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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
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
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*
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*
Curcumin, Piperine, and Capsaicin: A Comparative Study of Spice-Mediated Inhibition of Human Cytochrome P450 Isozyme Activities

Shamsi S, Tran H, Tan RS, Tan ZJ, Lim LY

Drug Metab. Dispos., 2017 01;45(1):49-55.
PMID: 27821437

Inhibition of cytochrome P450 (P450) enzymes (CYP) has been shown to lower the metabolism of drugs that are P450 substrates and to consequently alter their pharmacokinetic profiles. Curcumin (CUR), piperine (PIP), and capsaicin (CAP) are spice components (SC) that inhibit the activities of a range of P450 enzymes, but the selection of which SC to be prioritized for further development as an adjuvant will depend on the ranking order of the inhibitory potential of the SCs on specific P450 isozymes. We used common human recombinant enzyme platforms to provide a comparative evaluation of the inhibitory activities of CUR, PIP, and CAP on the principal drug-metabolizing P450 enzymes. SC-mediated inhibition of CYP3A4 was found to rank in the order of CAP (IC501.84 ± 0.71 µM) ∼ PIP (2.12 ± 0.45 µM) > CUR (11.93 ± 3.49 µM), while CYP2C9 inhibition was in the order of CAP (11.95 ± 4.24 µM) ∼ CUR (14.58 ± 4.57 µM) > PIP (89.62 ± 9.17 µM). CAP and PIP were significantly more potent inhibitors of CYP1A2 (IC502.14 ± 0.22 µM and 14.19 ± 4.15 µM, respectively) than CUR (IC50> 100 µM), while all three SCs exhibited weak activity toward CYP2D6 (IC5095.42 ± 12.09 µM for CUR, 99.99 ± 5.88 µM for CAP, and 110.40 ± 3.23 µM for PIP). Of the three SCs, CAP thus has the strongest potential for further development into an inhibitor of multiple CYPs for use in the clinic. Data from this study are also useful for managing potential drug-SC interactions.

Matched MeSH terms: Alkaloids/pharmacology*
Fulltext Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Chung FF, Tan PF, Raja VJ, Tan BS, Lim KH, Kam TS, et al.

Sci Rep, 2017 02 15;7:42504.
PMID: 28198434 DOI: 10.1038/srep42504

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.

Matched MeSH terms: Indole Alkaloids/pharmacology*
Activity of Pericampylus glaucus and periglaucine A in vitro against nasopharangeal carcinoma and anti-inflammatory activity

Shipton FN, Khoo TJ, Hossan MS, Wiart C

J Ethnopharmacol, 2017 Feb 23;198:91-97.
PMID: 28049063 DOI: 10.1016/j.jep.2016.12.045

ETHNOPHARMACOLOGICAL RELEVANCE: Pericampylus glaucus is a climbing plant found across Asia and used in traditional medicine to treat a number of conditions including splenomegaly, fever, cough, laryngitis, pulmonary disease, asthma, headache, hair loss, snake bite, boar bite, factures, boils, tumours, tetanus, rheumatic pain, itches and eclampsia.
AIM OF THE STUDY: To test extracts of P. glaucus in a number of bioassays and determine the legitimacy of its traditional use.
MATERIALS AND METHODS: The stems, leaves, roots and fruits of P. glaucus were collected and extracted sequentially with hexane, chloroform and ethanol, respectively. The anti-inflammatory activity was assessed by testing the ability of the extracts to inhibit heat induced protein denaturation, stabilise human red blood cells under hypotonic stress and by testing the inhibitory activity of the extracts against cyclooxygenases 1 and 2. Cytotoxicity was tested using the human lung epithelial cell line MRC-5 and nasopharangeal carcinoma cell line HK1 in the MTT assay.
RESULTS: Many of the samples showed an ability to prevent heat induced protein denaturation, as well as prevent lysis of red blood cells. Most of the extracts demonstrated inhibitory activity towards both of the COX enzymes. The ethanol extracts tended to demonstrate greater toxicity than other extracts, with some of the other extracts significantly enhancing growth and metabolism of the cells.
CONCLUSION: The benefit of P. glaucus for the treatment of diseases related to inflammation and cancer was supported by the in vitro assays adopted in this study.

Matched MeSH terms: Alkaloids/pharmacology*
Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice

Ismail NIW, Jayabalan N, Mansor SM, Müller CP, Muzaimi M

Addict Biol, 2017 Jul;22(4):967-976.
PMID: 26990882 DOI: 10.1111/adb.12385

Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum heterophyllum

Ahmad H, Ahmad S, Shah SAA, Latif A, Ali M, Khan FA, et al.

Bioorg Med Chem, 2017 07 01;25(13):3368-3376.
PMID: 28457693 DOI: 10.1016/j.bmc.2017.04.022

Extensive chromatographic separations performed on the basic (pH=8-10) chloroform soluble fraction of Aconitum heterophyllum resulted in the isolation of three new diterpenoid alkaloids, 6β-Methoxy, 9β-dihydroxylheteratisine (1), 1α,11,13β-trihydroxylhetisine (2), 6,15β-dihydroxylhetisine (3), and the known compounds iso-atisine (4), heteratisine (5), hetisinone (6), 19-epi-isoatisine (7), and atidine (8). Structures of the isolated compounds were established by means of mass and NMR spectroscopy as well as single crystal X-ray crystallography. Compounds 1-8 were screened for their antioxidant and enzyme inhibition activities followed by in silico studies to find out the possible inhibitory mechanism of the tested compounds. This work is the first report demonstrating significant antioxidant and anticholinesterase potentials of diterpenoid alkaloids isolated from a natural source.

Matched MeSH terms: Alkaloids/pharmacology*
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*
Gramine inhibits angiogenesis and induces apoptosis via modulation of TGF-β signalling in 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinoma

Ramu A, Kathiresan S, Ali Ahmed B

Phytomedicine, 2017 Sep 15;33:69-76.
PMID: 28887922 DOI: 10.1016/j.phymed.2017.05.008

BACKGROUND: Transforming growth factor-β (TGF-β) and its receptors are considered as a novel target in cancer chemotherapy. Gramine, an indole alkaloid, possesses various pharmacological properties including antiproliferative and anticancer. However, the anti-angiogenic property remains unexplored.
PURPOSE: The present study was designed to evaluate the anti-angiogenic and apoptosis induction properties of gramine through inhibiting TGF-β on DMBA induced oral squamous cell carcinoma (OSCC) in the hamster buccal pouch (HBP).
METHODS: The effects of gramine on TGF-β signalling in DMBA induced carcinogenic events such as angiogenesis and apoptosis were analysed by studying the mRNA expression using RT-PCR, protein expression by western blot and histopathological analysis using haematoxylin and eosin (H & E) staining.
RESULTS: Gramine significantly inhibited phosphorylation and nuclear translocation of Smad2 and Smad4 by blocking activity of the TGFβ-RII, RI and activation of inhibitory Smad7. Gramine inhibited angiogenic markers such as MMP-2, MMP-9, HIF-1α, VEGF, and VEGF-R2 as well as increased TIMP-2 expression. Furthermore, gramine induced apoptosis in DMBA induced tumour bearing animals by up regulating the pro apoptotic proteins Bax, cytochrome C, apaf-1, caspase-9 caspase-3 and PARP.
CONCLUSION: In this study, we clearly demonstrated that gramine treatment diminishes angiogenesis and induces apoptosis in hamster buccal pouch (HBP) carcinogenesis by modulating TGF-β signals.

Matched MeSH terms: Alkaloids/pharmacology*
Fulltext In Vitro Testing of Potential Entamoeba histolytica Pyruvate Phosphate Dikinase Inhibitors

Saidin S, Othman N, Noordin R

Am J Trop Med Hyg, 2017 Oct;97(4):1204-1213.
PMID: 28820699 DOI: 10.4269/ajtmh.17-0132

Adverse effects and resistance to metronidazole have motivated the search for new antiamoebic agents against Entamoeba histolytica. Control of amoeba growth may be achieved by inhibiting the function of the glycolytic enzyme and pyruvate phosphate dikinase (PPDK). In this study, we screened 10 compounds using an in vitro PPDK enzyme assay. These compounds were selected from a virtual screening of compounds in the National Cancer Institute database. The antiamoebic activity of the selected compounds was also evaluated by determining minimal inhibitory concentrations (MICs) and IC50 values using the nitro-blue tetrazolium reduction assay. Seven of the 10 compounds showed inhibitory activities against the adenosine triphosphate (ATP)/inorganic phosphate binding site of the ATP-grasp domain. Two compounds, NSC349156 (pancratistatin) and NSC228137 (7-ethoxy-4-[4-methylphenyl] sulfonyl-3-oxido-2, 1, 3-benzoxadiazol-3-ium), exhibited inhibitory effects on the growth of E. histolytica trophozoites with MIC values of 25 and 50 μM, and IC50 values of 14 and 20.7 μM, respectively.

Matched MeSH terms: Amaryllidaceae Alkaloids/pharmacology*
A Bis-benzopyrroloisoquinoline Alkaloid Incorporating a Cyclobutane Core and a Chlorophenanthroindolizidine Alkaloid with Cytotoxic Activity from Ficus fistulosa var. tengerensis

Al-Khdhairawi AAQ, Krishnan P, Mai CW, Chung FF, Leong CO, Yong KT, et al.

J Nat Prod, 2017 10 27;80(10):2734-2740.
PMID: 28926237 DOI: 10.1021/acs.jnatprod.7b00500

Tengerensine (1), isolated as a racemate and constituted from a pair of bis-benzopyrroloisoquinoline enantiomers, and tengechlorenine (2), purified as a scalemic mixture and constituted from a pair of chlorinated phenanthroindolizidine enantiomers, were isolated from the leaves of Ficus fistulosa var. tengerensis, along with three other known alkaloids. The structures of 1 and 2 were determined by spectroscopic data interpretation and X-ray diffraction analysis. The enantiomers of 1 were separated by chiral-phase HPLC, and the absolute configurations of (+)-1 and (-)-1 were established via experimental and calculated ECD data. Compound 1 is notable in being a rare unsymmetrical cyclobutane adduct and is the first example of a dimeric benzopyrroloisoquinoline alkaloid, while compound 2 represents the first naturally occurring halogenated phenanthroindolizidine alkaloid. Compound (+)-1 displayed a selective in vitro cytotoxic effect against MDA-MB-468 cells (IC50 7.4 μM), while compound 2 showed pronounced in vitro cytotoxic activity against all three breast cancer cell lines tested (MDA-MB-468, MDA-MB-231, and MCF7; IC50 values of 0.038-0.91 μM).

Matched MeSH terms: Alkaloids/pharmacology*
Acanthamoebicidal activity of periglaucine A and betulinic acid from Pericampylus glaucus (Lam.) Merr. in vitro

Mahboob T, Azlan AM, Shipton FN, Boonroumkaew P, Nor Azman NS, Sekaran SD, et al.

Exp Parasitol, 2017 Dec;183:160-166.
PMID: 28916456 DOI: 10.1016/j.exppara.2017.09.002

Acanthamoeba species are pathogenic protozoa which account for amoebic keratitis, conjunctivitis and granulomatous amoebic encephalitis. These amoebae form cysts which resist drugs and more effective acanthamoebicidal agents are needed. Medicinal plants could be useful in improving the current treatment strategies for Acanthamoeba infections. In the present study, we examined the amoebicidal effects of Pericampylus glaucus (Lam.) Merr., a medicinal plant used for the treatment of conjunctivitis in Malaysia. Pathogenic Acanthamoeba triangularis were isolated from environmental water samples and treated with different concentrations of fractions obtained from Pericampylus glaucus (Lam.) Merr. as well as main constituents for 24-72 h. Chlorhexidine was used as a reference drug. Ethanol fraction of stem showed significant (p

Matched MeSH terms: Alkaloids/pharmacology*
Fulltext Anticancer and anti-inflammatory activities of girinimbine isolated from Murraya koenigii

Iman V, Mohan S, Abdelwahab SI, Karimian H, Nordin N, Fadaeinasab M, et al.

Drug Des Devel Ther, 2017;11:103-121.
PMID: 28096658 DOI: 10.2147/DDDT.S115135

Therapy that directly targets apoptosis and/or inflammation could be highly effective for the treatment of cancer. Murraya koenigii is an edible herb that has been traditionally used for cancer treatment as well as inflammation. Here, we describe that girinimbine, a carbazole alkaloid isolated from M. koenigii, induced apoptosis and inhibited inflammation in vitro as well as in vivo. Induction of apoptosis in human colon cancer cells (HT-29) by girinimbine revealed decreased cell viability in HT-29, whereas there was no cytotoxic effect on normal colon cells. Changes in mitochondrial membrane potential, nuclear condensation, cell permeability, and cytochrome c translocation in girinimbine-treated HT-29 cells demonstrated involvement of mitochondria in apoptosis. Early-phase apoptosis was shown in both acridine orange/propidium iodide and annexin V results. Girinimbine treatment also resulted in an induction of G0/G1 phase arrest which was further corroborated with the upregulation of two cyclin-dependent kinase proteins, p21 and p27. Girinimbine treatment activated apoptosis through the intrinsic pathway by activation of caspases 3 and 9 as well as cleaved caspases 3 and 9 which ended by triggering the execution pathway. Moreover, apoptosis was confirmed by downregulation of Bcl-2 and upregulation of Bax in girinimbine-treated cells. In addition, the key tumor suppressor protein, p53, was seen to be considerably upregulated upon girinimbine treatment. Induction of apoptosis by girinimbine was also evidenced in vivo in zebrafish embryos, with results demonstrating significant distribution of apoptotic cells in embryos after a 24-hour treatment period. Meanwhile, anti-inflammatory action was evidenced by the significant dose-dependent girinimbine inhibition of nitric oxide production in lipopolysaccharide/interferon-gamma-induced cells along with significant inhibition of nuclear factor-kappa B translocation from the cytoplasm to nucleus in stimulated RAW 264.7 cells. Girinimbine was also shown to have considerable antioxidant activity whereby 20 μg/mL of girinimbine was equivalent to 82.17±1.88 μM of Trolox. In mice with carrageenan-induced peritonitis, oral pretreatment with girinimbine helped limit total leukocyte migration (mainly of neutrophils), and reduced pro-inflammatory cytokine levels (interleukin-1beta and tumor necrosis factor-alpha) in the peritoneal fluid. These findings strongly suggest that girinimbine could act as a chemopreventive and/or chemotherapeutic agent by inducing apoptosis while suppressing inflammation. There is a potential for girinimbine to be further investigated for its applicability in treating early stages of cancer.

Matched MeSH terms: Alkaloids/pharmacology*
Physicochemical Characterization of Mitragyna speciosa Alkaloid Extract and Mitragynine using In Vitro High Throughput Assays

Kong WM, Chik Z, Mohamed Z, Alshawsh MA

Comb Chem High Throughput Screen, 2017;20(9):796-803.
PMID: 29076424 DOI: 10.2174/1386207320666171026121820

AIM AND OBJECTIVE: Mitragynine, a major active alkaloid of Mitragyna speciosa, acts as an agonist on µ-opioid receptors, producing effects similar to morphine and other opioids. It has been traditionally utilized to alleviate opiate withdrawal symptoms. Besides consideration about potency and selectivity, a good drug must possess a suitable pharmacokinetic profile, with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile, in order to have a high chance of success in clinical trials.
MATERIAL AND METHOD: The purity of mitragynine in a Mitragyna speciosa alkaloid extract (MSAE) was determined using Ultra-Fast Liquid Chromatography (UFLC). In vitro high throughput ADMETox studies such as aqueous solubility, plasma protein binding, metabolic stability, permeability and cytotoxicity tests were carried out to analyze the physicochemical properties of MSAE and mitragynine. The UFLC quantification revealed that the purity of mitragynine in the MSAE was 40.9%.
RESULTS: MSAE and mitragynine are highly soluble in aqueous solution at pH 4.0 but less soluble at pH 7.4. A parallel artificial membrane permeability assay demonstrated that it is extensively absorbed through the semi-permeable membrane at pH 7.4 but very poorly at pH 4.0. Both are relatively highly bound to plasma proteins (> 85 % bound) and are metabolically stable to liver microsomes (> 84 % remained unchanged). In comparison to MSAE, mitragynine showed higher cytotoxicity against WRL 68, HepG2 and Clone 9 hepatocytes after 72 h treatment.
CONCLUSION: The obtained ADME and cytotoxicity data demonstrated that both MSAE and mitragynine have poor bioavailability and have the potential to be significantly cytotoxic.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
Fulltext Antifungal Activity of Aqueous Extracts of Some Dominant Algerian Medicinal Plants

Salhi N, Mohammed Saghir SA, Terzi V, Brahmi I, Ghedairi N, Bissati S

Biomed Res Int, 2017;2017:7526291.
PMID: 29226147 DOI: 10.1155/2017/7526291

Aim: This study investigated the antifungal properties of aqueous extracts obtained from indigenous plants that grow spontaneously in the Northern Sahara of Algeria. The activities of these plants in controlling two fungal species that belong to Fusarium genus were evaluated in an in vitro assay.
Materials and Methods: Fresh aerial parts of four plant species (Artemisia herba alba, Cotula cinerea, Asphodelus tenuifolius, and Euphorbia guyoniana) were collected for the preparation of aqueous extracts. Two levels of dilution (10% and 20%) of the pure extracts were evaluated against Fusarium graminearum and Fusarium sporotrichioides.
Results: The results of this study revealed that the A. herba alba, C. cinerea, A. tenuifolius, and E. guyoniana aqueous extracts are effective at both concentrations of 10% and 20% for the Fusarium mycelia growth inhibition. In particular, A. tenuifolius extract is effective against F. graminearum, whereas F. sporotrichioides mycelium growth is strongly affected by the E. guyoniana 20% extract. The phytochemical characterization of the compositions of the aqueous extracts has revealed that the presence of some chemical compounds (tannins, flavonoids, saponins, steroids, and alkaloids) is likely to be responsible for the antifungal activities sought.
Conclusion: The antifungal properties of A. herba alba, C. cinerea, A. tenuifolius, and E. guyoniana make these plants of potential interest for the control of fungi affecting both wheat yield and safety.

Matched MeSH terms: Alkaloids/pharmacology
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*
Fulltext Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site

Smedley CJ, Stanley PA, Qazzaz ME, Prota AE, Olieric N, Collins H, et al.

Sci Rep, 2018 Jul 13;8(1):10617.
PMID: 30006510 DOI: 10.1038/s41598-018-28880-2

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

Matched MeSH terms: Indole Alkaloids/pharmacology*
Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors

Ahmad H, Ahmad S, Ali M, Latif A, Shah SAA, Naz H, et al.

Bioorg Chem, 2018 08;78:427-435.
PMID: 29698893 DOI: 10.1016/j.bioorg.2018.04.008

Three new norditerpenoids alkaloids, 1β-hydroxy,14β-acetyl condelphine (1), jadwarine-A (2), jadwarine-B (3) along with two known alkaloids isotalatizidine hydrate (4) and dihydropentagynine (5) were isolated from medicinal plant Delphinium denudatum. The structures of natural products 1-5 were established on the basis of HR-EIMS, 1H and 13C NMR (1D & 2D) spectroscopic data as well as by comparison from literature data. The structures of compound 1 and 4 were also confirmed by single crystal X-ray diffraction studies. In-vitro AChE and BChE enzyme inhibitory activities of compounds 1-5 and molecular docking studies were performed to investigate the possible molecular inhibitory mechanism of the isolated natural products. Compound 2, 4 and 5 showed competitive inhibitory effects by inhibiting AChE and BChE, respectively, while 1 and 3 showed non-competitive inhibition. This work is the first report that provides a supporting evidence about the use of constituents of Delphinium denudatum in cerebral dementia and Alzheimer diseases.

Matched MeSH terms: Alkaloids/pharmacology*

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