (5:5:1:9, v/v/v/v), 10 mM triethylamine in upper phase and 10 mM hydrochloric acid in lower phase. From 3.5 g of crude extract, 356 mg of Guanfu base I, 578 mg of Guanfu base A, 74 mg of atisine, 94 mg of Guanfu base F, 423 mg of Guanfu base G, 67 mg of Guanfu base R and 154 mg of Guanfu base P were obtained with the purity of 96.40%, 97.2%, 97.5%, 98.1%, 98.9%, 98.3% and 98.4%. Their chemical structures were identified by TOF-MS and ¹H-NMR. This study indicated that pH-zone-refining counter-current chromatography was an efficient method for separating the kind of alkaloids with low absorbance values. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

α-Solanine Inhibits Invasion of Human Prostate Cancer Cell by Suppressing Epithelial-Mesenchymal Transition and MMPs Expression

by Kun-Hung Shen, Alex Chien-Hwa Liao, Jui-Hsiang Hung, Wei-Jiunn Lee, Kai-Chieh Hu, Pin-Tsen Lin, Ruei-Fang Liao and Pin-Shern Chen

Molecules 2014, 19(8), 11896-11914; https://doi.org/10.3390/molecules190811896 - 11 Aug 2014

Cited by 74 | Viewed by 12167

Abstract

α-Solanine, a naturally occurring steroidal glycoalkaloid found in nightshade (Solanum nigrum Linn.), was found to inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism involved in suppression of cancer cell metastasis by α-solanine remains unclear. This study investigates the suppression mechanism [...] Read more.

α-Solanine, a naturally occurring steroidal glycoalkaloid found in nightshade (Solanum nigrum Linn.), was found to inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism involved in suppression of cancer cell metastasis by α-solanine remains unclear. This study investigates the suppression mechanism of α-solanine on motility of the human prostate cancer cell PC-3. Results show that α-solanine reduces the viability of PC-3 cells. When treated with non-toxic doses of α-solanine, cell invasion is markedly suppressed by α-solanine. α-Solanine also significantly elevates epithelial marker E-cadherin expression, while it concomitantly decreases mesenchymal marker vimentin expression, suggesting it suppresses epithelial-mesenchymal transition (EMT). α-Solanine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and extracellular inducer of matrix metalloproteinase (EMMPRIN), but increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), and tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Immunoblotting assays indicate α-solanine is effective in suppressing the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt and ERK. Moreover, α-solanine downregulates oncogenic microRNA-21 (miR-21) and upregulates tumor suppressor miR-138 expression. Taken together, the results suggest that inhibition of PC-3 cell invasion by α-solanine may be, at least in part, through blocking EMT and MMPs expression. α-Solanine also reduces ERK and PI3K/Akt signaling pathways and regulates expression of miR-21 and miR-138. These findings suggest an attractive therapeutic potential of α-solanine for suppressing invasion of prostate cancer cell. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides and Their Acetylcholinesterase Inhibitory Activity

by Dong-Bo Zhang, Jian-Jun Chen, Qiu-Yan Song, Li Zhang and Kun Gao

Molecules 2014, 19(7), 9999-10010; https://doi.org/10.3390/molecules19079999 - 10 Jul 2014

Cited by 23 | Viewed by 7329

Abstract

Four new lycodine-type alkaloids, namely 16-hydroxyhuperzine B (1), N-methyl-11-acetoxyhuperzine B (2), 8,15-dihydrolycoparin A (3) and (7S,12S,13R)-huperzine D-16-O-β-d-glucopyranoside (4), along with ten known analogues 5−14 [...] Read more.

Four new lycodine-type alkaloids, namely 16-hydroxyhuperzine B (1), N-methyl-11-acetoxyhuperzine B (2), 8,15-dihydrolycoparin A (3) and (7S,12S,13R)-huperzine D-16-O-β-d-glucopyranoside (4), along with ten known analogues 5−14, were isolated from the whole plant of Lycopodiastrum casuarinoides. The structures of the new compounds were elucidated by means of spectroscopic techniques (IR, MS, NMR, and CD) and chemical methods. Compounds 1 and 2 possessed four connected six-membered rings, while compounds 3 and 4 were piperidine ring cleavage products. In particular, compound 4 was a lycopodium alkaloidal glycoside which is reported for the first time. Among the isolated compounds N-demethylhuperzinine (7), huperzine C (8), huperzine B (9) and lycoparin C (13) possessed significant inhibitory activity against acetylcholinesterase, and the new compound 1 showed moderate inhibitory activity. The structure activity relationships were discussed. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Cytotoxic Aporphine Alkaloids from Leaves and Twigs of Pseuduvaria trimera (Craib)

by Wuttikrai Sesang, Sittiporn Punyanitya, Siripit Pitchuanchom, Phansuang Udomputtimekakul, Narong Nuntasaen, Ratana Banjerdpongchai, Benjawan Wudtiwai and Wilart Pompimon

Molecules 2014, 19(7), 8762-8772; https://doi.org/10.3390/molecules19078762 - 25 Jun 2014

Cited by 12 | Viewed by 6520

Abstract

From ethyl acetate-methanol extracts of leaves and twigs of Pseuduvaria trimera a new aporphine alkaloid; 8-hydroxy-1,4,5-trimethoxy-7-oxoaporphine or 8-hydroxyartabonatine C (1) was isolated, together with the known 1,2,3-trimethoxy-4,5-dioxo-6a,7-dehydroaporphine (ouregidione, 2). Their structures were elucidated by a combination of spectral methods; mainly [...] Read more.

From ethyl acetate-methanol extracts of leaves and twigs of Pseuduvaria trimera a new aporphine alkaloid; 8-hydroxy-1,4,5-trimethoxy-7-oxoaporphine or 8-hydroxyartabonatine C (1) was isolated, together with the known 1,2,3-trimethoxy-4,5-dioxo-6a,7-dehydroaporphine (ouregidione, 2). Their structures were elucidated by a combination of spectral methods; mainly 2D NMR; IR and MS. Compounds 1 and 2 exhibited cytotoxic activity with IC₅₀ values of 26.36 ± 5.18 μM and 12.88 ± 2.49 μM, respectively, for human hepatocellular carcinoma HepG2 cells, and 64.75 ± 4.45 and 67.06 ± 3.5 μM, respectively, for human breast cancer MDA-MB231 cells. Both compounds displayed anti-cancer activity but less than that of doxorubicin; a conventional chemotherapeutic drug, the IC₅₀ levels of which were 2.21 ± 1.72 and 1.83 ± 0.09 μM for HepG2 and MDA-MB231 cells, respectively. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Acetylcholinesterase-inhibiting Alkaloids from Zephyranthes concolor

by Ricardo Reyes-Chilpa, Strahil Berkov, Simón Hernández-Ortega, Christopher K. Jankowski, Sebastien Arseneau, Imma Clotet-Codina, José A. Esté, Carles Codina, Francesc Viladomat and Jaume Bastida

Molecules 2011, 16(11), 9520-9533; https://doi.org/10.3390/molecules16119520 - 15 Nov 2011

Cited by 25 | Viewed by 8042

Abstract

The bulbs and aerial parts of Zephyranthes concolor (Lindl.) Benth. & Hook. f. (Amaryllidaceae), an endemic species to Mexico, were found to contain the alkaloids chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. Since currently only partial and low resolution ¹H-NMR data [...] Read more.

The bulbs and aerial parts of Zephyranthes concolor (Lindl.) Benth. & Hook. f. (Amaryllidaceae), an endemic species to Mexico, were found to contain the alkaloids chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. Since currently only partial and low resolution ¹H-NMR data for chlidanthine acetate are available, and none for chlidanthine, its 1D and 2D high resolution ¹H- and ¹³C-NMR spectra were recorded. Unambiguousassignations were achieved with HMBC, and HSQC experiments, and its structure was corroborated by X-ray diffraction. Minimum energy conformation for structures of chlidanthine, and its positional isomer galanthamine, were calculated by molecular modelling. Galanthamine is a well known acetylcholinesterase inhibitor; therefore, the isolated alkaloids were tested for this activity. Chlidanthine and galanthamine N-oxide inhibited electric eel acetylcholinesterase (2.4 and 2.6 × 10⁻⁵ M, respectively), indicating they are about five times less potent than galanthamine, while galwesine was inactive at 10⁻³ M. Inhibitory activity of HIV-1 replication, and cytotoxicity of the isolated alkaloids were evaluated in human MT-4 cells; however, the alkaloids showed poor activity as compared with standard anti-HIV drugs, but most of them were not cytotoxic. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Polar Compounds Isolated from the Leaves of Albertisia delagoensis (Menispermaceae)

by Geoffrey E. Hawkes, Helene de Wet and Jia Li

Molecules 2011, 16(11), 9153-9160; https://doi.org/10.3390/molecules16119153 - 02 Nov 2011

Cited by 3 | Viewed by 5046

Abstract

Aqueous infusions of the leaves of the shrub Albertisia delagoensis (Menispermaceae) are used in South Africa in traditional Zulu medicine to alleviate a variety of symptoms, including fever, and intestinal problems. We report the analysis of such an aqueous extract using the HPLC-NMR [...] Read more.

Aqueous infusions of the leaves of the shrub Albertisia delagoensis (Menispermaceae) are used in South Africa in traditional Zulu medicine to alleviate a variety of symptoms, including fever, and intestinal problems. We report the analysis of such an aqueous extract using the HPLC-NMR technique. A number of polar compounds were identified, including proto-quercitol, nicotinic acid, allantoic acid, 3,4-dihydroxy-benzoic acid, phthalic acid and the aporphine alkaloid derivative roemrefidine. Allantoic acid and roemrefidine have been fully characterised by ¹H- and ¹³C-NMR and mass spectrometry. Earlier reports of antiplasmodial activity of roemrefidine and of A. delagoensis extracts are correlated with this study and with the antipyretic properties of neutral aqueous extracts. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Application of Preparative High-Speed Counter-Current Chromatography for the Separation of Two Alkaloids from the Roots of Tabernaemontana catharinensis (Apocynaceae)

by Milena S. Gonçalves, Ivo J. Curcino Vieira, Rodrigo R. Oliveira and Raimundo Braz-Filho

Molecules 2011, 16(9), 7480-7487; https://doi.org/10.3390/molecules16097480 - 02 Sep 2011

Cited by 9 | Viewed by 5889

Abstract

The methanolic extract of Tabernaemontana catharinensis (Apocynaceae) roots, which contains alkaloids with several biological activities, was separated on a preparative scale using high-speed counter-current chromatography. The optimum solvent system was found to be a mixture of CHCl₃-MeOH-H₂O [5:10:6 ( [...] Read more.

The methanolic extract of Tabernaemontana catharinensis (Apocynaceae) roots, which contains alkaloids with several biological activities, was separated on a preparative scale using high-speed counter-current chromatography. The optimum solvent system was found to be a mixture of CHCl₃-MeOH-H₂O [5:10:6 (v/v/v)] and led to a successful separation of two monoterpenic indole alkaloids, voachalotine (1) and 12-methoxy-N_b-methylvoachalotine (2) in approximately 4.0 hours. The alkaloids were all isolated at purities over 95%, and their structures were established on the basis of spectroscopic methods, including 1D and 2D NMR and EI/MS. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay

by Wai Mun Kong, Zamri Chik, Murali Ramachandra, Umarani Subramaniam, Raja Elina Raja Aziddin and Zahurin Mohamed

Molecules 2011, 16(9), 7344-7356; https://doi.org/10.3390/molecules16097344 - 29 Aug 2011

Cited by 65 | Viewed by 12046

Abstract

The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi [...] Read more.

The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC₅₀) values of 0.78 µg/mL and 0.636 µg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC₅₀ of 39 µg/mL, and weak inhibition was detected for CYP2C19. The IC₅₀ of CYP2C19 could not be determined, however, because inhibition was < 50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Chirality and Numbering of Substituted Tropane Alkaloids

by Munir Humam, Tarik Shoul, Damien Jeannerat, Orlando Muñoz and Philippe Christen

Molecules 2011, 16(9), 7199-7209; https://doi.org/10.3390/molecules16097199 - 25 Aug 2011

Cited by 13 | Viewed by 7099

Abstract

The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based [...] Read more.

The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based on NMR and MS data, without taking into account the absolute configuration of these two carbons. This paper discusses the problem and the relevance of CD and NMR to determine molecular configurations. We report on the use of ¹H-NMR anisochrony (Δd) induced by the Mosher’s chiral auxiliary reagents (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of (3R,6R)-3α-hydroxy-6b-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial parts of Schizanthus grahamii (Solanaceae). These analytical tools should help future works in correctly assigning the configuration of additional 3, 6/7 disubstituted tropane derivatives. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

The Growth Suppressing Effects of Girinimbine on Hepg2 Involve Induction of Apoptosis and Cell Cycle Arrest

by Suvitha Syam, Ahmad Bustamam Abdul, Mohd. Aspollah Sukari, Syam Mohan, Siddig Ibrahim Abdelwahab and Tang Sook Wah

Molecules 2011, 16(8), 7155-7170; https://doi.org/10.3390/molecules16087155 - 23 Aug 2011

Cited by 64 | Viewed by 13431

Abstract

Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that [...] Read more.

Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G₀/G₁ peak (hypodiploid) and caused G₀/G₁-phase arrest. Together, these results demonstrated for the first time that girinimbine could effectively induce programmed cell death in HepG2 cells and suggests the importance of conducting further investigations in preclinical human hepatocellular carcinoma models, especially on in vivo efficacy, to promote girinimbine for use as an anticancer agent against hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessCommunication

Azaphenanthrene Alkaloids with Antitumoral Activity from Anaxagorea dolichocarpa Sprague & Sandwith (Annonaceae)

by Ana Silvia Suassuna Carneiro Lúcio, Jackson Roberto Guedes Da Silva Almeida, José Maria Barbosa-Filho, João Carlos Lima Rodrigues Pita, Marianna Vieira Sobral Castello Branco, Margareth De Fátima Formiga Melo Diniz, Maria De Fátima Agra, Emidio V.L. Da-Cunha, Marcelo Sobral Da Silva and Josean Fechine Tavares

Molecules 2011, 16(8), 7125-7131; https://doi.org/10.3390/molecules16087125 - 22 Aug 2011

Cited by 15 | Viewed by 7674

Abstract

Phytochemical investigation of Anaxagorea dolichocarpa Sprague & Sandwith led to isolation of three azaphenanthrene alkaloids: eupolauramine, sampangine and imbiline 1. Their chemical structures were established on the basis of spectroscopic data from IR, HR-ESI-MS, NMR (including 2D experiments) and comparison with the literature. [...] Read more.

Phytochemical investigation of Anaxagorea dolichocarpa Sprague & Sandwith led to isolation of three azaphenanthrene alkaloids: eupolauramine, sampangine and imbiline 1. Their chemical structures were established on the basis of spectroscopic data from IR, HR-ESI-MS, NMR (including 2D experiments) and comparison with the literature. Sampangine and imbiline 1 are being described in the Anaxagorea genus for the first time. Eupolauramine and sampangine show concentration-dependent antitumoral activity in leukemic cells K562 with IC₅₀ of 18.97 and 10.95 µg/mL, respectively. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Alkaloids from Hippeastrum papilio

by Jean Paulo de Andrade, Strahil Berkov, Francesc Viladomat, Carles Codina, José Angelo S. Zuanazzi and Jaume Bastida

Molecules 2011, 16(8), 7097-7104; https://doi.org/10.3390/molecules16087097 - 18 Aug 2011

Cited by 35 | Viewed by 8809

Abstract

Galanthamine, an acetylcholinesterase inhibitor marketed as a hydrobromide salt (Razadyne®, Reminyl®) for the treatment of Alzheimer’s disease (AD), is obtained from Amaryllidaceae plants, especially those belonging to the genera Leucojum, Narcissus, Lycoris and Ungernia. The growing demand for galanthamine has [...] Read more.

Galanthamine, an acetylcholinesterase inhibitor marketed as a hydrobromide salt (Razadyne®, Reminyl®) for the treatment of Alzheimer’s disease (AD), is obtained from Amaryllidaceae plants, especially those belonging to the genera Leucojum, Narcissus, Lycoris and Ungernia. The growing demand for galanthamine has prompted searches for new sources of this compound, as well as other bioactive alkaloids for the treatment of AD. In this paper we report the isolation of the new alkaloid 11β-hydroxygalanthamine, an epimer of the previously isolated alkaloid habranthine, which was identified using NMR techniques. It has been shown that 11β-hydroxygalanthamine has an important in vitro acetylcholinesterase inhibitory activity. Additionally, Hippeastrum papilio yielded substantial quantities of galanthamine. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Rauniticine-allo-Oxindole B and Rauniticinic-allo Acid B, New Heteroyohimbine-Type Oxindole Alkaloids from the Stems of Malaysian Uncaria longiflora var. pteropoda

by Fatimah Salim, Nor Hadiani Ismail, Khalijah Awang and Rohaya Ahmad

Molecules 2011, 16(8), 6541-6548; https://doi.org/10.3390/molecules16086541 - 04 Aug 2011

Cited by 12 | Viewed by 5464

Abstract

Two new heteroyohimbine-type oxindole alkaloids, rauniticine-allo-oxindole B and rauniticinic-allo acid B, have been successfully isolated from the stems extract of Malaysian Uncaria longiflora var. pteropoda. The structures of the two new alkaloids were determined by spectroscopic analysis. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Acute Oral Toxicity of Methanolic Seed Extract of Cassia fistula in Mice

by Subramanion L. Jothy, Zuraini Zakaria, Yeng Chen, Yee Ling Lau, Lachimanan Yoga Latha and Sreenivasan Sasidharan

Molecules 2011, 16(6), 5268-5282; https://doi.org/10.3390/molecules16065268 - 23 Jun 2011

Cited by 148 | Viewed by 14492

Abstract

Background and objective: Cassia fistula is widely used in traditional medicine to treat various types of ailments. The evaluation of toxic properties of C. fistula is crucial when considering public health protection because exposure to plant extracts can result in undesirable effects on [...] Read more.

Background and objective: Cassia fistula is widely used in traditional medicine to treat various types of ailments. The evaluation of toxic properties of C. fistula is crucial when considering public health protection because exposure to plant extracts can result in undesirable effects on consumers. Hence, in this study the acute oral toxicity of C. fistula seeds extract was investigated in mice. Results: Oral administration of crude extract at the highest dose of 5000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that C. fistula in nontoxic. Throughout 14 days of the treatment no changes in behavioural pattern, clinical sign and body weight of mice in both control and treatment groups. Also there were no any significant elevations observed in the biochemical analysis of the blood serum. Further, histopathological examination revealed normal architecture and no significant adverse effects observed on the kidney, heart, liver, lung and spleen. Conclusions: Overall, the results suggest that, the oral administration of C. fistula methanolic seeds extract did not produce any significant toxic effect in mice. Hence, the extract can be utilized for pharmaceutical formulations. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Identification of Diterpenoid Alkaloids from the Roots of Aconitum kusnezoffii Reihcb.

by Ning Xu, De-Feng Zhao, Xin-Miao Liang, Hua Zhang and Yuan-Sheng Xiao

Molecules 2011, 16(4), 3345-3350; https://doi.org/10.3390/molecules16043345 - 19 Apr 2011

Cited by 16 | Viewed by 7375

Abstract

Three diterpenoid alkaloids, including an unreported compound, were isolated from the roots of Aconitum kusnezoffii Reichb. On the basis of spectral analysis, these three compounds were determined to be 1,15-dimethoxy-3-hydroxy-14-benzoyl-16-ketoneoline, benzoylaconine and aconitine. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Alkaloids Induce Programmed Cell Death in Bloodstream Forms of Trypanosomes (Trypanosoma b. brucei)

by Vera Rosenkranz and Michael Wink

Molecules 2008, 13(10), 2462-2473; https://doi.org/10.3390/molecules13102462 - 03 Oct 2008

Cited by 73 | Viewed by 14817

Abstract

The potential induction of a programmed cell death (PCD) in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the [...] Read more.

The potential induction of a programmed cell death (PCD) in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the induction of apoptosis by the same alkaloids in human leukemia cells (Jurkat APO-S) was tested. Several alkaloids of the isoquinoline, quinoline, indole and steroidal type (berberine, chelerythrine, emetine, sanguinarine, quinine, ajmalicine, ergotamine, harmine, vinblastine, vincristine, colchicine, chaconine, demissidine and veratridine) induced programmed cell death, whereas quinolizidine, tropane, terpene and piperidine alkaloids were mostly inactive. Effective PCD induction (EC₅₀ below 10 µM) was caused in T. brucei by chelerythrine, emetine, sanguinarine, and chaconine. The active alkaloids can be characterized by their general property to inhibit protein biosynthesis, to intercalate DNA, to disturb membrane fluidity or to inhibit microtubule formation. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

HPLC-ESI-MS/MS of Imidazole Alkaloids in Pilocarpus microphyllus

by Alexandra Sawaya, Ilka Nacif Abreu, Nathalia Luiza Andreazza, Marcos N. Eberlin and Paulo Mazzafera

Molecules 2008, 13(7), 1518-1529; https://doi.org/10.3390/molecules13071518 - 30 Jul 2008

Cited by 20 | Viewed by 15347

Abstract

Pilocarpine, an important imidazole alkaloid, is extracted from the leaves of Pilocarpus microphyllus (Rutaceae), known in Brazil as jaborandi and used mainly for the treatment of glaucoma. Jaborandi leaves also contain other imidazole alkaloids, whose pharmacological and physiological properties are unknown, and whose [...] Read more.

Pilocarpine, an important imidazole alkaloid, is extracted from the leaves of Pilocarpus microphyllus (Rutaceae), known in Brazil as jaborandi and used mainly for the treatment of glaucoma. Jaborandi leaves also contain other imidazole alkaloids, whose pharmacological and physiological properties are unknown, and whose biosynthetic pathways are under investigation. In the present study, a HPLC method coupled with ESI-MSⁿ was developed for their qualitative and quantitative analysis. This method permits the chromatographic separation of the imidazole alkaloids found in extracts of jaborandi, as well as the MS/MS analysis of the individual compounds. Thus two samples: leaves of P. microphyllus and a paste that is left over after the industrial extraction of pilocarpine; were compared. The paste was found to contain significant amounts of pilocarpine and other imidazole alkaloids, but had a slightly different alkaloid profile than the leaf extract. The method is suitable for the routine analysis of samples containing these alkaloids, as well as for the separation and identification of known and novel alkaloids from this family, and may be applied to further studies of the biosynthetic pathway of pilocarpine in P. microphyllus. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Simplexidine, a 4-Alkylpyridinium Alkaloid from the Caribbean Sponge Plakortis simplex

by Ernesto Fattorusso, Adriana Romano, Fernando Scala and Orazio Taglialatela-Scafati

Molecules 2008, 13(7), 1465-1471; https://doi.org/10.3390/molecules13071465 - 17 Jul 2008

Cited by 7 | Viewed by 9434

Abstract

Chemical analysis of the secondary metabolites of the Caribbean sponge Plakortis simplex, a source of many bioactive compounds, showed the presence of the new metabolite simplexidine (4), belonging to the extremely rare class of 4-alkyl-pyridinium alkaloids. The structural characterization of this molecule, [...] Read more.

Chemical analysis of the secondary metabolites of the Caribbean sponge Plakortis simplex, a source of many bioactive compounds, showed the presence of the new metabolite simplexidine (4), belonging to the extremely rare class of 4-alkyl-pyridinium alkaloids. The structural characterization of this molecule, based on spectroscopic methods, is reported. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessArticle

Effects of Anonaine on Dopamine Biosynthesis and L-DOPA-Induced Cytotoxicity in PC12 Cells

by Jae Joon Lee, Chun Mei Jin, Young Kyoon Kim, Shi Yong Ryu, Sung Cil Lim and Myung Koo Lee

Molecules 2008, 13(2), 475-487; https://doi.org/10.3390/molecules13020475 - 27 Feb 2008

Cited by 10 | Viewed by 12110

Abstract

The effects of anonaine, an aporphine isoquinoline alkaloid, on dopaminebiosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaineat concentration ranges of 0.01-0.2 μM showed a significant inhibition of dopaminecontent at 24 h, with an IC₅₀ value of 0.05 μM. Anonaine at [...] Read more.

The effects of anonaine, an aporphine isoquinoline alkaloid, on dopaminebiosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaineat concentration ranges of 0.01-0.2 μM showed a significant inhibition of dopaminecontent at 24 h, with an IC₅₀ value of 0.05 μM. Anonaine at 0.05 μM inhibited tyrosinehydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) activities to 38.4-40.2% and 78.4-90.2% of control levels at 12-24 h and 3-6 h, respectively. TH activity wasmore influenced than AADC activity. Anonaine also decreased intracellular cyclic AMPlevels, but not intracellular Ca²⁺ concentrations. In addition, anonaine (0.05 μM) reducedL-DOPA (50 μM and 100 μM)-induced increases in dopamine content at 24 h. However,anonaine (0.05 μM) did not enhance L-DOPA (50 μM and 100 μM)-induced cell death 476after 24 h. These results suggest that anonaine inhibits dopamine biosynthesis by mainlyreducing TH activity without aggravating L-DOPA-induced cytotoxicity in PC12 cells. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessCommunication

NMR Spectra of Sparteine N1-oxide and α-Isosparteine N-oxide

by Beata Jasiewicz

Molecules 2008, 13(1), 3-10; https://doi.org/10.3390/molecules13010003 - 09 Jan 2008

Cited by 6 | Viewed by 7856

Abstract

Sparteine N1-oxide and α-isosparteine N-oxide were prepared and theirstructures determined for the first time by ¹H- and ¹³C-NMR spectroscopy using twodimensionaltechniques. The N-oxide effects were also calculated. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Review

Jump to: Research

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Open AccessReview

Anti-Allergic Properties of Curine, a Bisbenzylisoquinoline Alkaloid

by Jaime Ribeiro-Filho, Márcia Regina Piuvezam and Patrícia T. Bozza

Molecules 2015, 20(3), 4695-4707; https://doi.org/10.3390/molecules20034695 - 13 Mar 2015

Cited by 15 | Viewed by 10854

Abstract

Curine is a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae). Recent findings have shed light on the actions of curine in different models of allergy and inflammation. Here we review the properties and mechanisms of action of curine focusing on its anti-allergic effects. [...] Read more.

Curine is a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae). Recent findings have shed light on the actions of curine in different models of allergy and inflammation. Here we review the properties and mechanisms of action of curine focusing on its anti-allergic effects. Curine pre-treatment significantly inhibited the scratching behavior, paw edema and systemic anaphylaxis induced by either ovalbumin (OVA) in sensitized animals or compound 48/80, through mechanisms of mast cell stabilization and inhibition of mast cell activation to generate lipid mediators. In addition, oral administration of curine significantly inhibited eosinophil recruitment and activation, as well as, OVA-induced airway hyper-responsiveness in a mouse model of asthma, through inhibition of the production of IL-13 and eotaxin, and of Ca²⁺ influx. In conclusion, curine exhibit anti-allergic effects in models of lung, skin and systemic allergy in the absence of significant toxicity, and as such has the potential for anti-allergic drug development. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Indole Alkaloids from Catharanthus roseus: Bioproduction and Their Effect on Human Health

by Lorena Almagro, Francisco Fernández-Pérez and Maria Angeles Pedreño

Molecules 2015, 20(2), 2973-3000; https://doi.org/10.3390/molecules20022973 - 12 Feb 2015

Cited by 179 | Viewed by 15458

Abstract

Catharanthus roseus is a medicinal plant belonging to the family Apocynaceae which produces terpenoid indole alkaloids (TIAs) of high medicinal importance. Indeed, a number of activities like antidiabetic, bactericide and antihypertensive are linked to C. roseus. Nevertheless, the high added value of [...] Read more.

Catharanthus roseus is a medicinal plant belonging to the family Apocynaceae which produces terpenoid indole alkaloids (TIAs) of high medicinal importance. Indeed, a number of activities like antidiabetic, bactericide and antihypertensive are linked to C. roseus. Nevertheless, the high added value of this plant is based on its enormous pharmaceutical interest, producing more than 130 TIAs, some of which exhibit strong pharmacological activities. The most striking biological activity investigated has been the antitumour effect of dimeric alkaloids such as anhydrovinblastine, vinblastine and vincristine which are already in pre-, clinical or in use. The great pharmacological importance of these indole alkaloids, contrasts with the small amounts of them found in this plant, making their extraction a very expensive process. To overcome this problem, researches have looked for alternative sources and strategies to produce them in higher amounts. In this sense, intensive research on the biosynthesis of TIAs and the regulation of their pathways has been developed with the aim to increase by biotechnological approaches, the production of these high added value compounds. This review is focused on the different strategies which improve TIA production, and in the analysis of the beneficial effects that these compounds exert on human health. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation

by Xaver Koenig and Karlheinz Hilber

Molecules 2015, 20(2), 2208-2228; https://doi.org/10.3390/molecules20022208 - 29 Jan 2015

Cited by 69 | Viewed by 24350

Abstract

The plant indole alkaloid ibogaine has shown promising anti-addictive properties in animal studies. Ibogaine is also anti-addictive in humans as the drug alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug and despite safety concerns, ibogaine is [...] Read more.

The plant indole alkaloid ibogaine has shown promising anti-addictive properties in animal studies. Ibogaine is also anti-addictive in humans as the drug alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug and despite safety concerns, ibogaine is currently used as an anti-addiction medication in alternative medicine in dozens of clinics worldwide. In recent years, alarming reports of life-threatening complications and sudden death cases, temporally associated with the administration of ibogaine, have been accumulating. These adverse reactions were hypothesised to be associated with ibogaine’s propensity to induce cardiac arrhythmias. The aim of this review is to recapitulate the current knowledge about ibogaine’s effects on the heart and the cardiovascular system, and to assess the cardiac risks associated with the use of this drug in anti- addiction therapy. The actions of 18-methoxycoronaridine (18-MC), a less toxic ibogaine congener with anti-addictive properties, are also considered. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Activity of Alkaloids on Peptic Ulcer: What’s New?

by Raphaela Francelino Do Nascimento, Igor Rafael Praxedes De Sales, Rodrigo De Oliveira Formiga, José Maria Barbosa-Filho, Marianna Vieira Sobral, Josean Fechine Tavares, Margareth De Fátima Formiga Melo Diniz and Leônia Maria Batista

Molecules 2015, 20(1), 929-950; https://doi.org/10.3390/molecules20010929 - 08 Jan 2015

Cited by 19 | Viewed by 8547

Abstract

Peptic ulcer is a common disease characterized by lesions that affect the mucosa of the esophagus, stomach and/or duodenum, and may extend into the muscular layer of the mucosa. Natural products have played an important role in the process of development and discovery [...] Read more.

Peptic ulcer is a common disease characterized by lesions that affect the mucosa of the esophagus, stomach and/or duodenum, and may extend into the muscular layer of the mucosa. Natural products have played an important role in the process of development and discovery of new drugs, due to their wide structural diversity and present, mostly specific and selective biological activities. Among natural products the alkaloids, biologically active secondary metabolites, that can be found in plants, animals or microorganisms stand out. The alkaloids are compounds consisting of a basic nitrogen atom that may or may not be part of a heterocyclic ring. This review will describe 15 alkaloids with antiulcer activity in animal models and in vitro studies. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

by Concetta Imperatore, Anna Aiello, Filomena D'Aniello, Maria Senese and Marialuisa Menna

Molecules 2014, 19(12), 20391-20423; https://doi.org/10.3390/molecules191220391 - 05 Dec 2014

Cited by 56 | Viewed by 11028

Abstract

The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their [...] Read more.

The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Alkaloids from the Tribe Bocconieae (Papaveraceae): A Chemical and Biological Review

by Xuelong Yu, Xiaoli Gao, Zhixiang Zhu, Yuan Cao, Qian Zhang, Pengfei Tu and Xingyun Chai

Molecules 2014, 19(9), 13042-13060; https://doi.org/10.3390/molecules190913042 - 25 Aug 2014

Cited by 40 | Viewed by 8044

Abstract

The Bocconieae tribe, consisting of only the genera Macleaya and Bocconia, possesses significant economic and medicinal value and plays an important role in health management for people in developing countries. During the past decades, research on metabolites and relative pharmacology, including the [...] Read more.

The Bocconieae tribe, consisting of only the genera Macleaya and Bocconia, possesses significant economic and medicinal value and plays an important role in health management for people in developing countries. During the past decades, research on metabolites and relative pharmacology, including the isolation and identification of a variety of molecules, has shed light on the tribe. Among those molecules, isoquinoline alkaloids, and their antimicrobial, antifungal, and anti-inflammatory activities are especially noteworthy. This paper presents a comprehensive compilation of current research progress, with emphasis on the alkaloids and their distribution, phytochemical and pharmacological investigation, toxicity and side effects, related chemotaxonomy and future use prospects, and hopefully provides a valuable reference as an effort to promote further exploration and application of this tribe. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Berberine, an Epiphany Against Cancer

by Luis Miguel Guamán Ortiz, Paolo Lombardi, Micol Tillhon and Anna Ivana Scovassi

Molecules 2014, 19(8), 12349-12367; https://doi.org/10.3390/molecules190812349 - 15 Aug 2014

Cited by 208 | Viewed by 28385

Abstract

Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range [...] Read more.

Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

PM00104 (Zalypsis^®): A Marine Derived Alkylating Agent

by Bradley J. Petek and Robin L. Jones

Molecules 2014, 19(8), 12328-12335; https://doi.org/10.3390/molecules190812328 - 15 Aug 2014

Cited by 27 | Viewed by 6546

Abstract

PM00104 (Zalypsis^®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological malignancies. PM00104 is a DNA binding agent, [...] Read more.

PM00104 (Zalypsis^®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological malignancies. PM00104 is a DNA binding agent, causing inhibition of the cell cycle and transcription, which can lead to double stranded DNA breaks. After rigorous pre-clinical testing, the drug has been evaluated in a number of phase II clinical trials. This manuscript provides a review of current trials and appraises the efficacy of PM00104 as a future cancer treatment. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

The Pharmacological Activities of (−)-Anonaine

by Hsing-Tan Li, Hui-Ming Wu, Hsin-Liang Chen, Chi-Ming Liu and Chung-Yi Chen

Molecules 2013, 18(7), 8257-8263; https://doi.org/10.3390/molecules18078257 - 12 Jul 2013

Cited by 34 | Viewed by 8547

Abstract

Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (−)-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (−)-anonaine. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Chromone and Flavonoid Alkaloids: Occurrence and Bioactivity

by Shahriar Khadem and Robin J. Marles

Molecules 2012, 17(1), 191-206; https://doi.org/10.3390/molecules17010191 - 27 Dec 2011

Cited by 172 | Viewed by 12336

Abstract

The chromone and flavonoid alkaloids represent an unusual group of structurally diverse secondary metabolites, derived from the convergence of multiple biosynthetic pathways that are widely distributed through the plant and animal kingdoms. Many of them have been discovered through bioassay-guided chemical investigations of [...] Read more.

The chromone and flavonoid alkaloids represent an unusual group of structurally diverse secondary metabolites, derived from the convergence of multiple biosynthetic pathways that are widely distributed through the plant and animal kingdoms. Many of them have been discovered through bioassay-guided chemical investigations of traditional medicines, suggesting potential therapeutic significance. Their unique structures and varied pharmacological activities may provide important new leads for the discovery of drugs with novel mechanisms of action. Potential therapeutic indications are as diverse as cancer and viral infections, inflammation and immunomodulation, neurological and psychiatric conditions, and diabetes. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

A Journey Under the Sea: The Quest for Marine Anti-Cancer Alkaloids

by Rita Tohme, Nadine Darwiche and Hala Gali-Muhtasib

Molecules 2011, 16(11), 9665-9696; https://doi.org/10.3390/molecules16119665 - 23 Nov 2011

Cited by 77 | Viewed by 10236

Abstract

The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many [...] Read more.

The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Anti-Inflammatory Activity of Alkaloids: An Update from 2000 to 2010

by Augusto Lopes Souto, Josean Fechine Tavares, Marcelo Sobral Da Silva, Margareth de Fátima Formiga Melo Diniz, Petrônio Filgueiras De Athayde-Filho and José Maria Barbosa Filho

Molecules 2011, 16(10), 8515-8534; https://doi.org/10.3390/molecules16108515 - 11 Oct 2011

Cited by 146 | Viewed by 12644

Abstract

Many natural substances with proven anti-inflammatory activity have been isolated throughout the years. The aim of this review is to review naturally sourced alkaloids with anti-inflammatory effects reported from 2000 to 2010. The assays were conducted mostly in vivo, and carrageenan-induced pedal [...] Read more.

Many natural substances with proven anti-inflammatory activity have been isolated throughout the years. The aim of this review is to review naturally sourced alkaloids with anti-inflammatory effects reported from 2000 to 2010. The assays were conducted mostly in vivo, and carrageenan-induced pedal edema was the most used experimental model. Of the 49 alkaloids evaluated, 40 demonstrated anti-inflammatory activity. Of these the most studied type were the isoquinolines. This review was based on NAPRALERT data bank, Web of Science and Chemical Abstracts. In this review, 95 references are cited. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

The Potential of Tetrandrine as a Protective Agent for Ischemic Stroke

by Yun Chen, Ya-Hui Tsai and Sheng-Hong Tseng

Molecules 2011, 16(9), 8020-8032; https://doi.org/10.3390/molecules16098020 - 16 Sep 2011

Cited by 34 | Viewed by 7569

Abstract

Stroke is one of the leading causes of mortality, with a high incidence of severe morbidity in survivors. The treatment to minimize tissue injury after stroke is still unsatisfactory and it is mandatory to develop effective treatment strategies for stroke. The pathophysiology of [...] Read more.

Stroke is one of the leading causes of mortality, with a high incidence of severe morbidity in survivors. The treatment to minimize tissue injury after stroke is still unsatisfactory and it is mandatory to develop effective treatment strategies for stroke. The pathophysiology of ischemic stroke is complex and involves many processes including energy failure, loss of ion homeostasis, increased intracellular calcium level, platelet aggregation, production of reactive oxygen species, disruption of blood brain barrier, and inflammation and leukocyte infiltration, etc. Tetrandrine, a bisbenzylisoquinoline alkaloid, has many pharmacologic effects including anti-inflammatory and cytoprotective effects. In addition, tetrandrine has been found to protect the liver, heart, small bowel and brain from ischemia/reperfusion injury. It is a calcium channel blocker, and can inhibit lipid peroxidation, reduce generation of reactive oxygen species, suppress the production of cytokines and inflammatory mediators, inhibit neutrophil recruitment and platelet aggregation, which are all devastating factors during ischemia/reperfusion injury of the brain. Because tetrandrine can counteract these important pathophysiological processes of ischemic stroke, it has the potential to be a protective agent for ischemic stroke. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Gastric and Duodenal Antiulcer Activity of Alkaloids: A Review

by Heloina De Sousa Falcão, Jacqueline Alves Leite, José Maria Barbosa-Filho, Petrônio Filgueiras De Athayde-Filho, Maria Célia De Oliveira Chaves, Marcelo Dantas Moura, Anderson Luiz Ferreira, Ana Beatriz Albino De Almeida, Alba Regina Monteiro Souza-Brito, Margareth De Fátima Formiga Melo Diniz and Leônia Maria Batista

Molecules 2008, 13(12), 3198-3223; https://doi.org/10.3390/molecules13123198 - 17 Dec 2008

Cited by 112 | Viewed by 18683

Abstract

Peptic ulcer disease is a deep gastrointestinal erosion disorder that involves the entire mucosal thickness and can even penetrate the muscular mucosa. Numerous natural products have been evaluated as therapeutics for the treatment of a variety of diseases, including this one. These products [...] Read more.

Peptic ulcer disease is a deep gastrointestinal erosion disorder that involves the entire mucosal thickness and can even penetrate the muscular mucosa. Numerous natural products have been evaluated as therapeutics for the treatment of a variety of diseases, including this one. These products usually derive from plant and animal sources that contain active constituents such as alkaloids, flavonoids, terpenoids, tannins and others. The alkaloids are natural nitrogen-containing secondary metabolites mostly derived from amino acids and found in about 20% of plants. There has been considerable pharmacological research into the antiulcer activity of these compounds. In this work we review the literature on alkaloids with antiulcer activity, which covers about sixty-one alkaloids, fifty-five of which have activity against this disease when induced in animals. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Rigorous Biogenetic Network for a Group of Indole Alkaloids Derived from Strictosidine

by László F. Szabó

Molecules 2008, 13(8), 1875-1896; https://doi.org/10.3390/molecules13081875 - 27 Aug 2008

Cited by 84 | Viewed by 16017

Abstract

Strictosidine, the precursor of more than 2,500 indole alkaloids, was isolated from four species of three plant families. By searching the Dictionary of Natural Products on DVD it was found that about 150 indole alkaloids were obtained from the same species (coalkaloids), which [...] Read more.

Strictosidine, the precursor of more than 2,500 indole alkaloids, was isolated from four species of three plant families. By searching the Dictionary of Natural Products on DVD it was found that about 150 indole alkaloids were obtained from the same species (coalkaloids), which is a direct proof of their common origin. On the base of their threedimensional structure, taxonomic properties and standard reaction mechanisms an extended network was established which involved the four fundamental skeletons, the three types of carbon framework in the secologanin subunit and all major groups of indole alkaloids derived from secologanin and tryptamine (except a few minor groups, in which only less then 10 alkaloids were known). The system was extended to the heterodimer indole alkaloids and the quinoindole alkaloids as well. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Application of Metabolic Engineering to the Production of Scopolamine

by Javier Palazón, Arturo Navarro-Ocaña, Liliana Hernandez-Vazquez and Mohammad Hossein Mirjalili

Molecules 2008, 13(8), 1722-1742; https://doi.org/10.3390/molecules13081722 - 18 Aug 2008

Cited by 75 | Viewed by 18968

Abstract

Scopolamine is an alkaloid widely used in medicine for its anticholinergic activity. The aim of this review is to show that metabolic engineering techniques constitute a suitable tool to improve the production of tropane alkaloids, focusing in particular on scopolamine. We present an [...] Read more.

Scopolamine is an alkaloid widely used in medicine for its anticholinergic activity. The aim of this review is to show that metabolic engineering techniques constitute a suitable tool to improve the production of tropane alkaloids, focusing in particular on scopolamine. We present an overview of results obtained by various research groups, including our own, who have studied the overexpression of genes involved in the biosynthesis of scopolamine in different plant species that produce tropane alkaloids. Experiments carried out to improve production in hairy root cultures will also be described, as well as those attempting to biotransform hyoscyamine into scopolamine in roots and transgenic tobacco cells. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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Open AccessReview

Progress in the Studies on Rutaecarpine

by Seung Ho Lee, Jong-Keun Son, Byeong Seon Jeong, Tae-Cheon Jeong, Hyeon Wook Chang, Eung-Seok Lee and Yurngdong Jahng

Molecules 2008, 13(2), 272-300; https://doi.org/10.3390/molecules13020272 - 06 Feb 2008

Cited by 147 | Viewed by 14723

Abstract

Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodiarutaecarpa and related herbs, which has shown a variety of intriguing biological propertiessuch as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity andthermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular andendocrine systems. Recent progress in the [...] Read more.

Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodiarutaecarpa and related herbs, which has shown a variety of intriguing biological propertiessuch as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity andthermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular andendocrine systems. Recent progress in the studies on the isolation, synthesis, structureactivityrelationship studies, biological activities and metabolism of rutaecarpine arereviewed. Full article

(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

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