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1.
Article in English | MEDLINE | ID: mdl-30448629

ABSTRACT

The aim of this study is to develop validated methods for the extraction and quantification of antimalarial triterpene esters from Keetia leucantha and from plasma samples. These compounds, showing in vitro and in vivo antiplasmodial activities, were optimally extracted from Keetia leucantha twigs using ultrasounds with dichloromethane and from plasma using protein precipitation with acetonitrile. We then developed and validated HPLC-UV quantification methods, which proved to be selective, accurate, linear, true and precise, both in plant and plasma samples for the eight triterpenic esters in mixture. Based on the total error concept as decision criteria, the validated dosage ranges of the triterpene esters mixture were set between 14.68 and 73.37 µg/mL in plants and 15.90 and 106.01 µg/mL in plasma injected solutions, corresponding to 7.95 and 53.01 µg/mL in plasma. These reliable methods were used to determine effectively triterpene esters content in collected samples, that seems highly variable in plant extracts, and will be helpful to further investigate pharmacokinetics parameters of these interesting bioactive compounds.


Subject(s)
Antimalarials , Plant Extracts/chemistry , Rubiaceae/chemistry , Triterpenes , Antimalarials/analysis , Antimalarials/blood , Antimalarials/isolation & purification , Humans , Linear Models , Reproducibility of Results , Sensitivity and Specificity , Triterpenes/analysis , Triterpenes/blood , Triterpenes/isolation & purification
2.
J Pharm Biomed Anal ; 141: 87-94, 2017 Jul 15.
Article in English | MEDLINE | ID: mdl-28432941

ABSTRACT

The aim of this work is to develop the first validated HPLC-UV method quantification in blood serum for a new endoplasmic reticulum (ER)-specific benzophenazine photosensitizer (OR-141). A fast solid phase extraction (SPE) cleaning sample procedure was achieved on C18 encapped (ec) SPE cartridges and the separation was performed on a RP-18e column (5µM) using an isocratic elution with methanol. The method has been fully validated according to accuracy profiles based on total error and tolerance intervals. Calibration was performed in the matrix and trueness (<4.25% relative bias), repeatability (<4.75% relative standard deviation (RSD)), intermediate precision (<5.37% RSD), selectivity, response function, linearity, and dilution effect were evaluated for both OR-141 regio-isomers. Afterwards the developed method was successfully applied to perform the quantitative determination of OR-141 in mouse blood serum samples in a preliminary pharmacokinetic study.


Subject(s)
Endoplasmic Reticulum , Animals , Chromatography, High Pressure Liquid , Mice , Photosensitizing Agents , Reproducibility of Results , Serum , Solid Phase Extraction
3.
J Neurochem ; 139(4): 624-639, 2016 11.
Article in English | MEDLINE | ID: mdl-27569447

ABSTRACT

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice.


Subject(s)
Annona , Brain/metabolism , Fruit and Vegetable Juices , Plant Extracts/administration & dosage , tau Proteins/biosynthesis , Animals , Annona/adverse effects , Brain/drug effects , Cell Line , Fruit and Vegetable Juices/adverse effects , Humans , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Phosphorylation/drug effects , Phosphorylation/physiology , Plant Extracts/adverse effects , Random Allocation , tau Proteins/genetics
4.
J Ethnopharmacol ; 192: 264-272, 2016 Nov 04.
Article in English | MEDLINE | ID: mdl-27451258

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Morinda citrifolia L. (Noni) is a medicinal plant used in Polynesia for many properties such as anti-inflammatory, anti-diabetic and antineoplastic effects. Recent studies showed that noni juice have anti-oxidant and acute anti-inflammatory activities likely due to polyphenols, iridoids and vitamin C content. The present study was undertaken to evaluate chronic anti-inflammatory and spasmolytic effects of noni juice. MATERIALS AND METHODS: Therefore, we evaluated the effect of oral or intraperitoneal administrations of noni juice in vivo on the lung inflammation in ovalbumin (OVA) sensitized Brown Norway rat (with prednisolone 10mg/kg intraperitoneously as reference compound) and the ex vivo effect of noni juice on BaCl2 (calcium signal) or methacholine (cholinergic signal) induced spasms in jejunum segments. RESULTS: We found that noni juice (intraperitoneously 2.17mL/kg and orally 4.55mL/kg) reduced the inflammation in OVA-sensitized Brown Norway rat with regard to the decreased number of inflammatory cells in lung (macrophages minus 20-26%, lymphocytes minus 58-34%, eosinophils minus 53-30%, neutrophils minus 70-28% respectively). Noni juice demonstrated a dose-dependent NO scavenging effect up to 8.1nmol of nitrites for 50µL of noni juice. In addition noni juice inhibited (up to 90%) calcium and cholinergic induced spasms on the jejunum segments model with a rightward shift of the concentration response curve. CONCLUSION: We describe for the first time that noni juice demonstrate (1) a chronic anti-inflammatory activity on sensitized lungs along with (2) a spasmolytic effect integrating a calcium channel blocker activity component.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Jejunum/drug effects , Morinda/chemistry , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Parasympatholytics/pharmacology , Plant Extracts/pharmacology , Pneumonia/prevention & control , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Antioxidants/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Signaling/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Fruit/chemistry , In Vitro Techniques , Injections, Intraperitoneal , Jejunum/metabolism , Lung/drug effects , Lung/metabolism , Muscle, Smooth/metabolism , Nitric Oxide/metabolism , Nitrites/metabolism , Ovalbumin , Parasympatholytics/administration & dosage , Parasympatholytics/chemistry , Parasympatholytics/isolation & purification , Phytotherapy , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plants, Medicinal , Pneumonia/chemically induced , Pneumonia/metabolism , Prednisolone/pharmacology , Rats, Inbred BN
5.
Cancer Cell ; 28(2): 170-82, 2015 Aug 10.
Article in English | MEDLINE | ID: mdl-26267534

ABSTRACT

Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.


Subject(s)
Carcinogenesis/drug effects , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Protein Multimerization/drug effects , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , ras Proteins/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Chick Embryo , Female , HEK293 Cells , Humans , Immunoblotting , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Mitogen-Activated Protein Kinase 1/chemistry , Mitogen-Activated Protein Kinase 1/metabolism , Models, Molecular , Molecular Structure , Protein Binding/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Xenograft Model Antitumor Assays/methods , Zebrafish
6.
Plant Foods Hum Nutr ; 67(4): 384-92, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23230009

ABSTRACT

Awara (Astrocaryum vulgare M.) pulp oil has been shown to possess anti-inflammatory properties in vivo, and contains an unsaponifiable matter rich in bioactive compounds. This study focused on the ethanolic unsaponifiable fraction (EUF) of awara pulp oil. Its chemical composition has been characterized: carotenoid, phytosterol, and tocopherol contents represent 125.7, 152.6, and 6.8 µg/mg of EUF, respectively. We further evaluated this fraction for anti-inflammatory properties in J774 macrophages activated by lipopolysaccharide (LPS) plus interferon (IFN) γ to understand the biological effects of awara pulp oil. EUF strongly decreased nitric oxide (NO), prostaglandin E(2), tumour necrosis factor (TNF) α, and interleukin (IL) -6 and -10 production in activated J774 cells. Moreover, it inhibited expression of inducible NO synthase and cyclooxygenases-2 in vitro. The anti-inflammatory properties of EUF were also confirmed in vivo by modulation of TNFα, IL-6 and IL-10 serum concentration in an endotoxic shock model. Pre-treatment with awara oil fraction offers promise as a protective means to lower the production of excessive amounts of pro-inflammatory molecules.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Arecaceae/chemistry , Fruit/chemistry , Plant Oils/pharmacology , Shock, Septic/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Antioxidants/metabolism , Carotenoids/analysis , Carotenoids/metabolism , Cell Line , Cyclooxygenase 1/drug effects , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/metabolism , Cytokines/blood , Cytokines/drug effects , Cytokines/metabolism , Dinoprostone/blood , Dose-Response Relationship, Drug , Interferon-gamma/adverse effects , Lipopolysaccharides/adverse effects , Macrophages/drug effects , Macrophages/immunology , Male , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/drug effects , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/drug effects , Nitric Oxide Synthase Type II/metabolism , Nitrites/metabolism , Phytosterols/analysis , Phytosterols/metabolism , Plant Oils/chemistry , Random Allocation , Shock, Septic/chemically induced , Shock, Septic/immunology , Tocopherols/analysis , Tocopherols/metabolism
7.
Fitoterapia ; 83(1): 33-43, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21958966

ABSTRACT

Awara (Astrocaryum vulgare M.) is a palm fruit mainly used in nutrition. We analysed the pulp oil for fatty acid, tocopherol, carotenoid, and phytosterol and we evaluated whether this oil may attenuate inflammation in vivo. In an endotoxic shock model, awara pulp oil treatment decreased pro-inflammatory cytokines and increased anti-inflammatory cytokines. In a pulmonary inflammation model, awara pulp oil treatment reduced eosinophil and lymphocyte numbers recovered into the broncho-alveolar lavages. These results suggest that awara pulp oil administration can efficiently counteract an acute and chronic inflammatory response in vivo that is probably mediated by fatty acids and minor compounds.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Arecaceae/chemistry , Lung Diseases/drug therapy , Plant Oils/pharmacology , Shock, Septic/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Carotenoids/chemistry , Fatty Acids/chemistry , Lipopolysaccharides/toxicity , Lung Diseases/chemically induced , Male , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Phytosterols/chemistry , Plant Oils/chemistry , Random Allocation , Rats , Shock, Septic/chemically induced , Tocopherols/chemistry
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