Flindissone, a Limonoid Isolated from Trichilia prieuriana, Is an LXR Agonist.

In this study, the ability of six limonoids from Trichilia prieuriana (Meliaceae) to activate the liver X receptor (LXR) was assessed. One of these limonoids, flindissone, was shown to activate LXR by reporter-gene assays. Flindissone is a ring-intact limonoid, structurally similar to sterol-like LXR ligands. In endogenous cellular settings, flindissone showed an activity profile that is characteristic of LXR agonists. It induced cholesterol efflux in THP-1 macrophages by increasing the cholesterol transporter ABCA1 and ABCG1 gene expression. In HepG2 cells, flindissone induced the expression of IDOL, an LXR-target gene that is associated with the downregulation of the LDL receptor. However, unlike synthetic and similarly to sterol-based LXR agonists, flindissone did not induce the expression of the SREBP1c gene, a major transcription factor regulating de novo lipogenesis. Additionally, flindissone also appeared to be able to inhibit post-translational activation of SREBP1c. The results presented here reveal a natural product as a new LXR agonist and point to an additional property of T. prieuriana and other plant extracts containing flindissone.

Investigation of dengue-malaria coinfection among febrile patients consulting at Ngaoundere Regional Hospital, Cameroon.

This study aimed at evaluating the seroprevalence of dengue among malarious patients consulting at the Ngaoundere Regional Hospital. During 2 months and a half, 174 participants were recruited and their blood samples were screened for Plasmodium spp and then for Dengue virus (DENV) infection using rapid diagnostic tests. Also, hematological asparameters were measured using a hematology autoanalyzer. Among patients tested, 134 (77.01%) were malaria-positive, and 12/134 (8.95%) were coinfected. In this population, 8/12 (66.67%) were only anti-DENV IgM-positive, 3/12 (25%) were both NS1 and anti-DENV IgM positive, and 1/12 (8.33%) were anti-DENV IgG-positive. Furthermore, women were more affected (58.3%) than men (41.7%). The most affected age groups were young people aged less than or equal to 15 years (33.3%) and adults aged between 30 and 45 years (33.3%). A significant association (p < .05; odds ratio [OR] = 5.16) was found between the age range (30-45) and dengue-malaria coinfection. Similarly, we noted a significant association between the coinfection, and joint pain (p < .05; OR = 6.15), fatigue (p < .01; OR = 5.74), and chills (p < .05; OR = 0). Analysis of hematologic parameters showed a significant decrease (p < .001) in platelets in coinfected patients compared with monoinfected patients. In conclusion, dengue-malaria coinfection is a reality in Ngaoundere city and associated with the appearance of clinical features which predict the disease severity.

Hepatoprotective Activity of Leptadenia hastata (Asclepiadaceae) on Acetaminophen-Induced Toxicity in Mice: In Vivo Study and Characterization of Bioactive Compounds through Molecular Docking Approaches.

MATERIALS AND METHODS: Various aqueous extracts were prepared from this plant and preadministered per os to albino mice 3 h before APAP administration, once daily for one week. Animals from the normal group were given only distilled water while those from negative control received only APAP 250 mg/kg. After treatment, mice were sacrificed, the liver was collected for histopathology analysis, and different biochemical markers (alanine aminotransferase (ALT), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNFα)) were measured. The content of the active extract was analyzed by HPLC/UV. Molecular docking was conducted using iGEMDOCK software, and the drug-likeness and pharmacokinetic profiles were evaluated using Swiss ADME. RESULTS: APAP administration significantly increased (p < 0.001) ALT in liver homogenates when compared to normal controls whereas the stem decoction at 250 mg/kg significantly (p < 0.001) reduced this activity to a normal value comparable to silymarin 50 mg/kg which is better than leaf and root extracts. Moreover, the stem decoction also significantly reduced the MDA levels (p < 0.05) and increased those of GSH, SOD, and CAT (p < 0.001) at doses of 250 and 500 mg/kg compared to the negative control. A significant (p < 0.001) decrease of TNFα levels and leukocyte infiltration was observed following treatment with this extract. The HPLC/UV analysis of the decoction revealed the presence of dihydroxycoumarin, quinine, and scopoletin with the following retention times: 2.6, 5.1, and 7.01 min, respectively. In silico studies showed that quinine and dihydroxycoumarin had great potentials to be orally administered drugs and possessed strong binding affinities with TNFα, TNF receptor, cyclooxygenase-2, iNOS, cytochrome P450 2E1, and GSH reductase. CONCLUSION: Based on these results, L. hastata could be considered a source of promising hepatoprotective compounds with antioxidant and anti-inflammatory properties.

Plant extracts from Cameroonian medicinal plants strongly inhibit hepatitis C virus infection in vitro.

According to some recent studies, Cameroon is one of the sub-Saharan African countries most affected by hepatitis C, with low access to the standard therapy based on the combination of pegylated interferon and ribavirin. A first ethnobotanical survey, conducted in the Western region of Cameroon, reported the use of several medicinal plants in traditional medicine for the healing of liver-related disorders. Crude organic extracts of five plants surveyed were prepared and their effect against hepatitis C virus (HCV) infection investigated. The HCV JFH1 strain cell culture system HCVcc was used. The antiviral activity was quantified by immunofluorescent labeling of HCV E1 envelope protein at 30 h post-infection in the presence of the plant extracts. Active compounds were then tested in time course infection experiments. Dose-response and cellular toxicity assays were also determined. Three extracts, methanol extracts from roots of Trichilia dregeana, stems of Detarium microcarpum and leaves of Phragmanthera capitata, showed anti-HCV activity, with half-maximal inhibitory concentration of 16.16, 1.42, and 13.17 µg/mL, respectively. Huh-7 cells were incubated with the extracts for 72 h and it appears that T. dregeana extract is not toxic up to 200 µg/mL, D. microcarpum up to 100 µg/mL and P. capitata up to 800 µg/mL. All the three extracts showed a strong inhibition of HCV entry and no effect on replication or secretion. Taken together, these results showed that extracts from Cameroonian medicinal plants are promising sources of anti-HCV agents.

Differential regulation of calcium signalling pathways by components of Piper methysticum ('Awa).

Kava is a soporific, anxiolytic and relaxant in widespread ritual and recreational use throughout the Pacific. Traditional uses of kava by indigenous Pacific Island peoples reflect a complex pharmacopeia, centered on GABA-ergic effects of the well-characterized kavalactones. However, peripheral effects of kava suggest active components other than the CNS-targeted kavalactones. We have previously shown that immunocytes exhibit calcium mobilization in response to traditionally prepared kava extracts, and that the kavalactones do not induce these calcium responses. Here, we characterize the complex calcium-mobilizing activity of traditionally prepared and partially HPLC-purified kava extracts, noting induction of both calcium entry and store release pathways. Kava components activate intracellular store depletion of thapsigargin-sensitive and -insensitive stores that are coupled to the calcium release activated (CRAC) current, and cause calcium entry through non-store-operated pathways. Together with the pepper-like potency reported by kava users, these studies lead us to hypothesize that kava extracts contain one or more ligands for the transient receptor potential (TRP) family of ion channels. Indeed, TRP-like conductances are observed in kava-treated cells under patch clamp. Thus TRP-mediated cellular effects may be responsible for some of the reported pharmacology of kava.

Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3.

A novel nortriterpene, termed correolide, purified from the tree Spachea correae, inhibits Kv1.3, a Shaker-type delayed rectifier potassium channel present in human T lymphocytes. Correolide inhibits 86Rb+ efflux through Kv1.3 channels expressed in CHO cells (IC50 86 nM; Hill coefficient 1) and displays a defined structure-activity relationship. Potency in this assay increases with preincubation time and with time after channel opening. Correolide displays marked selectivity against numerous receptors and voltage- and ligand-gated ion channels. Although correolide is most potent as a Kv1.3 inhibitor, it blocks all other members of the Kv1 family with 4-14-fold lower potency. C20-29-[3H]dihydrocorreolide (diTC) was prepared and shown to bind in a specific, saturable, and reversible fashion (Kd = 11 nM) to a single class of sites in membranes prepared from CHO/Kv1.3 cells. The molecular pharmacology and stoichiometry of this binding reaction suggest that one diTC site is present per Kv1.3 channel tetramer. This site is allosterically coupled to peptide and potassium binding sites in the pore of the channel. DiTC binding to human brain synaptic membranes identifies channels composed of other Kv1 family members. Correolide depolarizes human T cells to the same extent as peptidyl inhibitors of Kv1.3, suggesting that it is a candidate for development as an immunosuppressant. Correolide is the first potent, small molecule inhibitor of Kv1 series channels to be identified from a natural product source and will be useful as a probe for studying potassium channel structure and the physiological role of such channels in target tissues of interest.

8-O-acetylharpagide is a nonsteroidal ecdysteroid agonist.

We have identified a novel nonsteroidal ecdysteroid agonist. This compound was isolated from a methanol extract of Ajuga reptans L. (Lamiaceae) and the structure was identified by spectroscopic methods as 8-O-acetylharpagide. We have characterised this compound as an ecdysteroid agonist in a transactivation assay using beta-galactosidase as the reporter gene regulated by ecdysteroid response elements. In this assay, 8-O-acetylharpagide has an EC50 of 22 microM. The compound also competes with tritiated-ponasterone A for binding to the Drosophila ecdysteroid receptor. Finally, it induces differentiation of Drosophila Kc cells as would be expected of an ecdysteroid agonist. This iridoid glycoside is common to several plant species and may play a role in the natural defense mechanisms of plants.

Natural products research: perspectives from a major pharmaceutical company.

Natural products research continues to provide a tremendous variety of lead structures which are used as templates for the development of new drugs by the pharmaceutical industry. Advances in bioassay technology and in chemical methodology have combined to make natural products a cost effective source for new leads. While microbial products have been the mainstay of industrial natural products discovery, in recent years phytochemistry has again become a field of active interest. Drug discovery programs based on microbial products and phytochemicals are discussed and contrasted.

Natural product drug discovery and development: new perspectives on international collaboration.

Until recently, the prevailing attitude in developed nations regarded the world's genetic resources, which are mainly concentrated in the developing world, as a common resource of humankind, to be exploited freely irrespective of national origin. With the devastation being wreaked in the tropical rainforests and the resurgence in interest in recent years in the discovery of novel drugs from natural sources, particularly plants and marine organisms, the international scientific community has realized that the conservation of these global genetic resources and the indigenous knowledge associated with their use are of primary importance if their potential is to be fully explored. With this realization has come a recognition that these goals must be achieved through collaboration with, and fair and equitable compensation of, the scientists and communities of the genetically rich source countries. The signing of the United Nations Convention on Biological Diversity by nearly all of the World's nations has emphasized the need for the implementation of such policies. In this review, the articles of the Convention of relevance to the activities and practices of the natural products scientific community are briefly discussed. This discussion is followed by a summary of policies for international collaboration and compensation being implemented by several developed country organizations, and the perspectives on the current developments given by representatives of some of the source countries located in the regions of greatest biodiversity.

L-741,494, a fungal metabolite that is an inhibitor of interleukin-1 beta converting enzyme.

gamma-Pyrone-3-acetic acid (L-741,494) is a novel metabolite produced by a culture of the fungal genus Xylaria. This substance is a water-soluble, competitive, irreversible inhibitor of Interleukin-1 beta Converting Enzyme that is inactive against papain and trypsin. It has a mol wt of 154 and an empirical formula of C7H6O4. We propose the name xylaric acid for this compound.

Novel nematocidal agents from Curcuma comosa.

Curcuma comosa is a member of the economically important plant family, Zingiberaceae. A methanolic extract of C. comosa was shown to be nematocidal when tested against the free-living nematode Caenorhabditis elegans. Five diphenylheptanoids [1-5], one new and four known, have been isolated and shown to be responsible for the activity. This is the first report of three of these compounds [1, 2, 4] being isolated from a natural source.

Ethnopharmacologic and phytochemical studies of the Thymelaeaceae.

The ethnobotany, ethnopharmacology and phytochemistry of the Thymelaeaceae are reviewed. Some members of this family find wide use commercially whilst others are used as deadly poisons or possess extreme irritant properties. The phytochemical evidence thus far available indicates that the daphnane and tigliane diterpene esters are clearly responsible for the toxic reactions observed, but chemotaxonomically it is not possible to predict which additional genera are likely to contain these toxins. Caution should therefore be exercised when studying members of this plant family.

Studies of the Thymelaeaceae II. Antineoplastic principles of Gnidia kraussiana.

The acetone and methanol extracts of Gnidia kraussiana roots displayed activity against the P-388 lymphocytic leukemia. Bioactivity-directed fractionation led to the isolation of five daphnane orthoesters , all possessing potent antineoplastic activity. Four of these isolates, gnidilatin (1), gnidilatidin (2), Excoecaria toxin (3), and Pimelea factor P2 (4) have been isolated previously from plants in the Thymelaeaceae and Euphorbiaceae. The fifth compound, kraussianin (5), is a new member of the macrocyclic daphnane orthoester series of compounds.