Secondary Metabolites Isolated from Artemisia afra and Artemisia annua and Their Anti-Malarial, Anti-Inflammatory and Immunomodulating Properties-Pharmacokinetics and Pharmacodynamics: A Review.

There are over 500 species of the genus Artemisia in the Asteraceae family distributed over the globe, with varying potentials to treat different ailments. Following the isolation of artemisinin (a potent anti-malarial compound with a sesquiterpene backbone) from Artemisia annua, the phytochemical composition of this species has been of interest over recent decades. Additionally, the number of phytochemical investigations of other species, including those of Artemisia afra in a search for new molecules with pharmacological potentials, has increased in recent years. This has led to the isolation of several compounds from both species, including a majority of monoterpenes, sesquiterpenes, and polyphenols with varying pharmacological activities. This review aims to discuss the most important compounds present in both plant species with anti-malarial properties, anti-inflammatory potentials, and immunomodulating properties, with an emphasis on their pharmacokinetics and pharmacodynamics properties. Additionally, the toxicity of both plants and their anti-malaria properties, including those of other species in the genus Artemisia, is discussed. As such, data were collected via a thorough literature search in web databases, such as ResearchGate, ScienceDirect, Google scholar, PubMed, Phytochemical and Ethnobotanical databases, up to 2022. A distinction was made between compounds involved in a direct anti-plasmodial activity and those expressing anti-inflammatory and immunomodulating activities or anti-fever properties. For pharmacokinetics activities, a distinction was made between compounds influencing bioavailability (CYP effect or P-Glycoprotein effect) and those affecting the stability of pharmacodynamic active components.

Cytotoxicity of Poupartone B, an Alkyl Cyclohexenone Derivative from Poupartia borbonica, against Human Cancer Cell Lines.

Poupartia borbonica is an endemic tree from the Mascarene Islands that belongs to the Anacardiaceae family. The leaves of this plant were phytochemically studied previously, and isolated alkyl cyclohexenone derivatives, poupartones A - C, demonstrated antiplasmodial and antimalarial activities. In addition to their high potency against the Plasmodium sp., high toxicity on human cells was also displayed. The present study aims to investigate in more detail the cytotoxicity and pharmacological interest of poupartone B, one of the most abundant derivatives in the leaves of P. borbonica. For that purpose, real-time live-cell imaging of different human cancer cell lines and normal fibroblasts, treated or not treated with poupartone B, was performed. A potent inhibition of cell proliferation associated with the induction of cell death was observed. A detailed morphological analysis of different adherent cell lines exposed to high concentrations of poupartone B (1 - 2 µg/mL) demonstrated that this compound induced an array of cellular alterations, including a rapid retraction of cellular protrusions associated with cell rounding, massive cytoplasmic vacuolization, loss of plasma membrane integrity, and plasma membrane bubbling, ultimately leading to paraptosis-like cell death. The structure-activity relation of this class of compounds, their selective toxicity, and pharmacological potential are discussed.

In Vitro Antiplasmodial and Cytotoxic Activities of Compounds from the Roots of Eriosema montanum Baker f. (Fabaceae).

Malaria remains one of the leading causes of death in sub-Saharan Africa, ranked in the top three infectious diseases in the world. Plants of the Eriosema genus have been reported to be used for the treatment of this disease, but scientific evidence is still missing for some of them. In the present study, the in vitro antiplasmodial activity of the crude extract and compounds from Eriosema montanum Baker f. roots were tested against the 3D7 strain of Plasmodium falciparum and revealed using the SYBR Green, a DNA intercalating compound. The cytotoxicity effect of the compounds on a human cancer cell line (THP-1) was assessed to determine their selectivity index. It was found that the crude extract of the plant displayed a significant antiplasmodial activity with an IC50 (µg/mL) = 17.68 ± 4.030 and a cytotoxic activity with a CC50 (µg/mL) = 101.5 ± 12.6, corresponding to a selective antiplasmodial activity of 5.7. Bioactivity-guided isolation of the major compounds of the roots' crude extract afforded seven compounds, including genistein, genistin and eucomic acid. Under our experimental conditions, using Artemisinin as a positive control, eucomic acid showed the best inhibitory activity against the P. falciparum 3D7, a well-known chloroquine-sensitive strain. The present results provide a referential basis to support the traditional use of Eriosema species in the treatment of malaria.

The Inhibition of NLRP3 Inflammasome and IL-6 Production by Hibiscus noldeae Baker f. Derived Constituents Provides a Link to Its Anti-Inflammatory Therapeutic Potentials.

The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1ß (IL-1ß) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1ß and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1ß and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments.

Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption.

NLRP3 inflammasome plays a key role in Western diet-induced systemic inflammation and was recently shown to mediate long-lasting trained immunity in myeloid cells. Saturated fatty acids (SFAs) are sterile triggers able to induce the assembly of the NLRP3 inflammasome in macrophages, leading to IL-1ß secretion while unsaturated ones (UFAs) prevent SFAs-mediated NLRP3 activation. Unlike previous studies using LPS-primed bone marrow derived macrophages, we do not see any ROS or IRE-1α involvement in SFAs-mediated NLRP3 activation in human monocytes-derived macrophages. Rather we show that SFAs need to enter the cells and to be activated into acyl-CoA to lead to NLRP3 activation in human macrophages. However, their ß-oxidation is dispensable. Instead, they are channeled towards phospholipids but redirected towards lipid droplets containing triacylglycerol in the presence of UFAs. Lipidomic analyses and Laurdan fluorescence experiments demonstrate that SFAs induce a dramatic saturation of phosphatidylcholine (PC) correlated with a loss of membrane fluidity, both events inhibited by UFAs. The silencing of CCTα, the key enzyme in PC synthesis, prevents SFA-mediated NLRP3 activation, demonstrating the essential role of the de novo PC synthesis. This SFA-induced membrane remodeling promotes a disruption of the plasma membrane Na, K-ATPase, instigating a K+ efflux essential and sufficient for NLRP3 activation. This work opens novel therapeutic avenues to interfere with Western diet-associated diseases such as those targeting the glycerolipid pathway.

Capillary electrophoresis, high-performance liquid chromatography, and thin-layer chromatography analyses of phenolic compounds from rapeseed plants and evaluation of their antioxidant activity.

Rapeseed plants, known for oil production, are also known to contain phenolic compounds such as phenolic acids and flavonoids, with potential antioxidant and anticancer activities. The separation and identification of 11 phenolic acids in rapeseed extracts (including leaves, flowers, Chinese seeds, Belgian seeds, and cake) by capillary electrophoresis were investigated. The results were compared with those obtained with high-performance liquid chromatography and thin-layer chromatography and showed that the capillary electrophoresis technique offers several advantages for the identification of phenolic compounds in various rapeseed extracts. The antioxidant activity of rapeseed extracts and reference compounds was evaluated using four different approaches, namely, 2,2'-azinobis- (3-ethylbenzohiazoline-6-sulfonic acid assay, free radical 2,2-diphenyl-1-picrylhydrazyl assay, electron paramagnetic resonance spectroscopy and the measurement of the total polyphenol content. The contents of total polyphenols in the tested extracts were ranging between 5.4 and 21.1% m/m and ranked as follows: Chinese seeds ˃ Belgian seeds ˃ Flowers ˃ Cake ˃ Leaves.

Antimalarial Activities of Alkyl Cyclohexenone Derivatives Isolated from the Leaves of Poupartia borbonica.

Bioactivity-guided fractionation of the ethyl acetate extract of the leaves of Poupartia borbonica led to the isolation of three new alkyl cyclohexenone derivatives 1-3, and named Poupartone A-C. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic data analysis and MS, whereas calculated and experimental ECD spectra were used to define the absolute configurations. These compounds were active against 3D7 and W2 Plasmodium falciparum strains with IC50 values between 0.55 and 1.81 µM. In vitro cytotoxicity against WI38 human fibroblasts and the human cervical cancer cell line HeLa (WST-1 assay) showed that these compounds were also cytotoxic, but no hemolytic activity was observed for the extract and pure compounds. An in vivo antimalarial assay was performed on the major cyclohexenone using P. berghei-infected mice at a dose of 15 mg/kg/day ip. The assay revealed growth inhibition of 59.1 and 69.5% at days 5 and 7 postinfection, respectively, although some toxicity was observed. Zebrafish larvae were used as a model to determine the type of toxicity, and the results showed cardiac toxicity. The methanol extract was also studied, and it displayed moderate antiplasmodial properties in vitro. This extract contained the known flavonoids, quercetin, 3'-O-hydroxysulfonylquercetin, quercitrin, and isoquercitrin as well as ellagic acid, which showed high to low activity against the 3D7 P. falciparum strain.

In vitro cytotoxicity of some medicinal plants from Georgian Amaryllidaceae.

Using an ethnomedical data approach, some Georgian plants, which are used in Georgian traditional medicine for cancer or non-cancer diseases, were collected and evaluated for cytotoxic activity. The cytotoxic effect of the methanol extracts of species from the genera Galanthus and Leucojum was evaluated in vitro on three human cell lines (Hela, ephitheloid cervix carcinoma; HCT-116, colon carcinoma; HL-60, acute myeloid leukaemia). Cell type cytotoxic specificity was observed for some extracts. Overall, the HCT-116 cells were much more sensitive to most of the extracts than were the other cell lines. Plants that showed pronounced cytotoxic activity will be further evaluated for the possible isolation of active antitumour compounds.

HPLC quantification of alkaloids from Haplophyllum extracts and comparison with their cytotoxic properties.

An efficient system for the analysis of total alkaloids extracted from the aerial parts from different species of genus Haplophyllum (Rutaceae) by HPLC on a reversed-phase column is described. The HPLC method described was validated for its specificity, linearity and precision using external standards (haplopine, skimmianine and haplamine). The chromatographic conditions allowed the separation of alkaloids and the quantification of haplopine, skimmianine and haplamine in different samples of species of Haplophyllum collected in Uzbekistan. The alkaloidal contents of samples were compared with their in vitro cytotoxic properties against two cancer cell lines (HeLa and HCT-116). The cytotoxicity of extracts was correlated with the concentration of haplopine, skimmianine or haplamine in aerial parts of species of Haplophyllum.

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.

Screening of 14 alkaloids isolated from Haplophyllum A. Juss. for their cytotoxic properties.

Further to a systematic chemotaxonomic study of Uzbek Haplophyllum A. Juss. plants selected on ethnopharmacological data, 14 alkaloids were screened for their cytotoxic properties. As a first selection for interesting compounds, each alkaloid was tested against two human cancer cell lines (HeLa and HCT-116), using WST-1 reagent. Of the 14 alkaloids, 5 were cytotoxic when tested against the HeLa line with an IC50 < 100 microM. These five compounds consisted of three furoquinolines: skimmianine; haplopine and gamma-fagarine and two pyranoquinolones: flindersine and haplamine. Only haplamine was active against the HCT-116 line. The cytotoxic properties of these five alkaloids were further investigated against five additional human cancer cell lines. Their structure-activity relationships will be discussed. Of these five pre-selected alkaloids, only haplamine showed significant cytotoxic activity against all the tested cell lines. This is the first report of the cytotoxic activity of haplamine. Finally, this pyranoquinolone alkaloid was tested here against 14 different cancer cell lines and against normal skin fibroblasts.