Displaying publications 1 - 20 of 126 in total

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  1. Antithrombocytopenic activity of carpaine and alkaloidal extract of Carica papaya Linn. leaves in busulfan induced thrombocytopenic Wistar rats
    Zunjar V, Dash RP, Jivrajani M, Trivedi B, Nivsarkar M
    J Ethnopharmacol, 2016 Apr 02;181:20-5.
    PMID: 26812680 DOI: 10.1016/j.jep.2016.01.035
    ETHNOPHARMACOLOGICAL RELAVANCE: The decoction of Carica papaya Linn. leaves is used in folklore medicine in certain parts of Malaysia and Indonesia for the treatment of different types of thrombocytopenia associated with diseases and drugs. There are several scientific studies carried out on humans and animal models to confirm the efficacy of decoction of papaya leave for the treatment of disease induced and drug induced thrombocytopenia, however very little is known about the bio-active compounds responsible for the observed activity. The aim of present study was to identify the active phytochemical component of Carica papaya Linn. leaves decoction responsible for anti-thrombocytopenic activity in busulfan-induced thrombocytopenic rats.

    MATERIALS AND METHODS: Antithrombocytopenic activity was assessed on busulfan induced thrombocytopenic Wistar rats. The antithrombocytopenic activity of different bio-guided fractions was evaluated by monitoring blood platelet count. Bioactive compound carpaine was isolated and purified by chromatographic methods and confirmed by spectroscopic methods (LC-MS and 1D/2D-1H/13C NMR) and the structure was confirmed by single crystal X-ray diffraction. Quantification of carpaine was carried out by LC-MS/MS equipped with XTerra(®) MS C18 column and ESI-MS detector using 90:10 CH3CN:CH3COONH4 (6mM) under isocratic conditions and detected with multiple reaction monitoring (MRM) in positive ion mode.

    RESULTS: Two different phytochemical groups were isolated from decoction of Carica papaya leaves: phenolics, and alkaloids. Out of these, only alkaloid fraction showed good biological activity. Carpaine was isolated from the alkaloid fraction and exhibited potent activity in sustaining platelet counts upto 555.50±85.17×10(9)/L with no acute toxicity.

    CONCLUSIONS: This study scientifically validates the popular usage of decoction of Carica papaya leaves and it also proves that alkaloids particularly carpaine present in the leaves to be responsible for the antithrombocytopenic activity.

    Matched MeSH terms: Alkaloids/pharmacology
  2. Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata
    Zahari A, Cheah FK, Mohamad J, Sulaiman SN, Litaudon M, Leong KH, et al.
    Planta Med, 2014 May;80(7):599-603.
    PMID: 24723007 DOI: 10.1055/s-0034-1368349
    The crude extract of the bark of Dehaasia longipedicellata exhibited antiplasmodial activity against the growth of Plasmodium falciparum K1 isolate (resistant strain). Phytochemical studies of the extract led to the isolation of six alkaloids: two morphinandienones, (+)-sebiferine (1) and (-)-milonine (2); two aporphines, (-)-boldine (3) and (-)-norboldine (4); one benzlyisoquinoline, (-)-reticuline (5); and one bisbenzylisoquinoline, (-)-O-O-dimethylgrisabine (6). Their structures were determined on the basis of 1D and 2D NMR, IR, UV, and LCMS spectroscopic techniques and upon comparison with literature values. Antiplasmodial activity was determined for all of the isolated compounds. They showed potent to moderate activity with IC50 values ranging from 0.031 to 30.40 µM. (-)-O-O-dimethylgrisabine (6) and (-)-milonine (2) were the two most potent compounds, with IC50 values of 0.031 and 0.097 µM, respectively, that were comparable to the standard, chloroquine (0.090 µM). The compounds were also assessed for their antioxidant activities with di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (IC50 = 18.40-107.31 µg/mL), reducing power (27.40-87.40 %), and metal chelating (IC50 = 64.30 to 257.22 µg/mL) having good to low activity. (-)-O-O-dimethylgrisabine (6) exhibited a potent antioxidant activity of 44.3 % reducing power, while di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium and metal chelating activities had IC50 values of 18.38 and 64.30 µg/mL, respectively. Thus it may be considered as a good reductant with the ability to chelate metal and prevent pro-oxidant activity. In addition to the antiplasmodial and antioxidant activities, the isolated compounds were also tested for their cytotoxicity against a few cancer and normal cell lines. (-)-Norboldine (4) exhibited potent cytotoxicity towards pancreatic cancer cell line BxPC-3 with an IC50 value of 27.060 ± 1.037 µM, and all alkaloids showed no toxicity towards the normal pancreatic cell line (hTERT-HPNE).
    Matched MeSH terms: Alkaloids/pharmacology*
  3. Baclofen blocks the acquisition and expression of mitragynine-induced conditioned place preference in rats
    Yusoff NHM, Mansor SM, Müller CP, Hassan Z
    Behav Brain Res, 2018 06 01;345:65-71.
    PMID: 29499286 DOI: 10.1016/j.bbr.2018.02.039
    Mitragynine is the major alkaloid found in the leaves of M. speciosa Korth (Rubiaceae), a plant that is native to Southeast Asia. This compound has been used, either traditionally or recreationally, due to its psychostimulant and opioid-like effects. Recently, mitragynine has been shown to exert conditioned place preference (CPP), indicating the rewarding and motivational properties of M. speciosa. Here, the involvement of GABAB receptors in mediating mitragynine reward is studied using a CPP paradigm in rats. First, we examined the effects of GABAB receptor agonist baclofen (1.25, 2.5 and 5 mg/kg) on the acquisition of mitragynine (10 mg/kg)-induced CPP. Second, the involvement of GABAB receptors in the expression of mitragynine-induced CPP was tested. We found that the acquisition of mitragynine-induced CPP could be blocked by higher doses (2.5 and 5 mg/kg) of baclofen. Baclofen at a high dose inhibited locomotor activity and caused a CPP. Furthermore, we found that baclofen (2.5 and 5 mg/kg) also blocked the expression of mitragynine-induced CPP. These findings suggest that both, the acquisition and expression of mitragynine's reinforcing properties is controlled by the GABAB receptor.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  4. Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats
    Yusoff NHM, Mansor SM, Müller CP, Hassan Z
    Behav Brain Res, 2017 08 14;332:1-6.
    PMID: 28559179 DOI: 10.1016/j.bbr.2017.05.059
    Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  5. Abuse potential and adverse cognitive effects of mitragynine (kratom)
    Yusoff NH, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al.
    Addict Biol, 2016 Jan;21(1):98-110.
    PMID: 25262913 DOI: 10.1111/adb.12185
    Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  6. Macroline-Sarpagine Bisindole Alkaloids with Antiproliferative Activity from Alstonia penangiana
    Yeap JS, Saad HM, Tan CH, Sim KS, Lim SH, Low YY, et al.
    J Nat Prod, 2019 11 22;82(11):3121-3132.
    PMID: 31642315 DOI: 10.1021/acs.jnatprod.9b00712
    A methanol extract of the stem bark of the Malayan Alstonia penangiana provided seven new bisindole alkaloids, comprising six macroline-sarpagine alkaloids (angustilongines E-K, 1-6) and one macroline-pleiocarpamine bisindole alkaloid (angustilongine L, 7). Analysis of the spectroscopic data (NMR and MS) of these compounds led to the proposed structures of these alkaloids. The macroline-sarpagine alkaloids (1-6) showed in vitro growth inhibitory activity against a panel of human cancer cell lines, inclusive of KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, HCT 116, and A549 cells (IC50 values: 0.02-9.0 μM).
    Matched MeSH terms: Alkaloids/pharmacology*; Indole Alkaloids/pharmacology*
  7. Aspidofractinine and Eburnane Alkaloids from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused, and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora
    Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS
    J Nat Prod, 2016 Jan 22;79(1):230-9.
    PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992
    Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.
    Matched MeSH terms: Indole Alkaloids/pharmacology*
  8. Grandilodines A-C, biologically active indole alkaloids from Kopsia grandifolia
    Yap WS, Gan CY, Low YY, Choo YM, Etoh T, Hayashi M, et al.
    J Nat Prod, 2011 May 27;74(5):1309-12.
    PMID: 21428274 DOI: 10.1021/np200008g
    Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Indole Alkaloids/pharmacology*
  9. A Cytotoxic Indole Characterized by Incorporation of a Unique Carbon-Nitrogen Skeleton and Two Pentacyclic Corynanthean Alkaloids Incorporating a Substituted Tetrahydrofuranone Ring from Kopsia arborea
    Wong SK, Wong SP, Sim KS, Lim SH, Low YY, Kam TS
    J Nat Prod, 2019 07 26;82(7):1902-1907.
    PMID: 31241923 DOI: 10.1021/acs.jnatprod.9b00255
    Three new alkaloids were isolated from the bark extract of the Malayan Kopsia arborea, viz., arbophyllidine (1), an unusual pentacyclic, monoterpenoid indole characterized by an absence of oxygen atoms and incorporating a new carbon-nitrogen skeleton, and arbophyllinines A (2) and B (3), two pentacyclic corynanthean alkaloids incorporating a hydroxyethyl-substituted tetrahydrofuranone ring. The structures of the alkaloids were deduced based on analysis of the MS and NMR data and confirmed by X-ray diffraction analyses. The absolute configuration of arbophyllidine (1) was established based on experimental and calculated ECD data, while that of arbophyllinine A was based on X-ray diffraction analysis (Cu Kα). A reasonable biosynthetic route to arbophyllidine (1) from a pericine precursor is presented. Arbophyllidine (1) showed pronounced in vitro growth inhibitory activity against the HT-29 human cancer cell line with IC50 6.2 μM.
    Matched MeSH terms: Indole Alkaloids/pharmacology
  10. Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway
    Wong CP, Seki A, Horiguchi K, Shoji T, Arai T, Nugroho AE, et al.
    J Nat Prod, 2015 Jul 24;78(7):1656-62.
    PMID: 26176165 DOI: 10.1021/acs.jnatprod.5b00258
    We have previously reported that bisleuconothine A (Bis-A), a novel bisindole alkaloid isolated from Leuconotis griffithii, showed cytostatic activity in several cell lines. In this report, the mechanism of Bis-A-induced cytostatic activity was investigated in detail using A549 cells. Bis-A did not cause apoptosis, as indicated by analysis of annexin V and propidium iodide staining. Expression of all tested apoptosis-related proteins was also unaffected by Bis-A treatment. Bis-A was found to increase LC3 lipidation in MCF7 cells as well as A549 cells, suggesting that Bis-A cytostatic activity may be due to induction of autophagy. Subsequent investigation via Western blotting and immunofluorescence staining indicated that Bis-A induced formation but prevented degradation of autophagosomes. Mechanistic studies showed that Bis-A down-regulated phosphorylation of protein kinase B (AKT) and its downstream kinase, PRAS40, which is an mTOR repressor. Moreover, phosphorylation of p70S6K, an mTOR-dependent kinase, was also down-regulated. Down-regulation of these kinases suggests that the increase in LC3 lipidation may be due to mTOR deactivation. Thus, the cytostatic activity shown by Bis-A may be attributed to its induction of autophagosome formation. The Bis-A-induced autophagosome formation was suggested to be caused by its interference with the AKT-mTOR signaling pathway.
    Matched MeSH terms: Indole Alkaloids/pharmacology*
  11. Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae)
    Wan Othman WNN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K
    Bioorg Med Chem, 2016 09 15;24(18):4464-4469.
    PMID: 27492195 DOI: 10.1016/j.bmc.2016.07.043
    Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively.
    Matched MeSH terms: Alkaloids/pharmacology*
  12. Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E₂ production induced by lipopolysaccharide in RAW264.7 macrophage cells
    Utar Z, Majid MI, Adenan MI, Jamil MF, Lan TM
    J Ethnopharmacol, 2011 Jun 14;136(1):75-82.
    PMID: 21513785 DOI: 10.1016/j.jep.2011.04.011
    ETHNOPHARMACOLOGICAL RELEVANCE: [corrected] Mitragyna speciosa Korth (Rubiaceae) is one of the medicinal plants used traditionally to treat various types of diseases especially in Thailand and Malaysia. Its anti-inflammatory and analgesic properties in its crude form are well documented. In this study, the cellular mechanism involved in the anti-inflammatory effects of mitragynine, the major bioactive constituent, was investigated.

    MATERIALS AND METHODS: The effects of mitragynine on the mRNA and protein expression of COX-1 and COX-2 and the production of prostaglandin E(2) (PGE(2)) were investigated in LPS-treated RAW264.7 macrophage cells. Quantitative RT-PCR was used to assess the mRNA expression of COX-1 and COX-2. Protein expression of COX-1 and COX-2 were assessed using Western blot analysis and the level of PGE(2) production was quantified using Parameter™ PGE(2) Assay (R&D Systems).

    RESULTS: Mitragynine produced a significant inhibition on the mRNA expression of COX-2 induced by LPS, in a dose dependent manner and this was followed by the reduction of PGE(2) production. On the other hand, the effects of mitragynine on COX-1 mRNA expression were found to be insignificant as compared to the control cells. However, the effect of mitragynine on COX-1 protein expression is dependent on concentration, with higher concentration of mitragynine producing a further reduction of COX-1 expression in LPS-treated cells.

    CONCLUSIONS: These findings suggest that mitragynine suppressed PGE(2) production by inhibiting COX-2 expression in LPS-stimulated RAW264.7 macrophage cells. Mitragynine may be useful for the treatment of inflammatory conditions.

    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  13. Fulltext Antidiabetic and antioxidant properties of alkaloids from Catharanthus roseus (L.) G. Don
    Tiong SH, Looi CY, Hazni H, Arya A, Paydar M, Wong WF, et al.
    Molecules, 2013 Aug 15;18(8):9770-84.
    PMID: 23955322 DOI: 10.3390/molecules18089770
    Catharanthus roseus (L.) G. Don is a herbal plant traditionally used by local populations in India, South Africa, China and Malaysia to treat diabetes. The present study reports the in vitro antioxidant and antidiabetic activities of the major alkaloids isolated from Catharanthus roseus (L.) G. Don leaves extract. Four alkaloids--vindoline I, vindolidine II, vindolicine III and vindolinine IV--were isolated and identified from the dichloromethane extract (DE) of this plant's leaves. DE and compounds I-III were not cytotoxic towards pancreatic β-TC6 cells at the highest dosage tested (25.0 µg/mL). All four alkaloids induced relatively high glucose uptake in pancreatic β-TC6 or myoblast C2C12 cells, with III showing the highest activity. In addition, compounds II-IV demonstrated good protein tyrosine phosphatase-1B (PTP-1B) inhibition activity, implying their therapeutic potential against type 2 diabetes. III showed the highest antioxidant potential in ORAC and DPPH assays and it also alleviated H₂O₂-induced oxidative damage in β-TC6 cells at 12.5 µg/mL and 25.0 µg/mL.
    Matched MeSH terms: Alkaloids/pharmacology
  14. The Significance of Tinospora crispa in Treatment of Diabetes Mellitus
    Thomas A, Rajesh EK, Kumar DS
    Phytother Res, 2016 Mar;30(3):357-66.
    PMID: 26749336 DOI: 10.1002/ptr.5559
    Tinospora crispa is a medicinal plant belonging to the botanical family Menispermiaceae. The plant is widely distributed in Southeast Asia and the northeastern region of India. A related species Tinospora cordifolia is used in Ayurveda for treating a large spectrum of diseases. Traditional healers of Thailand, Malaysia, Guyana, Bangladesh and the southern Indian province of Kerala use this plant in the treatment of diabetes. Many diterpenes, triterpenes, phytosteroids, alkaloids and their glycosides have been isolated from T. crispa. Cell culture and animal studies suggest that the herb stimulates secretion of insulin from β-cells. It also causes dose-dependent and time-dependent enhancement of glucose uptake in muscles. However, in view of the reported hepatotoxicity, this herb may be used with caution. This article reviews the animal studies and human clinical trials carried out using this herb. Areas of future research are also identified.
    Matched MeSH terms: Alkaloids/pharmacology
  15. A new phytochemical survey of Malaysia. V. Preliminary screening and plant chemical studies
    Teo LE, Pachiaper G, Chan KC, Hadi HA, Weber JF, Deverre JR, et al.
    J Ethnopharmacol, 1990 Feb;28(1):63-101.
    PMID: 2314111
    A large phytochemical survey of the flora of the Malaysian Peninsula and Sabah is described, covering the systematic search for alkaloids, and partly, for saponins and flavonoids. Details of some chemical studies are reported. This emphasizes the great interest of such a study.
    Matched MeSH terms: Alkaloids/pharmacology
  16. Mitragynine and its potential blocking effects on specific cardiac potassium channels
    Tay YL, Teah YF, Chong YM, Jamil MFA, Kollert S, Adenan MI, et al.
    Toxicol Appl Pharmacol, 2016 08 15;305:22-39.
    PMID: 27260674 DOI: 10.1016/j.taap.2016.05.022
    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  17. Fulltext Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells
    Tay YL, Amanah A, Adenan MI, Wahab HA, Tan ML
    Sci Rep, 2019 12 24;9(1):19757.
    PMID: 31874991 DOI: 10.1038/s41598-019-56106-6
    Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
    Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
  18. Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia
    Tan YS, Ng MP, Tan CH, Tang WK, Sim KS, Yong KT, et al.
    J Nat Prod, 2024 Feb 23;87(2):286-296.
    PMID: 38284153 DOI: 10.1021/acs.jnatprod.3c00960
    Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 μM, respectively.
    Matched MeSH terms: Indole Alkaloids/pharmacology; Secologanin Tryptamine Alkaloids/pharmacology
  19. Strychnan and secoangustilobine A type alkaloids from Alstonia spatulata. Revision of the C-20 configuration of scholaricine
    Tan SJ, Low YY, Choo YM, Abdullah Z, Etoh T, Hayashi M, et al.
    J Nat Prod, 2010 Nov 29;73(11):1891-7.
    PMID: 21043460 DOI: 10.1021/np100552b
    A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Indole Alkaloids/pharmacology
  20. Antiproliferative and Microtubule-stabilizing Activities of Two Iboga-vobasine Bisindoles Alkaloids from Tabernaemontana corymbosa in Colorectal Adenocarcinoma HT-29 Cells
    Tan CH, Sim DSY, Lim SH, Mohd Mohidin TB, Mohan G, Low YY, et al.
    Planta Med, 2022 Nov;88(14):1325-1340.
    PMID: 35100653 DOI: 10.1055/a-1755-5605
    Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the β-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.
    Matched MeSH terms: Indole Alkaloids/pharmacology
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