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Biomedical subjects

Luc Angenot

Publications and source records attributed to Luc Angenot.

At least 19 recordsLinked to original sources

Validation of a high-performance thin-layer chromatography/densitometry method for the quantitative determination of glucosamine in a herbal dietary supplement.

A quantitative densitometric high-performance thin-layer chromatography (HPTLC) method was developed for the determination of glucosamine in a dietary supplement containing dried extracts of the main plants traditionally used for rheumatic disorders. The HPTLC method was chosen in order to circumvent the tedious and time-consuming sample preparation steps necessarily performed before using HPLC methods when analysing complex matrixes. Glucosamine was separated from the plant extracts on a silica gel 60 F(254) HPTLC plate using a saturated mixture of 2-propanol-ethyl acetate-ammonia solution (8%) (10:10:10, v/v/v). The plates were developed vertically up to a distance of 80 mm. For visualization, the plate was dipped into a modified anisaldehyde reagent and heated at 120 degrees C for 30 min in a drying oven. Glucosamine appeared as brownish-red chromatographic zones on a colourless background. Densitometric quantification was performed at lambda = 415 nm by reflectance scanning. The HPTLC method was successfully validated by applying the novel validation protocol proposed by a commission of the "Société Française des Sciences et Techniques Pharmaceutiques" (SFSTP). In the pre-validation phase, the appropriate response function was determined, while in the validation phase the method showed good performance thereby fulfilling its objective of quantifying accurately. The relative standard deviations for repeatability and intermediate precision were between 4.9 and 8.6%. Moreover, the method was found to be accurate, as the two-sided 95% beta-expectation tolerance interval did not exceed the acceptance limits of 85 and 115% on the whole analytical range (800-1,200 ng of glucosamine).

Chromatography, High Pressure Liquid↗

Phytochemical and pharmacological study of roots and leaves of Guiera senegalensis J.F. Gmel (Combretaceae).

The chemical composition of total alkaloids from leaves and roots of Guiera senegalensis was investigated. Three beta-carboline alkaloids were purified: in addition to harman and tetrahydroharman, known in roots and leaves, harmalan (dihydroharman) was isolated for the first time from roots of Guiera senegalensis. Guieranone A, a naphthyl butenone, was also purified from leaves and roots. The in vitro antiplasmodial activity and the cytotoxicity of extracts and pure compounds were evaluated. Each total alkaloid extract and beta-carboline alkaloids presented an interesting antiplasmodial activity associated with a low cytotoxicity. Harmalan was less active than harman and tetrahydroharman. Guieranone A showed a strong antiplasmodial activity associated with a high cytotoxicity toward human monocytes. Its cytotoxicity was performed against two cancer cell lines and normal skin fibroblasts in order to study its anticancer potential: guieranone A presented a strong cytotoxicity against each cell strains. Finally, we evaluated the potent synergistic antimalarial interaction between Guiera senegalensis and two plants commonly associated in traditional remedies: Mitragyna inermis and Pavetta crassipes. Three associations evaluated were additive. A synergistic effect was shown between total alkaloids extracted from leaves of Guiera senegalensis and those of Mitragyna inermis. This result justified the traditional use of the plants in combination to treat malaria.

Alkaloids↗

Study of the interaction of antiplasmodial strychnine derivatives with the glycine receptor.

Strychnos icaja Baill. (Loganiaceae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric indolomonoterpenic alkaloids with antiplasmodial properties have been isolated from its rootbark. Since these alkaloids are derivatives of strychnine, it was important, in view of their potential use as antimalarial drugs, to assess their possible convulsant strychnine-like properties. In that regard, their interaction with the strychnine-sensitive glycine receptor was investigated by whole-cell patch-clamp recordings on glycine-gated currents in mouse spinal cord neurons in culture and by [(3)H]strychnine competition assays on membranes from adult rat spinal cord. These experiments were carried out on sungucine (leading compound of the chemical class) and on the antiplasmodial strychnogucine B (dimeric) and strychnohexamine (trimeric). In comparison with strychnine, all compounds interact with a very poor efficacy and only at concentrations >1 microM with both [(3)H]strychnine binding and glycine-gated currents. Furthermore, the effects of strychnine and protostrychnine, a monomeric alkaloid (without antiplasmodial activity) also isolated from S. icaja and differing from strychnine only by a cycle opening, were compared in the same way. The weak interaction of protostrychnine confirms the importance of the G cycle ring structure in strychnine for its binding to the glycine receptor and its antagonist properties.

Alkaloids↗

Recent developments in the field of arrow and dart poisons.

Arrow and dart poisons, considered as conventional natural sources for future drug discovery, have already provided numerous biologically active molecules used as drugs in therapeutic applications or in pharmacological research. Plants containing alkaloids or cardiotonic glycosides have generally been the main ingredients responsible for the efficacy of these poisons, although some animals, such as frogs, have also been employed. This paper, without being exhaustive, reports the greater strides made during the past 15 years in the understanding of the chemical nature and biological properties of arrow and dart poison constituents. Examples both of promising biological properties shown by these molecules and of crucial discoveries achieved by their use as pharmacological tools are given. Further studies of these toxic principles are likely to enable scientists to find new valuable lead compounds, useful in many fields of research, like oncology, inflammation and infectious diseases.

Animals↗

Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides.

OBJECTIVE: To report a case of chronic ingestion of very large amounts of senna fruits as an herbal tea, possibly leading to severe hepatotoxicity. CASE SUMMARY: A 52-year-old woman who had ingested, for >3 years, one liter of an herbal tea each day made from a bag containing 70 g of dry senna fruits, developed acute hepatic failure and renal impairment requiring intensive care therapy. The severity of the hepatic failure was reflected by the increase in prothrombin time (international normalized ratio >7) and the development of encephalopathy. Liver transplantation was discussed, but the patient ultimately recovered with supportive therapy. Renal impairment was consistent with proximal tubular acidosis, also with marked polyuria refractory to vasopressin administration. Suprisingly, large amounts of cadmium were transiently recovered in the urine. DISCUSSION: Cassia acutifolia and angustifolia plants are widely used as laxatives. Their chronic abuse may be associated with serious manifestations, including fluid and electrolyte loss, with chronic diarrhea. Severe hepatotoxicity is unusual, but could be explained by the exposure of the liver to unusual amounts of toxic metabolites of anthraquinone glycosides (sennosides). An objective causality assessment suggests that hepatotoxicity was possibly related to senna laxative abuse. Regarding nephrotoxicity, there are no available human data on sennosides, while experimental models suggest that anthraquinone derivatives may also accumulate in the kidneys. The finding of high urinary concentrations of cadmium would suggest contamination of the herbal tea by metals, but this hypothesis could not be verified. CONCLUSIONS: Ingestion of large doses of senna laxatives may expose people to the risk of hepatotoxicity.

Acidosis↗

In vitro screening of some Strychnos species for antiplasmodial activity.

The antiplasmodial activity of crude extracts of 19 species of Strychnos (Loganiaceae) was assessed in vitro against a chloroquine-susceptible strain of Plasmodium falciparum. For each species, ethyl acetate (EtOAc) extracts were analysed and, for the most active species, methanolic (MeOH) extracts were also tested. Among them, Strychnos variabilis De Wild. seemed to be very promising (inhibitory concentration 50% (IC50) < 5 microg/ml) whereas two other species, Strychnos gossweileri Exell and Strychnos mellodora S. Moore, could be interesting (IC50 < 15 microg/ml) in further antimalarial studies.

Animals↗

Inhibitory effects of proanthocyanidins from Ribes nigrum leaves on carrageenin acute inflammatory reactions induced in rats.

BACKGROUND: The anti-inflammatory effects of proanthocyanidins (PACs), isolated from blackcurrant (Ribes nigrum L.) leaves, were analysed using carrageenin-induced paw oedema and carrageenin-induced pleurisy in rats. RESULTS: Pretreatment of the animals with PACs (10, 30, 60 and 100 mg/kg, i.p.) reduced paw oedema induced by carrageenin in a dose and time-dependent manner. PACs also inhibited dose-dependently carrageenin-induced pleurisy in rats. They reduced (A) lung injury, (B) pleural exudate formation, (C) polymorphonuclear cell infiltration, (D) pleural exudate levels of TNF-alpha, IL-1beta and CINC-1 but did not affect IL-6 and IL-10 levels. They reduced (E) pleural exudate levels of nitrite/nitrate (NOx). In indomethacin treated rats, the volume of pleural exudate was low, its content in leukocytes and its contents in TNF-alpha, IL-1beta, IL-6 and IL-10 but not in NOx were reduced. These data suggest that the anti-inflammatory properties of PACs are achieved through a different pattern from those of indomethacin. CONCLUSION: These results suggest that the main mechanism of the anti-inflammatory effect of PACs mainly lies in an interference with the migration of the leukocytes. Moreover, PACs inhibited in vivo nitric oxide release.

Animals↗

About the toxicity of some Strychnos species and their alkaloids.

Poisons are widespread in plants and animals and humankind has often tried to turn them to its own advantage. Owing to their poisonous properties, some species of Strychnos genus have been employed mainly in hunting and fishing, as an adjunct to weapons used not only in the search of food and clothes, but also for preventing depredation by wild animals. They have been employed for martial and criminal purposes and also as a means of determining guilt or innocence. By their nature, poisons such as strychnine and curare affect the functioning of the victim's body; this also means that they have been, and are, an important source of pharmacological tools and medicines all over the world. With such potentially dangerous substances, care in medication is essential to avoid complications by overdose. All these points are approached in the present review.

Alkaloids↗

LC/MS/NMR analysis of isomeric divanilloylquinic acids from the root bark of Fagara zanthoxyloides Lam.

Gradient HPLC coupled to DAD/UV, MS/MS and NMR has been applied to the rapid structure determination of three new isomeric divanilloylquinic acids from Fagara zanthoxyloides collected in Burkina Faso: 3,4-O-divanilloylquinic acid, 3,5-O-divanilloylquinic acid and 4,5-O-divanilloylquinic acid. Furthermore these new compounds named burkinabins A-C could play a useful role in sickle cell disease, as the active agents of Fagara zanthoxyloïdes are said to be unidentified aromatic compounds with carboxylic acid grouping (Adesanya, S.A., Sofowora, A., 1983. Biological standardisation of Zanthoxylum roots for antisickling activity. Planta Med. 48, 27-33).

Anemia, Sickle Cell↗

Metabolomic analysis of Strychnos nux-vomica, Strychnos icaja and Strychnos ignatii extracts by 1H nuclear magnetic resonance spectrometry and multivariate analysis techniques.

1H Nuclear magnetic resonance spectrometry and multivariate analysis techniques were applied for the metabolic profiling of three Strychnos species: Strychnos nux-vomica (seeds, stem bark, root bark), Strychnos ignatii (seeds), and Strychnos icaja (leaves, stem bark, root bark, collar bark). The principal component analysis (PCA) of the 1H NMR spectra showed a clear discrimination between all samples, using the three first components. The key compounds responsible for the discrimination were brucine, loganin, fatty acids, and Strychnos icaja alkaloids such as icajine and sungucine. The method was then applied to the classification of several "false angostura" samples. These samples were, as expected, identified as S. nux-vomica by PCA, but could not be clearly discriminated as root bark or stem bark samples after further statistical analysis.

Magnetic Resonance Spectroscopy↗

Chrysopentamine, an antiplasmodial anhydronium base from Strychnos usambarensis leaves.

A new derivative of strychnopentamine was isolated from the leaves of Strychnos usambarensis. This compound, named chrysopentamine, was identified by detailed spectroscopic methods (UV, IR, HR-ESI-MS, 1D and 2D NMR). Chrysopentamine presented an original hydroxy substitution on C-14 and an aromatization of the ring D of strychnopentamine leading to anhydronium base properties and exhibited strong antiplasmodial properties (IC (50) less than 1 microM).

Animals↗

In vitro and in vivo antimalarial properties of isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis.

Isostrychnopentamine (ISP) is an asymmetric indolomonoterpenic alkaloid isolated from the leaves of Strychnos usambarensis. The in vitro antiplasmodial activities against five Plasmodium falciparum cell lines were evaluated: ISP possessed an in vitro IC (50) near 0.1 microM against all P. falciparum cell lines tested (chloroquine-resistant and chloroquine-sensitive lines) and showed antiplasmodial selectivity compared to cytotoxicity on human cell lines. The stage-dependent susceptibility to a short exposure of ISP was then investigated. The ring stage was shown to be the most sensitive one, but all stages were affected by ISP treatment. By means of fluorescence microscopy, it was shown that ISP was not accumulated inside the food vacuole of the parasite. Finally, the in vivo antimalarial activities against the P. berghei NK173 and P. vinckei petteri murine strains were determined. The ED (50) in vivo was about 30 mg/kg/day by the intraperitoneal route (after 4 days treatment).

Alkaloids↗

Bisindole alkaloids from Strychnos guianensis are effective antagonists of nicotinic acetylcholine receptors in cultured human TE671 cells.

Several mono- and bisindole quaternary alkaloids isolated from the stem bark of Strychnos guianensis have recently been shown to be effective blockers of neuromuscular transmission in mice. In this study, we used a human clonal cell line (TE671) expressing muscle-type nicotinic acetylcholine receptors. The agonist carbamylcholine activated a receptor-mediated (86)Rb(+) efflux and this activation was antagonized by the indole alkaloids, the most active being bisindole bisquaternary compounds. The most effective antagonist, guiachrysine, had an IC(50) around 0.43 microM in the presence of 0.5 mM carbamylcholine, compared to 0.16 microM for d-tubocurarine, the most potent curarizing alkaloid. Guiaflavine and 5',6'-dehydroguiaflavine were slightly less effective. Monoindole compounds were 10 to 100 times less potent than bisindole alkaloids. Kinetic analysis showed that the inhibition of the carbamylcholine-dependent (86)Rb(+) efflux by guiaflavine was of mixed competitive and uncompetitive type. The competitive component (K(I)=0.21 microM) is presumably due to binding at the acetylcholine site, while the uncompetitive component (K'(I)=0.92 microM) may be due to open channel block.

Carbachol↗

Apoptosis induction in human cancer cells by sungucine from Strychnos icaja root.

Sungucine (SG) and isosungucine (ISG) are bisindole alkaloids characterized by a 5'-23 link between the two parts of the compounds, which are till now specific to Strychnos icaja. In this work, SG and ISG were submitted to the NCI's in vitro 60 human tumor cell line screen, where SG showed interesting selectivity (6X) against the tested leukemia cell lines. In HL60-treated cells, apoptosis was demonstrated by observation of apoptotic bodies formation, and phosphatidylserine exposition at cell surface. In HeLa-treated cells, the analysis of cellular cycle by flow cytometry showed G1 accumulation and a small sub-G1 peak that could be related to DNA fragmentation characteristic of apoptosis. The eventual role of p53 was analyzed using wild-type HCT-116 colon cancer cells. Nevertheless, p53 and Bax expression were not modified in SG-treated cells. The cleavage of PARP by caspase-3 protease proved that apoptosis was also induced in this line. These results demonstrate that SG induces apoptosis, but also necrosis, in human cancer cell lines.

Antineoplastic Agents↗

Indolomonoterpenic alkaloids from Strychnos icaja roots.

In the course of our search for new antiplasmodial alkaloids from Strychnos icaja, we have isolated five alkaloids: three monomers, protostrychnine and genostrychnine, previously described in Strychnos nux-vomica, pseudostrychnine, already found in the leaves of the plant, a new bisindolic alkaloid, named strychnogucine C, and the first naturally occurring trimeric indolomonoterpenic alkaloid: strychnohexamine. This latter trimeric alkaloid presented an antiplasmodial activity against the FCA Plasmodium falciparum line near 1 microM.

Animals↗

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, induces cell cycle arrest and apoptosis in human colon cancer cells.

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids, which are used to make a curare-like arrow poison. However, tertiary alkaloids isolated from the same plant possess cytotoxic activities against mammalian cells and protozoa. The effect of ISP has been investigated on the growth and viability of HCT-116 colon cancer cells during their exponentially growing phase. ISP induced apoptotic cell death as shown by the translocation of phosphatidylserine from the inner layer to the outer layer of the plasma membrane, chromatin condensation, DNA fragmentation, and caspase-3 and -9 activation. ISP provoked also cell cycle arrest in the G(2)-M phase. We also showed that the expression of p53 was not modified in ISP-treated cells, but that p21 was induced in a p53-independent manner. Finally, we demonstrated that ISP did not affect the catalytic activity of human topoisomerases I and II. In conclusion, ISP, which promotes cell death by a p53-independent apoptotic pathway, could be an interesting lead for cancer chemotherapy.

Alkaloids↗

Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity.

Articular diseases, such as osteoarthritis, is the clinical expression of the loss of cartilage function. COX inhibitors are widely used in the treatment of such pathologies for their beneficial effects on inflammation but often produce a negative activity on cartilage synthesis. In this study, we determined the effect of different prodelphinidins, the major compounds isolated from Ribes nigrum leaves, on the proteoglycans (PGs), type II collagen (coll. II) and prostaglandin E(2) (PGE(2)) production by differentiated human chondrocytes cultivated in long term (12 days) and in clusters as well as their inhibition potential on COX-1 and COX-2 in vitro. Gallocatechin trimer (GC-GC-GC) showed the higher stimulation of PGs and coll. II production (1 microg ml(-1)) and the synthesis of PGE(2) was significantly reduced by gallocatechin dimer (GC-GC), gallocatechin-epigallocatechin (GC-EGC) and GC-GC-GC at 10 and 100 microg ml(-1). The inhibition of PGE(2) synthesis was confirmed by the in vitro test on purified COX enzymes, showing the selectivity of prodelphinidins on COX-2. However, the prodelphinidins had no effects on COX activity in the whole blood assay. Our studies suggest that the prodelphinidins fractions from R. nigrum may be useful as an additive agent in the prevention of osteoarthritis.

Anthocyanins↗

Antiplasmodial activity of alkaloids from various strychnos species.

The in vitro antiplasmodial activities of 69 alkaloids from various Strychnos species were evaluated against chloroquine-resistant and chloroquine-sensitive lines of Plasmodium falciparum. The compounds, comprising mainly indolomonoterpenoid alkaloids, exhibited a wide range of biological potencies in the antiplasmodial assays. The most active alkaloids were also tested for cytotoxicity against HCT-116 colon cancer cells to determine their antiplasmodial selectivity. As a result of these studies, structure-activity relationships for these alkaloids have begun to emerge. Alkaloids presenting four types of bisindole skeleton exhibited potent and selective activities against Plasmodium. They were sungucine-type (IC(50) values ranging from 80 nM to 10 microM), longicaudatine-type (IC(50) values ranging from 0.5 to 10 microM), matopensine-type (IC(50) values ranging from 150 nM to 10 microM), and usambarine-type alkaloids. Within the last structural type, isostrychnopentamine (49) and ochrolifuanine A (46) were found to be active against chloroquine-sensitive and -resistant strains (IC(50) values of 100-150 and 100-500 nM, respectively), and dihydrousambarensine (51) exhibited a 30-fold higher activity against the chloroquine-resistant strain (IC(50) = 32 nM) than against the chloroquine-sensitive one.

Alkaloids↗