Methyl jasmonate counteracts boron toxicity by preventing oxidative stress and regulating antioxidant enzyme activities and artemisinin biosynthesis in Artemisia annua L.

PubMed

Aftab, Tariq; Khan, M Masroor A; Idrees, Mohd; Naeem, M; Moinuddin; Hashmi, Nadeem

2011-07-01

Boron is an essential plant micronutrient, but it is phytotoxic if present in excessive amounts in soil for certain plants such as Artemisia annua L. that contains artemisinin (an important antimalarial drug) in its areal parts. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge. It is quite expensive compound because the only commercial source available is A. annua and the compound present in the plant is in very low concentration. Since A. annua is a major source of the antimalarial drug and B stress is a deadly threat to its cultivation, the present research was conducted to determine whether the exogenous application of methyl jasmonate (MeJA) could combat the ill effects of excessive B present in the soil. According to the results obtained, the B toxicity induced oxidative stress and reduced the stem height as well as fresh and dry masses of the plant remarkably. The excessive amounts of soil B also lowered the net photosynthetic rate, stomatal conductance, internal CO(2) concentration and total chlorophyll content in the leaves. In contrast, the foliar application of MeJA enhanced the growth and photosynthetic efficiency both in the stressed and non-stressed plants. The excessive B levels also increased the activities of antioxidant enzymes, such as catalase, peroxidase and superoxide dismutase. Endogenous H(2)O(2) and O(2)(-) levels were also high in the stressed plants. However, the MeJA application to the stressed plants reduced the amount of lipid peroxidation and stimulated the synthesis of antioxidant enzymes, enhancing the content and yield of artemisinin as well. Thus, it was concluded that MeJA might be utilized in mitigating the B toxicity and improving the content and yield of artemisinin in A. annua plant.

Potential ecological roles of Artemisinin produced by Artemisis annua L

USDA-ARS?s Scientific Manuscript database

Artemisia annua L. (annual wormwood, Asteraceae) and its secondary metabolite artemisinin, a unique sesquiterpene lactone with an endoperoxide bridge, has gained much attention due to its antimalarial properties. Artemisinin is a complex structure that is requires a significant amount of energy for ...

Optimization of artemisinin extraction from Artemisia annua L. with supercritical carbon dioxide + ethanol using response surface methodology.

PubMed

Ciftci, Ozan Nazim; Cahyadi, Jessica; Guigard, Selma E; Saldaña, Marleny D A

2018-05-13

Malaria is a high priority life-threatening public health concern in developing countries, and therefore there is a growing interest to obtain artemisinin for the production of artemisinin-based combination therapy products. In this study, artemisinin was extracted from the Artemisia annua L. plant using supercritical carbon dioxide (SC-CO 2 ) modified with ethanol. Response surface methodology based on central composite rotatable design was employed to investigate and optimize the extraction conditions of pressure (9.9-30 MPa), temperature (33-67°C), and co-solvent (ethanol, 0-12.6 wt.%). Optimum SC-CO 2 extraction conditions were found to be 30 MPa and 33°C without ethanol. Under optimized conditions, the predicted artemisinin yield was 1.09% whereas the experimental value was 0.71 ± 0.07%. Soxhlet extraction with hexane resulted in higher artemisinin yields and there was no significant difference in the purity of the extracts obtained with SC-CO 2 and Soxhlet extractions. Results indicated that SC-CO 2 and SC-CO 2 +ethanol extraction is a promising alternative for the extraction of artemisinin to eliminate the use of organic solvents, such as hexane, and produce extracts that can be used for the production of antimalarial products. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Overexpression of a type-I isopentenyl pyrophosphate isomerase of Artemisia annua in the cytosol leads to high arteannuin B production and artemisinin increase.

PubMed

Ma, Dongming; Li, Gui; Alejos-Gonzalez, Fatima; Zhu, Yue; Xue, Zhen; Wang, Aimin; Zhang, Hui; Li, Xing; Ye, Hechun; Wang, Hong; Liu, Benye; Xie, De-Yu

2017-08-01

We recently characterized a gene-terpene network that is associated with artemisinin biosynthesis in self-pollinated (SP) Artemisia annua, an effective antimalarial plant. We hypothesize that an alteration of gene expression in the network may improve the production of artemisinin and its precursors. In this study, we cloned an isopentenyl pyrophosphate isomerase (IPPI) cDNA, AaIPPI1, from Artemisia annua (Aa). The full-length cDNA encodes a type-I IPPI containing a plastid transit peptide (PTP) at its amino terminus. After the removal of the PTP, the recombinant truncated AaIPPI1 isomerized isopentenyl pyrophosphate (IPP) to dimethyl allyl pyrophosphate (DMAPP) and vice versa. The steady-state equilibrium ratio of IPP/DMAPP in the enzymatic reactions was approximately 1:7. The truncated AaIPPI1 was overexpressed in the cytosol of the SP A. annua variety. The leaves of transgenic plants produced approximately 4% arteannuin B (g g -1 , dry weight, dw) and 0.17-0.25% artemisinin (g g -1 , dw), the levels of which were significantly higher than those in the leaves of wild-type plants. In addition, transgenic plants showed an increase in artemisinic acid production of more than 1% (g g -1 , dw). In contrast, isoprene formation was significantly reduced in transgenic plants. These results provide evidence that overexpression of AaIPPI1 in the cytosol can lead to metabolic alterations of terpenoid biosynthesis, and show that these transgenic plants have the potential to yield high production levels of arteannuin B as a new precursor source for artemisinin. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Enhancing the growth, photosynthetic capacity and artemisinin content in Artemisia annua L. by irradiated sodium alginate

NASA Astrophysics Data System (ADS)

Aftab, Tariq; Khan, M. Masroor A.; Idrees, M.; Naeem, M.; Moinuddin; Hashmi, Nadeem; Varshney, Lalit

2011-07-01

Degrading the natural bioactive agents by ionizing radiation and then using them as growth promoting substances is a novel emerging technology to exploit the genetic potential of crops in terms of growth, yield and quality. Polysaccharides, such as sodium alginate, have proven to be wonderful growth promoting substances in their depolymerized form for various plants. The effect of depolymerized form of sodium alginate, produced by irradiating the latter by 60Co gamma rays, was studied on Artemisia annua L. with regard to growth attributes, physiological and biochemical parameters and artemisinin content. The study revealed that the irradiated sodium alginate (ISA), applied as leaf-sprays at a concentration of 20-120 mg L -1, improved the growth attributes, photosynthetic capability, enzyme activities and artemisinin content of the plant significantly. Application of ISA at 80 mg L -1 increased the values of the attributes studied to the maximum extent. The enhancement of leaf-artemisinin content was ascribed to the ISA-enhanced H 2O 2 content in the leaves.

Potential ecological roles of artemisinin produced by Artemisia annua L.

PubMed

Knudsmark Jessing, Karina; Duke, Stephen O; Cedergreeen, Nina

2014-02-01

Artemisia annua L. (annual wormwood, Asteraceae) and its secondary metabolite artemisinin, a unique sesquiterpene lactone with an endoperoxide bridge, has gained much attention due to its antimalarial properties. Artemisinin has a complex structure that requires a significant amount of energy for the plant to synthesize. So, what are the benefits to A. annua of producing this unique compound, and what is the ecological role of artemisinin? This review addresses these questions, discussing evidence of the potential utility of artemisinin in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species. Abiotic factors affecting the artemisinin production, as well as mechanisms of artemisinin release to the surroundings also are discussed, and new data are provided on the toxicity of artemisinin towards soil and aquatic organisms. The antifungal and antibacterial effects reported are not very pronounced. Several studies have reported that extracts of A. annua have insecticidal effects, though few studies have proven that artemisinin could be the single compound responsible for the observed effects. However, the pathogen(s) or insect(s) that may have provided the selection pressure for the evolution of artemisinin synthesis may not have been represented in the research thus far conducted. The relatively high level of phytotoxicity of artemisinin in soil indicates that plant/plant allelopathy could be a beneficial function of artemisinin to the producing plant. The release routes of artemisinin (movement from roots and wash off from leaf surfaces) from A. annua to the soil support the rationale for allelopathy.

Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism.

PubMed

Czechowski, Tomasz; Larson, Tony R; Catania, Theresa M; Harvey, David; Brown, Geoffrey D; Graham, Ian A

2016-12-27

Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in the most effective treatment for malaria currently available. We identified a mutation that disrupts the amorpha-4,11-diene C-12 oxidase (CYP71AV1) enzyme, responsible for a series of oxidation reactions in the artemisinin biosynthetic pathway. Detailed metabolic studies of cyp71av1-1 revealed that the consequence of blocking the artemisinin biosynthetic pathway is the redirection of sesquiterpene metabolism to a sesquiterpene epoxide, which we designate arteannuin X. This sesquiterpene approaches half the concentration observed for artemisinin in wild-type plants, demonstrating high-flux plasticity in A. annua glandular trichomes and their potential as factories for the production of novel alternate sesquiterpenes at commercially viable levels. Detailed metabolite profiling of leaf maturation time-series and precursor-feeding experiments revealed that nonenzymatic conversion steps are central to both artemisinin and arteannuin X biosynthesis. In particular, feeding studies using 13 C-labeled dihydroartemisinic acid (DHAA) provided strong evidence that the final steps in the synthesis of artemisinin are nonenzymatic in vivo. Our findings also suggest that the specialized subapical cavity of glandular secretory trichomes functions as a location for both the chemical conversion and the storage of phytotoxic compounds, including artemisinin. We conclude that metabolic engineering to produce high yields of novel secondary compounds such as sesquiterpenes is feasible in complex glandular trichomes. Such systems offer advantages over single-cell microbial hosts for production of toxic natural products.

Development of a Specific Monoclonal Antibody for the Quantification of Artemisinin in Artemisia annua and Rat Serum.

PubMed

Guo, Suqin; Cui, Yongliang; Wang, Kunbi; Zhang, Wei; Tan, Guiyu; Wang, Baomin; Cui, Liwang

2016-03-01

Artemisinin, extracted from Artemisia annua, and its derivatives are important frontline antimalarials. To produce specific antibodies for the detection and quantification of artemisinin, artemisinin was transformed to 9-hydroxyartemisinin by microbial fermentation, which was used to prepare a 9-succinate artemisinin hapten for conjugation with ovalbumin. A monoclonal antibody (mAb), designated as 3H7A10, was selected from hybridoma cell lines which showed high specificity to artemisinin. No competitive inhibition was observed with artesunate, dihydroartemisinin, and artemether for up to 20,000 ng mL(-1). An indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed, which showed a concentration causing 50% of inhibition (IC50) for artemisinin as 2.6 ng mL(-1) and a working range of 0.6-11.5 ng mL(-1). The icELISA was applied for the quantification of artemisinin in crude extracts of wild A. annua and the study of pharmacokinetics of artemisinin in rat serum after intraperitoneal injection. The results were highly correlated with those determined by HPLC-UV analysis (R(2) = 0.9919). In comparison with reported antiartemisinin mAbs which have broad cross-reactivity with other artemisinin derivatives, the high specificity of 3H7A10 for artemisinin will enable development of methods for quantification of artemisinin in Artemisia plants and antimalarial drugs such as Arco and for pharmacokinetic studies.

Flower morphology and development in Artemisia annua, a medicinal plant used as a treatment against malaria

USDA-ARS?s Scientific Manuscript database

Artemisia annua produces a wide spectrum of bioactive phytochemicals that possess pharmacological properties including antimalarial, antitumor, anti-inflammatory, and anthelmintic activities. The main active ingredient, artemisinin, is extremely effective against multi-drug resistant Plasmodium fal...

Dried-leaf Artemisia annua: A practical malaria therapeutic for developing countries?

PubMed Central

Weathers, Pamela J; Towler, Melissa; Hassanali, Ahmed; Lutgen, Pierre; Engeu, Patrick Ogwang

2015-01-01

Artemisinin from the plant Artemisia annua (A. annua) L, and used as artemisinin combination therapy (ACT), is the current best therapeutic for treating malaria, a disease that hits children and adults especially in developing countries. Traditionally, A. annua was used by the Chinese as a tea to treat “fever”. More recently, investigators have shown that tea infusions and oral consumption of the dried leaves of the plant have prophylactic and therapeutic efficacy. The presence of a complex matrix of chemicals within the leaves seems to enhance both the bioavailability and efficacy of artemisinin. Although about 1000-fold less potent than artemisinin in their antiplasmodial activity, these plant chemicals are mainly small molecules that include other artemisinic compounds, terpenes (mainly mono and sesqui), flavonoids, and polyphenolic acids. In addition, polysaccharide constituents of A. annua may enhance bioavailability of artemisinin. Rodent pharmacokinetics showed longer T1/2 and Tmax and greater Cmax and AUC in Plasmodium chabaudi-infected mice treated with A. annua dried leaves than in healthy mice. Pharmacokinetics of deoxyartemisinin, a liver metabolite of artemisinin, was more inhibited in infected than in healthy mice. In healthy mice, artemisinin serum levels were > 40-fold greater in dried leaf fed mice than those fed with pure artemisinin. Human trial data showed that when delivered as dried leaves, 40-fold less artemisinin was required to obtain a therapeutic response compared to pure artemisinin. ACTs are still unaffordable for many malaria patients, and cost estimates for A. annua dried leaf tablet production are orders of magnitude less than for ACT, despite improvements in the production capacity. Considering that for > 2000 years this plant was used in traditional Chinese medicine for treatment of fever with no apparent appearance of artemisinin drug resistance, the evidence argues for inclusion of affordable A. annua dried leaf tablets into the arsenal of drugs to combat malaria and other artemisinin-susceptible diseases. PMID:25678989

TRICHOME AND ARTEMISININ REGULATOR 1 Is Required for Trichome Development and Artemisinin Biosynthesis in Artemisia annua.

PubMed

Tan, Hexin; Xiao, Ling; Gao, Shouhong; Li, Qing; Chen, Junfeng; Xiao, Ying; Ji, Qian; Chen, Ruibing; Chen, Wansheng; Zhang, Lei

2015-09-01

Trichomes, small protrusions on the surface of many plant species, can produce and store various secondary metabolic products. Artemisinin, the most famous and potent medicine for malaria, is synthesized, stored, and secreted by Artemisia annua trichomes. However, the molecular basis regulating the biosynthesis of artemisinin and the development of trichomes in A. annua remains poorly understood. Here, we report that an AP2 transcription factor, TRICHOME AND ARTEMISININ REGULATOR 1 (TAR1), plays crucial roles in regulating the development of trichomes and the biosynthesis of artemisinin in A. annua. TAR1, which encodes a protein specially located in the nucleus, is mainly expressed in young leaves, flower buds, and some trichomes. In TAR1-RNAi lines, the morphology of trichomes and the composition of cuticular wax were altered, and the artemisinin content was dramatically reduced, which could be significantly increased by TAR1 oeverexpression. Expression levels of several key genes that are involved in artemisinin biosynthesis were altered when TAR1 was silenced or overexpressed. By the electrophoretic mobility shift, yeast one-hybrid and transient transformation β-glucuronidase assays, we showed that ADS and CYP71AV1, two key genes in the biosynthesis pathway of artemisinin, are likely the direct targets of TAR1. Taken together, our results indicate that TAR1 is a key component of the molecular network regulating trichome development and artemisinin biosynthesis in A. annua. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

Overexpression of AaWRKY1 Leads to an Enhanced Content of Artemisinin in Artemisia annua.

PubMed

Jiang, Weimin; Fu, Xueqing; Pan, Qifang; Tang, Yueli; Shen, Qian; Lv, Zongyou; Yan, Tingxiang; Shi, Pu; Li, Ling; Zhang, Lida; Wang, Guofeng; Sun, Xiaofen; Tang, Kexuan

2016-01-01

Artemisinin is an effective component of drugs against malaria. The regulation of artemisinin biosynthesis is at the forefront of artemisinin research. Previous studies showed that AaWRKY1 can regulate the expression of ADS, which is the first key enzyme in artemisinin biosynthetic pathway. In this study, AaWRKY1 was cloned, and it activated ADSpro and CYPpro in tobacco using dual-LUC assay. To further study the function of AaWRKY1, pCAMBIA2300-AaWRKY1 construct under 35S promoter was generated. Transgenic plants containing AaWRKY1 were obtained, and four independent lines with high expression of AaWRKY1 were analyzed. The expression of ADS and CYP, the key enzymes in artemisinin biosynthetic pathway, was dramatically increased in AaWRKY1-overexpressing A. annua plants. Furthermore, the artemisinin yield increased significantly in AaWRKY1-overexpressing A. annua plants. These results showed that AaWRKY1 increased the content of artemisinin by regulating the expression of both ADS and CYP. It provides a new insight into the mechanism of regulation on artemisinin biosynthesis via transcription factors in the future.

Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism

PubMed Central

Czechowski, Tomasz; Larson, Tony R.; Catania, Theresa M.; Harvey, David; Brown, Geoffrey D.; Graham, Ian A.

2016-01-01

Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in the most effective treatment for malaria currently available. We identified a mutation that disrupts the amorpha-4,11-diene C-12 oxidase (CYP71AV1) enzyme, responsible for a series of oxidation reactions in the artemisinin biosynthetic pathway. Detailed metabolic studies of cyp71av1-1 revealed that the consequence of blocking the artemisinin biosynthetic pathway is the redirection of sesquiterpene metabolism to a sesquiterpene epoxide, which we designate arteannuin X. This sesquiterpene approaches half the concentration observed for artemisinin in wild-type plants, demonstrating high-flux plasticity in A. annua glandular trichomes and their potential as factories for the production of novel alternate sesquiterpenes at commercially viable levels. Detailed metabolite profiling of leaf maturation time-series and precursor-feeding experiments revealed that nonenzymatic conversion steps are central to both artemisinin and arteannuin X biosynthesis. In particular, feeding studies using 13C-labeled dihydroartemisinic acid (DHAA) provided strong evidence that the final steps in the synthesis of artemisinin are nonenzymatic in vivo. Our findings also suggest that the specialized subapical cavity of glandular secretory trichomes functions as a location for both the chemical conversion and the storage of phytotoxic compounds, including artemisinin. We conclude that metabolic engineering to produce high yields of novel secondary compounds such as sesquiterpenes is feasible in complex glandular trichomes. Such systems offer advantages over single-cell microbial hosts for production of toxic natural products. PMID:27930305

Si-Accumulation In Artemisia annua Glandular Trichomes Increases Artemisinin Concentration, but Does Not Interfere In the Impairment of Toxoplasma gondii Growth

PubMed Central

Rostkowska, Cristina; Mota, Caroline M.; Oliveira, Taísa C.; Santiago, Fernanda M.; Oliveira, Lilian A.; Korndörfer, Gaspar H.; Lana, Regina M. Q.; Rossi, Monica L.; Nogueira, Neusa L.; Simonnet, Xavier; Mineo, Tiago W. P.; Silva, Deise A.O.; Mineo, José R.

2016-01-01

Artemisia annua is used as a source of artemisinin, a potent therapeutic agent used for the treatment of infectious diseases, chiefly malaria. However, the low concentration (from 0.01 to 1.4% of dried leaf matter) of artemisinin in the plant obtained with the traditional cropping system makes it a relatively expensive drug, especially in developing countries. Considering that artemisinin and silicon (Si) are both stored in A. annua glandular trichomes, and that Si accumulation has never been investigated, this study aimed to look into Si effects on A. annua trichome artemisinin concentration, and whether leaf infusion from Si-treated A. annua plants is able to control Toxoplasma gondii growth. T. gondii is the etiologic agent of toxoplasmosis, a zoonotic parasitic disease whose traditional treatment shows significant side effects. The experimental design consisted of A. annua seedlings randomly planted in soil treated with different doses of calcium/magnesium silicate (0, 200, 400, 800, and 1600 kg ha-1). Analysis of foliar macronutrients showed significant increases of nitrogen content only at the highest dose of silicate. Foliar micronutrients, Si concentrations, and plant height were not affected by any of the silicate doses. However, the dose of 400 kg ha-1 of silicate increased the trichome size, which in turn raised artemisinin concentration in leaves and the infusion. In contrast, the 800 and 1600 kg ha-1 doses dramatically decreased artemisinin concentration. HeLa cell treatment with the infusion of A. annua grown in soil treated with 400 kg ha-1 of silicate decreased parasite proliferation in a dose-dependent manner when the treatment was carried out after or along with T. gondii infection. However, this effect was similar to A. annua grown in soil without silicate treatment. Thus, it can be concluded that, even though Si applied to the soil at 400 kg ha-1 has a positive effect on the A. annua glandular trichome size and the artemisinin concentration, this outcome cannot be directly associated with the efficiency of A. annua infusion on T. gondii growth, suggesting that other components from A. annua leaves could be acting in synergy with artemisinin. PMID:27721819

Effects of artemisinin and Artemisia annua extracts on Haemonchus contortus in gerbils (Meriones unguiculatus)

USDA-ARS?s Scientific Manuscript database

Haemonchus contortus is a blood-sucking abomasal parasite of small ruminants that is responsible for major losses to producers worldwide. Resistance of this nematode to commercial anthelmintics has produced a demand for alternative control methods. Artemisia annua is the sole commercial source of ...

Cytotoxicity of ethanolic extracts of Artemisia annua to Molt-4 human leukemia cells

USDA-ARS?s Scientific Manuscript database

Cancer is the second cause of death in the United States, and current treatment is expensive and kills also healthy cells. Affordable alternatives that kill only cancer cells are needed. Artemisinin, extracted from the Artemisia annua, has potent anticancer activity and low toxicity to normal cell...

The activity of the artemisinic aldehyde Δ11(13) reductase promoter is important for artemisinin yield in different chemotypes of Artemisia annua L.

PubMed

Yang, Ke; Monfared, Sajad Rashidi; Monafared, Rashidi Sajad; Wang, Hongzhen; Lundgren, Anneli; Brodelius, Peter E

2015-07-01

The artemisinic aldehyde double bond reductase (DBR2) plays an important role in the biosynthesis of the antimalarial artemisinin in Artemisia annua. Artemisinic aldehyde is reduced into dihydroartemisinic aldehyde by DBR2. Artemisinic aldehyde can also be oxidized by amorpha-4,11-diene 12-hydroxylase and/or aldehyde dehydrogenase 1 to artemisinic acid, a precursor of arteannuin B. In order to better understand the effects of DBR2 expression on the flow of artemisinic aldehyde into either artemisinin or arteannuin B, we determined the content of dihydroartemisinic aldehyde, artemisinin, artemisinic acid and arteannuin B content of A. annua varieties sorted into two chemotypes. The high artemisinin producers (HAPs), which includes the '2/39', 'Chongqing' and 'Anamed' varieties, produce more artemisinin than arteannuin B; the low artemisinin producers (LAPs), which include the 'Meise', 'Iran#8', 'Iran#14', 'Iran#24' and 'Iran#47' varieties, produce more arteannuin B than artemisinin. Quantitative PCR showed that the relative expression of DBR2 was significantly higher in the HAP varieties. We cloned and sequenced the promoter of the DBR2 gene from varieties of both the LAP and the HAP groups. There were deletions/insertions in the region just upstream of the ATG start codon in the LAP varities, which might be the reason for the different promoter activities of the HAP and LAP varieties. The relevance of promoter variation, DBR2 expression levels and artemisinin biosynthesis capabilities are discussed and a selection method for HAP varieties with a DNA marker is suggested. Furthermore, putative cis-acting regulatory elements differ between the HAP and LAP varieties.

Cellular engineering of Artemisia annua and Artemisia dubia with the rol ABC genes for enhanced production of potent anti-malarial drug artemisinin.

PubMed

Kiani, Bushra Hafeez; Suberu, John; Mirza, Bushra

2016-05-04

Malaria is causing more than half of a million deaths and 214 million clinical cases annually. Despite tremendous efforts for the control of malaria, the global morbidity and mortality have not been significantly changed in the last 50 years. Artemisinin, extracted from the medicinal plant Artemisia sp. is an effective anti-malarial drug. In 2015, elucidation of the effectiveness of artemisinin as a potent anti-malarial drug was acknowledged with a Nobel prize. Owing to the tight market and low yield of artemisinin, an economical way to increase its production is to increase its content in Artemisia sp. through different biotechnological approaches including genetic transformation. Artemisia annua and Artemisia dubia were transformed with rol ABC genes through Agrobacterium tumefacienes and Agrobacterium rhizogenes methods. The artemisinin content was analysed and compared between transformed and untransformed plants with the help of LC-MS/MS. Expression of key genes [Cytochrome P450 (CYP71AV1), aldehyde dehydrogenase 1 (ALDH1), amorpha-4, 11 diene synthase (ADS)] in the biosynthetic pathway of artemisinin and gene for trichome development and sesquiterpenoid biosynthetic (TFAR1) were measured using Quantitative real time PCR (qRT-PCR). Trichome density was analysed using confocal microscope. Artemisinin content was significantly increased in transformed material of both Artemisia species when compared to un-transformed plants. The artemisinin content within leaves of transformed lines was increased by a factor of nine, indicating that the plant is capable of synthesizing much higher amounts than has been achieved so far through traditional breeding. Expression of all artemisinin biosynthesis genes was significantly increased, although variation between the genes was observed. CYP71AV1 and ALDH1 expression levels were higher than that of ADS. Levels of the TFAR1 expression were also increased in all transgenic lines. Trichome density was also significantly increased in the leaves of transformed plants, but no trichomes were found in control roots or transformed roots. The detection of significantly raised levels of expression of the genes involved in artemisinin biosynthesis in transformed roots correlated with the production of significant amounts of artemisinin in these tissues. This suggests that synthesis is occurring in tissues other than the trichomes, which contradicts previous theories. Transformation of Artemisia sp. with rol ABC genes can lead to the increased production of artemisinin, which will help to meet the increasing demand of artemisinin because of its diverse pharmacological and anti-malarial importance.

Effects of ethanol extract of Artemisia annua L. against monogenean parasites of Heterobranchus longifilis.

PubMed

Ekanem, Albert P; Brisibe, Ebiamadon Andi

2010-04-01

Ethanol extract of Artemisia annua was effective in the dislodgement and mortality of monogenean parasites of juvenile Heterobranchus longifilis at concentrations ranging from 50 to 200 mg/l. Five hundred 1-week-old juvenile fish were stocked in hapa in earthen pond for 7 days to accumulate parasites. The approximate number of parasites per fish was confirmed by counting the number of parasites attached to body surfaces and the gills with a stereo-microscope before being exposed to the extract under in vivo conditions. The bioactivity of the extract was conducted in plastic Petri dishes with three replications and controls. The results obtained from A. annua extract were matched against those produced by pure artemisinin and artesunate powder, respectively, under similar experimental conditions. There was a faster effect of pure artemisinin crystals on the parasites as compared to A. annua extract and artesunate. Coagulation of parasite cells was observed with artemisinin treatment, whereas parasites were merely dislodged from their attachment organs and killed some hours later in the same concentration of A. annua. There were positive correlations between the number of parasites dislodged/killed and the concentration of A. annua extract, artemisinin, and artesunate powder, respectively, as well as the duration of exposure of affected fish to the substances. This led to the conclusion that A. annua contains substances that are effective against helminthes parasites of H. longifilis.

GLANDULAR TRICHOME-SPECIFIC WRKY 1 promotes artemisinin biosynthesis in Artemisia annua.

PubMed

Chen, Minghui; Yan, Tingxiang; Shen, Qian; Lu, Xu; Pan, Qifang; Huang, Youran; Tang, Yueli; Fu, Xueqing; Liu, Meng; Jiang, Weimin; Lv, Zongyou; Shi, Pu; Ma, Ya-Nan; Hao, Xiaolong; Zhang, Lida; Li, Ling; Tang, Kexuan

2017-04-01

Artemisinin is a type of sesquiterpene lactone well known as an antimalarial drug, and is specifically produced in glandular trichomes of Artemisia annua. However, the regulatory network for the artemisinin biosynthetic pathway remains poorly understood. Exploration of trichome-specific transcription factors would facilitate the elucidation of regulatory mechanism of artemisinin biosynthesis. The WRKY transcription factor GLANDULAR TRICHOME-SPECIFIC WRKY 1 (AaGSW1) was cloned and analysed in A. annua. AaGSW1 exhibited similar expression patterns to the trichome-specific genes of the artemisinin biosynthetic pathway and AP2/ERF transcription factor AaORA. A β-glucuronidase (GUS) staining assay further demonstrated that AaGSW1 is a glandular trichome-specific transcription factor. AaGSW1 positively regulates CYP71AV1 and AaORA expression by directly binding to the W-box motifs in their promoters. Overexpression of AaGSW1 in A. annua significantly improves artemisinin and dihydroartemisinic acid contents; moreover, AaGSW1 can be directly regulated by AaMYC2 and AabZIP1, which are positive regulators of jasmonate (JA)- and abscisic acid (ABA)-mediated artemisinin biosynthetic pathways, respectively. These results demonstrate that AaGSW1 is a glandular trichome-specific WRKY transcription factor and a positive regulator in the artemisinin biosynthetic pathway. Moreover, we propose that two trifurcate feed-forward pathways involving AaGSW1, CYP71AV1 and AaMYC2/AabZIP1 function in the JA/ABA response in A. annua. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Global characterization of Artemisia annua glandular trichome transcriptome using 454 pyrosequencing

PubMed Central

Wang, Wei; Wang, Yejun; Zhang, Qing; Qi, Yan; Guo, Dianjing

2009-01-01

Background Glandular trichomes produce a wide variety of commercially important secondary metabolites in many plant species. The most prominent anti-malarial drug artemisinin, a sesquiterpene lactone, is produced in glandular trichomes of Artemisia annua. However, only limited genomic information is currently available in this non-model plant species. Results We present a global characterization of A. annua glandular trichome transcriptome using 454 pyrosequencing. Sequencing runs using two normalized cDNA collections from glandular trichomes yielded 406,044 expressed sequence tags (average length = 210 nucleotides), which assembled into 42,678 contigs and 147,699 singletons. Performing a second sequencing run only increased the number of genes identified by ~30%, indicating that massively parallel pyrosequencing provides deep coverage of the A. annua trichome transcriptome. By BLAST search against the NCBI non-redundant protein database, putative functions were assigned to over 28,573 unigenes, including previously undescribed enzymes likely involved in sesquiterpene biosynthesis. Comparison with ESTs derived from trichome collections of other plant species revealed expressed genes in common functional categories across different plant species. RT-PCR analysis confirmed the expression of selected unigenes and novel transcripts in A. annua glandular trichomes. Conclusion The presence of contigs corresponding to enzymes for terpenoids and flavonoids biosynthesis suggests important metabolic activity in A. annua glandular trichomes. Our comprehensive survey of genes expressed in glandular trichome will facilitate new gene discovery and shed light on the regulatory mechanism of artemisinin metabolism and trichome function in A. annua. PMID:19818120

Artemisia annua respon to various types of organic fertilizer and dose in lowland

NASA Astrophysics Data System (ADS)

Yunus, A.; Samanhudi; Brahmanto, N.; Widyastuti, Y.

2018-03-01

Artemisia annua belongs to asteraceae genus which has many benefits in the medical field. Artemisia contains artemisinin which is used to cure malaria disease. The obstacle of artemisia development in Indonesia is low artemisinin content and the fact that artemisia only able to grow well in the highland area. For that this experiment aimed to increase the artemisinin content through enhancing artemisia biomass in the lowland using the application of organic fertilizer. Experiment was conducted in GreenhouseLab, Faculty of Agriculture, Sebelas Maret University, Surakarta from October 2015 to January 2016. Two factor of treatment and three replications was performed during experiment. The first factor is the organic fertilizer type and the second is the application dose. Result showed that Rabbit manure at 40% application dose give best influence on the plant height (172,62 cm), number of branches (68,3 branch), flowering time (102,67 day after planted), fresh weight (56,47 g) and dry weight (43,15 g), moreover Rabbit manure at 80% dose give the best influence on the root length (27,33 cm).

Investigation of Glandular Trichome Proteins in Artemisia annua L. Using Comparative Proteomics

PubMed Central

Wu, Ting; Wang, Yejun; Guo, Dianjing

2012-01-01

Glandular secreting trichomes (GSTs) are called biofactories because they are active in synthesizing, storing and secreting various types of plant secondary metabolites. As the most effective drug against malaria, artemisinin, a sesquiterpene lactone is derived from GSTs of Artemisia annua. However, low artemisinin content (0.001%∼1.54% of dry weight) has hindered its wide application. We investigate the GST-expressed proteins in Artemisia annua using a comparative proteomics approach, aiming for a better understanding of the trichome proteome and arteminisin metabolism. 2D-electrophoresis was employed to compare the protein profiles of GSTs and leaves. More than 700 spots were resolved for GSTs, of which ∼93 non-redundant proteins were confidently identified by searching NCBI and Artemisia EST databases. Over 70% of these proteins were highly expressed in GTSs. Functional classification of these GSTs enriched proteins revealed that many of them participate in major plant metabolic processes such as electron transport, transcription and translation. PMID:22905110

Detecting the antimalarial artemisinin in plant extracts using near-infrared spectroscopy

USDA-ARS?s Scientific Manuscript database

The antimalarial artemisinin is produced by Artemisia annua L and can be used to kill the protozoan parasite Plasmodium, which is spread by mosquitoes. Artemisinin is extracted from these plants through tea preparation. The artemisinin content of the tea varies depending on how much artemisinin was ...

The application of biotic elicitor on Artemisia annua L. to increase artemisinin content

NASA Astrophysics Data System (ADS)

Darwati, I.; Manohara, D.; Rohimatun; Nurhayati, H.

2018-01-01

Artemisinin-based Combination Therapy (ACT) has been recommended by WHO as an alternative to treat malaria overcoming drug resistance. The secondary metabolic products in plants, including artemisinin, can be increased by utilizing biotic elicitor from fungi. The research was conducted in Gunung Putri Research Installation, Cipanas, West Java from 2010 to 2011. Phytophthora sp. from eggplant and Colletotrichum sp. from Artemisia annua were applied as biotic elicitor. The types of biotic elicitor applied to the plants were 1) the medium of potato dextrose broth were inoculated with fungi and harvested after 10 days (filtrate), 2) powdery mycelium of both fungi. There were 16 treatments: control negative, control positive (uninoculated medium) 1%, 2%, 3% (v/v)], Phytophthora sp. filtrate [1, 2% and 3% (v/v)], Colletotrichum sp. filtrate [1, 2% and 3% (v/v)], Phytophthora sp. mycelium [1%, 2% and 3% (w/v)], Colletotrichum sp mycelium [1%, 2% and 3% (w/v)]. The elicitor application increased plant production by 26.21% and artemisinin yield by 72% compared to control. Furthermore, the artemisinin production of the plants treated with medium inoculated with 2% filtrate of Phytophthora sp (FP2) (25.19 kg/ha) and 1% powdery mycelium of Colletotrichum sp (MC1) (26.42 kg/ha) were higher than control (K) (11.17 kg/ha).

Laboratory evaluation of Artemisia annua L. extract and artemisinin activity against Epilachna paenulata and Spodoptera eridania.

PubMed

Maggi, María E; Mangeaud, Arnaldo; Carpinella, María C; Ferrayoli, Carlos G; Valladares, Graciela R; Palacios, Sara M

2005-07-01

Ethanolic extract of aerial parts of Artemisia annua L. and artemisinin were evaluated as anti-insect products. In a feeding deterrence assay on Epilachna paenulata Germ (Coleoptera: Coccinellidae) larvae, complete feeding rejection was observed at an extract concentration of 1.5 mg/cm2 on pumpkin leaf tissue. The same concentration produced a feeding inhibition of 87% in Spodoptera eridania (Cramer) (Lepidoptera: Noctuidae). In a no-choice assay, both species ate less and gained less weight when fed on leaves treated with the extract. Complete mortality in E. paenulata and 50% mortality in S. eridania were observed with extract at 1.5 mg/cm2. Artemisinin exhibited a moderate antifeedant effect on E. paenulata and S. eridania at 0.03-0.375 mg/cm2. However, a strong effect on survival and body weight was observed when E. paenulata larvae were forced to feed on leaves treated at 0.03 and 0.075 mg/cm2. Artemisia annua ethanolic extract of aerial parts at 1.5 mg/cm2 showed no phytotoxic effect on pumpkin seedlings.

Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice.

PubMed

Weathers, Pamela J; Elfawal, Mostafa A; Towler, Melissa J; Acquaah-Mensah, George K; Rich, Stephen M

2014-05-14

The Chinese have used Artemisia annua as a tea infusion to treat fever for >2000 years. The active component is artemisinin. Previously we showed that when compared to mice fed an equal amount of pure artemisinin, a single oral dose of dried leaves of Artemisia annua (pACT) delivered to Plasmodium chabaudi-infected mice reduced parasitemia at least fivefold. Dried leaves also delivered >40 times more artemisinin in the blood with no toxicity. The pharmacokinetics (PK) of artemisinin delivered from dried plant material has not been adequately studied. Healthy and Plasmodium chabaudi-infected mice were oral gavaged with pACT to deliver a 100 mg kg(-1) body weight dose of artemisinin. Concentrations of serum artemisinin and one of its liver metabolites, deoxyartemisinin, were measured over two hours by GCMS. The first order elimination rate constant for artemisinin in pACT-treated healthy mice was estimated to be 0.80 h(-1) with an elimination half-life (T½) of 51.6 min. The first order absorption rate constant was estimated at 1.39 h(-1). Cmax and Tmax were 4.33 mg L(-1) and 60 min, respectively. The area under the curve (AUC) was 299.5 mg min L(-1). In contrast, the AUC for pACT-treated infected mice was significantly greater at 435.6 mg min L(-1). Metabolism of artemisinin to deoxyartemisinin was suppressed in infected mice over the period of observation. Serum levels of artemisinin in the infected mice continued to rise over the 120 min of the study period, and as a result, the T½ was not determined; the Cmax and Tmax were estimated at ≥6.64 mgL(-1) and ≥120 min, respectively. Groups of healthy mice were also fed either artemisinin or artemisinin mixed in mouse chow. When compared at 60 min, artemisinin was undetectable in the serum of mice fed 100 mg AN kg(-1) body weight. When plant material was present either as mouse chow or Artemisia annua pACT, artemisinin levels in the serum rose to 2.44 and 4.32 mg L(-1), respectively, indicating that the presence of the plant matrix, even that of mouse chow, had a positive impact on the appearance of artemisinin in the blood. These results showed that artemisinin and one of its drug metabolites were processed differently in healthy and infected mice. The results have implications for possible therapeutic use of pACT in treating malaria and other artemisinin-susceptible diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Studies on the Expression of Sesquiterpene Synthases Using Promoter-β-Glucuronidase Fusions in Transgenic Artemisia annua L

PubMed Central

Wang, Hongzhen; Han, Junli; Kanagarajan, Selvaraju; Lundgren, Anneli; Brodelius, Peter E.

2013-01-01

In order to better understand the influence of sesquiterpene synthases on artemisinin yield in Artemisia annua, the expression of some sesquiterpene synthases has been studied using transgenic plants expressing promoter-GUS fusions. The cloned promoter sequences were 923, 1182 and 1510 bp for β-caryophyllene (CPS), epi-cedrol (ECS) and β-farnesene (FS) synthase, respectively. Prediction of cis-acting regulatory elements showed that the promoters are involved in complex regulation of expression. Transgenic A. annua plants carrying promoter-GUS fusions were studied to elucidate the expression pattern of the three sesquiterpene synthases and compared to the previously studied promoter of amorpha-4,11-diene synthase (ADS), a key enzyme of artemisinin biosynthesis. The CPS and ECS promoters were active in T-shaped trichomes of leaves and stems, basal bracts of flower buds and also in some florets cells but not in glandular secretory trichome while FS promoter activity was only observed in leaf cells and trichomes of transgenic shoots. ADS, CPS, ECS and FS transcripts were induced by wounding in a time depended manner. The four sesquiterpene synthases may be involved in responsiveness of A. annua to herbivory. Methyl jasmonate treatment triggered activation of the promoters of all four sesquiterpene synthases in a time depended manner. Southern blot result showed that the GUS gene was inserted into genomic DNA of transgenic lines as a single copy or two copies. The relative amounts of CPS and ECS as well as germacrene A synthase (GAS) transcripts are much lower than that of ADS transcript. Consequently, down-regulation of the expression of the CPS, ECS or GAS gene may not improve artemsinin yield. However, blocking the expression of FS may have effects on artemisinin production. PMID:24278301

Extraction mechanism of ultrasound assisted extraction and its effect on higher yielding and purity of artemisinin crystals from Artemisia annua L. leaves.

PubMed

Chemat, Smain; Aissa, Abdallah; Boumechhour, Abdenour; Arous, Omar; Ait-Amar, Hamid

2017-01-01

This study proposes an ultrasound-horn system for the extraction of a natural active compound "artemisinin" from Artemisia annua L. leaves as an alternative to hot maceration technique. Ultrasound leaching improves artemisinin recovery at all temperatures where only ten minutes is required to recover 70% (4.42mgg -1 ) compared to 60min of conventional hot leaching for the same yield. For instance, ultrasound treatment at 30°C produced a higher yield than the one obtained by conventional maceration at 40°C. Kinetic study suggests that the extraction pattern can be assimilated, during the first ten minutes, to a first order steady state, from which activation energy calculations revealed that each gram of artemisinin required 7.38kJ in ultrasound versus 10.3kJ in the conventional system. Modeling results indicate the presence of two extraction stages, a faster stage with a diffusion coefficient of 19×10 -5 cm 2 min -1 for ultrasound technique at 40°C, seven times higher than the conventional one; and a second deceleration stage similar for both techniques with diffusion coefficient ranging from 1.7 to 3.1×10 -5 cm 2 min -1 . It is noted that the efficient ultrasound extraction potential implies extraction of higher amount of co-metabolites so low artemisinin crystal purity is engendered but a combination with a purification step using activated charcoal and celite adsorbents produced crystals with comparable purity for conventional and ultrasound samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Examining the extraction of artemisinin from artemisia annua using ultrasound

NASA Astrophysics Data System (ADS)

Briars, Rhianna; Paniwnyk, Larysa

2012-05-01

Artemisinin suppresses the life-cycle of the plasmodium parasite which causes malaria. It is found naturally occurring within the trichome glands of the Artemisia annua plant. Traditional methods for extracting artemisinin are time-consuming and have high environmental impact due to the temperatures and organic solvents which must be employed. Ultrasound decreases these through acoustic streaming and micro-jets. But to fully utilise this technology parameters, such as frequency, temperature and the properties of leaf and solvent, must be explored. As with the extraction process there is also no set analysis method for identification of artemisinin. Therefore several methods of analysing these extracts are employed. Initial results indicate that sonication is able to enhance levels of artemisinin extracted when compared to the conventional/traditional extraction process. In addition Thin Layer Chromatography (TLC) and High Performance Liquid Chromatography (HPLC) have been shown to have a high level of reproducible calibration.

The growth response of Artemisia annua L. to organic fertilizer type in lowland

NASA Astrophysics Data System (ADS)

Prasetyo, L.; Widyastuti, Y.; Yunus, A.; Samanhudi

2018-03-01

Artemisia annua L. is a medicinal plant known in long period of time. Artemisia annua has a drug content therein, the compound is artemisinin, these compounds are useful as anti-malarial compounds. Growth of Artemisia annua L. in normal conditions is on the plateau. Planting can be done in lowland, but there is a risk that must be faced. This study was conducted to evaluate the response of the growth of the plant Artemisia annua conducted in lowland. This research was conducted at the Laboratory Jumantono of the Faculty of Agriculture, University of Sebelas Maret Surakarta. Data were analyzed using analysis of variance and if there is a significant difference continued with Duncan Multiple Range Test (DMRT) level of 5%. The results showed that the application of goat manure has a positive effect on plant height by 201.9 cm, the number of branches by 57, 30.67 ml root volume and root length of 25 cm, and weight 12.4 grams interest.

Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria.

PubMed

Desrosiers, Matthew R; Weathers, Pamela J

2016-08-22

Artemisia annua L. produces the antimalarial sesquiterpene lactone, artemisinin (AN), and was traditionally used by the Chinese to treat fever, which was often caused by malaria. To measure effects of plant-based and dietary components on release of artemisinin and flavonoids from A. annua dried leaves (DLA) after simulated digestion. Simulated digestion was performed on DLA in four types of capsules, or in conjunction with protein, and protein-based foods: dry milk, casein, bovine serum albumin, peanuts, peanut butter, Plumpy'nut(®), and A. annua essential oils. Artemisinin and total flavonoids were measured in the liquid phase of the intestinal stage of digestion. After simulated digestion, peanuts and Plumpy'nut(®) lowered AN and flavonoids, respectively, recovered from the liquid digestate fraction. None of the compositions of the tested capsules altered AN or flavonoid release. Surprisingly, bovine serum albumin (BSA) increased both AN and flavonoids recovered from liquid simulated digestate fractions while casein had no effect. AN delivered as DLA was about 4 times more soluble in digestates than AN delivered as pure drug. Addition of a volume of essential oil equivalent to that found in a high essential oil producing A. annua cultivar also significantly increased AN solubility in simulated digestates. These results indicate encapsulating DLA may provide a way to mask the taste of A. annua without altering bioavailability. Similarly, many peanut-based products can be used to mask the flavor with appropriate dosing. Finally, the essential oil fraction of A. annua contributes to the increased AN solubility in DLA after simulated digestion. Our results suggest that use of DLA in the treatment of malaria and other artemisinin-susceptible diseases should be further tested in animals and humans. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prolonged exposure to salt stress affects specialized metabolites-artemisinin and essential oil accumulation in Artemisia annua L.: metabolic acclimation in preferential favour of enhanced terpenoid accumulation accompanying vegetative to reproductive phase transition.

PubMed

Yadav, Ritesh Kumar; Sangwan, Rajender Singh; Srivastava, Avadesh K; Sangwan, Neelam S

2017-01-01

Artemisia annua accumulates substantial quantities of unique and highly useful antimalarial sesquiternoid artemisinin and related phytomolecules as well as its characteristic essential oil in its glandular trichomes. The phytomolecules are mainly produced in its leaves and inflorescences. Artemisia annua plants were grown under NaCl salinity (50, 100 and 200 mM) stress conditions imposed throughout the entire life cycle of the plant. Results revealed that specialized metabolites like artemisinin, arteannuin-B, artemisinic acid + dihydroartemisinic acid and essential oil accumulation were positively modulated by NaCl salinity stress. Interestingly, total content of monoterpenoids and sesquiterpenoids of essential oil was induced by NaCl salinity treatment, contrary to previous observations. Production of camphor, the major essential oil constituent was induced under the influence of treatment. The metabolic acclimation and manifestations specific to terpenoid pathway are analysed vis-a-vis vegetative to reproductive periods and control of the modulation. WRKY and CYP71AV1 play a key role in mediating the responses through metabolism in glandular trichomes. The distinctness of the salinity induced responses is discussed in light of differential mechanism of adaptation to abiotic stresses and their impact on terpenoid-specific metabolic adjustments in A. annua. Results provide potential indications of possible adaptation of A. annua under saline conditions for agrarian techno-economic benefaction.

The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives.

PubMed

van der Kooy, Frank; Sullivan, Shaun Edward

2013-10-28

Artemisia annua has a long tradition of use for the treatment of intermittent fevers which we now relate to malarial infections. The active principle artemisinin has been isolated from Artemisia annua and today forms the backbone of the global fight against malaria. The traditionally prepared Artemisia annua formulation is however still being used on a global scale for the treatment of malaria, and it is claimed that its action is superior to the single purified drug. Artemisia annua is therefore on the forefront of the heated debate between the single drug-single target approach of western based medicine and the holistic approach of traditional medicinal systems. This review aims to highlight the complexities we face in the general study of medicinal plants at the hand of three levels of complexity. These levels consist of (a) the chemistry of the medicinal plant, (b) the influence of the preparation method on the chemistry of the final formulation and (c) the influence of metabolism on the chemistry of the formulation. We also aim to provide an up-to-date report on all scientific work that has been conducted and published in English on the traditional formulation of Artemisia annua. All English scientific literatures published until the first quarter of 2013 were retrieved from well-known scientific databases (Scifinder scholar, Web of Science, PubMed, Google scholar) and Non-governmental organisations active in this field were consulted. A draft version of this manuscript was sent to the African office of the World Health Organisation (WHO), and to the Non-governmental organisations "Action Médicine Naturelle" (ANAMED) and "Iwerliewen fir bedreete Volleker - Réseau belgo-luxembourgeois pour la valorisation des herbes médicinales" (IFBV-BELHERB) for comments. Very little scientific work has been conducted on the Artemisia annua formulation. The available literature contains many discrepancies which are unfortunately selectively being used by the two different sides in this debate to further their arguments. On one side of the argument we have the low content of artemisinin in Artemisia annua, the low bioavailability of artemisinin when the traditional formulation is administered and the high levels of recrudescence, which are being emphasised, while on the other side the possible role of synergism and prodrugs are being highlighted. This review reports that there are still too many gaps in our existing knowledge to provide conclusive evidence for either of the two sides of the argument. Much more research is needed into Artemisia annua formulations. We stand to gain invaluable knowledge into how traditional medicinal plant works, discover the identities of new active compounds (which can be used against other diseases such as HIV, diarrhoea, and cancer) and possibly bring both sides of this debate closer together. © 2013 Elsevier Ireland Ltd. All rights reserved.

Strategies to enhance biologically active-secondary metabolites in cell cultures of Artemisia - current trends.

PubMed

Ali, Mohammad; Abbasi, Bilal Haider; Ahmad, Nisar; Khan, Haji; Ali, Gul Shad

2017-11-01

The genus Artemisia has been utilized worldwide due to its immense potential for protection against various diseases, especially malaria. Artemisia absinthium, previously renowned for its utilization in the popular beverage absinthe, is gaining resurgence due to its extensive pharmacological activities. Like A. annua, this species exhibits strong biological activities like antimalarial, anticancer and antioxidant. Although artemisinin was found to be the major metabolite for its antimalarial effects, several flavonoids and terpenoids are considered to possess biological activities when used alone and also to synergistically boost the bioavailability of artemisinin. However, due to the limited quantities of these metabolites in wild plants, in vitro cultures were established and strategies have been adopted to enhance medicinally important secondary metabolites in these cultures. This review elaborates on the traditional medicinal uses of Artemisia species and explains current trends to establish cell cultures of A. annua and A. absinthium for enhanced production of medicinally important secondary metabolites.

A basic leucine zipper transcription factor, AabZIP1, connects abscisic acid signaling with artemisinin biosynthesis in Artemisia annua.

PubMed

Zhang, Fangyuan; Fu, Xueqing; Lv, Zongyou; Lu, Xu; Shen, Qian; Zhang, Ling; Zhu, Mengmeng; Wang, Guofeng; Sun, Xiaofen; Liao, Zhihua; Tang, Kexuan

2015-01-01

Artemisinin is a sesquiterpenoid especially synthesized in the Chinese herbal plant, Artemisia annua, which is widely used in the treatment of malaria. Artemisinin accumulation can be enhanced by exogenous abscisic acid (ABA) treatment. However, it is not known how ABA signaling regulates artemisinin biosynthesis. A global expression profile and phylogenetic analysis as well as the dual-LUC screening revealed that a basic leucine zipper family transcription factor from A. annua (namely AabZIP1) was involved in ABA signaling to regulate artemisinin biosynthesis. AabZIP1 had a higher expression level in the inflorescences than in other tissues; ABA treatment, drought, and salt stress strongly induced the expression of AabZIP1. Yeast one-hybrid assay and electrophoretic mobility shift assay (EMSA) showed that AabZIP1 bound to the ABA-responsive elements (ABRE) in the promoter regions of the amorpha-4,11-diene synthase (ADS) gene and CYP71AV1, which are two key structural genes of the artemisinin biosynthetic pathway. A mutagenesis assay showed that the C1 domain in the N-terminus of AabZIP1 was important for its transactivation activity. Furthermore, the activation of ADS and CYP71AV1 promoters by AabZIP1 was enhanced by ABA treatment in transient dual-LUC analysis. The AabZIP1 variant with C1 domain deletion lost the ability to activate ADS and CYP71AV1 promoters regardless of ABA treatment. Notably, overexpression of AabZIP1 in A. annua resulted in significantly increased accumulation of artemisinin. Our results indicate that ABA promotes artemisinin biosynthesis, likely through 1 activation of ADS and CYP71AV1 expression by AabZIP in A. annua. Meanwhile, our findings reveal the potential value of AabZIP1 in genetic engineering of artemisinin production. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

Artemisinin-based antimalarial research: application of biotechnology to the production of artemisinin, its mode of action, and the mechanism of resistance of Plasmodium parasites.

PubMed

Muangphrom, Paskorn; Seki, Hikaru; Fukushima, Ery Odette; Muranaka, Toshiya

2016-07-01

Malaria is a worldwide disease caused by Plasmodium parasites. A sesquiterpene endoperoxide artemisinin isolated from Artemisia annua was discovered and has been accepted for its use in artemisinin-based combinatorial therapies, as the most effective current antimalarial treatment. However, the quantity of this compound produced from the A. annua plant is very low, and the availability of artemisinin is insufficient to treat all infected patients. In addition, the emergence of artemisinin-resistant Plasmodium has been reported recently. Several techniques have been applied to enhance artemisinin availability, and studies related to its mode of action and the mechanism of resistance of malaria-causing parasites are ongoing. In this review, we summarize the application of modern technologies to improve the production of artemisinin, including our ongoing research on artemisinin biosynthetic genes in other Artemisia species. The current understanding of the mode of action of artemisinin as well as the mechanism of resistance against this compound in Plasmodium parasites is also presented. Finally, the current situation of malaria infection and the future direction of antimalarial drug development are discussed.

Antioxidant Properties of Artemisia annua Extracts in Model Food Emulsions

PubMed Central

Skowyra, Monika; Gallego, Maria Gabriela; Segovia, Francisco; Almajano, Maria Pilar

2014-01-01

Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin. Although artemisinin is a major bioactive component present in this Chinese herb, leaf flavonoids have shown a variety of biological activities. The polyphenolic profile of extract from leaves of A. annua was assessed as a source of natural antioxidants. Total phenolic content and total flavonoid content were established and three assays were used to measure the antioxidant capacity of the plant extract. The measurement of scavenging capacity against the 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation, the oxygen radical absorbance capacity (ORAC) and the ferric reducing antioxidant power (FRAP) were 314.99 µM Trolox equivalents (TE)/g DW, 736.26 µM TE/g DW and 212.18 µM TE/g DW, respectively. A. annua extracts also showed good antioxidant properties in 10% sunflower oil-in-water emulsions during prolonged storage (45 days) at 32 °C. Artemisia extract at 2 g/L was as effective as butylated hydroxyanisole (BHA) at 0.02 g/L in slowing down the formation of hydroperoxides as measured by peroxide value and thiobarbituric acid reactive substances. The results of this study indicate that extract of A. annua may be suitable for use in the food matrix as substitutes for synthetic antioxidants. PMID:26784667

[Extraction of artemisinin and synthesis of its derivates artesunate and artemether].

PubMed

Chekem, L; Wierucki, S

2006-12-01

Artemisinin is extracted from Artemisia annua, a shrub also known as sweet wormwood that was used in traditional medicine in Asia for more than 1500 years. Recent studies in numerous malarious zones have demonstrated the effectiveness of artemisinin and have reported no evidence of the resistance now associated with almost all other antimalarials on the market. Despite its remarkable activity, artermisinin is not accessible to many patients due to high cost. This situation confronts all players in the fight against malaria with the urgent need to develop a simple process to produce massive supplies of artemisinin and its derivative at an affordable price. The purpose of the study described here was to develop a simple, cost-effective method that could be used by all professionals to extract artemisinin and transform it into artesunate or artemether. Artemisinin was extracted with dichloromethane and purified on the basis of variations in polarity and in the hydrophile/lipophile balance of solvents. Transformation into artesunate was a two-step process involving reduction to dihydroartemisinin using diisobutylaluminium hydride (DIBAL) followed by esterification using succinic anhydride. Artemether was obtained from dihydroartemisinin using boron trifluoride. Extraction using dichloromethane presents several advantages. Since dichloromethane is not explosive it can be safely transported and used for extraction on farms where Artemisia annua is grown. Evaporation and recovery of dichloromethane is relatively easy so that it can be re-used. These advantages result in a significant decrease in purchasing and shipping costs. Extraction on the farm eliminates the expense and facilities that would otherwise be required to transport and store leaves at the laboratory (250 kg of leaves yield 4 to 5 kg of raw artemisinin extract that yields approximately 1 kg of pure artemisinin). The low-cost process described here is feasible for any pharmaceutical laboratory including those in developing countries.

Anti-Plasmodial Polyvalent Interactions in Artemisia annua L. Aqueous Extract – Possible Synergistic and Resistance Mechanisms

PubMed Central

Suberu, John O.; Gorka, Alexander P.; Jacobs, Lauren; Roepe, Paul D.; Sullivan, Neil

2013-01-01

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L-1), dihydroartemisinic acid (70.0±0.3 mg L-1), arteannuin B (1.3±0.0 mg L-1), isovitexin (105.0±7.2 mg L-1) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B’s potentiation of artemisinin. PMID:24244716

Simulated Digestion of Dried Leaves of Artemisia annua Consumed as a Treatment (pACT) for Malaria

PubMed Central

Weathers, Pamela J.; Jordan, Nikole; Lasin, Praphapan; Towler, Melissa J.

2014-01-01

Ethnopharmacological Relevance Artemisinin (AN) is produced by Artemisia annua, a medicinal herb long used as a tea infusion in traditional Chinese medicine to treat fever; it is also the key ingredient in current artemisinin-based combination therapies (ACTs) effective in treating malaria. Recently we showed that dried leaves from the whole plant A. annua that produces artemisinin and contains artemisinin-synergistic flavonoids seems to be more effective and less costly than ACT oral malaria therapy; however little is known about how digestion affects release of artemisinin and flavonoids from dried leaves. Material and Methods In the current study we used a simulated digestion system to determine how artemisinin and flavonoids are released prior to absorption into the bloodstream. Various delivery methods and staple foods were combined with dried leaves for digestion in order to investigate their impact on the bioavailability of artemisinin and flavonoids. Digestate was recovered at the end of the oral, gastric, and intestinal stages, separated into solid and liquid fractions, and extracted for measurement of artemisinin and total flavonoids. Results Compared to unencapsulated digested dried leaves, addition of sucrose, various cooking oils, and rice did not reduce the amount of artemisinin released in the intestinal liquid fraction, but the amount of released flavonoids nearly doubled. When dried leaves were encapsulated into either hydroxymethylcellulose or gelatin capsules, there was >50% decrease in released artemisinin but no change in released flavonoids. In the presence of millet or corn meal, the amount of released artemisinin declined, but there was no change in released flavonoids. Use of a mutant A. annua lacking artemisinin showed that the plant matrix is critical in determining how artemisinin is affected during the digestion process. Conclusions This study provides evidence showing how both artemisinin and flavonoids are affected by digestion and dietary components for an orally consumed plant delivered therapeutic and that artemisinin delivered via dried leaves would likely be more bioavailable if provided as a tablet instead of in a capsule. PMID:24316176

A phylogenetic road map to antimalarial Artemisia species.

PubMed

Pellicer, Jaume; Saslis-Lagoudakis, C Haris; Carrió, Esperança; Ernst, Madeleine; Garnatje, Teresa; Grace, Olwen M; Gras, Airy; Mumbrú, Màrius; Vallès, Joan; Vitales, Daniel; Rønsted, Nina

2018-06-21

The discovery of the antimalarial agent artemisinin is considered one of the most significant success stories of ethnopharmacological research in recent times. The isolation of artemisinin was inspired by the use of Artemisia annua in traditional Chinese medicine (TCM) and was awarded a Nobel Prize in 2015. Antimalarial activity has since been demonstrated for a range of other Artemisia species, suggesting that the genus could provide alternative sources of antimalarial treatments. Given the stunning diversity of the genus (c. 500 species), a prioritisation of taxa to be investigated for their likely antimalarial properties is required. Here we use a phylogenetic approach to explore the potential for identifying species more likely to possess antimalarial properties. Ethnobotanical data from literature reports is recorded for 117 species. Subsequent phylogenetically informed analysis was used to identify lineages in which there is an overrepresentation of species used to treat malarial symptoms, and which could therefore be high priority for further investigation of antimalarial activity. We show that these lineages indeed include several species with documented antimalarial activity. To further inform our approach, we use LC-MS/MS analysis to explore artemisinin content in fifteen species from both highlighted and not highlighted lineages. We detected artemisinin in nine species, in eight of them for the first time, doubling the number of Artemisia taxa known to content this molecule. Our findings indicate that artemisinin may be widespread across the genus, providing an accessible local resource outside the distribution area of Artemisia annua. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Effect aquadest-extracted Gloriosa superba seed as mutagen on morphology of Artemisia annua

NASA Astrophysics Data System (ADS)

Rahmawati, S. I.; Susilowati, A.; Yunus, A.; Widyastuti, Y.

2018-03-01

Gloriosa superba is a plant that contains colchicine in all parts of organs, especially in the seeds. Its extract is as a mutagen to produce plants with polyploid cells. Artemisia annua is a plant that produces active ingredients artemisinin as malarial drugs, hemorrhoids therapy, aromatherapy, antiviral, anticancer, and anti-bacterial. The aims of this research was to determine the effect aquadest-extracted Gloriosa superba seed as a mutagen to Artemisia annua morphology. Extraction of Gloriosa superba seeds obtained from Sukoharjo using maceration method with aquadest solvent (1: 1). The extracts were diluted (0, 25, 50, 75 and 100%) for Artemisia annua sprinkling with different times (0, 30, 60 and 90 minutes). Observations of morphology Artemisia annua included height, stem circumference, number of branches, number of leaves, leaf width and leaf length. The treatments did not affect plant morphology observation included height, stem circumference, number of branches, number of leaves, leaf width, and leaf length. The EB treatment (100%, 30 minutes) was higher (120 cm) than other. In all treatments stem circumference about 2.5 cm, number of branches ranged between 40-50, leaves width ranged 9-16c m, and leaf length ranged 8-15 cm.

Changes in key constituents of clonally propagated Artemisia annua L. during preparation of compressed leaf tablets for possible therapeutic use

PubMed Central

Weathers, Pamela J.; Towler, Melissa J.

2014-01-01

Artemisia annua L., long used as a tea infusion in traditional Chinese medicine, produces artemisinin. Although artemisinin is currently used as artemisinin-based combination therapy (ACT) against malaria, oral consumption of dried leaves from the plant showed efficacy and will be less costly than ACT. Many compounds in the plant have some antimalarial activity. Unknown, however, is how these plant components change as leaves are processed into tablets for oral consumption. Here we compared extracts from fresh and dried leaf biomass with compressed leaf tablets of A. annua. Using GC-MS, nineteen endogenous compounds, including artemisinin and several of its pathway metabolites, nine flavonoids, three monoterpenes, a coumarin, and two phenolic acids, were identified and quantified from solvent extracts to determine how levels of these compounds changed during processing. Results showed that compared to dried leaves, artemisinin, arteannuin B, artemisinic acid, chlorogenic acid, scopoletin, chrysoplenetin, and quercetin increased or remained stable with powdering and compression into tablets. Dihydroartemisinic acid, monoterpenes, and chrysoplenol-D decreased with tablet formation. Five target compounds were not detectable in any of the extracts of this cultivar. In contrast to the individually measured aglycone flavonoids, using the AlCl3 method, total flavonoids increased nearly fivefold during the tablet formation. To our knowledge this is the first study documenting changes that occurred in processing dried leaves of A. annua into tablets. These results will improve our understanding of the potential use of not only this medicinal herb, but also others to afford better quality control of intact plant material for therapeutic use. PMID:25228784

Transcriptome Analysis of Genes Associated with the Artemisinin Biosynthesis by Jasmonic Acid Treatment under the Light in Artemisia annua

PubMed Central

Hao, Xiaolong; Zhong, Yijun; Fu, Xueqing; Lv, Zongyou; Shen, Qian; Yan, Tingxiang; Shi, Pu; Ma, Yanan; Chen, Minghui; Lv, Xueying; Wu, Zhangkuanyu; Zhao, Jingya; Sun, Xiaofen; Li, Ling; Tang, Kexuan

2017-01-01

Artemisinin is a sesquiterpene lactone endoperoxide extracted from a traditional Chinese medicinal plant Artemisia annua. Artemisinin-based combination therapies (ACTs) are recommended as the best treatment of malaria by the World Health Organization (WHO). Both the phytohormone jasmonic acid (JA) and light promote artemisinin biosynthesis in A. annua. Interestingly, we found that the increase of artemisinin biosynthesis by JA was dependent on light. However, the relationship between the two signal pathways mediated by JA and light remains unclear. Here, we collected the A. annua seedlings of 24 h continuous light (Light), 24 h dark treatment (Dark), 4 h MeJA treatment under the continuous light conditions (Light-MeJA-4h) and 4 h MeJA treatment under the dark conditions (Dark-MeJA-4h) and performed the transcriptome sequencing using Illumina HiSeq 4000 System. A total of 266.7 million clean data were produced and assembled into 185,653 unigenes, with an average length of 537 bp. Among them, 59,490 unigenes were annotated and classified based on the public information. Differential expression analyses were performed between Light and Dark, Light and Light-MeJA-4h, Dark and Dark-MeJA-4h, Light-MeJA-4h, and Dark-MeJA-4h, respectively. Furthermore, transcription factor (TF) analysis revealed that 1588 TFs were identified and divided into 55 TF families, with 284 TFs down-regulated in the Dark relative to Light and 96 TFs up-regulated in the Light-MeJA-4h relative to Light. 8 TFs were selected as candidates for regulating the artemisinin biosynthesis and one of them was validated to be involved in artemisinin transcriptional regulation by Dual-Luciferase (Dual-LUC) assay. The transcriptome data shown in our study offered a comprehensive transcriptional expression pattern influenced by the MeJA and light in A. annua seedling, which will serve as a valuable resource for further studies on transcriptional regulation mechanisms underlying artemisinin biosynthesis. PMID:28642777

Artemisinin production by plant hairy root cultures in gas- and liquid-phase bioreactors.

PubMed

Patra, Nivedita; Srivastava, Ashok K

2016-01-01

Alternative biotechnological protocol for large-scale artemisinin production was established. It featured enhanced growth and artemisinin production by cultivation of hairy roots in nutrient mist bioreactor (NMB) coupled with novel cultivation strategies. Artemisinin is used for the treatment of cerebral malaria. Presently, its main source is from seasonal plant Artemisia annua. This study featured investigation of growth and artemisinin production by A. annua hairy roots (induced by Agrobacterium rhizogenes-mediated genetic transformation of explants) in three bioreactor configurations-bubble column reactor, NMB and modified NMB particularly to establish their suitability for commercial production. It was observed that cultivation of hairy roots in a non-stirred bubble column reactor exhibited a biomass accumulation of 5.68 g/l only while batch cultivation in a custom-made NMB exhibited a higher biomass concentration of 8.52 g/l but relatively lower artemisinin accumulation of 0.22 mg/g was observed in this reactor. A mixture of submerged liquid-phase growth (for 5 days) followed by gas-phase cultivation in nutrient mist reactor operation strategy (for next 15 days) was adopted for hairy root cultivation in this investigation. Reasonably, high (23.02 g/l) final dry weight along with the artemisinin accumulation (1.12 mg/g, equivalent to 25.78 mg/l artemisinin) was obtained in this bioreactor, which is the highest reported artemisinin yield in the gas-phase NMB cultivation.

Artemisia annua dried leaf tablets treated malaria resistant to ACT and i.v. artesunate: Case reports.

PubMed

Daddy, Nsengiyumva Bati; Kalisya, Luc Malemo; Bagire, Pascal Gisenya; Watt, Robert L; Towler, Melissa J; Weathers, Pamela J

2017-08-15

Dried leaf Artemisia annua (DLA) has shown efficacy against Plasmodium sp. in rodent studies and in small clinical trials. Rodent malaria also showed resiliency against the evolution of artemisinin drug resistance. This is a case report of a last resort treatment of patients with severe malaria who were responding neither to artemisinin combination therapy (ACT) nor i.v. artesunate. Of many patients treated with ACTs and i.v. artesunate during the 6 mon study period, 18 did not respond and were subsequently treated with DLA Artemisia annua. Patients were given a dose of 0.5g DLA per os, twice daily for 5d. Total adult delivered dose of artemisinin was 55mg. Dose was reduced for body weight under 30kg. Clinical symptoms, e.g. fever, coma etc., and parasite levels in thick blood smears were tracked. Patients were declared cured and released from hospital when parasites were microscopically undetectable and clinical symptoms fully subsided. All patients were previously treated with Coartem® provided through Santé Rurale (SANRU) and following the regimen prescribed by WHO. Of 18 ACT-resistant severe malaria cases compassionately treated with DLA, all fully recovered. Of the 18, this report details two pediatric cases. Successful treatment of all 18 ACT-resistant cases suggests that DLA should be rapidly incorporated into the antimalarial regimen for Africa and possibly wherever else ACT resistance has emerged. Copyright © 2017. Published by Elsevier GmbH.

Isolation of dihydroatemisinic acid from the artemisia annua l. by-product by combining Ultrasound-assisted extraction with response surface methodology

USDA-ARS?s Scientific Manuscript database

Malaria is one of the world’s most important parasitic diseases, affecting 300-500 million people worldwide and killing more than one million per year. Artemisinin is currently the only raw material for the production of artemisinin combination therapies (ACT), the only medicine that cures drug-resi...

Literally Green Chemical Synthesis of Artemisinin from Plant Extracts.

PubMed

Triemer, Susann; Gilmore, Kerry; Vu, Giang T; Seeberger, Peter H; Seidel-Morgenstern, Andreas

2018-05-04

Active pharmaceutical ingredients are either extracted from biological sources-where they are synthesized in complex, dynamic environments-or prepared in stepwise chemical syntheses by reacting pure reagents and catalysts under controlled conditions. A combination of these two approaches, where plant extracts containing reagents and catalysts are utilized in intensified chemical syntheses, creates expedient and sustainable processes. We illustrate this principle by reacting crude plant extract, oxygen, acid, and light to produce artemisinin, a key active pharmaceutical ingredient of the most powerful antimalarial drugs. The traditionally discarded extract of Artemisia annua plants contains dihydroartemisinic acid-the final biosynthetic precursor-as well as chlorophyll, which acts as a photosensitizer. Efficient irradiation with visible light in a continuous-flow setup produces artemisinin in high yield, and the artificial biosynthetic process outperforms syntheses with pure reagents. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Adaption and agronomic performance of Artemisia annua L. under lowland humid tropical conditions

USDA-ARS?s Scientific Manuscript database

Demand for new chemotherapies against malaria is increasing as Plasmodium, the causative organism of the disease, has shown a high degree of resistance against most standard anti-malarial drugs. One the few highly effective compounds is artemisinin, the major sesquiterpene for the production of art...

Degradation and ecotoxicity of the biomedical drug artemisinin in soil.

PubMed

Jessing, Karina K; Cedergreen, Nina; Jensen, John; Hansen, Hans C B

2009-04-01

The plant Artemisia annua L. is cropped in many countries for production of the antimalarial drug artemisinin. Artemisinin is phytotoxic and has insecticidal activity. Large-scale cultivation of A. annua may cause transfer of artemisinin to soil and, hence, may affect both soil organisms and the aquatic environment if the compound is leachable. In the present study, a new method for extraction of artemisinin from soil was developed, and field concentrations and degradation kinetics of artemisinin in sandy and loamy soils were measured. The soil concentrations in a Danish A. annua field were up to 11.7 mg/kg. The degradation kinetics could be modeled as the sum of two first-order reactions, a fast initial degradation followed by a reaction that was 11- to 25-fold slower. It took at least 35 d before artemisinin could not be detected (<0.36 mg/kg) at 20 degrees C, classifying artemisinin as being relatively persistent in the environment. Combined with its water solubility of 49.7 +/- 3.7 mg/L, this makes it potentially leachable. In soil, artemisinin repelled the earthworm (Eisenia fetida; the 10 and 50% effect concentrations [EC10s and EC50s, respectively] were 5.24 +/- 2.64 and 21.57 +/- 4.73 mg/kg, respectively) and inhibited growth of lettuce (Lactuca sativa L.; EC50, 2.48 mg/kg). Springtails (Folsomia candida) were not affected in the tested concentration range of 1 to 100 mg/kg. Artemisinin had toxicity to the freshwater algae (Pseudokirchneriella subcapitata; EC50, 0.24 +/- 0.01 mg/L) and duckweed (Lemna minor; EC50, 0.19 +/- 0.03 mg/L) similar to that of the commercial herbicide atrazine. Based on the presented data, the risks of adverse environmental effects because of cultivation of A. annua are high and comparable to those when using commercial pesticides.

Differences in chemical constituents of Artemisia annua L from different geographical regions in China.

PubMed

Zhang, Xiaobo; Zhao, Yuping; Guo, Lanping; Qiu, Zhidong; Huang, Luqi; Qu, Xiaobo

2017-01-01

Daodi-herb is a part of Chinese culture, which has been naturally selected by traditional Chinese medicine clinical practice for many years. Sweet wormwood herb is a kind of Daodi-herb, and comes from Artemisia annua L. Artemisinin is a kind of effective antimalarial drug being extracted from A. annua. Because of artemisinin, Sweet wormwood herb earns a reputation. Based on the Pharmacopoeia of the People's Republic of China (PPRC), Sweet wormwood herb can be used to resolve summerheat-heat, and prevent malaria. Besides, it also has other medical efficacies. A. annua, a medicinal plant that is widely distributed in the world contains many kinds of chemical composition. Research has shown that compatibility of artemisinin, scopoletin, arteannuin B and arteannuic acid has antimalarial effect. Compatibility of scopoletin, arteannuin B and arteannuic acid is conducive to resolving summerheat-heat. Chemical constituents in A. annua vary significantly according to geographical locations. So, distribution of A. annua may play a key role in the characteristics of efficacy and chemical constituents of Sweet wormwood herb. It is of great significance to study this relationship. We mainly analyzed the relationship between the chemical constituents (arteannuin B, artemisinin, artemisinic acid, and scopoletin) with special efficacy in A. annua that come from different provinces in china, and analyzed the relationship between chemical constituents and spatial distribution, in order to find out the relationship between efficacy, chemical constituents and distribution. A field survey was carried out to collect A. annua plant samples. A global positioning system (GPS) was used for obtaining geographical coordinates of sampling sites. Chemical constituents in A. annua were determined by liquid chromatography tandem an atmospheric pressure ionization-electrospray mass spectrometry. Relationship between chemical constituents including proportions, correlation analysis (CoA), principal component analysis (PCA) and cluster analysis (ClA) was displayed through Excel and R software version2.3.2(R), while the one between efficacy, chemical constituents and spatial distribution was presented through ArcGIS10.0, Excel and R software. According to the results of CoA, arteannuin B content presented a strong positive correlation with artemisinic acid content (p = 0), and a strong negative correlation with artemisinin content (p = 0). Scopoletin content presented a strong positive correlation with artemisinin content (p = 0), and a strong negative correlation with artemisinic acid content (p = 0). According to the results of PCA, the first two principal components accounted for 81.57% of the total accumulation contribution rate. The contribution of the first principal component is about 45.12%, manly including arteannuin B and artemisinic acid. The contribution of the second principal component is 36.45% of the total, manly including artemisinin and scopoletin. According to the ClA by using the principal component scores, 19 provinces could be divided into two groups. In terms of provinces in group one, the proportions of artemisinin are all higher than 80%. Based on the results of PCA, ClA, percentages and scatter plot analysis, chemical types are defined as "QHYS type", "INT type" and "QHS type." As a conclusion, this paper shows the relationship between efficacy, chemical constituents and distribution. Sweet wormwood herb with high arteannuin B and artemisinic acid content, mainly distributes in northern China. Sweet wormwood herb with high artemisinin and scopoletin content has the medical function of preventing malaria, which mainly distributes in southern China. In this paper, it is proved that Sweet wormwood Daodi herb growing in particular geographic regions, has more significant therapeutical effect and higher chemical constituents compared with other same kind of CMM. And also, it has proved the old saying in China that Sweet wormwood Daodi herb which has been used to resolve summerheat-heat and prevent malaria, which distributed in central China. But in modern time, Daodi Sweet wormwood herb mainly has been used to extract artemisinin and prevent malaria, so the Daod-region has transferred to the southern China.

Anthelmintic activity of Artemisia annua L. extracts in vitro and the effect of an aqueous extract and artemisinin in sheep naturally infected with gastrointestinal nematodes

USDA-ARS?s Scientific Manuscript database

There is no effective natural alternative control for gastrointestinal nematodes (GIN) of small ruminants, with Haemonchus contortus being the most economically important GIN. Despite frequent reports of multidrug-resistant GIN, there is no new commercial anthelmintic to substitute failing ones. Alt...

Artemisinin reduces cell proliferation and induces apoptosis in neuroblastoma.

PubMed

Zhu, Shunqin; Liu, Wanhong; Ke, Xiaoxue; Li, Jifu; Hu, Renjian; Cui, Hongjuan; Song, Guanbin

2014-09-01

Artemisinin, a natural product from the Chinese medicinal plant, Artemisia annua L., is commonly used in the treatment of malaria, and has recently been reported to have potent anticancer activity in various types of human tumors. Yet, the effect of artemisinin on neuroblastoma is still unclear. In the present study, we aimed to investigate the effects of artemisinin on neuroblastoma cells. We observed that artemisinin significantly inhibited cell growth and proliferation, and caused cell cycle arrest in the G1 phase in neuroblastoma cell lines. Annexin V-FITC/PI staining assay revealed that artemisinin markedly induced apoptosis. Soft agar assays revealed that artemisinin suppressed the ability of clonogenic formation of neuroblastoma cells and a xenograft study in NOD/SCID mice showed that artemisinin inhibited tumor growth and development in vivo. Therefore, our results suggest that the Chinese medicine artemisinin could serve as a novel potential therapeutic agent in the treatment of neuroblastoma.

Effect of mineral nutrition, growth regulators, and environmental stresses on biomass production and artemisinin concentration of Artemisia annua (L.)

USDA-ARS?s Scientific Manuscript database

Malaria is a mosquito-borne disease caused by different species of Plasmodium. It is the world’s most severe parasitic infection and kills almost two million people a year, afflicting more than one-third of the global population. The burden of malaria has increased by the worldwide spread of multi-d...

Investigation of the component in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin via regulation of its metabolism.

PubMed

Cai, Tian-Yu; Zhang, Yun-Rui; Ji, Jian-Bo; Xing, Jie

2017-07-31

The chemical matrix of the herb Artemisia annua L. (A. annua), from which artemisinin (QHS) is isolated, can enhance both the bioavailability and efficacy of QHS. However, the exact mechanism of this synergism remains unknown. The biotransformation of QHS and potential "enzyme inhibitors" in plant matrix could be of great importance in understanding the improved efficacy of QHS in A. annua, which has been limited to the synergism with flavonoid components. To investigate the component in A. annua extracts (MAE) leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The efficacy of QHS in combination with the synergistic component was also evaluated. The total MAE extract and its three MAE fractions (MAE-I eluted using 3% methanol, MAE-II eluted using 50% methanol and MAE-III eluted using 85% methanol) were obtained from dry plant materials and prepared after lyophilization. The pharmacokinetic profiles of QHS and its major phase I metabolite monohydroxylated artemisinin (QHS-M) were investigated in healthy rats after a single oral administration of QHS in each MAE extract. Major components isolated from the target MAE fraction were evaluated for their enzyme inhibition. The antimalarial activity of QHS in combination with the potential synergistic component against Plasmodium falciparum was studied in vivo (murine Plasmodium yoelii). The recrudescence and survival time of infected mice were also recorded after drug treatment. Compared to pure QHS, a 2-fold increase in QHS exposure (AUC and C max ) was found in healthy rats after a single oral dose of QHS in the total MAE extract or its fraction MAE-III. In addition, metabolic biotransformation of QHS to the metabolite QHS-M (mediated by CYP3A) was inhibited by MAE or MAE-III. Among nine major components isolated from MAE-III (five sesquiterpenenes, three flavonoids and one phenolic acid), only arteannuin B (AB) showed an inhibition of CYP3A4 (IC 50 1.2μM). The synergism between QHS and AB was supported using in vivo antiplasmodial assay and a pharmacokinetic study in mice. Unfortunately, the synergism cannot reduce the rate of recrudescence. AB was one of main contributors in A. annua leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The final recrudescence indicated the careful use of A. annua for malaria treatment unless additional contributing components or antiplasmodial mechanism were found. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Comparative cytotoxicity of artemisinin and cisplatin and their interactions with chlorogenic acids in MCF7 breast cancer cells.

PubMed

Suberu, John O; Romero-Canelón, Isolda; Sullivan, Neil; Lapkin, Alexei A; Barker, Guy C

2014-12-01

In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5-fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity. © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Isoprenoid drugs, biofuels, and chemicals--artemisinin, farnesene, and beyond.

PubMed

George, Kevin W; Alonso-Gutierrez, Jorge; Keasling, Jay D; Lee, Taek Soon

2015-01-01

Isoprenoids have been identified and used as natural pharmaceuticals, fragrances, solvents, and, more recently, advanced biofuels. Although isoprenoids are most commonly found in plants, researchers have successfully engineered both the eukaryotic and prokaryotic isoprenoid biosynthetic pathways to produce these valuable chemicals in microorganisms at high yields. The microbial synthesis of the precursor to artemisinin--an important antimalarial drug produced from the sweet wormwood Artemisia annua--serves as perhaps the most successful example of this approach. Through advances in synthetic biology and metabolic engineering, microbial-derived semisynthetic artemisinin may soon replace plant-derived artemisinin as the primary source of this valuable pharmaceutical. The richness and diversity of isoprenoid structures also make them ideal candidates for advanced biofuels that may act as "drop-in" replacements for gasoline, diesel, and jet fuel. Indeed, the sesquiterpenes farnesene and bisabolene, monoterpenes pinene and limonene, and hemiterpenes isopentenol and isopentanol have been evaluated as fuels or fuel precursors. As in the artemisinin project, these isoprenoids have been produced microbially through synthetic biology and metabolic engineering efforts. Here, we provide a brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels. In each case, we highlight the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts. In addition, we present a current outlook on microbial isoprenoid production, with an eye towards the many challenges that must be addressed to achieve higher yields and industrial-scale production.

Development of the protocol for purification of artemisinin based on combination of commercial and computationally designed adsorbents.

PubMed

Piletska, Elena V; Karim, Kal; Cutler, Malcolm; Piletsky, Sergey A

2013-01-01

A polymeric adsorbent for extraction of the antimalarial drug artemisinin from Artemisia annua L. was computationally designed. This polymer demonstrated a high capacity for artemisinin (120 mg g(-1) ), quantitative recovery (87%) and was found to be an effective material for purification of artemisinin from complex plant matrix. The artemisinin quantification was conducted using an optimised HPLC-MS protocol, which was characterised by high precision and linearity in the concentration range between 0.05 and 2 μg mL(-1) . Optimisation of the purification protocol also involved screening of commercial adsorbents for the removal of waxes and other interfering natural compounds, which inhibit the crystallisation of artemisinin. As a result of a two step-purification protocol crystals of artemisinin were obtained, and artemisinin purity was evaluated as 75%. By performing the second stage of purification twice, the purity of artemisinin can be further improved to 99%. The developed protocol produced high-purity artemisinin using only a few purification steps that makes it suitable for large scale industrial manufacturing process. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetic Transformation of Artemisia carvifolia Buch with rol Genes Enhances Artemisinin Accumulation.

PubMed

Dilshad, Erum; Cusido, Rosa Maria; Ramirez Estrada, Karla; Bonfill, Mercedes; Mirza, Bushra

2015-01-01

The potent antimalarial drug artemisinin has a high cost, since its only viable source to date is Artemisia annua (0.01-0.8% DW). There is therefore an urgent need to design new strategies to increase its production or to find alternative sources. In the current study, Artemisia carvifolia Buch was selected with the aim of detecting artemisinin and then enhancing the production of the target compound and its derivatives. These metabolites were determined by LC-MS in the shoots of A. carvifolia wild type plants at the following concentrations: artemisinin (8μg/g), artesunate (2.24μg/g), dihydroartemisinin (13.6μg/g) and artemether (12.8μg/g). Genetic transformation of A. carvifolia was carried out with Agrobacterium tumefaciens GV3101 harboring the rol B and rol C genes. Artemisinin content increased 3-7-fold in transgenics bearing the rol B gene, and 2.3-6-fold in those with the rol C gene. A similar pattern was observed for artemisinin analogues. The dynamics of artemisinin content in transgenics and wild type A.carvifolia was also correlated with the expression of genes involved in its biosynthesis. Real time qPCR analysis revealed the differential expression of genes involved in artemisinin biosynthesis, i.e. those encoding amorpha-4, 11 diene synthase (ADS), cytochrome P450 (CYP71AV1), and aldehyde dehydrogenase 1 (ALDH1), with a relatively higher transcript level found in transgenics than in the wild type plant. Also, the gene related to trichome development and sesquiterpenoid biosynthesis (TFAR1) showed an altered expression in the transgenics compared to wild type A.carvifolia, which was in accordance with the trichome density of the respective plants. The trichome index was significantly higher in the rol B and rol C gene-expressing transgenics with an increased production of artemisinin, thereby demonstrating that the rol genes are effective inducers of plant secondary metabolism.

Isolation and Characterization of Three New Monoterpene Synthases from Artemisia annua

PubMed Central

Ruan, Ju-Xin; Li, Jian-Xu; Fang, Xin; Wang, Ling-Jian; Hu, Wen-Li; Chen, Xiao-Ya; Yang, Chang-Qing

2016-01-01

Artemisia annua, an annual herb used in traditional Chinese medicine, produces a wealth of monoterpenes and sesquiterpenes, including the well-known sesquiterpene lactone artemisinin, an active ingredient in the treatment for malaria. Here we report three new monoterpene synthases of A. annua. From a glandular trichome cDNA library, monoterpene synthases of AaTPS2, AaTPS5, and AaTPS6, were isolated and characterized. The recombinant proteins of AaTPS5 and AaTPS6 produced multiple products with camphene and 1,8-cineole as major products, respectively, and AaTPS2 produced a single product, β-myrcene. Although both Mg2+ and Mn2+ were able to support their catalytic activities, altered product spectrum was observed in the presence of Mn2+ for AaTPS2 and AaTPS5. Analysis of extracts of aerial tissues and root of A. annua with gas chromatography–mass spectrometry detected more than 20 monoterpenes, of which the three enzymes constituted more than 1/3 of the total. Mechanical wounding induced the expression of all three monoterpene synthase genes, and transcript levels of AaTPS5 and AaTPS6 were also elevated after treatments with phytohormones of methyl jasmonate, salicylic acid, and gibberellin, suggesting a role of these monoterpene synthases in plant–environment interactions. The three new monoterpene synthases reported here further our understanding of molecular basis of monoterpene biosynthesis and regulation in plant. PMID:27242840

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martinez Isaza, B.C.

Production of artemisinin was studied in both plants and tissue cultures of Artemisia annua L. Incorporation of (3{prime}-{sup 14}C) mevalonic acid sodium salt into artemisinin or arteannuin B was not found when field-grown plants were fed once with 10 or 50 {mu}Ci and harvested after 44, 144 or 288 hr. Artemisinin was not present in root organ cultures, but was present in the shoot cultures in a concentration of less than 5 mg/100 g dry weight. The content of artemisinin in a shoot culture line with elongated and indented shoots was significantly higher at p value of 0.01 from thatmore » with short and compact shoots. Induction of roots on shoot cultures was associated with increased artemisinin production. Shoot cultures that developed into plants with roots had higher artemisinin content than those shoots cultures with aerial roots, or shoots cultures with basal roots. The artemisinin content in shoot cultures apparently increased with age. Preliminary studies on the metabolism of arteannuin B demonstrated that shoot cultures absorbed the exogenous arteannuin B from the medium without an increase in artemisinin content.« less

Comparison of Artemisia annua Bioactivities between Traditional Medicine and Chemical Extracts

PubMed Central

Nageeb, Ahmed; Al-Tawashi, Azza; Mohammad Emwas, Abdul-Hamid; Abdel-Halim Al-Talla, Zeyad; Al-Rifai, Nahla

2013-01-01

The present work investigates the efficacy of using Artemisia annua in traditional medicine in comparison with chemical extracts of its bioactive molecules. In addition, the effects of location (Egypt and Jericho) on the bioactivities of the plant were investigated. The results showed that water extracts of Artemisia annua from Jericho have stronger antibacterial activities than organic solvent extracts. In contrast, water and organic solvent extracts of the Artemisia annua from Egypt do not have anti-bacterial activity. Furthermore, while the methanol extract of EA displayed high anticancer affects, the water extract of Egypt and the extracts of Jericho did not show significant anticancer activity. Finally, the results showed that the methanol and water extracts of Jericho had the highest antioxidant activity, while the extracts of Egypt had none. The current results validate the scientific bases for the use of Artemisia annua in traditional medicine. In addition, our results suggest that the collection location of the Artemisia annua has an effect on its chemical composition and bioactivities. PMID:24761137

High-level semi-synthetic production of the potent antimalarial artemisinin.

PubMed

Paddon, C J; Westfall, P J; Pitera, D J; Benjamin, K; Fisher, K; McPhee, D; Leavell, M D; Tai, A; Main, A; Eng, D; Polichuk, D R; Teoh, K H; Reed, D W; Treynor, T; Lenihan, J; Fleck, M; Bajad, S; Dang, G; Dengrove, D; Diola, D; Dorin, G; Ellens, K W; Fickes, S; Galazzo, J; Gaucher, S P; Geistlinger, T; Henry, R; Hepp, M; Horning, T; Iqbal, T; Jiang, H; Kizer, L; Lieu, B; Melis, D; Moss, N; Regentin, R; Secrest, S; Tsuruta, H; Vazquez, R; Westblade, L F; Xu, L; Yu, M; Zhang, Y; Zhao, L; Lievense, J; Covello, P S; Keasling, J D; Reiling, K K; Renninger, N S; Newman, J D

2013-04-25

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

The effects of dried leaves of Manihot esculenta and Artemisia annua on coccidiosis in organically reared pullets in Brazil

USDA-ARS?s Scientific Manuscript database

The effects of Manihot esculenta and Artemisia annua as natural coccidiostats were investigated as compared to a vaccinated group. The inclusion of Artemisia annua showed poorer performance compared to the vaccinated group whereas dried leaves of M. esculenta presented similar results of a commercia...

Yeast Model Uncovers Dual Roles of Mitochondria in the Action of Artemisinin

PubMed Central

Li, Wei; Mo, Weike; Shen, Dan; Sun, Libo; Wang, Juan; Lu, Shan; Gitschier, Jane M; Zhou, Bing

2005-01-01

Artemisinins, derived from the wormwood herb Artemisia annua, are the most potent antimalarial drugs currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. Here we use yeast, Saccharamyces cerevisiae, to probe the core working mechanism of this class of antimalarial agents. We demonstrate that artemisinin's inhibitory effect is mediated by disrupting the normal function of mitochondria through depolarizing their membrane potential. Moreover, in a genetic study, we identify the electron transport chain as an important player in artemisinin's action: Deletion of NDE1 or NDI1, which encode mitochondrial NADH dehydrogenases, confers resistance to artemisinin, whereas overexpression of NDE1 or NDI1 dramatically increases sensitivity to artemisinin. Mutations or environmental conditions that affect electron transport also alter host's sensitivity to artemisinin. Sensitivity is partially restored when the Plasmodium falciparum NDI1 ortholog is expressed in yeast ndi1 strain. Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species. Our results demonstrate that artemisinin's effect is primarily mediated through disruption of membrane potential by its interaction with the electron transport chain, resulting in dysfunctional mitochondria. We propose a dual role of mitochondria played during the action of artemisinin: the electron transport chain stimulates artemisinin's effect, most likely by activating it, and the mitochondria are subsequently damaged by the locally generated free radicals. PMID:16170412

Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production

PubMed Central

Pulice, Giuseppe; Pelaz, Soraya; Matías-Hernández, Luis

2016-01-01

Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further efforts should be addressed toward optimization of the most cost-effective biofarming approaches for synthesis and production of medicines against the malaria parasite. PMID:27047510

Anti-inflammatory and acetylcholinesterase activity of extract, fractions and five compounds isolated from the leaves and twigs of Artemisia annua growing in Cameroon.

PubMed

Chougouo, Rosine D K; Nguekeu, Yves M M; Dzoyem, Jean P; Awouafack, Maurice D; Kouamouo, Jonas; Tane, Pierre; McGaw, Lyndy J; Eloff, Jacobus N

2016-01-01

Natural products, including those derived from higher plants have, over the years, contributed greatly to the development of modern therapeutic drugs. Due to the medicinal importance in traditional practice and the diversified biology and chemistry of the constituents from Artemisia spp., the genus has been receiving growing attention. The aim of this study was to investigate the ability of the ethanol extract, four fractions (F1-F4) and five compounds namely artemisinin (1), scopoletin (2), chrysosplenetin (3), eupatin (4) and 3-O-β-d-glucopyranoside of sitosterol (5) isolated from A. annua to modulate the activity of anticholinesterase (AchE) and the production of nitric oxide (NO) in LPS-activated RAW 264.7 macrophages. At the lowest concentration tested (6.25 µg/mL), the crude extract and fraction F2 had the highest NO inhibitory activity (72.39 and 71.00 % inhibition respectively) without significant toxicity on the viability of macrophage cells (93.86 and 79.87 % of cell viability respectively). The crude extract inhibited AchE activity by 71.83 % (at 1 mg/mL) with an IC50 value of 87.43 µg/mL while F2 and F4 were the most active fractions (IC50 values of 36.75 and 28.82 µg/mL). Artemisinin (1) and chrysosplenetin (3) had the highest AChE activity with 71.67 and 80.00 % inhibition (at 0.1 mg/mL) and IC50 values of 29.34 and 27.14 µg/mL, respectively. Our results validate the traditional use of A. annua and could help to support the usefulness of this plant in the treatment of inflammatory and neurological disorders especially where nitric oxide and a cholinesterase are involved.

Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

PubMed

Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

2013-09-01

Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone.

Response of Artemisia annua L. to shade and manure fertilizer application in lowland altitude

NASA Astrophysics Data System (ADS)

Permana, H. H.; Widyastuti, Y.; Samanhudi; Yunus, A.

2018-03-01

Artemisia is a plant producing artemisinin substance which is the main compound in the treatment of malaria. Artemisia comes from China, usually grows wild in native habitats in the plains with an altitude of 1,000-1,500 meters above the sea level. Artemisia development efforts in Indonesia hampered by limited land with the required altitude due to their competition with vegetable crops. Based on this reason, this research is conducted to observe the growth of artemisia planted in lowland with the help of shade and manure. This study aims to determine the level of shade and best manure on the growth of Artemisia. Research conducted at the Laboratory of the Faculty of Agriculture UNS Jumantono using nested design with two factors, shade as main factor and manure fertilizer as sub factor. The data analysis used F test with confidence level of 5%, if significant, then continued with DMRT (Duncan Multiple Range Test). The results showed the treatment of shade gave no difference in growth within 50% shade, 75% shade as well as without shade treatment. Goat manure fertilizer gave the highest result and able to increase plant height, number of branches, flower weight and root volume.

Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways.

PubMed

Wang, Ke Si; Li, Junbo; Wang, Zhe; Mi, Chunliu; Ma, Juan; Piao, Lian Xun; Xu, Guang Hua; Li, Xuezheng; Jin, Xuejun

2017-02-01

Artemisinin, isolated from the Chinese plant Artemisia annua, has been used for many years to treat different forms of malarial parasites. In this study, we explored the anti-inflammatory activity of artemisinin and the underlying mechanism of this action. We demonstrated that the anti-inflammatory effects of artemisinin in TPA-induced skin inflammation in mice. Then the artemisinin significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner. Artemisinin also inhibited TNF-α induced phosphorylation and degradation of IκBα, p65 nuclear translocation. Artemisinin also has an impact on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Furthermore, pretreatment of cells with artemisinin prevented the TNF-α-induced expression of NF-κB target genes, such as anti-apoptosis (c-IAP1, Bcl-2, and FLIP), proliferation (COX-2, cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, iNOS, and MCP1). We also proved that artemisinin potentiated TNF-α-induced apoptosis. Moreover, artemisinin significantly impaired the ROS production and phosphorylation of p38 and ERK, but did not affect the phosphorylation of JNK. Taken together, artemisinin may be a potentially useful therapeutic agent for inflammatory-related diseases.

Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions

PubMed Central

2011-01-01

Background In traditional medicine whole plants or mixtures of plants are used rather than isolated compounds. There is evidence that crude plant extracts often have greater in vitro or/and in vivo antiplasmodial activity than isolated constituents at an equivalent dose. The aim of this paper is to review positive interactions between components of whole plant extracts, which may explain this. Methods Narrative review. Results There is evidence for several different types of positive interactions between different components of medicinal plants used in the treatment of malaria. Pharmacodynamic synergy has been demonstrated between the Cinchona alkaloids and between various plant extracts traditionally combined. Pharmacokinetic interactions occur, for example between constituents of Artemisia annua tea so that its artemisinin is more rapidly absorbed than the pure drug. Some plant extracts may have an immunomodulatory effect as well as a direct antiplasmodial effect. Several extracts contain multidrug resistance inhibitors, although none of these has been tested clinically in malaria. Some plant constituents are added mainly to attenuate the side-effects of others, for example ginger to prevent nausea. Conclusions More clinical research is needed on all types of interaction between plant constituents. This could include clinical trials of combinations of pure compounds (such as artemisinin + curcumin + piperine) and of combinations of herbal remedies (such as Artemisia annua leaves + Curcuma longa root + Piper nigum seeds). The former may enhance the activity of existing pharmaceutical preparations, and the latter may improve the effectiveness of existing herbal remedies for use in remote areas where modern drugs are unavailable. PMID:21411015

Compartmentalized Metabolic Engineering for Artemisinin Biosynthesis and Effective Malaria Treatment by Oral Delivery of Plant Cells

PubMed Central

Malhotra, Karan; Subramaniyan, Mayavan; Rawat, Khushboo; Kalamuddin, Md.; Qureshi, M. Irfan; Malhotra, Pawan; Mohmmed, Asif; Cornish, Katrina; Daniell, Henry; Kumar, Shashi

2017-01-01

Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills >500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (~0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of dihydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants. PMID:27773616

Effects of Artemisia annua extracts on sporulation of Eimeria oocysts.

PubMed

Fatemi, Ahmadreza; Razavi, Seyyed Mostafa; Asasi, Keramat; Goudarzi, Majid Torabi

2015-03-01

The present study aimed to compare the effect of different Artemisia annua extracts on sporulation rate of mixed oocysts of Eimeria acervulina, Eimeria necatrix, and Eimeria tenella. Three types of A. annua extracts including petroleum ether (PE), ethanol 96° (E), and water (W) extracts were prepared. Artemisinin, a sesquiterpene lactone endoperoxide derived from the A. annua analysis of each extract was done by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Fresh fecal samples containing three Eimeria species were floated and counted, and the oocysts were transferred into 50 tubes, each containing 10(5) oocysts per milliliter. Five tubes were control. Each of the other 45 tubes contained one of three doses (1 part per thousand (ppt), 2 ppt, and 5 ppt) and one of three extracts (PE, E, and W extracts) with five replications. The tubes were incubated for 48 h at 25-29 °C and aerated. Sporulation inhibition assay was used to evaluate the activity of extracts. The results showed that the E and PE extracts inhibit sporulation in 2 and 5 ppt concentrations, but the W extract stimulates it in all concentrations. The proportions of oocyst inhibition relative to control were 31 % (5 ppt) and 29 % (2 ppt) for PE and 34 % (5 ppt) and 46 % (2 ppt) for E extract. Furthermore, many oocysts in PE and E groups were wrinkled and contained abnormal sporocysts. The proportions of sporulation stimulation relative to control were 22 % (5 ppt), 24 % (2 ppt), and 27 % (1 ppt) in W extract. Our study is the first to demonstrate that all types of A. annua extracts do not necessarily have a similar activity, and the interaction of all contents and their relative concentrations is an important factor for sporulation stimulation or inhibition. It seems, some parts of unmetabolized excreted PE and E extracts could inhibit oocyst sporulation and eventually affect infection transmission.

Artemisinin and Artemisia annua leaves alleviate Eimeria tenella infection by facilitating apoptosis of host cells and suppressing inflammatory response.

PubMed

Jiao, JinYing; Yang, YunQiao; Liu, MingJiang; Li, JinGui; Cui, Yi; Yin, ShaoJie; Tao, JianPing

2018-04-30

Evasion strategies of intracellular parasites by hijacking cellular pathways, are necessary to ensure successful survival and replication. Eimeria tenella (E. tenella) has the ability to circumvent apoptosis of infected cells through increased expression of the transcriptional factor NF-κB and the anti-apoptotic factor Bcl-x L during the development of second generation schizonts. Artemisinin (ART) and its original plant, the dried leaves of Artemisia annua (LAA) have been shown to be effective against avian coccidiosis, however, the underlying mechanism remains unclear. We showed that E. tenella infection promoted the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic proteins Bax and cleaved caspase-3 at 60 h post infection (PI), with a higher ratio of Bcl-2 to Bax. Nevertheless, the expression trends of Bcl-2, Bax and caspase-3 were reversed at 120 h and 192 h PI. ART treatment significantly abrogated Bcl-2 expression, whereas it promoted the expression levels of Bax and cleaved caspase-3 at the three time points above. Additionally, ART remarkably suppressed the increased mRNA expressions of NF-κB and interleukin-17A in ceca during infection by E. tenella. Compared with the ART treatment, LAA treatment exerted more improvements in clinical symptoms, promoting apoptosis and suppressing inflammatory response. These alterations caused by ART and LAA treatments were consistent with the reduced clinical diarrhea and pathological improvements in chicken ceca. Collectively, these results indicate that the inhibitory effects of ART or LAA on E. tenella infection may work through facilitating the apoptosis of infected host cells and inhibiting the inflammatory response. Copyright © 2018 Elsevier B.V. All rights reserved.

Compartmentalized Metabolic Engineering for Artemisinin Biosynthesis and Effective Malaria Treatment by Oral Delivery of Plant Cells.

PubMed

Malhotra, Karan; Subramaniyan, Mayavan; Rawat, Khushboo; Kalamuddin, Md; Qureshi, M Irfan; Malhotra, Pawan; Mohmmed, Asif; Cornish, Katrina; Daniell, Henry; Kumar, Shashi

2016-11-07

Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills >500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (∼0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of dihydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Synthetic biology: Emerging bioengineering in Indonesia

NASA Astrophysics Data System (ADS)

Suhandono, Sony

2017-05-01

The development of synthetic biology will shape the new era of science and technology. It is an emerging bioengineering technique involving genetic engineering which can alter the phenotype and behavior of the cell or the new product. Synthetic biology may produce biomaterials, drugs, vaccines, biosensors, and even a recombinant secondary metabolite used in herbal and complementary medicine, such as artemisinin, a malaria drug which is usually extracted from the plant Artemisia annua. The power of synthetic biology has encouraged scientists in Indonesia, and is still in early development. This paper also covers some research from an Indonesian research institute in synthetic biology such as observing the production of bio surfactants and the enhanced production of artemisinin using a transient expression system. Synthetic biology development in Indonesia may also be related to the iGEM competition, a large synthetic biology research competition which was attended by several universities in Indonesia. The application of synthetic biology for drug discovery will be discussed.

Anticancer activity of botanical compounds in ancient fermented beverages (review).

PubMed

McGovern, P E; Christofidou-Solomidou, M; Wang, W; Dukes, F; Davidson, T; El-Deiry, W S

2010-07-01

Humans around the globe probably discovered natural remedies against disease and cancer by trial and error over the millennia. Biomolecular archaeological analyses of ancient organics, especially plants dissolved or decocted as fermented beverages, have begun to reveal the preliterate histories of traditional pharmacopeias, which often date back thousands of years earlier than ancient textual, ethnohistorical, and ethnological evidence. In this new approach to drug discovery, two case studies from ancient Egypt and China illustrate how ancient medicines can be reconstructed from chemical and archaeological data and their active compounds delimited for testing their anticancer and other medicinal effects. Specifically, isoscopoletin from Artemisia argyi, artemisinin from Artemisia annua, and the latter's more easily assimilated semi-synthetic derivative, artesunate, showed the greatest activity in vitro against lung and colon cancers. In vivo tests of these compounds previously unscreened against lung and pancreatic cancers are planned for the future.

The genus Artemisia: a comprehensive review.

PubMed

Bora, Kundan Singh; Sharma, Anupam

2011-01-01

Medicinal plants are nature's gift to human beings to make disease free healthy life, and play a vital role to preserve our health. They are believed to be much safer and proven elixir in the treatment of various ailments. The genus Artemisia (Astraceae) consists of about 500 species, occurring throughout the world. The present review comprises the ethnopharmacological, phytochemical and therapeutic potential of various species of Artemisia. The aim of this this review is to bring together most of the available scientific research conducted on the genus Artemisia, which is currently scattered across various publications. Through this review the authors hope to attract the attention of natural product researchers throughout the world to focus on the unexplored potential of Artemisia species. This review has been compiled using references from major databases such as Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, ScienceDirect, SciFinder, PubMed, King's American Dispensatory, Henriette's Herbal Homepage, Dr. Duke's Phytochemical and Ethnobotanical Databases. An exhaustive survey of literature revealed that the different species of Artemisia have a vast range of biological activities including antimalarial, cytotoxic, antihepatotoxic, antibacterial, antifungal and antioxidant activity. Some very important drug leads have been discovered from this genus, notably artemisinin, the well known antimalarial drug isolated from the Chinese herb Artemisia annua. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes constitute major classes of phytoconstituents of the genus. Various species of Artemisia seems to hold great potential for in-depth investigation for various biological activities, especially their effects on the central nervous and cardiovascular systems.

Artemisia spp. essential oils against the disease-carrying blowfly Calliphora vomitoria.

PubMed

Bedini, Stefano; Flamini, Guido; Cosci, Francesca; Ascrizzi, Roberta; Echeverria, Maria Cristina; Guidi, Lucia; Landi, Marco; Lucchi, Andrea; Conti, Barbara

2017-02-13

Synanthropic flies play a considerable role in the transmission of pathogenic and non-pathogenic microorganisms. In this work, the essential oil (EO) of two aromatic plants, Artemisia annua and Artemisia dracunculus, were evaluated for their abilities to control the blowfly Calliphora vomitoria. Artemisia annua and A. dracunculus EOs were extracted, analysed and tested in laboratory bioassays. Besides, the physiology of EOs toxicity and the EOs antibacterial and antifungal properties were evaluated. Both Artemisia EOs deterred C. vomitoria oviposition on fresh beef meat. At 0.05 μl cm -2 A. dracunculus EO completely inhibited C. vomitoria oviposition. Toxicity tests, by contact, showed LD 50 of 0.49 and 0.79 μl EO per fly for A. dracunculus and A. annua, respectively. By fumigation, LC 50 values were 49.55 and 88.09 μl l -1 air for A. dracunculus and A. annua, respectively. EOs AChE inhibition in C. vomitoria (IC 50  = 202.6 and 472.4 mg l -1 , respectively, for A. dracunculus and A. annua) indicated that insect neural sites are targeted by the EOs toxicity. Finally, the antibacterial and antifungal activities of the two Artemisia EOs may assist in the reduction of transmission of microbial infections/contaminations. Results suggest that Artemisia EOs could be of use in the control of C. vomitoria, a common vector of pathogenic microorganisms and agent of human and animal cutaneous myiasis. The prevention of pathogenic and parasitic infections is a priority for human and animal health. The Artemisia EOs could represent an eco-friendly, low-cost alternative to synthetic repellents and insecticides to fight synanthropic disease-carrying blowflies.

Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein.

PubMed

Steely, Andrea M; Willoughby, Jamin A; Sundar, Shyam N; Aivaliotis, Vasiliki I; Firestone, Gary L

2017-10-01

Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

Artemisinin induces ROS-mediated caspase3 activation in ASTC-a-1 cells

NASA Astrophysics Data System (ADS)

Xiao, Feng-Lian; Chen, Tong-Sheng; Qu, Jun-Le; Liu, Cheng-Yi

2010-02-01

Artemisinin (ART), an antimalarial phytochemical from the sweet wormwood plant or a naturally occurring component of Artemisia annua, has been shown a potential anticancer activity by apoptotic pathways. In our report, cell counting kit (CCK-8) assay showed that treatment of human lung adenocarcinoma (ASTC-a-1) cells with ART effectively increase cell death by inducing apoptosis in a time- and dose-dependent fashion. Hoechst 33258 staining was used to detect apoptosis as well. Reactive oxygen species (ROS) generation was observed in cells exposed to ART at concentrations of 400 μM for 48 h. N-acetyl-L-cysteine (NAC), an oxygen radical scavenger, suppressed the rate of ROS generation and inhibited the ART-induced apoptosis. Moreover, AFC assay (Fluorometric assay for Caspase3 activity) showed that ROS was involved in ART-induced caspase3 acitvation. Taken together, our data indicate that ART induces ROS-mediated caspase3 activation in a time-and dose-dependent way in ASCT-a-1 cells.

Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin

PubMed Central

Elfawal, Mostafa A.; Towler, Melissa J.; Reich, Nicholas G.; Weathers, Pamela J.; Rich, Stephen M.

2015-01-01

Pharmaceutical monotherapies against human malaria have proven effective, although ephemeral, owing to the inevitable evolution of resistant parasites. Resistance to two or more drugs delivered in combination will evolve more slowly; hence combination therapies have become the preferred norm in the fight against malaria. At the forefront of these efforts has been the promotion of Artemisinin Combination Therapy, but despite these efforts, resistance to artemisinin has begun to emerge. In 2012, we demonstrated the efficacy of the whole plant (WP)—not a tea, not an infusion—as a malaria therapy and found it to be more effective than a comparable dose of pure artemisinin in a rodent malaria model. Here we show that WP overcomes existing resistance to pure artemisinin in the rodent malaria Plasmodium yoelii. Moreover, in a long-term artificial selection for resistance in Plasmodium chabaudi, we tested resilience of WP against drug resistance in comparison with pure artemisinin (AN). Stable resistance to WP was achieved three times more slowly than stable resistance to AN. WP treatment proved even more resilient than the double dose of AN. The resilience of WP may be attributable to the evolutionary refinement of the plant’s secondary metabolic products into a redundant, multicomponent defense system. Efficacy and resilience of WP treatment against rodent malaria provides compelling reasons to further explore the role of nonpharmaceutical forms of AN to treat human malaria. PMID:25561559

The effects of combining Artemisia annua and Curcuma longa ethanolic extracts in broilers challenged with infective oocysts of Eimeria acervulina and E. maxima

USDA-ARS?s Scientific Manuscript database

Due to an increasing demand for natural products to control coccidiosis in broilers we investigated the effects of supplementing a combination of ethanolic extracts of Artemisia annua and Curcuma longa in drinking water. Three different dosages of this herbal mixture were compared with a negative co...

In vitro and in vivo antileishmanial activity of Artemisia annua L. leaf powder and its potential usefulness in the treatment of uncomplicated cutaneous leishmaniasis in humans.

PubMed

Mesa, Luz Estella; Vasquez, Daniel; Lutgen, Pierre; Vélez, Iván Darío; Restrepo, Adriana María; Ortiz, Isabel; Robledo, Sara María

2017-01-01

Cutaneous leishmaniasis (CL) is a tropical disease that affects millions of individuals worldwide. The current drugs for CL may be effective but have serious side effects; hence, alternatives are urgently needed. Although plant-derived materials are used for the treatment of various diseases in 80% of the global population, the validation of these products is essential. Gelatin capsules containing dried Artemisia annua leaf powder were recently developed as a new herbal formulation (totum) for the oral treatment of malaria and other parasitic diseases. Here, we aimed to determine the usefulness of A. annua gel capsules in CL. The antileishmanial activity and cytotoxicity of A. annua L. capsules was determined via in vitro and in vivo studies. Moreover, a preliminary evaluation of its therapeutic potential as antileishmanial treatment in humans was conducted in 2 patients with uncomplicated CL. Artemisia annua capsules showed moderate in vitro activity in amastigotes of Leishmania (Viannia) panamensis; no cytotoxicity in U-937 macrophages or genotoxicity in human lymphocytes was observed. Five of 6 (83.3%) hamsters treated with A. annua capsules (500mg/kg/day) for 30 days were cured, and the 2 examined patients were cured 45 days after initiation of treatment with 30g of A. annua capsules, without any adverse reactions. Both patients remained disease-free 26 and 24 months after treatment completion. Capsules of A. annua L. represent an effective treatment for uncomplicated CL, although further randomized controlled trials are needed to validate its efficacy and safety.

Artesunate induces AIF-dependent apoptosis in A549 cells

NASA Astrophysics Data System (ADS)

Zhou, Chen-juan; Chen, Tong-Sheng

2012-03-01

Artesunate (ART), a semi-synthetic derivative of the sesquiterpene artemisinin extracted from the Chinese herb Artemisia annua, exerts a broad spectrum of clinical activity against human cancers. It has been shown that ART induces cancer cells death through apoptosis pathway. This study investigated whether ART treatment induced reactive oxygen species (ROS)-dependent cell death in the apoptosis fashion in human lung adenocarconoma A549 cell line and the proapoptotic protein apoptosis inducing factor (AIF) is involved in ART-induced apoptosis. Cells treated with ART exhibited typical apoptotic morphology as chromatin condensation, margination and shrunken nucleus. ART treatment also induced a loss of mitochondrial membrane potential and AIF release from mitochondria. Silencing AIF can remarkable attenuated ART-induced apoptosis. Collectively, ART induces apoptosis by caspase-independent intrinsic pathway in A549 cells.

Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid.

PubMed

Ro, Dae-Kyun; Ouellet, Mario; Paradise, Eric M; Burd, Helcio; Eng, Diana; Paddon, Chris J; Newman, Jack D; Keasling, Jay D

2008-11-04

Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required. Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (AMO or CYP71AV1), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 microg mL(-1) in shake-flask cultures and 1 g L(-1) in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (PDR) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by yeast microarray further demonstrated that the induction of drug-resistant genes such as ABC transporters and major facilitator superfamily (MSF) genes is the primary cellular stress-response; in addition, oxidative and osmotic stress responses were observed in the engineered yeast. The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses. The use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisinic acid production in the engineered yeast.

Effects of artemisinin in broiler chickens challenged with Eimeria acervulina, E. maxima and E. tenella in battery trials.

PubMed

Pop, Loredana; Györke, Adriana; Tǎbǎran, Alexandru Flaviu; Dumitrache, Mirabela Oana; Kalmár, Zsuzsa; Magdaş, Cristian; Mircean, Viorica; Zagon, Diana; Balea, Anamaria; Cozma, Vasile

2015-12-15

Four experiments were conceived in order to test the efficacy of artemisinin, a sesquiterpene lactone derived from Artemisia annua, in single experimental infection of broiler chickens with Eimeria acervulina (1 × 10(5) oocysts), Eimeria maxima (5 × 10(4) oocysts) or Eimeria tenella (1 × 10(4) oocysts), and mixed infection with all 3 species (3.2 × 10(4) Eimeria spp. oocysts). For each experiment, three different dosages of artemisinin (5, 50 and 500 ppm) were compared with a negative control (uninfected, unmedicated), a positive control (infected, unmedicated) and a classical anticoccidial (monensin). The weight gain (WG), feed conversion ratio (FCR), oocysts shedded per gram of feces (OPG), lesion score, oocysts sporulation rates and mortality rate were recorded in all groups. The dosage of 5 ppm of artemisinin improved the WG and FCR for the chickens infected with E. acervulina. The OPG was significantly decreased in all the groups medicated with artemisinin and challenged with a mixed infection (p ≤ 0.01). The lesion score of the chickens challenged with Eimeria was reduced by different concentrations of artemisinin, depending on the species involved, but this compound did not have a positive effect on the lesions caused by E. acervulina. Histopathological analysis revealed superficial erosions of the intestinal mucosa, mixt. mononuclear and heterophilic inflammatory infiltrate in the lamina propria and intralesional presence of various developmental stages of parasite in groups infected with Eimeria spp.The sporulation rate of E. acervulina and E. maxima oocysts was significantly affected by 500 ppm of artemisinin, whilst the dosage of 5 ppm affected the sporulation of E. tenella oocysts. These data suggest that artemisinin is not effective against single eimerian infections but could be used as an alternative in mixed coccidiosis, especially if its effect on the oocysts sporulation would be fully investigated. Copyright © 2015 Elsevier B.V. All rights reserved.

Emission spectral analysis of caspase-3 activation during artesunate (ART)-induced apoptosis of human lung adenocarcinoma cell

NASA Astrophysics Data System (ADS)

Pan, Wen-liang; Chen, Tong-sheng; Qu, Junle

2009-02-01

Artesunate (ART), a semi-synthetic derivative of the sesquiterpene artemisinin extracted from the Chinese herb Artemisia annua, exerts a broad spectrum of clinical activity against human cancers. Artemisinin-derivative combination chemotherapy is recommended by WHO since it acts rapidly and is well tolerated and particularly effective. In present investigation, we used CKK-8 assay to assess the inhibitory effects of ART on human lung adenocarcinoma (ASTC-a-1) cells. Apoptotic activity of ART in ASTC-a-1 cells was detected by means of nuclear staining with Hoechst33258. In order to monitor the activity of caspase-3 during ART-induced ASTC-a-1 cells apoptosis, the dynamical emission spectra of SCAT3, a FRET plasmid based on GFPs, were performed inside living cell expressed stably with SCAT3 after ART treatment. The results showed that (1) ART could inhibit ASTC-a-1 cells proliferation in a dose-dependent manner; (2) chromatin condensation was observed after ART treatment for 48 h; (3) the SCAT3 inside living cells were cleaved after ART treatment for 48 h, implying that caspase-3 was involved in the ART-induced apoptosis.

Bax translocation into mitochondria during dihydroartemisinin(DHA)-induced apoptosis in human lung adenocarcinoma cells

NASA Astrophysics Data System (ADS)

Lu, Ying-ying; Chen, Tong-sheng; Qu, Jun-Le

2009-02-01

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, isolated from the traditional Chinese herb Artemisia annua, has been shown to possess promising anticancer activities and induce cancer cell death through apoptotic pathways. However, the molecular mechanisms are not well understood. This study was investigated in human lung adenocarconoma ASTC-a-1 cell line and aimed to determine whether the apoptotic process was mediated by Bax activation and translocation during DHA-induced apoptosis. In this study, DHA induced a time-dependent apoptotic cell death, which was assayed by Cell Counting Kit (CCK-8) and Hoechst 33258 staining. Detection of Bax aggregation and translocation to mitochondria was observed in living cells which were co-transfected with GFP-Bax and Dsred-mito plasmid using confocal fluorescence microscope technique. Overall, these results demonstrated that Bax activation and translocation to mitochondria occurred during DHA-induced apoptosis.

Transcriptome Analysis of Thapsia laciniata Rouy Provides Insights into Terpenoid Biosynthesis and Diversity in Apiaceae

PubMed Central

Drew, Damian Paul; Dueholm, Bjørn; Weitzel, Corinna; Zhang, Ye; Sensen, Christoph W.; Simonsen, Henrik Toft

2013-01-01

Thapsia laciniata Rouy (Apiaceae) produces irregular and regular sesquiterpenoids with thapsane and guaiene carbon skeletons, as found in other Apiaceae species. A transcriptomic analysis utilizing Illumina next-generation sequencing enabled the identification of novel genes involved in the biosynthesis of terpenoids in Thapsia. From 66.78 million HQ paired-end reads obtained from T. laciniata roots, 64.58 million were assembled into 76,565 contigs (N50: 1261 bp). Seventeen contigs were annotated as terpene synthases and five of these were predicted to be sesquiterpene synthases. Of the 67 contigs annotated as cytochromes P450, 18 of these are part of the CYP71 clade that primarily performs hydroxylations of specialized metabolites. Three contigs annotated as aldehyde dehydrogenases grouped phylogenetically with the characterized ALDH1 from Artemisia annua and three contigs annotated as alcohol dehydrogenases grouped with the recently described ADH1 from A. annua. ALDH1 and ADH1 were characterized as part of the artemisinin biosynthesis. We have produced a comprehensive EST dataset for T. laciniata roots, which contains a large sample of the T. laciniata transcriptome. These transcriptome data provide the foundation for future research into the molecular basis for terpenoid biosynthesis in Thapsia and on the evolution of terpenoids in Apiaceae. PMID:23698765

[Stability analysis of reference gene based on real-time PCR in Artemisia annua under cadmium treatment].

PubMed

Zhou, Liang-Yun; Mo, Ge; Wang, Sheng; Tang, Jin-Fu; Yue, Hong; Huang, Lu-Qi; Shao, Ai-Juan; Guo, Lan-Ping

2014-03-01

In this study, Actin, 18S rRNA, PAL, GAPDH and CPR of Artemisia annua were selected as candidate reference genes, and their gene-specific primers for real-time PCR were designed, then geNorm, NormFinder, BestKeeper, Delta CT and RefFinder were used to evaluate their expression stability in the leaves of A. annua under treatment of different concentrations of Cd, with the purpose of finding a reliable reference gene to ensure the reliability of gene-expression analysis. The results showed that there were some significant differences among the candidate reference genes under different treatments and the order of expression stability of candidate reference gene was Actin > 18S rRNA > PAL > GAPDH > CPR. These results suggested that Actin, 18S rRNA and PAL could be used as ideal reference genes of gene expression analysis in A. annua and multiple internal control genes were adopted for results calibration. In addition, differences in expression stability of candidate reference genes in the leaves of A. annua under the same concentrations of Cd were observed, which suggested that the screening of candidate reference genes was needed even under the same treatment. To our best knowledge, this study for the first time provided the ideal reference genes under Cd treatment in the leaves of A. annua and offered reference for the gene expression analysis of A. annua under other conditions.

Chemical Composition and Antipathogenic Activity of Artemisia annua Essential Oil from Romania.

PubMed

Marinas, Ioana C; Oprea, Eliza; Chifiriuc, Mariana Carmen; Badea, Irinel Adriana; Buleandra, Mihaela; Lazar, Veronica

2015-10-01

The essential oil extracted by hydrodistillation from Romanian Artemisia annua aerial parts was characterized by GC/MS analysis, which allowed the identification of 94.64% of the total oil composition. The main components were camphor (17.74%), α-pinene (9.66%), germacrene D (7.55%), 1,8-cineole (7.24%), trans-β-caryophyllene (7.02%), and artemisia ketone (6.26%). The antimicrobial activity of this essential oil was evaluated by determining the following parameters: minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), minimal fungicidal concentration (MFC), and minimal biofilm eradication concentration (MBEC). Moreover, the soluble virulence factors were quantified with different biochemical substrates incorporated in the culture media. The reference and resistant, clinical strains proved to be susceptible to the A. annua oil, with MICs ranging from 0.51 to 16.33 mg/ml. The tested essential oil also showed good antibiofilm activity, inhibiting both the initial stage of the microbial cell adhesion to the inert substratum and the preformed mature biofilm. When used at subinhibitory concentrations, the essential oil proved to inhibit the phenotypic expression of five soluble virulence factors (hemolysins, gelatinase, DNase, lipases, and lecithinases). Briefly, the present results showed that the A. annua essential oil contained antimicrobial compounds with selective activity on Gram-positive and Gram-negative bacterial strains as well as on yeast strains and which also interfere with the expression of cell-associated and soluble virulence factors. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

The effect of Artemisia annua on broiler performance, on intestinal microbiota and on the course of a Clostridium perfringens infection applying a necrotic enteritis disease model.

PubMed

Engberg, Ricarda Margarete; Grevsen, Kai; Ivarsen, Elise; Fretté, Xavier; Christensen, Lars Porskjær; Højberg, Ole; Jensen, Bent Borg; Canibe, Nuria

2012-01-01

The aerial parts of the plant Artemisia annua contain essential oils having antimicrobial properties against Clostridium perfringens Type A, the causal agent for necrotic enteritis in broilers. In two experiments, the influence of increasing dietary concentrations of dried A. annua leaves (0, 5, 10 and 20 g/kg) and n-hexane extract from fresh A. annua leaves (0, 125, 250 and 500 mg/kg) on broiler performance was investigated. Dried plant material decreased feed intake and body weight in a dose-dependent manner, and 10 and 20 g/kg diet tended to improve the feed conversion ratio. The n-hexane extract also reduced feed intake, but broiler weight tended to decrease only at the highest dietary concentration. The feed conversion ratio tended to improve when birds received 250 and 500 mg/kg n-hexane extract. In a third experiment, a necrotic enteritis disease model was applied to investigate the effect of the dietary addition of dried A. annua leaves (10 g/kg on top) or n-hexane extract of A. annua (250 mg/kg) on the severity of the disease in broilers. The addition of n-hexane extract reduced the intestinal C. perfringens numbers and the severity of the disease-related small intestinal lesions. Over the infection period from day 17 to day 27, birds supplemented with the n-hexane extract gained more weight than both the challenged control birds and birds receiving dried plant material. The results indicate that n-hexane extracts derived from A. annua can modulate the course of necrotic enteritis and compensate to a certain extent for the disease-associated weight losses.

An in-silico insight into the substrate binding characteristics of the active site of amorpha-4, 11-diene synthase, a key enzyme in artemisinin biosynthesis.

PubMed

Eslami, Habib; Mohtashami, Seyed Kaveh; Basmanj, Maryam Taghavi; Rahati, Maryam; Rahimi, Hamzeh

2017-07-01

The enzyme amorphadiene synthase (ADS) conducts the first committed step in the biosynthetic conversion of the substrate farnesyl pyrophosphate (FPP) to artemisinin, which is a highly effective natural product against multidrug-resistant strains of malaria. Due to the either low abundance or low turn-over rate of the enzyme, obtaining artemisinin from both natural and synthetic sources is costly and laborious. In this in silico study, we strived to elucidate the substrate binding site specificities of the ADS, with the rational that unraveling enzyme features paves the way for enzyme engineering to increase synthesis rate. A homology model of the ADS from Artemisia annua L. was constructed based on the available crystal structure of the 5-epiaristolochene synthase (TEAS) and further analyzed with molecular dynamic simulations to determine residues forming the substrate recognition pocket. We also investigated the structural aspects of Mg 2+ binding. Results revealed DDYTD and NDLMT as metal-binding motifs in the putative active site gorge, which is composed of the D and H helixes and one loop region (aa519-532). Moreover, several representative residues including Tyr519, Asp444, Trp271, Asn443, Thr399, Arg262, Val292, Gly400 and Leu405, determine the FPP binding mode and its fate in terms of stereochemistry as well as the enzyme fidelity for the specific end product. These findings lead to inferences concerning key components of the ADS catalytic cavity, and provide evidence for the spatial localization of the FPP and Mg 2+ . Such detailed understanding will probably help to design an improved enzyme.

Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells.

PubMed

Melillo de Magalhães, Pedro; Dupont, Isabelle; Hendrickx, Aurélie; Joly, Aurélie; Raas, Thomas; Dessy, Stéphanie; Sergent, Thérèse; Schneider, Yves-Jacques

2012-09-15

In an attempt to understand the beneficial health effects of Artemisia annua other than its anti-malaria properties, extracts from different cultivars prepared as tea infusions were investigated using Caco-2 cells on the intestinal inflammation and cytochrome P450 (CYP) activities. The characterisation of their phenolic compound (PC) profile revealed rosmarinic and chlorogenic acids as the main PCs. The extracts, assayed on Caco-2 cells at a plausible intestinal concentration, significantly decreased the secretion of pro-inflammatory cytokines, IL-8 and IL-6. This effect could be attributable at least to their content in rosmarinic acid, detected as a potent anti-inflammatory compound. The extracts also inhibited the activity of CYP3A4, whose expression was induced by 1,25-dihydroxyvitamin D(3), and of CYP1A1, induced by benzo(a)pyrene. Our results highlight the advantage of drinking A. annua infusions for their potent anti-inflammatory effect, linked to PC content, which could synergise their antimalarial activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Anti-Helicobacter pylori Potential of Artemisinin and Its Derivatives

PubMed Central

Goswami, Suchandra; Chinniah, Annalakshmi; Pal, Anirban; Kar, Sudip K.

2012-01-01

The antimalarial drug artemisinin from Artemisia annua demonstrated remarkably strong activity against Helicobacter pylori, the pathogen responsible for peptic ulcer diseases. In an effort to develop a novel antimicrobial chemotherapeutic agent containing such a sesquiterpene lactone endoperoxide, a series of analogues (2 natural and 15 semisynthetic molecules), including eight newly synthesized compounds, were investigated against clinical and standard strains of H. pylori. The antimicrobial spectrum against 10 H. pylori strains and a few other bacterial and fungal strains indicated specificity against the ulcer causing organism. Of five promising molecules, a newly synthesized ether derivative β-artecyclopropylmether was found to be the most potent compound, which exhibited MIC range, MIC90, and minimum bactericidal concentration range values of 0.25 to 1.0 μg/ml, 1.0 μg/ml, and 1 to 16 μg/ml, respectively, against both resistant and sensitive strains of H. pylori. The molecule demonstrated strong bactericidal kinetics with extensive morphological degeneration, retained functional efficacy at stomach acidic pH unlike clarithromycin, did not elicit drug resistance unlike metronidazole, and imparted sensitivity to resistant strains. It is not cytotoxic and exhibits in vivo potentiality to reduce the H. pylori burden in a chronic infection model. Thus, β-artecyclopropylmether could be a lead candidate for anti-H. pylori therapeutics. Since the recurrence of gastroduodenal ulcers is believed to be mainly due to antibiotic resistance of the commensal organism H. pylori, development of a candidate drug from this finding is warranted. PMID:22687518

Dihydroartemisinin alleviates bile duct ligation-induced liver fibrosis and hepatic stellate cell activation by interfering with the PDGF-βR/ERK signaling pathway.

PubMed

Chen, Qin; Chen, Lianyun; Kong, Desong; Shao, Jiangjuan; Wu, Li; Zheng, Shizhong

2016-05-01

Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs), which is a pivotal event during liver fibrogenesis, is accompanied by enhanced expressions of a series of marker proteins and pro-fibrogenic signaling molecules. Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb Artemisia annua L., and can inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to attenuate lung injury and fibrosis. However, the effect of DHA on liver fibrosis remains unclear. The aim of this study was to investigate the effect of DHA on bile duct ligation-induced injury and fibrosis in rats. DHA improved the liver histological architecture and attenuated collagen deposition in the fibrotic rat liver. Experiments in vitro showed that DHA inhibited the proliferation of HSCs and arrested the cell cycle at the S checkpoint by altering several cell-cycle regulatory proteins. Moreover, DHA reduced the protein expressions of a-SMA, α1 (I) collagen and fibronectin, being associated with interference of the platelet-derived growth factor β receptor (PDGF-βR)-mediated ERK pathway. These data collectively revealed that DHA relieved liver fibrosis possibly by targeting HSCs via the PDGF-βR/ERK pathway. DHA may be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Use of Artemisia annua as a natural coccidiostat in free-range broilers and its effects on infection dynamics and performance.

PubMed

de Almeida, Gustavo F; Horsted, Klaus; Thamsborg, Stig M; Kyvsgaard, Niels C; Ferreira, Jorge F S; Hermansen, John E

2012-05-25

This work investigated the preventive effect of Artemisia annua L. dried leaves supplied as a botanical coccidiostat to two broiler genotypes reared in a Danish free-range system in a factorial experiment (two genotypes and ± supplement of dried A. annua leaves). The genotypes White Bresse L40, a pure slow-growing line, and Kosmos 8 Ross, a hybrid genotype with medium growing characteristics, were used. Broilers were raised indoor until 29-days-old and kept free of parasites. Twelve groups of 30 randomly selected broilers were placed in the range forming three replicates for each treatment combination. The paddocks were cultivated with a mix of grass and clover. A separate group of broilers was naturally infected with Eimeria spp. oocysts and five animals nominated as "seeders" were introduced to the above mentioned 12 groups, 10 days after its formation, with each group consisting of 35 animals per plot. This infection strategy was meant to imitate the transmission pathway observed at farm level. Ten individual birds from each of the 12 groups, in total 120 animals of mixed sex, were monitored twice weekly for 30 days for oocysts excretion. PCR of pooled faecal samples, oocyst morphology and localization upon necropsy were used to identify the Eimeria species involved in the infection. In general, broilers from both genotypes in the range coped well with a coccidia infection caused by Eimeria acervulina and Eimeria maxima as no clinical symptoms, or deaths, were reported during the experiment. In general, broilers supplemented with A. annua dried leaves showed a significantly (p<0.05) reduced number of excreted oocysts during the infection with no interaction to genotype. Females generally had a significantly higher shedding of oocysts than males (p<0.05). The overall body weight gain and the daily weight gain when infection was subdued showed a three-way interaction among genotype, sex and treatment - accounted mainly for the fact that Kosmos females responded positively to the Artemisia treatment while Kosmos males responded negatively, and only minor differences were found between sexes for the White Bresse genotype. In conclusion, supply of A. annua dried leaves as a botanical coccidiostat significantly reduced oocyst output in free ranged broilers and thus may form part of a strategy to prevent commercial losses. Copyright © 2011 Elsevier B.V. All rights reserved.

Phytoextract-induced developmental deformities in malaria vector.

PubMed

Sharma, Preeti; Mohan, Lalit; Srivastava, C N

2006-09-01

Larvicidal potential of petroleum ether (Pee), carbon tetrachloride (Cte) and methanol extract (Mee) of Artemisia annua, Chenopodium album and Sonchus oleraceus was observed against malaria vector, Anopheles stephensi Liston. The Pee of A. annua with LC50 16.85 ppm after 24 h and 11.45 ppm after 48 h of treatment was found most effective, followed by Cte of A. annua and Ch. album, Pee of Ch. album and Mee of A. annua. However, no significant larvicidal activity was observed in Mee of Ch. album and all the three extracts of S. oleraceous. The Pee of A. annua was further investigated for its effect on the metamorphosis and the development of the malaria vector. It influenced the early life cycle of An. stephensi by reducing the percentage of hatching, larval, pupal and adult emergence and also lengthening the larval and pupal periods. The growth index was also reduced significantly. As the extract has remarkable effect on the metamorphosis and high larvicidal potential, it could, therefore, be used as an effective biocontrol agent against the highly nuisant malaria vector.

Simple Field Assays to Check Quality of Current Artemisinin-Based Antimalarial Combination Formulations

PubMed Central

Ioset, Jean-Robert; Kaur, Harparkash

2009-01-01

Introduction Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin) derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO) has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT) for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. Methods and Findings Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride) salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP - artesunate/amodiaquine, Coartem®-artemether/lumefantrine and Duocortexcin - dihydroartemisinin/piperaquine). The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. Conclusions Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible, inexpensive and, have successfully resulted in detecting two counterfeit drugs within a small scale screening survey of over 100 declared artemisinin-containing drugs collected from various Asian and African countries. These promising results indicate that the assays will provide a useful first test to assure the quality of the ACTs formulations in resource poor malaria endemic areas when there is an absence of dedicated medicines quality laboratory facilities. PMID:19789707

Comparative transcriptomic analysis of key genes involved in flavonoid biosynthetic pathway and identification of a flavonol synthase from Artemisia annua L.

PubMed

Liu, S; Liu, L; Tang, Y; Xiong, S; Long, J; Liu, Z; Tian, N

2017-07-01

The regulatory mechanism of flavonoids, which synergise anti-malarial and anti-cancer compounds in Artemisia annua, is still unclear. In this study, an anthocyanidin-accumulating mutant callus was induced from A. annua and comparative transcriptomic analysis of wild-type and mutant calli performed, based on the next-generation Illumina/Solexa sequencing platform and de novo assembly. A total of 82,393 unigenes were obtained and 34,764 unigenes were annotated in the public database. Among these, 87 unigenes were assigned to 14 structural genes involved in the flavonoid biosynthetic pathway and 37 unigenes were assigned to 17 structural genes related to metabolism of flavonoids. More than 30 unigenes were assigned to regulatory genes, including R2R3-MYB, bHLH and WD40, which might regulate flavonoid biosynthesis. A further 29 unigenes encoding flavonoid biosynthetic enzymes or transcription factors were up-regulated in the mutant, while 19 unigenes were down-regulated, compared with the wild type. Expression levels of nine genes involved in the flavonoid pathway were compared using semi-quantitative RT-PCR, and results were consistent with comparative transcriptomic analysis. Finally, a putative flavonol synthase gene (AaFLS1) was identified from enzyme assay in vitro and in vivo through heterogeneous expression, and confirmed comparative transcriptomic analysis of wild-type and mutant callus. The present work has provided important target genes for the regulation of flavonoid biosynthesis in A. annua. © 2017 German Botanical Society and The Royal Botanical Society of the Netherlands.

Application of Partial Internal Transcribed Spacer Sequences for the Discrimination of Artemisia capillaris from Other Artemisia Species

PubMed Central

Doh, Eui Jeong; Paek, Seung-Ho; Lee, Guemsan; Lee, Mi-Young; Oh, Seung-Eun

2016-01-01

Several Artemisia species are used as herbal medicines including the dried aerial parts of Artemisia capillaris, which are used as Artemisiae Capillaris Herba (known as “Injinho” in Korean medicinal terminology and “Yin Chen Hao” in Chinese). In this study, we developed tools for distinguishing between A. capillaris and 11 other Artemisia species that grow and/or are cultured in China, Japan, and Korea. Based on partial nucleotide sequences in the internal transcribed spacer (ITS) that differ between the species, we designed primers to amplify a DNA marker for A. capillaris. In addition, to detect other Artemisia species that are contaminants of A. capillaris, we designed primers to amplify DNA markers of A. japonica, A. annua, A. apiacea, and A. anomala. Moreover, based on random amplified polymorphic DNA analysis, we confirmed that primers developed in a previous study could be used to identify Artemisia species that are sources of Artemisiae Argyi Folium and Artemisiae Iwayomogii Herba. By using these primers, we found that multiplex polymerase chain reaction (PCR) was a reliable tool to distinguish between A. capillaris and other Artemisia species and to identify other Artemisia species as contaminants of A. capillaris in a single PCR. PMID:27313651

Applying high-resolution melting (HRM) technology to identify five commonly used Artemisia species.

PubMed

Song, Ming; Li, Jingjian; Xiong, Chao; Liu, Hexia; Liang, Junsong

2016-10-04

Many members of the genus Artemisia are important for medicinal purposes with multiple pharmacological properties. Often, these herbal plants sold on the markets are in processed forms so it is difficult to authenticate. Routine testing and identification of these herbal materials should be performed to ensure that the raw materials used in pharmaceutical products are suitable for their intended use. In this study, five commonly used Artemisia species included Artemisia argyi, Artemisia annua, Artemisia lavandulaefolia, Artemisia indica, and Artemisia atrovirens were analyzed using high resolution melting (HRM) analysis based on the internal transcribed spacer 2 (ITS2) sequences. The melting profiles of the ITS2 amplicons of the five closely related herbal species are clearly separated so that they can be differentiated by HRM method. The method was further applied to authenticate commercial products in powdered. HRM curves of all the commercial samples tested are similar to the botanical species as labeled. These congeneric medicinal products were also clearly separated using the neighbor-joining (NJ) tree. Therefore, HRM method could provide an efficient and reliable authentication system to distinguish these commonly used Artemisia herbal products on the markets and offer a technical reference for medicines quality control in the drug supply chain.

Inhibition of Phenylpropanoid Biosynthesis in Artemisia annua L.: A Novel Approach to Reduce Oxidative Browning in Plant Tissue Culture

PubMed Central

Jones, Andrew Maxwell Phineas; Saxena, Praveen Kumar

2013-01-01

Oxidative browning is a common and often severe problem in plant tissue culture systems caused by the accumulation and oxidation of phenolic compounds. The current study was conducted to investigate a novel preventative approach to address this problem by inhibiting the activity of the phenylalanine ammonia lyase enzyme (PAL), thereby reducing the biosynthesis of phenolic compounds. This was accomplished by incorporating 2-aminoindane-2-phosphonic acid (AIP), a competitive PAL inhibitor, into culture media of Artemisia annua as a model system. Addition of AIP into culture media resulted in significant reductions in visual tissue browning, a reduction in total phenol content, as well as absorbance and autoflourescence of tissue extracts. Reduced tissue browning was accompanied with a significant increase in growth on cytokinin based medium. Microscopic observations demonstrated that phenolic compounds accumulated in discrete cells and that these cells were more prevalent in brown tissue. These cells were highly plasmolyzed and often ruptured during examination, demonstrating a mechanism in which phenolics are released into media in this system. These data indicate that inhibiting phenylpropanoid biosynthesis with AIP is an effective approach to reduce tissue browning in A. annua. Additional experiments with Ulmus americana and Acer saccharum indicate this approach is effective in many species and it could have a wide application in systems where oxidative browning restricts the development of biotechnologies. PMID:24116165

Artesunate inhibits adipogeneis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, Byeong-Churl, E-mail: jangbc123@gw.kmu.ac.kr

Differentiation of preadipocyte, also called adipogenesis, leads to the phenotype of mature adipocyte. However, excessive adipogenesis is closely linked to the development of obesity. Artesunate, one of artemisinin-type sesquiterpene lactones from Artemisia annua L., is known for anti-malarial and anti-cancerous activities. In this study, we investigated the effect of artesunate on adipogenesis in 3T3-L1 preadipocytes. Artesunate strongly inhibited lipid accumulation and triglyceride (TG) synthesis during the differentiation of 3T3-L1 preadipocytes into adipocytes at 5 μM concentration. Artesunate at 5 μM also reduced not only the expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A butmore » also the phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) during adipocyte differentiation. Moreover, artesunate at 5 μM reduced leptin, but not adiponectin, mRNA expression during adipocyte differentiation. Taken together, these findings demonstrate that artesunate inhibits adipogenesis in 3T3-L1 preadipoytes through the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. -- Highlights: •Artesunate, an artemisinin derivative, inhibits adipogenesis. •Artesunate inhibits C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3 in 3T3-L1 adipocytes. •Artesunate reduces leptin, but not adiponectin, expression in 3T3-L1 adipocytes. •Artesunate thus may have therapeutic potential against obesity.« less

Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy

PubMed Central

ZHANG, ZE-SHUN; WANG, JING; SHEN, YOU-BI; GUO, CHENG-CHENG; SAI, KE; CHEN, FU-RONG; MEI, XIN; HAN, FU; CHEN, ZHONG-PING

2015-01-01

Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb, Artemisia annua L., and has the ability to inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to inhibit the growth of a variety of types of human cancer. However, the effect of DHA on human glioma cells remains unclear. The aim of the present study was to investigate the effect of DHA on the proliferation of glioma cells, and whether DHA was able to enhance temozolomide (TMZ) sensitivity in vitro and in vivo. In total, 10 human glioma cell lines were used to analyze the growth inhibition ability of DHA by MTT assay. The typical autophagic vacuoles were monitored by the application of the autofluorescent agent, monodansylcadaverine. Western blotting was used to detect markers of apoptosis and autophagy, namely Caspase-3, Beclin-1 and LC3-B. The combination efficiency of DHA and TMZ was assessed in vitro and in vivo. The half maximal inhibitory concentration (IC50) of DHA differed among the ten human glioma cell lines. The number of autophagic vacuoles was higher in DHA-treated SKMG-4 cells; this was highest of all cell lines analyzed. The expression of autophagy molecular markers, Beclin-1 and LC3-B, was increased following DHA treatment, while no significant alteration was detected in the expression of apoptotic marker Caspase-3. When combined with DHA, the IC50 of TMZ decreased significantly in the four glioma cell lines analyzed. Furthermore, DHA enhanced the tumor inhibition ability of TMZ in tumor-burdened mice. The results of the present study demonstrated that DHA inhibited the proliferation of glioma cells and enhanced the tumor inhibition efficacy of TMZ in vitro and in vivo through the induction of autophagy. PMID:26171034

Study of artemisinin and sugar accumulation in Artemisia vulgaris and Artemisia dracunculus "hairy" root cultures.

PubMed

Drobot, Kateryna O; Matvieieva, Nadiia A; Ostapchuk, Andriy M; Kharkhota, Maxim A; Duplij, Volodymyr P

2017-09-14

We studied the effect of genetic transformation on biologically active compound (artemisinin and its co-products (ART) as well as sugars) accumulation in Artemisia vulgaris and Artemisia dracunculus "hairy" root cultures. Glucose, fructose, sucrose, and mannitol were accumulated in A. vulgaris and A. dracunculus "hairy" root lines. Genetic transformation has led in some cases to the sugar content increasing or appearing of nonrelevant for the control plant carbohydrates. Sucrose content was 1.6 times higher in A. vulgaris "hairy" root lines. Fructose content was found to be 3.4 times higher in A. dracunculus "hairy" root cultures than in the control roots. The accumulation of mannitol was a special feature of the leaves of A. vulgaris and A. dracunculus control roots. A. vulgaris "hairy" root lines differed also in ART accumulation level. The increase of ART content up to 1.02 mg/g DW in comparison with the nontransformed roots (up to 0.687 mg/g DW) was observed. Thus, Agrobacterium rhizogenes-mediated genetic transformation can be used for obtaining of A. vulgaris and A. dracunculus "hairy" root culture produced ART and sugars in a higher amount than mother plants.

Metabolic analysis of the increased adventitious rooting mutant of Artemisia annua reveals a role for the plant monoterpene borneol in adventitious root formation.

PubMed

Tian, Na; Liu, Shuoqian; Li, Juan; Xu, Wenwen; Yuan, Lin; Huang, Jianan; Liu, Zhonghua

2014-08-01

Adventitious root (AR) formation is a critical process for plant clonal propagation. The role of plant secondary metabolites in AR formation is still poorly understood. Chemical and physical mutagenesis in combination with somatic variation were performed on Artemisia annua in order to obtain a mutant with changes in adventitious rooting and composition of plant secondary metabolites. Metabolic and morphological analyses of the iar (increased adventitious rooting) mutant coupled with in vitro assays were used to elucidate the relationship between plant secondary metabolites and AR formation. The only detected differences between the iar mutant and wild-type were rooting capacity and borneol/camphor content. Consistent with this, treatment with borneol in vitro promoted adventitious rooting in wild-type. The enhanced rooting did not continue upon removal of borneol. The iar mutant displayed no significant differences in AR formation upon treatment with camphor. Together, our results suggest that borneol promotes adventitious rooting whereas camphor has no effect on AR formation. © 2013 Scandinavian Plant Physiology Society.

Biomass Production of Hairy Roots of Artemisia annua and Arachis hypogaea in a Scaled-Up Mist Bioreactor

PubMed Central

Sivakumar, Ganapathy; Liu, Chunzhao; Towler, Melissa J.

2014-01-01

Hairy roots have the potential to produce a variety of valuable small and large molecules. The mist reactor is a gas phase bioreactor that has shown promise for low-cost culture of hairy roots. Using a newer, disposable culture bag, mist reactor performance was studied with two species, Artemisia annua L. and Arachis hypogaea (peanut), at scales from 1 to 20 L. Both species of hairy roots when grown at 1 L in the mist reactor showed growth rates that surpassed that in shake flasks. From the information gleaned at 1 L, Arachis was scaled further to 4 and then 20 L. Misting duty cycle, culture medium flow rate, and timing of when flow rate was increased were varied. In a mist reactor increasing the misting cycle or increasing the medium flow rate are the two alternatives for increased delivery of liquid nutrients to the root bed. Longer misting cycles beyond 2–3 min were generally deemed detrimental to growth. On the other hand, increasing the medium flow rate to the sonic nozzle especially during the exponential phase of root growth (weeks 2–3) was the most important factor for increasing growth rates and biomass yields in the 20 L reactors. A. hypogaea growth in 1 L reactors was μ = 0.173 day−1 with biomass yield of 12.75 g DWL−1. This exceeded that in shake flasks at μ = 0.166 day−1 and 11.10 g DWL−1. Best growth rate and biomass yield at 20 L was μ = 0.147 and 7.77 g DWL−1, which was mainly achieved when medium flow rate delivery was increased. The mist deposition model was further evaluated using this newer reactor design and when the apparent thickness of roots (+hairs) was taken into account, the empirical data correlated with model predictions. Together these results establish the most important conditions to explore for future optimization of the mist bioreactor for culture of hairy roots. PMID:20687140

Flavonoids casticin and chrysosplenol D from Artemisia annua L. inhibit inflammation in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yu-Jie; Guo, Yan; Yang, Qing

Background: The aim of our experiments was to investigate the anti-inflammatory properties of casticin and chrysosplenol D, two flavonoids present in Artemisia annua L. Methods: Topical inflammation was induced in ICR mice using croton oil. Mice were then treated with casticin or chrysosplenol D. Cutaneous histological changes and edema were assessed. ICR mice were intragastrically administrated with casticin or chrysosplenol D followed by intraperitoneal injection of lipopolysaccharide (LPS). Mouse Raw264.7 macrophage cells were incubated with casticin or chrysosplenol D. Intracellular phosphorylation was detected, and migration was assessed by trans-well assay. HT-29/NFκB-luc cells were incubated with casticin or chrysosplenol D inmore » the presence or absence of LPS, and NF-κB activation was quantified. Results: In mice, administration of casticin (0.5, 1 and 1.5 μmol/cm{sup 2}) and chrysosplenol D (1 and 1.5 μmol/cm{sup 2}) inhibited croton oil-induced ear edema (casticin: 29.39–64.95%; chrysosplenol D: 37.76–65.89%, all P < 0.05) in a manner similar to indomethacin (0.5, 1 and 1.5 μmol/cm{sup 2}; 55.63–84.58%). Casticin (0.07, 0.13 and 0.27 mmol/kg) and chrysosplenol D (0.07, 0.14 and 0.28 mmol/kg) protected against LPS-induced systemic inflammatory response syndrome (SIRS) in mice (all P < 0.05), in a manner similar to dexamethasone (0.03 mmol/kg). Casticin and chrysosplenol D suppressed LPS-induced release of IL-1 beta, IL-6 and MCP-1, inhibited cell migration, and reduced LPS-induced IκB and c-JUN phosphorylation in Raw264.7 cells. JNK inhibitor SP600125 blocked the inhibitory effect of chrysosplenol D on cytokine release. Conclusions: The flavonoids casticin and chrysosplenol D from A. annua L. inhibited inflammation in vitro and in vivo. - Highlights: • We report a new activity of the flavonoids present in Artemisia annua L. • These flavonoids inhibit croton oil-induced ear edema in mice. • These flavonoids protect against LPS-induced SIRS in mice. • These flavonoids suppress inflammation through NF-κB and c-JUN.« less

Dihydroartemisinin sensitizes Lewis lung carcinoma cells to carboplatin therapy via p38 mitogen-activated protein kinase activation

PubMed Central

Zhang, Bicheng; Zhang, Zhimin; Wang, Jun; Yang, Bo; Zhao, Yong; Rao, Zhiguo; Gao, Jianfei

2018-01-01

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua, is an effective novel antimalarial agent. Studies have suggested that it also exhibits anticancer effects when administered alone or in combination with conventional chemotherapeutic agents. The present study investigated the therapeutic effect of DHA combined with carboplatin (CBP) on Lewis lung carcinoma (LLC) cells and the possible underlying molecular mechanisms. MTT and clonogenic assays demonstrated that the proliferation activity of LLC cells was inhibited in a dose-dependent manner by DHA combined with CBP. In addition, flow cytometry analysis revealed that cell cycle arrest was induced at the G0/G1 phase and apoptosis was induced following treatment with the combination. When administered in combination with CBP, DHA exhibited more effective anticancer activity compared with DHA or CBP used alone, via increased apoptosis. Following treatment with DHA with or without CBP, the expression of phosphorylated-p38 mitogen-activated protein kinase (MAPK), which can be inhibited with the selective inhibitor SB202190, was detected by western blotting. To summarize, the results of the present study indicated that DHA may sensitize LLC cells to CBP therapy via the activation of p38MAPK, which suggests that a combined treatment of DHA and CBP may be a potential novel therapeutic schedule for lung adenocarcinoma. PMID:29740482

Evaluation of DNA barcode candidates for the discrimination of Artemisia L.

PubMed

Liu, Geyu; Ning, Huixia; Ayidaerhan, Nurbolati; Aisa, Haji Akber

2017-11-01

Because of the very similar morphologies and wide diversity of Artemisia L. varieties, they are difficult to identify, and there have been many arguments about the systematic classification Artemisia L., especially concerning the division of species. DNA barcode technology is used to rapidly identify species based on standard short DNA sequences. To evaluate seven candidate DNA barcodes (ITS, ITS2, psbA-trnH, rbcL, matK, rpoB, and rpoC1) regarding their ability to identify closely related species of the Artemisia genus in Xinjiang. The corresponding PCR amplification efficiency, detectable genetic divergence, identification efficiency and phylogenetic tree were assessed. We found that the internal transcribed spacer (ITS) region exhibited the highest interspecific divergence, which was significantly higher than the observed intraspecific variation and showed the highest identification efficiency, followed by ITS2, psbA-trnH and, finally, rpoB. matK, rbcL, and rpoC1 performed poorly in this evaluation. ITS, ITS2, and psbA-trnH were able to perfectly identify the tested species Artemisia annua, A. absinthium, A. rupestris, A. tonurnefortiana, A. austriaca, A. dracunculus, A. vulgaris, and A. macrocephala. Therefore, we propose the ITS, ITS2, and psbA-trnH regions as promising DNA barcodes for the closely related species of Artemisia L. in Xinjiang.

Cloning and Functional Characterization of a β-Pinene Synthase from Artemisia annua That Shows a Circadian Pattern of Expression1

PubMed Central

Lu, Shan; Xu, Ran; Jia, Jun-Wei; Pang, Jihai; Matsuda, Seiichi P.T.; Chen, Xiao-Ya

2002-01-01

Artemisia annua plants produce a broad range of volatile compounds, including monoterpenes, which contribute to the characteristic fragrance of this medicinal species. A cDNA clone, QH6, contained an open reading frame encoding a 582-amino acid protein that showed high sequence identity to plant monoterpene synthases. The prokaryotically expressed QH6 fusion protein converted geranyl diphosphate to (−)-β-pinene and (−)-α-pinene in a 94:6 ratio. QH6 was predominantly expressed in juvenile leaves 2 weeks postsprouting. QH6 transcript levels were transiently reduced following mechanical wounding or fungal elicitor treatment, suggesting that this gene is not directly involved in defense reaction induced by either of these treatments. Under a photoperiod of 12 h/12 h (light/dark), the abundance of QH6 transcripts fluctuated in a diurnal pattern that ebbed around 3 h before daybreak (9th h in the dark phase) and peaked after 9 h in light (9th h in the light phase). The contents of (−)-β-pinene in juvenile leaves and in emitted volatiles also varied in a diurnal rhythm, correlating strongly with mRNA accumulation. When A. annua was entrained by constant light or constant dark conditions, QH6 transcript accumulation continued to fluctuate with circadian rhythms. Under constant light, advanced cycles of fluctuation of QH6 transcript levels were observed, and under constant dark, the cycle was delayed. However, the original diurnal pattern could be regained when the plants were returned to the normal light/dark (12 h/12 h) photoperiod. This is the first report that monoterpene biosynthesis is transcriptionally regulated in a circadian pattern. PMID:12226526

Effect of Sweet Wormwood Artemisia annua Crude Leaf Extracts on Some Biological and Physiological Characteristics of the Lesser Mulberry Pyralid, Glyphodes pyloalis

PubMed Central

Khosravi, Roya; Sendi, Jalal Jalali; Ghadamyari, Mohammad; Yezdani, Elham

2011-01-01

The lesser mulberry pyralid, Glyphodes pyloalis Walker (Lepidoptera: Pyralidae) is a monophagous and dangerous pest of mulberry that has been recently observed in Guilan province, northern Iran. In this study, the crude methanol extract of sweet wormwood Artemisia annua L. (Asterales: Asteracaea) was investigated on toxicity, biological and physiological characteristics of this pest under controlled conditions (24 ± 1 °C, 75 ± 5% RH, and 16:8 L:D photoperiod). The effect of acute toxicity and sublethal doses on physiological characteristics was performed by topical application. The LC50 and LC20 values on fourth instar larvae were calculated as 0.33 and 0.22 gram leaf equivalent/ mL, respectively. The larval duration of fifth instar larvae in LC50 treatment was prolonged (5.8 ± 0.52 days) compared with the control group (4.26 ± 0.29 days). However larval duration was reduced in the LC20 treatment. The female adult longevity in the LC50 dose was the least (4.53 ± 0.3 days), while longevity among controls was the highest (9.2 ± 0.29 days). The mean fecundity of adults after larval treatment with LC50 was recorded as 105.6 ± 16.84 eggs/female, while the control was 392.74 ± 22.52 eggs/female. The percent hatchability was reduced in all treatments compared with the control. The effect of extract in 0.107, 0.053, 0.026 and 0.013 gle/mL on biochemical characteristics of this pest was also studied. The activity of α-amylase and protease 48 hours post—treatment was significantly reduced compared with the control. Similarly lipase, esterase, and glutathione S-transferase activity were significantly affected by A. annua extract. PMID:22239100

Effect of varying ratios of produced water and municipal water on soil characteristics, plant biomass, and secondary metabolites of Artemisia annua and Panicum virgatum

USDA-ARS?s Scientific Manuscript database

Coal-bed natural gas production in the U.S. in 2012 was 1,655 billion cubic feet (bcf). A by-product of this production is co-produced water, which is categorized as a waste product by the Environmental Protection Agency. The effects of varying concentrations of coal-bed methane (produced) water wer...

Biosynthesis of silver nanoparticles using Artemisia annua callus for inhibiting stem-end bacteria in cut carnation flowers.

PubMed

Xia, Qian Hua; Zheng, Li Ping; Zhao, Pei Fei; Wang, Jian Wen

2017-03-01

A biological method for synthesising silver nanoparticles (AgNPs) was developed using the callus extracts from Artemisia annua L. under sunlight at 25,000 lx. The AgNPs were characterised using transmission electron microscopy, atomic force microscope, X-ray diffraction and Fourier transform infrared spectroscopy. The AgNPs were mostly spherical with the size of 2.1 to 45.2 nm (average 10.9 nm). Pulse treatments of AgNPs at 125, 250 and 500 mg/l for 1 h extended vase life of cut carnation ( Dianthus caryophyllus cv. Green Land) flowers. Four dominant bacteria strains Arthrobacter arilaitensis, Kocuria sp., Staphylococcus equorum and Microbacterium oxydans were isolated from the stem-ends of cut D. caryophyllus flowers. AgNP pulse inhibited significantly bacterial growth in vase solution and cut stem ends during all of the vase period. The bacteria related blockage in the stem-ends was significantly alleviated by AgNP pulse because of its higher antibacterial efficacy against the dominant bacteria. In addition, ethylene release of cut carnation flowers was inhibited in response to AgNP pulse. This is the first time that the biologically synthesised AgNPs could be applied as a promising preservative agent for cut carnation flowers.

Some popular medicinal plants and diseases of the Upper Palaeolithic in Western Georgia.

PubMed

Martkoplishvili, Inga; Kvavadze, Eliso

2015-05-26

Palynological studies of cultural layers of cave sediments have been used in order to better understand traditional practices. The Upper Palaeolithic in Georgia (36,000-11,000 cal. BP) provides a rich source of such material. However, up to day from such sediments the identification of medicinal plants has hardly been achieved. Large quantities of pollen most notably from entomophilous taxa in fossil spectra can serve as a tool to identify traditionally important species. As these plants are used in modern popular medicine on the territory of Georgia (like Achillea millefolium L., Artemisia annua L., Artemisia absinthium L., Centaurea jacea L., Urtica dioica L.) can be served as an indirect evidence for their medicinal relevance from the Palaeolithic Period up to days. Their modern uses may point that the main diseases during the Upper Palaeolithic were the same as today. The Upper Palaeolithic sediments were studied palynologically come from four caves: Dzudzuana, Satsurblia, Kotias Klde and Bondi. Modern sediments were investigated from 6 caves. Fossil and modern samples were taken according to the standard procedure in palynology. The laboratory treatment was carried out as follows: first, 50g of the sample was boiled in 10% KOH. At the second stage, centrifuging of the material in cadmium liquid was performed. At the final stage, acetolysis treatment was used. Pollen of A. absinthium L. (Asteraceae), A. annua L. (Asteraceae), A. millefolium L. (Asteraceae), C. jacea L. (Asteraceae), and U. dioica L. (Urticaceae) are identified to species level. This species are not edible and are popular in present-day folk medicine. In the Upper Palaeolithic layers, significant amounts of studies species pollen were recorded in the cave, likely due to their flowering branches being brought in by humans for use. Detailed consideration of the pharmacological characteristics of the examined species showed that almost all of them have anti-inflammatory, antibacterial, antimicrobial and antipyretic activity. The fossil pollen complex of medicinal herbs, dominated by A. millefolium and Artemisia (A. annua and A. absinthium), suggests that the ancient population living in the studied caves could have been prone to malaria, rheumatism and gastrointestinal diseases. In the Upper Palaeolithic, the population inhabiting cave sites might have suffered from gout and callouses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Biodegradable Chitosan Magnetic Nanoparticle Carriers for Sub-Cellular Targeting Delivery of Artesunate for Efficient Treatment of Breast Cancer

NASA Astrophysics Data System (ADS)

Subramanian, Natesan; Abimanyu, Sugumaran; Vinoth, Jeevanesan; Sekar, Ponnusamy Chandra

2010-12-01

Artesunate is a semi-synthetic derivative of artemisinin, the active principle extracted from Artemisia annua. It possesses good anti-proliferative activity and anti-angiogenic activity with very low toxicity to normal healthy cells. The drawback of most cancer drugs is their inability to accumulate selectively in the cancerous cells. So, large quantities of doses have to be administered to get the required therapeutic concentration in the target site and it resulted in many serious side effects due to the exposure of healthy cells to higher concentrations of cytotoxic drugs. The problem may be solved by selectively and quantitatively accumulating the drug at target site using magnetic nanoparticles guided by an externally applied magnetic field. A modest attempt has been made in this present study, the artesunate magnetic nanoparticle was successfully formulated using two forms of chitosan and evaluated for its in-vitro characteristics like surface morphology, particle size and distribution, zeta potential, magnetic susceptibility, encapsulation efficiency, loading capacity and in-vitro drug release. The synthesized magnetite size was 73 nm and the size of developed magnetic nanoparticles of artesunate was in the range of 90 to 575 nm. Acetic acid soluble chitosan at low concentration exhibit highest encapsulation efficiency and drug loading whereas increase in water soluble chitosan concentration increases the encapsulation efficiency and drug loading in formulations. The developed chitosan magnetic nanoparticles of artesunate shows better release characteristics and may be screened for its in-vivo breast cancer activity.

Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells

PubMed Central

Lu, Ying-Ying; Chen, Tong-Sheng; Qu, Jun-Le; Pan, Wen-Liang; Sun, Lei; Wei, Xun-Bin

2009-01-01

Background Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, isolated from the traditional Chinese herb Artemisia annua, is recommended as the first-line anti-malarial drug with low toxicity. DHA has been shown to possess promising anticancer activities and induce cancer cell death through apoptotic pathways, although the molecular mechanisms are not well understood. Methods In this study, cell counting kit (CCK-8) assay was employed to evaluate the survival of DHA-treated ASTC-a-1 cells. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. Collapse of mitochondrial transmembrane potential (ΔΨm) was measured by dynamic detection under a laser scanning confocal microscope and flow cytometry analysis using Rhodamine123. Caspase-3 activities measured with or without Z-VAD-fmk (a broad spectrum caspase inhibitor) pretreatment by FRET techniques, caspase-3 activity measurement, and western blotting analysis. Results Our results indicated that DHA induced apoptotic cell death in a dose- and time-dependent manner, which was accompanied by mitochondrial morphology changes, the loss of ΔΨm and the activation of caspase-3. Conclusion These results show for the first time that DHA can inhibit proliferation and induce apoptosis via caspase-3-dependent mitochondrial death pathway in ASTC-a-1 cells. Our work may provide evidence for further studies of DHA as a possible anticancer drug in the clinical treatment of lung adenocarcinoma. PMID:19272183

Cross-reactivity between pollen extracts from six artemisia species.

PubMed

Brandys, J; Grimsøen, A; Nilsen, B M; Paulsen, B S; Park, H S; Hong, C S

1993-06-01

Pollen extracts of six different ARTEMISIA species, A. VULGARIS, A. SCOPARIA, A. PRINCEPS, A. TRIDENTATA, A. ANNUA, and A. CAMPESTRIS were compared using SDS-PAGE, IEF, immunoblotting, and immunoelectrophoretic methods. The band patterns obtained after SDS-PAGE and IEF showed a large degree of similarity between the extracts. Immunoblotting of these gels using a pool of sera from patients allergic to A. VULGARIS gave essentially the same IgE-binding band pattern with all the extracts, demonstrating an extensive degree of cross-reactivity between A. VULGARIS and the other ARTEMISIA species. FRIE using a polyspecific antiserum against A. VULGARIS showed that all the extracts contained several antigens that were immunologically identical to antigens in A. VULGARIS extract. Antigens showing immunological identity to the important A. VULGARIS allergens Ag 12 and ART V II were present in all the extracts. The cross-reactivity between A. VULGARIS and A. PRINCEPS was further verified by screening of ten Korean and nine Norwegian individual patient sera against extracts of both species in SDS-PAGE or IEF immunoblotting. Both groups of patients had essentially the same pattern of reactivity towards both pollen extracts.

Insecticidal activity of essential oils from native medicinal plants of Central Argentina against the house fly, Musca domestica (L.).

PubMed

Palacios, Sara M; Bertoni, Alberto; Rossi, Yanina; Santander, Rocío; Urzúa, Alejandro

2009-12-01

The insecticidal activity of nine essential oils (EOs) against the house fly (Musca domestica) was evaluated by placing flies in a screw-cap glass jar holding a piece of EO-treated cotton yarn. The dose necessary to kill 50% of flies (LC(50)) in 30 min was determined at 26 +/- 1 degrees C. The EOs showed LC(50) values ranging from 0.5 to 46.9 mg/dm(3). The EO from Minthostachys verticillata was the most potent insecticide (LC(50) = 0.5 mg/dm(3)) followed by EOs from Hedeoma multiflora (LC(50) = 1.3 mg/dm(3)) and Artemisia annua (LC(50) = 6.5 mg/dm(3)). The compositions of the nine EOs, obtained by hydrodistillation of medicinal herbs, were analyzed by gas chromatography/mass spectroscopy. These analyses showed that (4R)(+)-pulegone (69.70%), menthone (12.17%), and limonene (2.75%) were the principal components of M. verticillata EO. (4R)(+)-pulegone was also the main constituent (52.80%) of H. multiflora, while artemisia ketone (22.36%) and 1,8-cineole (16.67%) were the major constituents of A. annua EO. The terpene (4R)(+)-pulegone showed a lower toxicity (LC(50) = 1.7 mg/dm(3)) than M. verticillata or H. multiflora EOs. Dimethyl 2,2-dichlorovinyl phosphate, selected as a positive control, showed an LC(50) of 0.5 mg/dm(3). EOs from M. verticillata and H. multiflora show promise as natural insecticides against houseflies.

Rice Cakes Containing Dietary Fiber Supplemented with or without Artemisia Annua and Gynura Procumbens Merr. Alleviated the Risk Factors of Metabolic Syndrome.

PubMed

Yoon, Na Rae; Yoon, Sun; Lee, Seung-Min

2016-04-01

We investigated whether the consumption of Korean rice cakes enriched with dietary fiber with or without polyphenol rich plants might decrease the risk factors of metabolic syndrome (MetS). Rice cakes were manufactured using fructooligosaccharides, resistant starch, and psyllium as sources of dietary fibers with and without polyphenol rich Artemisia annua and Gynura procumbens Merr. (RC+FP and RC+F, respectively), and prepared in three forms (songpyeon, seolgidduk, and chaldduk). Ninety subjects with at least one MetS risk factor were recruited for 6 weeks of dietary intervention. Sixty subjects were finally included for the analysis. Compared to the initial values, RC+FP group had decreased levels of fasting blood glucose (FBG), HOMA-IR and blood pressure after 6 weeks, whereas RC+F group didn't have significant changes in them. Regarding the improvement of individual MetS risk factors, RC+FP group showed significant reduction in FBG and blood pressures but RC+F group only had reduction in systolic blood pressure. After the intervention, a reduction in the number of MetS risk factors was greatert in the RC+FP group than in the RC+F group. In conclusion, Dietary fiber enriched rice cakes with or without polyphenols decreased the number and/or the levels of MetS risk factors. Polyphenol rich plant components may provide additional health benefits in controlling FBG and blood pressure.

Rice Cakes Containing Dietary Fiber Supplemented with or without Artemisia Annua and Gynura Procumbens Merr. Alleviated the Risk Factors of Metabolic Syndrome

PubMed Central

2016-01-01

We investigated whether the consumption of Korean rice cakes enriched with dietary fiber with or without polyphenol rich plants might decrease the risk factors of metabolic syndrome (MetS). Rice cakes were manufactured using fructooligosaccharides, resistant starch, and psyllium as sources of dietary fibers with and without polyphenol rich Artemisia annua and Gynura procumbens Merr. (RC+FP and RC+F, respectively), and prepared in three forms (songpyeon, seolgidduk, and chaldduk). Ninety subjects with at least one MetS risk factor were recruited for 6 weeks of dietary intervention. Sixty subjects were finally included for the analysis. Compared to the initial values, RC+FP group had decreased levels of fasting blood glucose (FBG), HOMA-IR and blood pressure after 6 weeks, whereas RC+F group didn't have significant changes in them. Regarding the improvement of individual MetS risk factors, RC+FP group showed significant reduction in FBG and blood pressures but RC+F group only had reduction in systolic blood pressure. After the intervention, a reduction in the number of MetS risk factors was greatert in the RC+FP group than in the RC+F group. In conclusion, Dietary fiber enriched rice cakes with or without polyphenols decreased the number and/or the levels of MetS risk factors. Polyphenol rich plant components may provide additional health benefits in controlling FBG and blood pressure. PMID:27152297

DNA Barcode for Identifying Folium Artemisiae Argyi from Counterfeits.

PubMed

Mei, Quanxi; Chen, Xiaolu; Xiang, Li; Liu, Yue; Su, Yanyan; Gao, Yuqiao; Dai, Weibo; Dong, Pengpeng; Chen, Shilin

2016-01-01

Folium Artemisiae Argyi is an important herb in traditional Chinese medicine. It is commonly used in moxibustion, medicine, etc. However, identifying Artemisia argyi is difficult because this herb exhibits similar morphological characteristics to closely related species and counterfeits. To verify the applicability of DNA barcoding, ITS2 and psbA-trnH were used to identify A. argyi from 15 closely related species and counterfeits. Results indicated that total DNA was easily extracted from all the samples and that both ITS2 and psbA-trnH fragments can be easily amplified. ITS2 was a more ideal barcode than psbA-trnH and ITS2+psbA-trnH to identify A. argyi from closely related species and counterfeits on the basis of sequence character, genetic distance, and tree methods. The sequence length was 225 bp for the 56 ITS2 sequences of A. argyi, and no variable site was detected. For the ITS2 sequences, A. capillaris, A. anomala, A. annua, A. igniaria, A. maximowicziana, A. princeps, Dendranthema vestitum, and D. indicum had single nucleotide polymorphisms (SNPs). The intraspecific Kimura 2-Parameter distance was zero, which is lower than the minimum interspecific distance (0.005). A. argyi, the closely related species, and counterfeits, except for Artemisia maximowicziana and Artemisia sieversiana, were separated into pairs of divergent clusters by using the neighbor joining, maximum parsimony, and maximum likelihood tree methods. Thus, the ITS2 sequence was an ideal barcode to identify A. argyi from closely related species and counterfeits to ensure the safe use of this plant.

Algicidal effects of four Chinese herb extracts on bloom-forming Microcystis aeruginosa and Chlorella pyrenoidosa.

PubMed

Ye, Liangtao; Qian, Jiazhong; Jin, Song; Zuo, Shengpeng; Mei, Hui; Ma, Suming

2014-01-01

Extracts from four Chinese herbs, Phellodendri chinensis cortex, Artemisia annua L., Scutellaria baicalensis G. and Citrus reticulate peel were tested for their algicidal effects on Microcystis aeruginosa and Chlorella pyrenoidosa. The results showed that M. aeruginosa was more susceptible than C. pyrenoidosa. The growth of M. aeruginosa was significantly inhibited (p < 0.05) by the four herb extracts. Among the four herbs, P. chinensis cortex and S. baicalensis had the greatest inhibitory effects on M. aeruginosa, followed by C reticulate peel and A. annua. The 50% effective concentrations (EC50) of S. baicalensis, P chinensis cortex, C. reticulate peel and A. annua were 0.87, 0.88, 5.27 and 1 1.16 gherb L-1, respectively. The growth of C. pyrenoidosa was moderately inhibited by the herb extracts individually. The EC5o concentrations for S. baicalensis, P. chinensis cortex, C. reticulate peel andA. annua were 8.67, 11.67, 12.81 and 12.44 g herb L-1', respectively. Extract from S. baicalensis displayed stronger algicidal effects on C. pyrenoidosa than the other three herbs, although no lethal effect on C. pyrenoidosa was observed during the cultivation period. Compared with corresponding individual extract at the same dosage, the binary mixtures of the four herb extracts enhanced the algicidal effects on M. aeruginosa. The maximum inhibitory rates of all binary mixtures of the four herb extracts were all above 92% during the 10-day incubation. The results demonstrate that Chinese herbs, such as P. chinensis cortex or S. baicalensis and their combinations, could offer an effective alternative for mitigating outbreaks of harmful algal blooms in water bodies.

Dietary modulation of avian coccidiosis.

PubMed

Allen, P C; Danforth, H D; Augustine, P C

1998-07-01

During the past several years, our laboratory has been investigating the anticoccidial activities of various natural products that have potential use as dietary supplements for coccidiosis control. Sources of fats containing high concentrations of n-3 fatty acids such as menhaden oil and flaxseed oil and flaxseed, when added to starter rations and fed to chicks from one day of age, effectively reduce lesions caused by the caecal parasite Eimeria tenella, but not lesions caused by Eimeria maxima. Our results are consistent with reports of effects of diets high in n-3 fatty acids on other protozoan parasites which suggest that the state of oxidative stress induced by these diets in the cells of both host and parasites is responsible for their parasitic actions. Artemisinin, a naturally occurring (Artemisia annua) endoperoxide and effective antimalarial significantly lowers lesions from E. tenella when given at low levels as a feed additive. The mechanism of its action is also considered to involve induction of oxidative stress. Diets supplemented with 8 p.p.m. gamma-tocopherol (abundant in flaxseeds) or with 1% of the spice tumeric, reduce mid-small intestinal lesion scores and improve weight gains during E. maxima infections. These compounds may exert their anticoccidial activity because they are effective antioxidants. Betaine, a choline analogue found in high concentrations in sugar beets, improves nutrient utilisation by animals under stress. When provided as a dietary supplement at a level of 0.15% it has enhanced the anticoccidial activity of the ionophore, salinomycin. Betaine may act as an osmoprotectant whereby it improves the integrity and function of the infected intestinal mucosa. In in vivo studies, betaine plus salinomycin significantly inhibit invasion of both E. tenella and E. acervulina. However, subsequent development of E. acervulina is inhibited more effectively with this combination treatment than development of E. tenella.

Antimalarials and the fight against malaria in Brazil.

PubMed

Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

2009-08-01

Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.

Chemical composition and antioxidant and anti-Listeria activities of essential oils obtained from some Egyptian plants.

PubMed

Viuda-Martos, Manuel; El Gendy, Abd El-Nasser G S; Sendra, Esther; Fernández-López, Juana; Abd El Razik, K A; Omer, Elsayed A; Pérez-Alvarez, Jose A

2010-08-25

The aim of this work was to (i) determine the chemical composition of the essential oils of six spices widely cultivated in Egypt (Origanum syriacum, Majorana hortensis, Rosmarinus officinalis, Cymbopogon citratus, Thymus vulgaris, and Artemisia annua); (ii) determine the antioxidant activity of the Egyptian essential oils by means of five different antioxidant tests; and (iii) determine the effectiveness of these essential oils on the inhibition of Listeria innocua CECT 910. There is a great variability in the chemical composition of essential oils obtained from the six Egyptian aromatic plants. Overall, thyme (highest percentage of inhibition of DPPH radical: 89.40%) and oregano (highest percentage of inhibition of TBARS: 85.79) essential oils presented the best antioxidant profiles, whereas marjoram, lemongrass, and artemisia were highly effective in metal chelating but had a pro-oxidative behavior by Rancimat induction test. Lemongrass essential oil showed the highest antibacterial activity against L. innocua with an inhibition zone of 49.00 mm, followed in effectiveness by thyme, marjoram, and oregano.

In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon.

PubMed

Lima, Renata B S; Rocha e Silva, Luiz F; Melo, Marcia R S; Costa, Jaqueline S; Picanço, Neila S; Lima, Emerson S; Vasconcellos, Marne C; Boleti, Ana Paula A; Santos, Jakeline M P; Amorim, Rodrigo C N; Chaves, Francisco C M; Coutinho, Julia P; Tadei, Wanderli P; Krettli, Antoniana U; Pohlit, Adrian M

2015-12-18

The anti-malarials quinine and artemisinin were isolated from traditionally used plants (Cinchona spp. and Artemisia annua, respectively). The synthetic quinoline anti-malarials (e.g. chloroquine) and semi-synthetic artemisinin derivatives (e.g. artesunate) were developed based on these natural products. Malaria is endemic to the Amazon region where Plasmodium falciparum and Plasmodium vivax drug-resistance is of concern. There is an urgent need for new anti-malarials. Traditionally used Amazonian plants may provide new treatments for drug-resistant P. vivax and P. falciparum. Herein, the in vitro and in vivo antiplasmodial activity and cytotoxicity of medicinal plant extracts were investigated. Sixty-nine extracts from 11 plant species were prepared and screened for in vitro activity against P. falciparum K1 strain and for cytotoxicity against human fibroblasts and two melanoma cell lines. Median inhibitory concentrations (IC50) were established against chloroquine-resistant P. falciparum W2 clone using monoclonal anti-HRPII (histidine-rich protein II) antibodies in an enzyme-linked immunosorbent assay. Extracts were evaluated for toxicity against murine macrophages (IC50) and selectivity indices (SI) were determined. Three extracts were also evaluated orally in Plasmodium berghei-infected mice. High in vitro antiplasmodial activity (IC50 = 6.4-9.9 µg/mL) was observed for Andropogon leucostachyus aerial part methanol extracts, Croton cajucara red variety leaf chloroform extracts, Miconia nervosa leaf methanol extracts, and Xylopia amazonica leaf chloroform and branch ethanol extracts. Paullinia cupana branch chloroform extracts and Croton cajucara red variety leaf ethanol extracts were toxic to fibroblasts and or melanoma cells. Xylopia amazonica branch ethanol extracts and Zanthoxylum djalma-batistae branch chloroform extracts were toxic to macrophages (IC50 = 6.9 and 24.7 µg/mL, respectively). Andropogon leucostachyus extracts were the most selective (SI >28.2) and the most active in vivo (at doses of 250 mg/kg, 71% suppression of P. berghei parasitaemia versus untreated controls). Ethnobotanical or ethnopharmacological reports describe the anti-malarial use of these plants or the antiplasmodial activity of congeneric species. No antiplasmodial activity has been demonstrated previously for the extracts of these plants. Seven plants exhibit in vivo and or in vitro anti-malarial potential. Future work should aim to discover the anti-malarial substances present.

Artemisinin Inhibits Chloroplast Electron Transport Activity: Mode of Action

PubMed Central

Bharati, Adyasha; Kar, Monaranjan; Sabat, Surendra Chandra

2012-01-01

Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo), behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the QB; the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth. PMID:22719995

Considerations on the mechanism of action of artemisinin antimalarials: part 1--the 'carbon radical' and 'heme' hypotheses.

PubMed

Haynes, Richard K; Cheu, Kwan-Wing; N'Da, David; Coghi, Paolo; Monti, Diego

2013-08-01

The isolation of artemisinin from the traditional medicinal herb qīng hāo (Artemisia annua), its characterization as a peroxide and preparation of the derivatives dihydroartemisinin, artemether and artesunate in the 1970s and 1980s by Chinese scientists under the umbrella of Project 523 collectively represents one of the great events in medicine in the latter third of the 20(th) Century. Artemisinins have become the most important component of chemotherapy of malaria: although used initially in monotherapy, they are now used in combination therapies or ACTs with longer half-life quinolines or arylmethanols. Nevertheless, the recent emergence of artemisinin-tolerant strains of the malaria parasite as reflected in increased clearance times of parasitaemia in patients treated with ACTs represents the greatest threat to control of malaria since resistance to chloroquine was first reported over 55 years ago. Importantly, the event brings into sharp focus the realization that relatively little is precisely understood, as opposed to widely assumed, for the mechanism of drug action of artemisinins and their synthetic peroxide analogues. Thus, we review here their antimalarial activities, the use of artemisinins in combination therapies, drug-drug interactions with the quinolines and arylmethanols, and metabolism of the artemisinins and synthetic peroxides. The mechanism of action of quinolines and arylmethanols, in particular their ability to induce redistribution of heme into the parasite cytosol, is also highlighted. This collective information is then used as a counterpoint to screen the validity of two of the prevailing hypotheses of drug action of artemisinins and synthetic peroxides, namely i. 'the C-radical hypothesis' wherein the peroxide undergoes 'bioactivation' by ferrous iron to generate C-radicals that are held to be the cytotoxic agents and ii. the 'heme hypothesis' wherein ferrous heme may generate either the same type of 'cytotoxic' C-radical, or the peroxide forms heme adducts that apparently inherit the exquisite cytotoxicities of the parent peroxide in one way or another. In a subsequent review, we screen the third and fourth hypotheses: the SERCA hypothesis wherein artemisinins modulate operation of the malaria parasite sarcoendo plasmic reticulum calcium pump SERCA Ca(2+)-ATPase ATP6 and the co-factor hypothesis wherein artemisinins act as oxidant drugs through rapidly oxidizing reduced conjugates of flavin cofactors, or those of flavin cofactor precursors such as riboflavin, and other susceptible endogenous substrates that play a role in maintaining intraparasitic redox homeostasis. For the C-radical hypothesis, details of in vitro chemical studies in the context of established chemistry of C-radicals and their ability to react with radical trapping agents such as nitroso compounds, cyclic nitrones, persistent nitroxyl radicals and atmospheric oxygen (dioxygen) are summarized. Overall, there is no correlation between antimalarial activities and abilities of the derived C-radicals to react with trapping agents in a chemical flask. This applies in particular to the reactions of C-radicals from artemisinins and steroidal tetraoxanes with the trapping agents vis-a-vis those from adamantyl capped systems. In an intraparasitic medium, it is not possible to intercept C-radicals either through use of a vast excess of a nitroxyl radical or dioxygen. The lack of correlation of antimalarial activities also applies to the Fe(2+)-mediated decomposition of artemisinins and synthetic peroxides, where literature data taken as indicating otherwise are critically assessed. The antagonism to antimalarial activities of artemisinins exerted by desferrioxamine (DFO) and related Fe(3+)-chelating agents is due to formation of stable chelates with bioavailable Fe(3+) that shuts down redox cycling through Fe(2+) and the subsequent generation of reactive oxygen species (ROS) via the Fenton reaction. The generation of ROS by Fe(2+) complements the action of artemisinins, to be discussed in Part 2; there is no need to posit a reaction of Fe(2+) with the artemisinins to account for their antimalarial activity. The ability of artemisinins and synthetic peroxides to elicit membrane damage is examined in the light of established processes of autoxidation. The oxidant character of the intraparasitic environment is incompatible with the reducing conditions required for generation of C-radicals, and in contrast to the expectation raised by the C-radical hypothesis, and indeed by the heme hypothesis outlined below, antimalarial activities of artemisinins are enhanced under higher partial pressures of dioxygen. Structure-activity data from a wide variety of artemisinins and synthetic peroxides cannot be accommodated within the bounds of the C-radical hypothesis. Finally, the antimalarial Cradical construct sharply contrasts with that of the potently antitumour-active ene-diyne antibiotics such as neocarzinostatin. In an iron-free process, these compounds generate highly reactive aryl C-radicals that abstract H atoms from deoxyribose units in DNA to generate alkyl C-radicals. The last do react with dioxygen in a normal intracellular environment to initiate DNA strand cleavage. Overall, it must be concluded that the C-radical hypothesis as the basis for antimalarial activities of artemisinins and synthetic peroxides is untenable. Heme has been intensively studied as an 'activator' of artemisinins and other antimalarial peroxides, and indeed the hypothesis seemingly has become firmly embedded in the underlying brickwork of the scientific edifice. The locus of activity of the peroxides interacting with the heme is considered to be the parasite digestive vacuole. The basis for the nanomolar activities of artemisinins and synthetic peroxides is variously ascribed to heme-Fe(2+)-mediated generation of C-radicals from the peroxides, formation of heme-artemisinin adducts that are held either to engage in redox cycling with concomitant generation of ROS or to inhibit formation of hemozoin. In the last case, just like the aminoquinolines and arylmethanols, the peroxides are not the active agents, but exert their parasiticidal effects through allowing the build-up of free heme-Fe(3+), the ultimate cytotoxic entity. We assess the literature relating to generation of heme by hemoglobin digestion, and the stage at which this process becomes significant in the intraerythrocytic parasite. The claims of production of heme and conversion into hemozoin occurring in a lipid environment may have to be put aside based on recent literature data that indicates crystallization of hemozoin must take place an aqueous interface; association of lipids with the heme/hemozoin is likely to be a reflection of attractive van der Waals interactions involving the hydrophobic surface of the heme or hemozoin aggregates. In addition, the observation leading to the claim that hemozoin manufacture commences at the mid-ring stage cannot be independently verified. That the quinoline and arylmethanol antimalarials have essentially no activities on the ring stage parasites and exert greatest efficacy at the trophozoite stage where heme production is maximal is consistent with this. Conversely, artemisinins, and indeed redox active drugs such as methylene blue and others, are highly active against early ring stage parasites. Thus, there is a prominent disconnect between stage specificities of artemisinins vis-a-vis those of 4-aminoquinolines and arylmethanols suggesting that heme is not the target of the former class of drug. Further, the ability of the Fe(3+) chelate DFO to antagonize antimalarial activities of artemisinins, but not the activities of 4-aminoquinolines, cannot be explained by involvement of heme as a target for artemisinins. We critically examine the basis for formation of products obtained from reaction of heme with artemisinins and synthetic peroxides under conditions ranging from biomimetic - reactions employing catalytic reagents under aqueous or semi-aqueous conditions - to those conducted under highly reducing and eminently artificial conditions, usually in the solvent dimethyl sulfoxide (DMSO) that both forms well characterized complexes with heme-Fe(2+) and actually assists in driving single electron transfer processes. It is noted that alkylated products tend to form in high yields under the last conditions, and this aspect is readily explained. Irrespective of product yields obtained under various conditions, an overarching correlation between facility of the reaction of the peroxide with heme and their antimalarial activities does not exist. The is underscored by the reproducible outcomes of reactions conducted under biomimetic conditions indicating adducts cannot form in physiologically meaningful concentrations and that heme is a recalcitrant reaction partner to artemisinins in general. Again, as in the case of the C-radical hypothesis, structure-activity data from a wide variety of artemisinins and synthetic peroxides is difficult to reconcile with the heme hypothesis. This applies in particular to dimeric and trimeric artemisinin derivatives where the ascribing of biological activity to reactions of the derived radicals or to the vastly encumbered artemisinin-heme adducts is physically unrealistic. Finally, the facile metabolism and induction of metabolism of the current clinically used artemisinins by members of the CYP superfamily - heme proteins that require an intimate interaction of the heme with the artemisinin for metabolism to occur - is incompatible with the oft-cited proclivity of the peroxide to associate via complex formation with heme as a prelude to its 'activation' as an antimalarial agent within the malaria parasite. (ABSTRACT TRUNCATED)

Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway

PubMed Central

Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

2016-01-01

Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

Dietary enzymatically treated Artemisia annua L. supplementation alleviates liver oxidative injury of broilers reared under high ambient temperature

NASA Astrophysics Data System (ADS)

Wan, Xiaoli; Zhang, Jingfei; He, Jintian; Bai, Kaiwen; Zhang, Lili; Wang, Tian

2017-09-01

Heat stress induced by high ambient temperature is a major concern in commercial broiler production. To evaluate the effects of dietary enzymatically treated Artemisia annua L. (EA) supplementation on growth performance and liver oxidative injury of broilers reared under heat stress, a total of 320 22-day-old male broilers were randomly allotted into five groups with eight replicates of eight birds each. Broilers in the control group were housed at 22 ± 1 °C and fed the basal diet. Broilers in the HS, HS-EA1, HS-EA2, and HS-EA3 groups were fed basal diet supplemented with 0, 0.75, 1.00, and 1.25 g/kg EA, respectively, and reared under cyclic high temperature (34 ± 1 °C for 8 h/day and 22 ± 1 °C for 16 h/day). Broilers fed EA diets had higher final body weight, average daily body weight gain, and average daily feed intake, as well as liver concentration of reduced glutathione, activities of antioxidant enzymes, abilities to inhibit hydroxyl radical and superoxide radical (HS-EA2 and HS-EA3), and lower liver concentrations of reactive oxygen metabolites, malondialdehyde, and protein carbonyl (HS-EA1, HS-EA2, and HS-EA3) than HS group ( P < 0.05). EA treatment downregulated the mRNA levels of heat shock proteins 70 and 90, upregulated the mRNA levels of nuclear factor erythroid 2-related factor 2 (HS-EA1, HS-EA2, and HS-EA3) and heme oxygenase 1 (HS-EA2 and HS-EA3) in liver of heat-treated broilers ( P < 0.05). In conclusion, EA alleviated heat stress-induced growth depression and liver oxidative injury in broilers, possibly through improving the antioxidant capacity and regulating the pertinent mRNA expression. The appropriate inclusion level of EA in broiler diet is 1.00-1.25 g/kg.

Ethnoveterinary medicines used to treat endoparasites and stomach problems in pigs and pets in British Columbia, Canada.

PubMed

Lans, Cheryl; Turner, Nancy; Khan, Tonya; Brauer, Gerhard

2007-09-30

This paper documents the medicinal plants used to treat endoparasites and stomach problems in dogs, cats and pigs in British Columbia, Canada. Ethnoveterinary data was collected over a 6-month period in 2003. The majority of the information on pets came from 2 naturopaths, 10 herbalists, 5 dog trainers, breeders and pet shop owners, 9 holistic veterinarians and 6 of 27 organic farmers. Two pig farmers joined the study in the final stages. The following plants were used as anthelmintics: Artemisia cina O. Berg and C.F. Schmidt, Artemisia vulgaris L., Artemisia annua, Calendula officinalis L., Echinacea purpurea (L.) Moench (all Asteraceae), Mentha piperita L. and Salvia officinalis L. (Lamiaceae) (Allium sativum L. (Alliaceae), Cucurbita pepo L. (Cucurbitaceae), Eugenia caryophyllata Thunb (Myrtaceae), Gentiana lutea L. (Gentianaceae), Hydrastis canadensis L. (Ranunculaceae), Juglans nigra L. (Juglandaceae), Olea europaea L. (Oleaceae) and Ruta graveolens L. (Rutaceae)). Stomach problems were treated with: Achillea millefolium L. (Asteraceae), Aloe vera (L.) Burm. f. (Asphodelaceae), Elytrigia repens (L.) Desv. ex Nevski (Poaceae), Frangula purshiana (DC.) Cooper (Rhamnaceae), Juniperus communis L. (Cupressaceae), Melissa officinalis L. and M. piperita L. (Lamiaceae), Petroselinum crispum L. (Apiaceae), Plantago major L. and Plantago ovata Forssk. (Plantaginaceae) Rumex crispus L. and Rumex obtusifolius L. (Polygonaceae), Ulmus fulva Michx. (Ulmaceae) and Zingiber officinalis Roscoe (Zingiberaceae). There is insufficient information available to assess the anthelmintic efficacies of C. officinalis, Salvia officinalis, Eugenia caryophyllata and O. europaea; the other plants have mid- to high-level validity for their ethnoveterinary uses.

Towards a better understanding of Artemisia vulgaris: Botany, phytochemistry, pharmacological and biotechnological potential.

PubMed

Abiri, Rambod; Silva, Abraão Lincoln Macedo; de Mesquita, Ludmilla Santos Silva; de Mesquita, José Wilson Carvalho; Atabaki, Narges; de Almeida, Eduardo Bezerra; Shaharuddin, Noor Azmi; Malik, Sonia

2018-07-01

Artemisia vulgaris is one of the important medicinal plant species of the genus Artemisia, which is usually known for its volatile oils. The genus Artemisia has become the subject of great interest due to its chemical and biological diversity as well as the discovery and isolation of promising anti-malarial drug artemisinin. A. vulgaris has a long history in treatment of human ailments by medicinal plants in various parts of the world. This medicinal plant possesses a broad spectrum of therapeutic properties including: anti-malarial, anti-inflammatory, anti-hypertensive, anti-oxidant, anti-tumoral, immunomodulatory, hepatoprotective, anti-spasmodic and anti-septic. These activities are mainly attributed to the presence of various classes of secondary metabolites, including flavonoids, sesquiterpene lactones, coumarins, acetylenes, phenolic acids, organic acids, mono- and sesquiterpenes. Studies related to A. vulgaris morphology, anatomy and phytochemistry has gained a significant interest for better understanding of production and accumulation of therapeutic compounds in this species. Recently, phytochemical and pharmacological investigations have corroborated the therapeutic potential of bioactive compounds of A. vulgaris. These findings provided further evidence for gaining deeper insight into the identification and isolation of novel compounds, which act as alternative sources of anti-malarial drugs in a cost-effective manner. Considering the rising demand and various medical applications of A. vulgaris, this review highlights the recent reports on the chemistry, biological activities and biotechnological interventions for controlled and continuous production of bioactive compounds from this plant species. Copyright © 2018 Elsevier Ltd. All rights reserved.

A new sesquiterpene and other constituents from Saussurea lappa root.

PubMed

Duan, Jin-Ao; Hou, Pengfei; Tang, Yuping; Liu, Pei; Su, Shulan; Liu, Hanqing

2010-10-01

Five sesquiterpenes, dehydrocostus lactone (1), santamarine (5), beta-cyclocostunolide (6), 4alpha-hydroxy-4beta-methyldihydrocostol (7) and 10alpha-hydroxyl-artemisinic acid (9), along with four other compounds, beta-sitosterol (2), daucosterol (3), 5-hydroxymethyl-furaldehyde (4), and trans-syingin (8), were isolated and identified from the roots of Saussurea lappa (Compositae). Based on previous reports and our study, sesquiterpene derivatives are common and characteristic constituents of the genus Saussurea. Among the nine compounds obtained, 9 is a new sesquiterpene. It is an artemisinic acid derivative, whose structural skeleton has not been reported for Saussurea species before, but artemisinic acid is a common compound in another Compositae species, Artemisia annua. Dehydrocostus lactone (1) is present in high-content and is a possible bioprecursor of 10alpha-hydroxyartemisinic acid (9).

Evaluation of enzymatically treated Artemisia annua L. on growth performance, meat quality, and oxidative stability of breast and thigh muscles in broilers.

PubMed

Wan, X L; Song, Z H; Niu, Y; Cheng, K; Zhang, J F; Ahmad, H; Zhang, L L; Wang, T

2017-04-01

An experiment was conducted to evaluate the effects of including enzymatically treated Artemisia annua L. (EA) in broiler diets on growth performance, meat quality, and oxidative stability of breast and thigh muscles. A total of 256 one-d-old Arbor Acres broiler chicks were randomly allotted into four groups with eight replicates of eight birds each. Broilers in the four groups were offered basal diet supplemented with 0.0, 0.5, 1.0, and 1.5 g/kg EA during the 42-d experiment, respectively. The ADG, ADFI, and feed/gain ratio (F:G) were measured at 42 d of age. Breast and thigh muscle samples from eight birds per treatment were obtained at 42 d to determine meat quality, free radical scavenging activity, and lipid peroxidation. All treatment groups had similar ADG, ADFI, and F:G during the 42 d experiment (P > 0.05). Drip loss at 24 h and shearing force of breast muscle were linearly (P < 0.05) and quadratically (P < 0.05) decreased by EA addition. The drip loss at 24 h and 48 h, cooking loss and shearing force of thigh muscle followed the same fashion. The supplementation of EA quadratically increased 2, 2-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) (P = 0.004) and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) (P = 0.035) free radical scavenging activities in breast muscle, and linearly (P < 0.05) and quadratically (P < 0.05) increased ABTS and DPPH scavenging activities of thigh muscle. Increasing levels of EA linearly (P < 0.05) or quadratically (P < 0.05) or both decreased the malondialdehyde (MDA) concentrations in breast and thigh muscle samples during 15 d of storage at 4°C. The results indicated that EA supplementation improved meat quality and oxidative stability of breast and thigh muscles in broilers. The inclusion level of 1.0 g/kg EA in broiler diet was recommended. © 2016 Poultry Science Association Inc.

Synthesis of new artemisinin analogues from artemisinic acid modified at C-3 and C-13 and their antimalarial activity.

PubMed

Han, J; Lee, J G; Min, S S; Park, S H; Angerhofer, C K; Cordell, G A; Kim, S U

2001-09-01

Artemisinic acid (2) was modified through allylic oxidation at C-3 or conjugate addition at C-13 to afford 12 methyl artemisinate derivatives (4-15). Photooxidation of the derivatives yielded eight new artemisinin analogues, including 13-cyanoartemisinin (16), 13-methoxycarbonyl artemisinin (17), 13-methoxyartemisinin (18), 13-ethylsulfonylartemisinin (19), 13-nitromethylartemisinin (20), 13-(1-nitroethyl)artemisinin (21), (3R)-3-hydroxyartemisinin (22), and (3R)-3-acetoxyartemisinin (23). Among the analogues, only compound 20 had antimalarial activity comparable to artemisinin (1).

Biotransformation of artemisinin using cell suspension cultures of Catharanthus roseus (L.) G.Don and Lavandula officinalis L.

PubMed

Patel, Suman; Gaur, Rashmi; Verma, Priyanka; Bhakuni, Rajendra S; Mathur, Archana

2010-08-01

Artemisinin, an antimalarial compound, at 5 mg/40 ml, was transformed by cell suspension cultures of Catharanthus roseus (L.) G.Don and Lavandula officinalis L. into deoxyartemisinin with yields >78% (3.93 mg deoxyartemisinin from 5 mg artemisinin). Maximum conversion (78.6 and 78%) occurred after 6 and 7 days of adding artemisinin to 20 and 9 days old cultures of C. roseus and L. officinalis, respectively. The procedure was scaled up by and 500 mg artemisinin was transformed into 390 mg deoxyartemisinin. Addition of artemisinin at the beginning of the culture cycle resulted in >50% reduction in dry biomass production with no bioconversion. Conversion of artemisinin occurred intracellularly followed by leaching of the product into the medium.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoehn, A.; Chamberlain, D.J.; Forsyth, S.W.

PGBA, a plant growth facility developed for space flight biotechnology research, successfully grew a total of 30 plants in a closed, multi-crop chamber for 10 days aboard the Space Shuttle Endeavor (STS-77). {ital Artemisia annua, Catharanthus roseus, Pinus taeda, Spinacia oleracea and Trifolium repens} were the five species studied during this mission. The primary mission objectives were to study the effects of microgravity for commercial and pharmaceutical production purposes. PGBA is a payload that represents a consortium of interests including BioServe Space Technologies (payload sponsor), NASA Ames Research Center (Controlled Ecological Life Support System, CELSS, Flight Program), Wisconsin Center formore » Space Automation and Robotics (WCSAR), and industrial affiliates (spaceflight effects on plants and formation of plant products such as pharmaceuticals). Although BioServe is responsible for the flight hardware development and integration of PGBA, NASA Ames, WSCAR and industrial affiliates provide significant hardware subsystems and technical biological expertise support. {copyright} {ital 1997 American Institute of Physics.}« less

Characterization of Xanthophyll Pigments, Photosynthetic Performance, Photon Energy Dissipation, Reactive Oxygen Species Generation and Carbon Isotope Discrimination during Artemisinin-Induced Stress in Arabidopsis thaliana

PubMed Central

Hussain, M. Iftikhar; Reigosa, Manuel J.

2015-01-01

Artemisinin, a potent antimalarial drug, is phytotoxic to many crops and weeds. The effects of artemisinin on stress markers, including fluorescence parameters, photosystem II photochemistry, photon energy dissipation, lipid peroxidation, reactive oxygen species generation and carbon isotope discrimination in Arabidopsis thaliana were studied. Arabidopsis ecotype Columbia (Col-0) seedlings were grown in perlite and watered with 50% Hoagland nutrient solution. Adult plants of Arabidopsis were treated with artemisinin at 0, 40, 80, 160 μM for one week. Artemisinin, in the range 40–160 μM, decreased the fresh biomass, chl a, b and leaf mineral contents. Photosynthetic efficiency, yield and electron transport rate in Arabidopsis were also reduced following exposure to 80 and 160 μM artemisinin. The ΦNPQ and NPQ were less than control. Artemisinin treatment caused an increase in root oxidizability and lipid peroxidation (MDA contents) of Arabidopsis. Calcium and nitrogen contents decreased after 80 and 160 μM artemisinin treatment compared to control. δ13C values were less negative following treatment with artemisinin as compared to the control. Artemisinin also decreased leaf protein contents in Arabidopsis. Taken together, these data suggest that artemisinin inhibits many physiological and biochemical processes in Arabidopsis. PMID:25635811

Optimization for ultrasound-assisted extraction of polysaccharides with chemical composition and antioxidant activity from the Artemisia sphaerocephala Krasch seeds.

PubMed

Zheng, Quan; Ren, Daoyuan; Yang, Nana; Yang, Xingbin

2016-10-01

Artemisia sphaerocephala Krasch seeds polysaccharides have been reported to have a variety of important biological activities. However, effective extraction of Artemisia sphaerocephala Krasch seeds polysaccharides is still an unsolved issue. In this study, the orthogonal rotatable central composite design was employed to optimize ultrasound-assisted extraction conditions of Artemisia sphaerocephala Krasch seeds polysaccharides. Based on a single-factor analysis method, ultrasonic power, extraction time, solid-liquid ratio and extraction temperature were shown to significantly affect the yield of polysaccharides extracted from the A. sphaerocephala Krasch seeds. The optimal conditions for extraction of Artemisia sphaerocephala Krasch seeds polysaccharides were determined as following: ultrasonic power 243W, extraction time 125min, solid-liquid ratio 64:1 and extraction temperature 64°C, where the experimental yield was 14.78%, which was well matched with the predicted value of 14.81%. Furthermore, ASKP was identified as a typical heteropolysaccharide with d-galacturonic acid (38.8%) d-galactose (20.2%) and d-xylose (15.5%) being the main constitutive monosaccharides. Moreover, Artemisia sphaerocephala Krasch seeds polysaccharides exhibited high total reducing power and considerable scavenging activities on DPPH, hydroxyl and superoxide radicals, in a concentration-dependent manner in vitro. Copyright © 2016 Elsevier B.V. All rights reserved.

The genus Artemisia L. in the northern region of Saudi Arabia: essential oil variability and antibacterial activities.

PubMed

Guetat, Arbi; Al-Ghamdi, Faraj A; Osman, Ahmed K

2017-03-01

Four species of the genus Artemisia L. (Artemisia monosperma, Artemisia scoparia, Artemisia judaica and Artemisia sieberi) growing in the northern region of Saudi Arabia were investigated with respect to their volatile oil contents. The yield of oil varied between 0.30 and 0.41%, % (w/w). A. monosperma showed the highest number of compounds with 30 components representing 93.78% of oil composition. However, A. judaica showed the lowest number of compounds with only 16 components representing 87.47% of essential oil. A. scoparia and A. sieberi are both composed of 17 components, representing 97.14 and 94.2% of total oil composition. A. sieberi and A. judaica were dominated by spathulenol (30.42 and 28.41%, respectively). For A. monosperma, butanoic acid (17.87%) was a major component. However, A. scoparia was a chemotype of acenaphthene. (83.23%). Essential oil of studied species showed high antibacterial activities against common human pathogens.

Drug Development Against Parasitic Diseases: Synthesis of the Antimalarial Agent Qinghaosu and Analogs.

DTIC Science & Technology

A stereoselective total synthesis of (+)- artemisinin has been improved from 18 steps to 13 steps with a resultant 12-fold increase in the overall...yield. A new class of tricyclic analogs of artemisinin has been discovered that possess good in vitro antimalarial activity. U.S. and foreign patents

Microbial transformation of artemisinin to 5-hydroxyartemisinin by Eurotium amstelodami and Aspergillus niger.

PubMed

Parshikov, Igor A; Miriyala, Brushapathy; Muraleedharan, Kannoth M; Avery, Mitchell A; Williamson, John S

2006-05-01

Transformation of the anti-malarial drug artemisinin by the fungi Eurotium amstelodami and Aspergillus niger were investigated. Cultures were grown in sucrose/malt broth with artemisinin for 14 days and extracted with ethyl acetate. Extracts were characterized by liquid chromatography. Two metabolites from each fungal extract were isolated and identified using mass spectrometry and nuclear magnetic resonance. 5Beta-hydroxyartemisinin and 7beta-hydroxyartemisinin were isolated in 63 and 32% yields, respectively, from the extract of E. amstelodami, and 80 and 19%, respectively, from the extract of A. niger.

10 day flight performance of the plant generic bioprocessing apparatus (PGBA) plant growth facility aboard STS-77

NASA Astrophysics Data System (ADS)

Hoehn, Alex; Chamberlain, Dale J.; Forsyth, Sasha W.; Hanna, David S.; Scovazzo, Paul; Horner, Michael B.; Stodieck, Louis S.; Todd, Paul; Heyenga, A. Gerard; Kliss, Mark H.; Bula, Raymond; Yetka, Robert

1997-01-01

PGBA, a plant growth facility developed for space flight biotechnology research, successfully grew a total of 30 plants in a closed, multi-crop chamber for 10 days aboard the Space Shuttle Endeavor (STS-77). Artemisia annua, Catharanthus roseus, Pinus taeda, Spinacia oleracea and Trifolium repens were the five species studied during this mission. The primary mission objectives were to study the effects of microgravity for commercial and pharmaceutical production purposes. PGBA is a payload that represents a consortium of interests including BioServe Space Technologies (payload sponsor), NASA Ames Research Center (Controlled Ecological Life Support System, CELSS, Flight Program), Wisconsin Center for Space Automation and Robotics (WCSAR), and industrial affiliates (spaceflight effects on plants and formation of plant products such as pharmaceuticals). Although BioServe is responsible for the flight hardware development and integration of PGBA, NASA Ames, WSCAR and industrial affiliates provide significant hardware subsystems and technical biological expertise support.

Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance.

PubMed

Cerqueira, Gustavo C; Cheeseman, Ian H; Schaffner, Steve F; Nair, Shalini; McDew-White, Marina; Phyo, Aung Pyae; Ashley, Elizabeth A; Melnikov, Alexandre; Rogov, Peter; Birren, Bruce W; Nosten, François; Anderson, Timothy J C; Neafsey, Daniel E

2017-04-28

Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014). We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.

Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.

PubMed

Pacorel, Bénédicte; Leung, Suet C; Stachulski, Andrew V; Davies, Jill; Vivas, Livia; Lander, Hollie; Ward, Stephen A; Kaiser, Marcel; Brun, Reto; O'Neill, Paul M

2010-01-28

In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.

Hydrogenation of artemisinin to dihydroartemisinin over heterogeneous metal catalysts

NASA Astrophysics Data System (ADS)

Kristiani, Anis; Pertiwi, Ralentri; Adilina, Indri Badria

2017-01-01

A series of heterogeneous metal catalysts of Ni, Pd, and Pt, both of synthesized and commercial catalysts were used for hydrogenation of artemisinin to dihydroartemisinin. Their catalytic properties were determsined by Surface Area Analyzer and Thermogravimetry Analyzer. The catalytic properties in various reaction conditions in terms of temperature, pressure, reaction time and reactant/catalyst ratio were also studied. The results catalytic activity tests showed that synthesized catalysts of Ni/zeolite, Ni-Sn/zeolite, Ni/bentonite and Ni-Sn/bentonite were not able to produced dihydroartemisinin and deoxyartemisinin was mainly formed. Meanwhile, commercial catalysts of Ni skeletal, Pd/activated charcoal and Pt/activated charcoal yielded the desired dihydroartemisinin product. Ni skeletal commercial catalyst gave the best performance of hydrogenation artemisinin to dihydroartemisinin in room temperature and low H2 pressure.

The efficacy of herbal medicines against Toxoplasma gondii during the last 3 decades: a systematic review.

PubMed

Sharif, Mahdi; Sarvi, Shahabeddin; Pagheh, Abdol Sattar; Asfaram, Shabnam; Rahimi, Mohammad Taghi; Mehrzadi, Saeed; Ahmadpour, Ehsan; Gholami, Shirzad; Daryani, Ahmad

2016-12-01

The objective of the current study was to systematically review papers discussing the efficacy of medicinal herbs against Toxoplasma gondii. Data were systematically collected from published papers about the efficacy of herbs used against T. gondii globally from 1988 to 2015, from PubMed, Google Scholar, ISI Web of Science, EBSCO, Science Direct, and Scopus. Forty-nine papers were included in the current systematic review reporting the evaluation of medicinal plants against T. gondii globally, both in vitro and in vivo. Sixty-one plants were evaluated. Most of the studies were carried out on Artemisia annua. The second highest number of studies were carried out on Glycyrrhiza glabra extracts. RH and ME49 were the predominant parasite strains used. Additionally, Swiss-Webster and BALB/c mice were the major animal models used. Alcoholic and aqueous extracts were used more than other types of extracts. Natural compounds mentioned here may be developed as novel and more effective therapeutic agents that improve the treatment of toxoplasmosis due to their lower side effects, higher availability, and better cultural acceptance compared with those of the chemical drugs that are currently being used.

Recent progress of research on medicinal mushrooms, foods, and other herbal products used in traditional Chinese medicine

PubMed Central

Lee, Kuo-Hsiung; Morris-Natschke, Susan L.; Yang, Xiaoming; Huang, Rong; Zhou, Ting; Wu, Shou-Fang; Shi, Qian; Itokawa, Hideji

2012-01-01

This article will review selected herbal products used in traditional Chinese medicine, including medicinal mushrooms (巴西蘑菇 bā xī mó gū; Agaricus blazei, 雲芝 yún zhī; Coriolus versicolor, 靈芝 líng zhī; Ganoderma lucidum, 香蕈 xiāng xùn; shiitake, Lentinus edodes, 牛樟芝 niú zhāng zhī; Taiwanofungus camphoratus), Cordyceps (冬蟲夏草 dōng chóng xià cǎo), pomegranate (石榴 shí liú; Granati Fructus), green tea (綠茶 lǜ chá; Theae Folium Non Fermentatum), garlic (大蒜 dà suàn; Allii Sativi Bulbus), turmeric (薑黃 jiāng huáng; Curcumae Longae Rhizoma), and Artemisiae Annuae Herba (青蒿 qīng hāo; sweet wormwood). Many of the discussed herbal products have gained popularity in their uses as dietary supplements for health benefits. The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011. PMID:24716120

Metabolomics study on the hepatoprotective effect of scoparone using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry.

PubMed

Zhang, Aihua; Sun, Hui; Dou, Shengshan; Sun, Wenjun; Wu, Xiuhong; Wang, Ping; Wang, Xijun

2013-01-07

Scoparone is an important constituent of Yinchenhao (Artemisia annua L.), a famous medicinal plant, and displayed bright prospects in the prevention and therapy of liver injury. However, the precise molecular mechanism of hepatoprotective effects has not been comprehensively explored. Here, metabolomics techniques are the comprehensive assessment of endogenous metabolites in a biological system and may provide additional insight into the mechanisms. The present investigation was designed to assess the effects and possible mechanisms of scoparone against carbon tetrachloride-induced liver injury. Ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-Q-TOF/MS) combined with pattern recognition approaches including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were integrated to discover differentiating metabolites. Results indicate five ions in the positive mode as differentiating metabolites. Functional pathway analysis revealed that the alterations in these metabolites were associated with primary bile acid biosynthesis, pyrimidine metabolism. Of note, scoparone has a potential pharmacological effect through regulating multiple perturbed pathways to the normal state. Our findings also showed that the robust metabolomics techniques are promising for getting biomarkers and clarifying mechanisms of disease, highlighting insights into drug discovery.

Effects of flavonoids from Martynia annua and Tephrosia purpurea on cutaneous wound healing

PubMed Central

Lodhi, Santram; Jain, Avijeet; Jain, Alok Pal; Pawar, Rajesh Singh; Singhai, Abhay Kumar

2016-01-01

Objective: Martynia annua L. (M. annua), (Martyniaccae) has been traditionally used in the treatment of epilepsy, sore throat and inflammatory disorders. The leaf paste is used topically on Tuberculosis of the lymphatic glands and wounds of domestic animals. Tephrosia purpurea (T. purpurea), (Fabaceae) has been used traditionally as a remedy for asthma, gonorrhea, rheumatism and ulcers. This study aimed to evaluate the potential wound healing effects of different fractions ofethanol extract of M. annua leaves and aerial parts of T. purpurea. Materials and Methods: Methanol fraction of M. annua (MAF-C) and ethyl acetate fraction of T. purpurea (TPF-A) were evaluated for healing potential in dead-space and burn wound models. An ointment (5% w/w) of MAF-C and TPF-A, pongamol (0.2 and 0.5% w/w) and luteolin (0.2 and 0.5% w/w) was applied topically twice a day. The effects were compared with Povidone Iodine ointment with respect to protein, collagen content, enzymatic assay and histopathological finding of granuloma tissues. Results: Ethanol extracts of M. annua and T. purpureawere exhibited total flavonoid contents of 126.2 ± 4.69 and 171.6 ± 6.38 mg (quercetin equivalent), respectively. HPLC fingerprinting confirmed the presence of luteolin in M. annua and quercetin in T. purpurea. TPF-A and MAF-C ointments (5% w/w) significantly increases the hydroxyproline and protein contents. Luteolin and pongamol ointments were also found to be effective in both wound models. Conclusion: Our findings suggested that 5% w/w ointment of TPF-A and MAF-C fractions were more effective than isolated flavonoids in wound healing which may be due to synergistic interactions between the flavonoids and other constituents. PMID:27761428

Metabolic analyses elucidate non-trivial gene targets for amplifying dihydroartemisinic acid production in yeast

PubMed Central

Misra, Ashish; Conway, Matthew F.; Johnnie, Joseph; Qureshi, Tabish M.; Lige, Bao; Derrick, Anne M.; Agbo, Eddy C.; Sriram, Ganesh

2013-01-01

Synthetic biology enables metabolic engineering of industrial microbes to synthesize value-added molecules. In this, a major challenge is the efficient redirection of carbon to the desired metabolic pathways. Pinpointing strategies toward this goal requires an in-depth investigation of the metabolic landscape of the organism, particularly primary metabolism, to identify precursor and cofactor availability for the target compound. The potent antimalarial therapeutic artemisinin and its precursors are promising candidate molecules for production in microbial hosts. Recent advances have demonstrated the production of artemisinin precursors in engineered yeast strains as an alternative to extraction from plants. We report the application of in silico and in vivo metabolic pathway analyses to identify metabolic engineering targets to improve the yield of the direct artemisinin precursor dihydroartemisinic acid (DHA) in yeast. First, in silico extreme pathway (ExPa) analysis identified NADPH-malic enzyme and the oxidative pentose phosphate pathway (PPP) as mechanisms to meet NADPH demand for DHA synthesis. Next, we compared key DHA-synthesizing ExPas to the metabolic flux distributions obtained from in vivo 13C metabolic flux analysis of a DHA-synthesizing strain. This comparison revealed that knocking out ethanol synthesis and overexpressing glucose-6-phosphate dehydrogenase in the oxidative PPP (gene YNL241C) or the NADPH-malic enzyme ME2 (YKL029C) are vital steps toward overproducing DHA. Finally, we employed in silico flux balance analysis and minimization of metabolic adjustment on a yeast genome-scale model to identify gene knockouts for improving DHA yields. The best strategy involved knockout of an oxaloacetate transporter (YKL120W) and an aspartate aminotransferase (YKL106W), and was predicted to improve DHA yields by 70-fold. Collectively, our work elucidates multiple non-trivial metabolic engineering strategies for improving DHA yield in yeast. PMID:23898325

In vitro antimalarial studies of novel artemisinin biotransformed products and its derivatives.

PubMed

Gaur, Rashmi; Darokar, Mahendra P; Ajayakumar, P V; Shukla, Ram Sajiwan; Bhakuni, Rajendra Singh

2014-11-01

Biotransformation of antimalarial drug artemisinin by fungi Rhizopus stolonifer afforded three sesquiterpenoid derivatives. The transformed products were 1α-hydroxyartemisinin (3), 3.0%, a new compound, 10β-hydroxyartemisinin, 54.5% (4) and deoxyartemisinin (2) in 9% yield. The fungus expressed high-metabolism activity (66.5%). The chemical structures of the compounds were elucidated by 1D, 2D NMR spectrometry and mass spectral data. The major compound 10β-hydroxyartemisinin (4) was chemically converted to five new derivatives 5-9. All the compounds 3-9 were subjected for in vitro anti-malarial activity. 10β-Hydroxy-12β-arteether (8), IC50 at 18.29nM was found to be 10 times better active than its precursor 4 (184.56nM) and equipotent antimalarial with natural drug artemisinin whereas the α-derivative 9 is 3 times better than 4 under in vitro conditions. Therefore, the major biotransformation product 4 can be exploited for further modification into new clinically potent molecules. The results show the versatility of microbial-catalyzed biotransformations leading to the introduction of a hydroxyl group at tertiary position in artemisinin in derivative (3). Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin.

PubMed

Zuma, Nonkululeko H; Smit, Frans J; de Kock, Carmen; Combrinck, Jill; Smith, Peter J; N'Da, David D

2016-10-21

In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Facile preparation of bioactive seco-guaianolides and guaianolides from Artemisia gorgonum and evaluation of their phytotoxicity.

PubMed

Macías, Francisco A; Santana, Alejandro; Yamahata, Azusa; Varela, Rosa M; Fronczek, Frank R; Molinillo, José M G

2012-11-26

Commercially available santonin was used to synthesize seven sesquiterpene lactones using a facile strategy that involved a high-yielding photochemical reaction. Three natural products from Artemisia gorgonum were synthesized in good yields, and in the case of two compounds, absolute configurations were determined from X-ray quality crystals. The structures previously reported for these compounds were revised. Sesquiterpene lactones were tested using the etiolated wheat coleoptile bioassay, and the most active compounds were assayed in standard target species. seco-Guaianolide (4) showed higher phytotoxic activities than the known herbicide Logran. This high activity could be due to the presence of a cyclopentenedione ring. These results suggest that compound 4 should be involved in defense of A. gorgorum, displaying a wide range of activities that allow proposing them as new leads for development of a natural herbicide model with a seco-guaianolide skeleton.

Metabolomics Coupled with Proteomics Advancing Drug Discovery toward More Agile Development of Targeted Combination Therapies*

PubMed Central

Wang, Xijun; Zhang, Aihua; Wang, Ping; Sun, Hui; Wu, Gelin; Sun, Wenjun; Lv, Haitao; Jiao, Guozheng; Xu, Hongying; Yuan, Ye; Liu, Lian; Zou, Dixin; Wu, Zeming; Han, Ying; Yan, Guangli; Dong, Wei; Wu, Fangfang; Dong, Tianwei; Yu, Yang; Zhang, Shuxiang; Wu, Xiuhong; Tong, Xin; Meng, Xiangcai

2013-01-01

To enhance the therapeutic efficacy and reduce the adverse effects of traditional Chinese medicine, practitioners often prescribe combinations of plant species and/or minerals, called formulae. Unfortunately, the working mechanisms of most of these compounds are difficult to determine and thus remain unknown. In an attempt to address the benefits of formulae based on current biomedical approaches, we analyzed the components of Yinchenhao Tang, a classical formula that has been shown to be clinically effective for treating hepatic injury syndrome. The three principal components of Yinchenhao Tang are Artemisia annua L., Gardenia jasminoids Ellis, and Rheum Palmatum L., whose major active ingredients are 6,7-dimethylesculetin (D), geniposide (G), and rhein (R), respectively. To determine the mechanisms underlying the efficacy of this formula, we conducted a systematic analysis of the therapeutic effects of the DGR compound using immunohistochemistry, biochemistry, metabolomics, and proteomics. Here, we report that the DGR combination exerts a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of hepatic injury. Thus, DGR synergistically causes intensified dynamic changes in metabolic biomarkers, regulates molecular networks through target proteins, has a synergistic/additive effect, and activates both intrinsic and extrinsic pathways. PMID:23362329

Reconstruction of vegetation and lake level at Moon Lake, North Dakota, from high-resolution pollen and diatom data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimm, E.C.; Laird, K.R.; Mueller, P.G.

High-resolution fossil-pollen and diatom data from Moon Lake, North Dakota, reveal major climate and vegetation changes near the western margin of the tall-grass prairie. Fourteen AMS radiocarbon dates provide excellent time control for the past {approximately}11,800 {sup 14}C years B.P. Picea dominated during the late-glacial until it abruptly declined {approximately}10,300 B.P. During the early Holocene ({approximately}10,300-8000 B.P.), deciduous trees and shrubs (Populus, Betula, Corylus, Quercus, and especially Ulmus) were common, but prairie taxa (Poaceae, Artemisia, and Chenopodiaceae/Amaranthaceae) gradually increased. During this period the diatoms indicate the lake becoming gradually more saline as water-level fell. By {approximately}8000 B.P., salinity had increasedmore » to the point that the diatoms were no longer sensitive to further salinity increases. However, fluctuating pollen percentages of mud-flat weeds (Ambrosia and Iva) indicate frequently changing water levels during the mid-Holocene ({approximately}8000-5000 B.P.). The driest millennium was 7000-6000 B.P., when Iva annua was common. After {approximately}3000 B.P. the lake became less-saline, and the diatoms were again sensitive to changing salinity. The Medieval Warm Period and Little Ice Age are clearly evident in the diatom data.« less

Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies.

PubMed

Wang, Xijun; Zhang, Aihua; Wang, Ping; Sun, Hui; Wu, Gelin; Sun, Wenjun; Lv, Haitao; Jiao, Guozheng; Xu, Hongying; Yuan, Ye; Liu, Lian; Zou, Dixin; Wu, Zeming; Han, Ying; Yan, Guangli; Dong, Wei; Wu, Fangfang; Dong, Tianwei; Yu, Yang; Zhang, Shuxiang; Wu, Xiuhong; Tong, Xin; Meng, Xiangcai

2013-05-01

To enhance the therapeutic efficacy and reduce the adverse effects of traditional Chinese medicine, practitioners often prescribe combinations of plant species and/or minerals, called formulae. Unfortunately, the working mechanisms of most of these compounds are difficult to determine and thus remain unknown. In an attempt to address the benefits of formulae based on current biomedical approaches, we analyzed the components of Yinchenhao Tang, a classical formula that has been shown to be clinically effective for treating hepatic injury syndrome. The three principal components of Yinchenhao Tang are Artemisia annua L., Gardenia jasminoids Ellis, and Rheum Palmatum L., whose major active ingredients are 6,7-dimethylesculetin (D), geniposide (G), and rhein (R), respectively. To determine the mechanisms underlying the efficacy of this formula, we conducted a systematic analysis of the therapeutic effects of the DGR compound using immunohistochemistry, biochemistry, metabolomics, and proteomics. Here, we report that the DGR combination exerts a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of hepatic injury. Thus, DGR synergistically causes intensified dynamic changes in metabolic biomarkers, regulates molecular networks through target proteins, has a synergistic/additive effect, and activates both intrinsic and extrinsic pathways.

Essential oil variation in wild populations of Artemisia saharae (Asteraceae) from Tunisia: chemical composition, antibacterial and antioxidant properties.

PubMed

Zouari, Sami; Ayadi, Imen; Fakhfakh, Nahed; Jdir, Hamida; Aloui, Latifa; Kossentini, Mohamed; Rebai, Ahmed; Zouari, Nacim

2014-12-01

Artemisia saharae Pomel is a new taxon of Artemisia herba-alba Asso (Asteraceae) which is endemic to Tunisia and Algeria. This shrub, commonly known as white wormwood or desert wormwood, is largely used in folk medicine and as a culinary herb. The bulks aromatic plants come from wild populations whose essential oils compositions as well as their biological properties are severely affected by several factors such as geographic conditions. Therefore, the aim of the present work is to provide more information about the influence of altitude variation on the essential oil composition, antimicrobial and antioxidant properties of Artemisia saharae growing wild in the same geographical area. Essential oils were extracted by hydrodistillation of leaves and flowers of the plant collected from seven different altitudes of the Baten Zamour region (southwest of Tunisia). The highest essential oil yields (2.70-2.80%) were obtained for populations of high altitudes. Seventy-five compounds, representing 92.78 to 96.95% of the total essential oils, were separated and identified. Essential oils were characterized by very high percentage of oxygenated monoterpenes (52.1-72.6%) which constituted the predominant class. From the analyzed populations, the major compounds (>7%) were α-thujone, β-thujone, chrysanthenone, camphor, chrysanthenyl acetate, and sabinyl acetate. Sabinyl acetate which was detected in some populations at relatively high percentages (7.7-10.8%) seems to be characteristic to Southern Tunisian A. saharae. The studied essential oil showed a chemical diversity depending on the population altitude as revealed by linear discriminant and cluster analyses. Three population groups associated with altitudinal levels were distinguished. It is worthy to note that the most discriminating compounds of chemical groups were the minor ones. Despite the high variation of essential oil compositions, the high altitude population did not affect severely the antibacterial activity against the most tested strains. Altitude seems to be an important factor influencing the yield and the chemical profile of Artemisia saharae essential oils. Knowledge of the chemical composition of essential oils in relation to environmental factors is a very important quality criterion for their marketing and contributes to their valorization as functional ingredient in food technology.

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

PubMed Central

Coppens, Isabelle; Mbengue, Alassane; Suresh, Niraja; Ghorbal, Mehdi; Slouka, Zdenek; Safeukui, Innocent; Tang, Hsin-Yao; Speicher, David W.; Stahelin, Robert V.; Mohandas, Narla

2018-01-01

Artemisinin resistance threatens worldwide malaria control and elimination. Elevation of phosphatidylinositol-3-phosphate (PI3P) can induce resistance in blood stages of Plasmodium falciparum. The parasite unfolded protein response (UPR) has also been implicated as a proteostatic mechanism that may diminish artemisinin-induced toxic proteopathy. How PI3P acts and its connection to the UPR remain unknown, although both are conferred by mutation in P falciparum Kelch13 (K13), the marker of artemisinin resistance. Here we used cryoimmunoelectron microscopy to show that K13 concentrates at PI3P tubules/vesicles of the parasite’s endoplasmic reticulum (ER) in infected red cells. K13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The PfEMP1-K13 proteome is comprehensively enriched in multiple proteostasis systems of protein export, quality control, and folding in the ER and cytoplasm and UPR. Synthetic elevation of PI3P that induces resistance in absence of K13 mutation also yields signatures of proteostasis and clinical resistance. These findings imply a key role for PI3P-vesicle amplification as a mechanism of resistance of infected red cells. As validation, the major resistance mutation K13C580Y quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Chemical inhibitors and fluorescence microscopy showed that alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor are features of multiple K13 mutants. Together these data suggest that amplified PI3P vesicles disseminate widespread proteostatic capacity that may neutralize artemisinins toxic proteopathy and implicate a role for the host red cell in artemisinin resistance. The mechanistic insights generated will have an impact on malaria drug development. PMID:29363540

Development of a greenhouse-based inoculation protocol for the fungus Colletotrichum cereale pathogenic to annual bluegrass (Poa annua)

USDA-ARS?s Scientific Manuscript database

The fungus Colletotrichum cereale incites anthracnose disease on Poa annua (annual bluegrass) turfgrass. Anthracnose disease is geographically widespread highly destructive, with infections by C. cereale resulting in extensive turfgrass loss. Comprehensive research aimed at controlling turfgrass a...

Pseudomonas fluorescens strains selectively suppress annual bluegrass (Poa annua L.)

USDA-ARS?s Scientific Manuscript database

Annual bluegrass (Poa annua L.) is a cool-season annual grass that is a major weed species in turf, turfgrass-seed production, sod production, and golf courses of the western United States. There are few selective herbicides available for the management of annual bluegrass. While the life cycles o...

Interim Regional Supplement to the Corps of Engineers Wetland Delineation Manual: Great Plans Region

DTIC Science & Technology

2008-03-01

artemisiifolia Iva annua Cardiospermum halicacabum Xanthium strumarium FACW FACU− FAC FAC FAC− 40 15 15 8 6 Yes Yes Yes No No Total...virgatum 50 40 90 2 180 FAC species Iva annua Celtis laevigata Cardiospermum halicacabum Xanthium strumarium Toxicodendron radicans3 15 12

Solubilization and partial purification of constituents of acyl-CoA elongase from Lunaria annua.

PubMed

Fehling, E; Lessire, R; Cassagne, C; Mukherjee, K D

1992-06-05

All the constituent enzymes of acyl-CoA elongase, i.e., beta-ketoacyl-CoA synthase, beta-ketoacyl-CoA reductase, beta-hydroxyacyl-CoA dehydrase and trans-2-enoyl-CoA reductase, have been solubilized from a 15,000 x g particulate fraction from developing seeds of honesty (Lunaria annua) using Triton X-100. All these activities were retained upon subsequent precipitation of the solubilized protein with polyethylene glycol and resuspension of the precipitate followed by ion exchange chromatography of the resulting protein on DEAE-cellulose. A 4.2-fold enrichment of the acyl-CoA elongase was thus obtained. Further chromatography of the DEAE fraction containing all the constituents of acyl-CoA elongase on Ultrogel yielded a major protein fraction exhibiting the activities of beta-ketoacyl-CoA synthase and beta-ketoacyl-CoA reductase only. Almost 30-fold purification of the beta-ketoacyl-CoA synthase was thus achieved. The beta-ketoacyl-CoA synthase was inhibited only at high concentrations of cerulenin, but at very low concentrations of iodoacetamide. Inhibition could be reduced by preincubation with thioesters, indicating that an enzyme thioester intermediate is involved in the condensation reaction of the acyl-CoA elongation.

Ethnopharmacological documentation of medicinal plants used for hypertension among the local communities of DIR Lower, Pakistan.

PubMed

Ahmad, Latif; Semotiuk, Andrew; Zafar, Muhammad; Ahmad, Mushtaq; Sultana, Shazia; Liu, Quan-Ru; Zada, Muhammad Pukhtoon; Ul Abidin, Sheikh Zain; Yaseen, Ghulam

2015-12-04

Local communities of the Dir Lower district in Northwest Khyber Pakhtunkhwa, Pakistan rely on botanical anti-hypertensive preparations. Insights into the traditional uses of local flora can direct investigation into phytochemical screening. This ethnobotanical study aims to identify plant species and recipes used by the local people for the treatment of hypertension in the district of Dir Lower. Inquiries and interviews were carried out from November 2012 to December 2013 from local herbalist and indigenous communities including village elders. A total of 46 plant species (43 genera and 29 botanical families) used by local people of study area to treat hypertension. Family Lamiaceae dominated with the highest percentage 15.21% (7 species). With respect to growth form, herbs constituted (63.05%), shrubs (30.43%) and trees (6.52%). Leaves (37.25%) were the most frequently used part in herbal preparations. The major mode of preparation was decoction (46.66%) and almost all recipes were orally administered. Use values (UV) revealed that the most preferred species for the treatment of hypertension by the indigenous community are Paeonia emodi Wall. ex Royle., followed by Sarcococca saligna (D. Don) Muell. Arg., Fumaria indica (Hausskn.) Pugsley and Teucrium stocksianum Boiss. Amongst the 46 medicinal plants, antihypertensive activity of 16 plants included Artemisia vulgiris L., Artemisia annua L., Sisymbrium brassiciforme C. A. Mey., T. stocksianum Boiss, Cichorium intybus L., Rosa brunonii Lindl., Chenopodium botrys L., Olea ferruginea Royle, Cotoneaster acuminatus Lindl, S. saligna (D. Don) Muell. Arg., Viola canescens Wall. ex Roxb, P. emodi Wall. ex Royle, Asparagus gracilis Royle, Maytenus royleanus (Wall. ex Lawson), Allium jacquemontii Kunth and Onosma hispidum Wall has not been reported previously in the scientific literature. Dir lower is a rich and biodiverse area of medicinal plant. The large number of plant species used for hypertension in this area shows the importance of herbal medicine in the primary health care of this remote area. In future studies, the plant should be further screened for phytochemical and new medicinal properties. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

An open-label six-month extension study to investigate the safety and efficacy of an extract of Artemisia annua for managing pain, stiffness and functional limitation associated with osteoarthritis of the hip and knee.

PubMed

Hunt, Sheena; Stebbings, Simon; McNamara, Debra

2016-10-28

This six-month single-centre open-label extension study, conducted at the University of Otago, Dunedin, follows from a previously published 12-week pilot double-blind randomised placebo-controlled study of dietary supplement, Arthrem® (ART) in patients with osteoarthritis (OA) of the hip or knee. The pilot double-blind study showed that treatment with ART 150 mg twice-daily was associated with clinically relevant pain reduction. The extension study aims were to assess longer-term safety and efficacy during six months' treatment following the pilot trial. Patients who completed the pilot double-blind study had the option to continue on open-label treatment with ART for a further six months. Safety was assessed by adverse event monitoring and laboratory tests at three and six months. Efficacy was assessed at three and six months using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®). Thirty-four patients entered the optional extension and 28 completed six months' treatment. ART was well tolerated when taken for up to nine months. Improvements in WOMAC® efficacy parameters reported in the double-blind phase of the study were maintained over six months. ART appears to be a safe and effective alternative for managing the symptoms of OA over an extended period.

Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

PubMed

Wu, Buchu; Hu, Ke; Li, Shu; Zhu, Jing; Gu, Liying; Shen, Haoran; Hambly, Brett D; Bao, Shisan; Di, Wen

2012-01-01

Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration.

Improving sustainable seed yield in Wyoming big sagebrush

Treesearch

Jeremiah C. Armstrong

2007-01-01

As part of the Great Basin Restoration Initiative, the effects of browsing, competition removal, pruning, fertilization and seed collection methods on increasing seed production in Wyoming big sagebrush (Artemisia tridentata Nutt. spp wyomingensis Beetle & Young) were studied. Study sites were located in Idaho, Nevada, and Utah. A split-plot...

Radical chemistry of artemisinin

NASA Astrophysics Data System (ADS)

Denisov, Evgenii T.; Solodova, S. L.; Denisova, Taisa G.

2010-12-01

The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

[Quality evaluation of Artemisiae Argyi Folium based on fingerprint analysis and quantitative analysis of multicomponents].

PubMed

Guo, Long; Jiao, Qian; Zhang, Dan; Liu, Ai-Peng; Wang, Qian; Zheng, Yu-Guang

2018-03-01

Artemisiae Argyi Folium, the dried leaves of Artemisia argyi, has been widely used in traditional Chinese and folk medicines for treatment of hemorrhage, pain, and skin itch. Phytochemical studies indicated that volatile oil, organic acid and flavonoids were the main bioactive components in Artemisiae Argyi Folium. Compared to the volatile compounds, the research of nonvolatile compounds in Artemisiae Argyi Folium are limited. In the present study, an accurate and reliable fingerprint approach was developed using HPLC for quality control of Artemisiae Argyi Folium. A total of 10 common peaks were marked，and the similarity of all the Artemisiae Argyi Folium samples was above 0.940. The established fingerprint method could be used for quality control of Artemisiae Argyi Folium. Furthermore, an HPLC method was applied for simultaneous determination of seven bioactive compounds including five organic acids and two flavonoids in Artemisiae Argyi Folium and Artemisiae Lavandulaefoliae Folium samples. Moreover, chemometrics methods such as hierarchical clustering analysis and principal component analysis were performed to compare and discriminate the Artemisiae Argyi Folium and Artemisiae Lavandulaefoliae Folium based on the quantitative data of analytes. The results indicated that simultaneous quantification of multicomponents coupled with chemometrics analysis could be a well-acceptable strategy to identify and evaluate the quality of Artemisiae Argyi Folium. Copyright© by the Chinese Pharmaceutical Association.

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

PubMed Central

Okebe, Joseph; Mbye, Haddijatou; Ceesay, Sukai; El-Fatouri, Fatima; Joof, Fatou; Nyang, Haddy; Janha, Ramatoulie; Affara, Muna; Ahmad, Abdullahi; Kolly, Olimatou; Nwakanma, Davis; D'Alessandro, Umberto

2017-01-01

ABSTRACT Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future. PMID:28971859

Multiplex PCR method to discriminate Artemisia iwayomogi from other Artemisia plants.

PubMed

Doh, Eui Jeong; Oh, Seung-Eun

2012-01-01

Some plants in the genus Artemisia have been used for medicinal purposes. Among them, Artemisia iwayomogi, commonly referred to as "Haninjin," is one of the major medicinal materials used in traditional Korean medicine. By contrast, Artemisia capillaris and both Artemisia argyi and Artemisia princeps, referred to as "Injinho" and "Aeyup," respectively, are used to treat diseases different from those for which "Haninjin" is prescribed. Therefore, the development of a reliable method to differentiate each Artemisia herb is necessary. We found that a random amplified polymorphic DNA (RAPD) method can be used to efficiently discriminate a few Artemisia plants from one another. To improve the reliability of RAPD amplification, we designed primer sets based on the nucleotide sequences of RAPD products to amplify a sequence-characterized amplified region (SCAR) marker of A. iwayomogi. In addition, we designed two other primer sets to amplify SCAR markers of "Aeyup" (A. argyi and A. princeps) along with "Injinho" (A. capillaris) and Artemisia japonica, which are also traded in Korean herbal markets. Using these three primer sets, we developed a multiplex PCR method concurrently not only to discriminate A. iwayomogi from other Artemisia plants, but also to identify Artemisia plants using a single PCR process.

Total Synthesis and Biological Investigation of (-)-Artemisinin: The Antimalarial Activity of Artemisinin is not Stereospecific.

PubMed

Krieger, Johannes; Smeilus, Toni; Kaiser, Marcel; Seo, Ean-Jeong; Efferth, Thomas; Giannis, Athanassios

2018-05-03

Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of the Artemisinin Binding Site for Translationally Controlled Tumor Protein (TCTP) by Bioorthogonal Click Chemistry.

PubMed

Li, Weichao; Zhou, Yiqing; Tang, Guanghui; Xiao, Youli

2016-12-21

Despite the fact that multiple artemisinin-alkylated proteins in Plasmodium falciparum have been identified in recent studies, the alkylation mechanism and accurate binding site of artemisinin-protein interaction have remained elusive. Here, we report the chemical-probe-based enrichment of the artemisinin-binding peptide and characterization of the artemisinin-binding site of P. falciparum translationally controlled tumor protein (TCTP). A peptide fragment within the N-terminal region of TCTP was enriched and found to be alkylated by an artemisinin-derived probe. MS2 fragments showed that artemisinin could alkylate multiple amino acids from Phe12 to Tyr22 of TCTP, which was supported by labeling experiments upon site-directed mutagenesis and computational modeling studies. Taken together, the "capture-and-release" strategy affords consolidated advantages previously unavailable in artemisinin-protein binding site studies, and our results deepened the understanding of the mechanism of protein alkylation via heme-activated artemisinin.

Effects of artemisinin sustained-release granules on mixed alga growth and microcystins production and release.

PubMed

Ni, Lixiao; Li, Danye; Hu, Shuzhen; Wang, Peifang; Li, Shiyin; Li, Yiping; Li, Yong; Acharya, Kumud

2015-12-01

To safely and effectively apply artemisinin sustained-release granules to control and prevent algal water-blooms, the effects of artemisinin and its sustained-release granules on freshwater alga (Scenedesmus obliquus (S. obliquus) and Microcystis aeruginosa (M. aeruginosa)), as well as the production and release of microcystins (MCs) were studied. The results showed that artemisinin sustained-release granules inhibited the growth of M. aeruginosa (above 95% IR) and S. obliquus (about 90% IR), with M. aeruginosa more sensitive. The artemisinin sustained-release granules had a longer inhibition effect on growth of pure algae and algal coexistence than direct artemisinin dosing. The artemisinin sustained-release granules could decrease the production and release of algal toxins due to the continued stress of artemisinin released from artemisinin sustained-release granules. There was no increase in the total amount of MC-LR in the algal cell culture medium.

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action.

PubMed

Wong, Yin Kwan; Xu, Chengchao; Kalesh, Karunakaran A; He, Yingke; Lin, Qingsong; Wong, W S Fred; Shen, Han-Ming; Wang, Jigang

2017-11-01

Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents. © 2017 Wiley Periodicals, Inc.

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

PubMed

Hindley, Stephen; Ward, Stephen A; Storr, Richard C; Searle, Natalie L; Bray, Patrick G; Park, B Kevin; Davies, Jill; O'Neill, Paul M

2002-02-28

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.

Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin.

PubMed

Park, Gab-Man; Park, Hyun; Oh, Sangtae; Lee, Seokjoon

2017-12-01

We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.

Multiwalled carbon nanotubes effect on the bioavailability of artemisinin and its cytotoxity to cancerous cells

NASA Astrophysics Data System (ADS)

Rezaei, Behzad; Majidi, Najmeh; Noori, Shokoofe; Hassan, Zuhair M.

2011-12-01

Artemisinin regarded as one of the most promising anticancer drugs can bind to DNA with a binding constant of 1.04 × 104 M-1. The electrochemical experiments indicated that for longer incubation time periods, the reduction peak current of artemisinin on carbon nanotube modified electrode increases. Therefore, the uptake of drug molecules from a solution into CNTs will be achieved automatically by adsorption of 88.7% of artemisinin onto carbon nanotubes surface without alteration in drug properties. Hence, capability of carbon nanotubes to have synergistic effect on the bioavailability of artemisinin was investigated. Experimental tests on K562 cancer cell lines growth by MTT assay proved that multi-walled carbon nanotubes can enhance the cytotoxity of artemisinin to the targeted cancer cells with unprecedented accuracy and efficiency. The IC50 values were 65 and 35 μM for artemisinin and artemisinin loaded on multi-walled carbon nanotubes, respectively; demonstrating that artemisinin loaded on multi-walled carbon nanotubes is more effective in inhibition of cancer cell lines growth.

Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment

PubMed Central

Zhong, Ting; Zhang, Li-ying; Wang, Zeng-yan; Wang, Yue; Song, Feng-mei; Zhang, Ya-hong; Yu, Jing-hua

2017-01-01

Human enterovirus 71 (EV71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (HFMD) in Asia. Currently, there are no drugs available for the prevention and treatment of HFMD. In this study, we compared the anti-EV71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from Chinese herbs Chinese rhubarb, Artemisia carvifolia and Astragalus, respectively, which have been traditionally used for the treatment and prevention of epidemic diseases. Human lung fibroblast cell line MRC5 was mock-infected or infected with EV71, and treated with drugs. The cytotoxicity of the drugs was detected with MTT assay. The cytopathic effects such as cell death and condensed nuclei were morphologically observed. The VP1-coding sequence required for EV71 genome replication was assayed with qRT-PCR. Viral protein expression was analyzed with Western blotting. Viral TCID50 was determined to evaluate EV71 virulence. Flow cytometry analysis of propidium iodide staining was performed to analyze the cell cycle distribution of MRC5 cells. Rheum emodin (29.6 μmol/L) effectively protected MRC5 cells from EV71-induced cytopathic effects, which resulted from the inhibiting viral replication: rheum emodin treatment decreased viral genomic levels by 5.34-fold, viral protein expression by less than 30-fold and EV71 virulence by 0.33107-fold. The fact that inhibition of rheum emodin on viral virulence was much stronger than its effects on genomic levels and viral protein expression suggested that rheum emodin inhibited viral maturation. Furthermore, rheum emodin treatment markedly diminished cell cycle arrest at S phase in MRC5 cells, which was induced by EV71 infection and favored the viral replication. In contrast, neither astragaloside (50 μmol/L) nor artemisinin (50 μmol/L) showed similar anti-EV71 activities. Among the three natural compounds tested, rheum emodin effectively suppressed EV71 viral replication, thus is a candidate anti-HFMD drug. PMID:27840410

Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment.

PubMed

Zhong, Ting; Zhang, Li-Ying; Wang, Zeng-Yan; Wang, Yue; Song, Feng-Mei; Zhang, Ya-Hong; Yu, Jing-Hua

2017-03-01

Human enterovirus 71 (EV71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (HFMD) in Asia. Currently, there are no drugs available for the prevention and treatment of HFMD. In this study, we compared the anti-EV71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from Chinese herbs Chinese rhubarb, Artemisia carvifolia and Astragalus, respectively, which have been traditionally used for the treatment and prevention of epidemic diseases. Human lung fibroblast cell line MRC5 was mock-infected or infected with EV71, and treated with drugs. The cytotoxicity of the drugs was detected with MTT assay. The cytopathic effects such as cell death and condensed nuclei were morphologically observed. The VP1-coding sequence required for EV71 genome replication was assayed with qRT-PCR. Viral protein expression was analyzed with Western blotting. Viral TCID50 was determined to evaluate EV71 virulence. Flow cytometry analysis of propidium iodide staining was performed to analyze the cell cycle distribution of MRC5 cells. Rheum emodin (29.6 μmol/L) effectively protected MRC5 cells from EV71-induced cytopathic effects, which resulted from the inhibiting viral replication: rheum emodin treatment decreased viral genomic levels by 5.34-fold, viral protein expression by less than 30-fold and EV71 virulence by 0.33107-fold. The fact that inhibition of rheum emodin on viral virulence was much stronger than its effects on genomic levels and viral protein expression suggested that rheum emodin inhibited viral maturation. Furthermore, rheum emodin treatment markedly diminished cell cycle arrest at S phase in MRC5 cells, which was induced by EV71 infection and favored the viral replication. In contrast, neither astragaloside (50 μmol/L) nor artemisinin (50 μmol/L) showed similar anti-EV71 activities. Among the three natural compounds tested, rheum emodin effectively suppressed EV71 viral replication, thus is a candidate anti-HFMD drug.

Unpacking 'Artemisinin Resistance'.

PubMed

Wang, Jigang; Xu, Chengchao; Lun, Zhao-Rong; Meshnick, Steven R

2017-06-01

Artemisinin and its derivatives, in combination with partner drugs, are currently the most effective treatments for malaria parasite infection. Even though artemisinin has been widely used for decades, its mechanism of action had remained controversial until recently. Artemisinin combination therapies (ACTs) have recently been found to be losing efficacy in Southeast Asia. This 'artemisinin resistance', defined by a delayed parasite clearance time, has been associated with several genetic mutations. As with any other drug resistance phenotype, resistance can best be understood based on its mechanism of action. Recently, it was demonstrated that artemisinin attacks multiple parasitic targets, suggesting that mutations in drug targets are unlikely to cause high-level artemisinin resistance. These findings will help us to better understand the mechanisms of artemisinin resistance and suggest protocol modifications that may improve the efficacy of ACTs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria.

PubMed

Jamsen, Kris M; Duffull, Stephen B; Tarning, Joel; Lindegardh, Niklas; White, Nicholas J; Simpson, Julie A

2012-07-11

Artemisinin-based combination therapy (ACT) is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK) properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine) co-administered with artemisinin derivatives. The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure. For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule) with five samples per patient resulted in acceptable precision of the model parameter estimates. The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.

Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation

PubMed Central

Wang, Juan; Huang, Liying; Li, Jian; Fan, Qiangwang; Long, Yicheng; Li, Ying; Zhou, Bing

2010-01-01

The biological mode of action of artemisinin, a potent antimalarial, has long been controversial. Previously we established a yeast model addressing its mechanism of action and found mitochondria the key in executing artemisinin's action. Here we present data showing that artemisinin directly acts on mitochondria and it inhibits malaria in a similar way as yeast. Specifically, artemisinin and its homologues exhibit correlated activities against malaria and yeast, with the peroxide bridge playing a key role for their inhibitory action in both organisms. In addition, we showed that artemisinins are distributed to malarial mitochondria and directly impair their functions when isolated mitochondria were tested. In efforts to explore how the action specificity of artemisinin is achieved, we found strikingly rapid and dramatic reactive oxygen species (ROS) production is induced with artemisinin in isolated yeast and malarial but not mammalian mitochondria, and ROS scavengers can ameliorate the effects of artemisinin. Deoxyartemisinin, which lacks an endoperoxide bridge, has no effect on membrane potential or ROS production in malarial mitochondria. OZ209, a distantly related antimalarial endoperoxide, also causes ROS production and depolarization in isolated malarial mitochondria. Finally, interference of mitochondrial electron transport chain (ETC) can alter the sensitivity of the parasite towards artemisinin. Addition of iron chelator desferrioxamine drastically reduces ETC activity as well as mitigates artemisinin-induced ROS production. Taken together, our results indicate that mitochondrion is an important direct target, if not the sole one, in the antimalarial action of artemisinins. We suggest that fundamental differences among mitochondria from different species delineate the action specificity of this class of drugs, and differing from many other drugs, the action specificity of artemisinins originates from their activation mechanism. PMID:20221395

Quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in Enugu, Nigeria.

PubMed

Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M; Onwujekwe, Obinna

2015-01-01

Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. ACAs were purchased using three sampling approaches--convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained.

The bZIP transcription factor HY5 interacts with the promoter of the monoterpene synthase gene QH6 in modulating its rhythmic expression.

PubMed

Zhou, Fei; Sun, Tian-Hu; Zhao, Lei; Pan, Xi-Wu; Lu, Shan

2015-01-01

The Artemisia annua L. β-pinene synthase QH6 was previously determined to be circadian-regulated at the transcriptional level, showing a rhythmic fluctuation of steady-state transcript abundances. Here we isolated both the genomic sequence and upstream promoter region of QH6. Different regulatory elements, such as G-box (TGACACGTGGCA, -421 bp from the translation initiation site) which might have effects on rhythmic gene expression, were found. Using the yeast one-hybrid and electrophoretic mobility shift assay (EMSA), we confirmed that the bZIP transcription factor HY5 binds to this motif of QH6. Studies with promoter truncations before and after this motif suggested that this G-box was important for the diurnal fluctuation of the transgenic β-glucuronidase gene (GUS) transcript abundance in Arabidopsis thaliana. GUS gene driven by the promoter region immediately after G-box showed an arrhythmic expression in both light/dark (LD) and constant dark (DD) conditions, whereas the control with G-box retained its fluctuation in both LD and DD. We further transformed A. thaliana with the luciferase gene (LUC) driven by an 1400 bp fragment upstream QH6 with its G-box intact or mutated, respectively. The luciferase activity assay showed that a peak in the early morning disappeared in the mutant. Gene expression analysis also demonstrated that the rhythmic expression of LUC was abolished in the hy5-1 mutant.

Plasmodium falciparum malaria: Convergent evolutionary trajectories towards delayed clearance following artemisinin treatment.

PubMed

Wilairat, Prapon; Kümpornsin, Krittikorn; Chookajorn, Thanat

2016-05-01

Malaria is a major global health challenge with 300million new cases every year. The most effective regimen for treating Plasmodium falciparum malaria is based on artemisinin and its derivatives. The drugs are highly effective, resulting in rapid clearance of parasites even in severe P. falciparum malaria patients. During the last five years, artemisinin-resistant parasites have begun to emerge first in Cambodia and now in Thailand and Myanmar. At present, the level of artemisinin resistance is relatively low with clinical presentation of delayed artemisinin clearance (a longer time to reduce parasite load) and a small decrease in artemisinin sensitivity in cultured isolates. Nevertheless, multiple genetic loci associated with delayed parasite clearance have been reported, but they cannot account for a large portion of cases. Even the most well-studied kelch 13 propeller mutations cannot always predict the outcome of artemisinin treatment in vitro and in vivo. Here we propose that delayed clearance by artemisinin could be the result of convergent evolution, driven by multiple trajectories to overcome artemisinin-induced stress, but precluded to become full blown resistance by high fitness cost. Genetic association studies by several genome-wide approaches reveal linkage disequilibrium between multiple loci and delayed parasite clearance. Genetic manipulations at some of these loci already have resulted in loss in artemisinin sensitivity. The notion presented here is by itself consistent with existing evidence on artemisinin resistance and has the potential to be explored using available genomic data. Most important of all, molecular surveillance of artemisinin resistance based on multi-genic markers could be more informative than relying on any one particular molecular marker. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fitness of artemisinin-resistant Plasmodium falciparum in vitro

PubMed Central

Hott, Amanda; Tucker, Matthew S.; Casandra, Debora; Sparks, Kansas; Kyle, Dennis E.

2015-01-01

Objectives Drug resistance confers a fitness advantage to parasites exposed to frequent drug pressure, yet these mutations also may incur a fitness cost. We assessed fitness advantages and costs of artemisinin resistance in Plasmodium falciparum in vitro to understand how drug resistance will spread and evolve in a competitive environment. Methods Genotyping of SNPs, drug susceptibility assays and copy number determination were used to assess the impact of artemisinin resistance on parasite fitness. An artemisinin-resistant clone (C9) selected in vitro from an isogenic parental clone (D6) was used to conduct competitive growth studies to assess fitness of artemisinin resistance. The resistant and susceptible clones were mixed or grown alone in the presence and absence of drug pressure (dihydroartemisinin or pyrimethamine) to quantify the rate at which artemisinin resistance was gained or lost. Results We experimentally demonstrate for the first time that artemisinin resistance provides a fitness advantage that is selected for with infrequent exposure to drug, but is lost in the absence of exposure to artemisinin drugs. The best correlations with artemisinin resistance were decreased in vitro drug susceptibility to artemisinin derivatives, increased copy number of Pf3D7_1030100 and an SNP in Pf3D7_0307600. An SNP conferring an E208K mutation in the kelch gene (Pf3D7_1343700) was not associated with resistance. Furthermore, we observed second-cycle ring-stage dormancy induced by pyrimethamine, suggesting that dormancy is a fitness trait that provides an advantage for survival from antimalarial drug stress. Conclusions Artemisinin-resistant P. falciparum have a fitness advantage to survive and predominate in the population even in the face of infrequent exposure to artemisinin drugs. PMID:26203183

Overview of the improvement of the ring-stage survival assay-a novel phenotypic assay for the detection of artemisinin-resistant Plasmodium falciparum.

PubMed

Zhang, Jie; Feng, Guo-Hua; Zou, Chun-Yan; Su, Pin-Can; Liu, Huai-E; Yang, Zhao-Qing

2017-11-18

Artemisinin resistance in Plasmodium falciparum threatens the remarkable efficacy of artemisinin-based combination therapies worldwide. Thus, greater insight into the resistance mechanism using monitoring tools is essential. The ring-stage survival assay is used for phenotyping artemisinin-resistance or decreased artemisinin sensitivity. Here, we review the progress of this measurement assay and explore its limitations and potential applications.

Development of solid dispersions of artemisinin for transdermal delivery.

PubMed

Shahzad, Yasser; Sohail, Sadia; Arshad, Muhammad Sohail; Hussain, Talib; Shah, Syed Nisar Hussain

2013-11-30

Solid dispersions of the poorly soluble drug artemisinin were developed using polymer blends of polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) with the aim of enhancing solubility and in vitro permeation of artemisinin through skin. Formulations were characterised using a combination of molecular dynamics (MD) simulations, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Solubility of artemisinin was determined in two solvents: de-ionised water and phosphate buffered saline (PBS; pH 7.4), while in vitro drug permeation studies were carried out using rabbit skin as a model membrane. MD simulations revealed miscibility between the drug and polymers. DSC confirmed the molecular dispersion of the drug in the polymer blend. Decrease in crystallinity of artemisinin with respect to polymer content and the absence of specific drug-polymer interactions were confirmed using XRD and FT-IR, respectively. The solubility of artemisinin was dramatically enhanced for the solid dispersions, as was the permeation of artemisinin from saturated solid-dispersion vehicles relative to that from saturated solutions of the pure drug. The study suggests that high energy solid forms of artemisinin could possibly enable transdermal delivery of artemisinin. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigation on the relationship between solubility of artemisinin and polyvinylpyrroli done addition by using DAOSD approach

NASA Astrophysics Data System (ADS)

Zhang, Jin; Guo, Ran; He, Anqi; Weng, Shifu; Gao, Xiuxiang; Xu, Yizhuang; Noda, Isao; Wu, Jinguang

2017-07-01

In this work, we investigated the influence of polyvinylpyrrolidone (PVP) on the solubility of artemisinin in aqueous solution by using quantitative 1H NMR. Experimental results demonstrate that about 4 times of incremental increase occurs on the solubility of artemisinin upon introducing PVP. In addition, dipole-dipole interaction between the ester group of artemisinin and the amide group of N-methylpyrrolidone (NMP), a model compound of PVP, is characterized by two-dimensional (2D) correlation FTIR spectroscopy with the DAOSD (Double Asynchronous Orthogonal Sample Design) approach developed in our previous work. The observation of cross peaks in a pair of 2D asynchronous spectra suggests that dipole-dipole interaction indeed occurs between the ester group of artemisinin and amide group of NMP. Moreover, the pattern of cross peaks indicates that the carbonyl band of artemisinin undergoes blue-shift while the bandwidth and absorptivity increases via interaction with NMP, and the amide band of NMP undergoes blue-shift while the absorptivity increases via interaction with artemisinin. Dipole-dipole interaction, as one of the strongest intermolecular interaction between artemisinin and excipient, may play an important role in the enhancement of the solubility of artemisinin in aqueous solution.

Complete Chloroplast Genome Sequences of Mongolia Medicine Artemisia frigida and Phylogenetic Relationships with Other Plants

PubMed Central

Liu, Yue; Huo, Naxin; Dong, Lingli; Wang, Yi; Zhang, Shuixian; Young, Hugh A.; Feng, Xiaoxiao; Gu, Yong Qiang

2013-01-01

Background Artemisia frigida Willd. is an important Mongolian traditional medicinal plant with pharmacological functions of stanch and detumescence. However, there is little sequence and genomic information available for Artemisia frigida, which makes phylogenetic identification, evolutionary studies, and genetic improvement of its value very difficult. We report the complete chloroplast genome sequence of Artemisia frigida based on 454 pyrosequencing. Methodology/Principal Findings The complete chloroplast genome of Artemisia frigida is 151,076 bp including a large single copy (LSC) region of 82,740 bp, a small single copy (SSC) region of 18,394 bp and a pair of inverted repeats (IRs) of 24,971 bp. The genome contains 114 unique genes and 18 duplicated genes. The chloroplast genome of Artemisia frigida contains a small 3.4 kb inversion within a large 23 kb inversion in the LSC region, a unique feature in Asteraceae. The gene order in the SSC region of Artemisia frigida is inverted compared with the other 6 Asteraceae species with the chloroplast genomes sequenced. This inversion is likely caused by an intramolecular recombination event only occurred in Artemisia frigida. The existence of rich SSR loci in the Artemisia frigida chloroplast genome provides a rare opportunity to study population genetics of this Mongolian medicinal plant. Phylogenetic analysis demonstrates a sister relationship between Artemisia frigida and four other species in Asteraceae, including Ageratina adenophora, Helianthus annuus, Guizotia abyssinica and Lactuca sativa, based on 61 protein-coding sequences. Furthermore, Artemisia frigida was placed in the tribe Anthemideae in the subfamily Asteroideae (Asteraceae) based on ndhF and trnL-F sequence comparisons. Conclusion The chloroplast genome sequence of Artemisia frigida was assembled and analyzed in this study, representing the first plastid genome sequenced in the Anthemideae tribe. This complete chloroplast genome sequence will be useful for molecular ecology and molecular phylogeny studies within Artemisia species and also within the Asteraceae family. PMID:23460871

Artemisinin protects against dextran sulfate-sodium-induced inflammatory bowel disease, which is associated with activation of the pregnane X receptor.

PubMed

Hu, Donghua; Wang, Yuguang; Chen, Zhiwu; Ma, Zengchun; You, Qing; Zhang, Xianxie; Zhou, Tao; Xiao, Yong; Liang, Qiande; Tan, Hongling; Xiao, Chengrong; Tang, Xianglin; Zhang, Boli; Gao, Yue

2014-09-05

Artemisinin has been used to treat malaria for centuries in the context of traditional Chinese medicine. In the present study, the effects of artemisinin on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in inflammatory bowel disease were investigated. LS174T cells exposed to artemisinin at various concentrations and for different periods of time were examined with respect to the specific induction of CYP3A4 and PXR mRNA expression. Transient transfection experiments showed transcriptional activation of the CYP3A4 gene through artemisinin to be PXR-dependent. An electrophoretic-mobility shift assay (EMSA) showed that artemisinin activates the DNA-binding capacity of the PXR for the CYP3A4 element. These results indicate that the induction of CYP3A4 by artemisinin is mediated through the activation of PXR. Using animal models, it was demonstrated that artemisinin abrogates dextran sulfate sodium (DDS)-induced intestinal inflammation. Preadministration of artemisinin ameliorated the clinical hallmarks of colitis in DSS-treated mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Artemisinin was found to prevent or reduce the severity of colonic inflammation by inducing CYP3A expression by activation of PXR. Copyright © 2014 Elsevier B.V. All rights reserved.

Do plants adjust their sex allocation and secondary sexual morphology in response to their neighbours?

PubMed Central

Vilas, Julia Sánchez; Pannell, John R.

2012-01-01

Background and aims Changes in the sex allocation (i.e. in pollen versus seed production) of hermaphroditic plants often occur in response to the environment. In some homosporous ferns, gametophytes choose their gender in response to chemical cues sent by neighbours, such that spores develop as male gametophytes if they perceive a female or hermaphrodite nearby. Here it is considered whether a similar process might occur in the androdioecious angiosperm species Mercurialis annua, in which males co-occur with hermaphrodites; previous work on a Spanish population of M. annua found that individuals were more likely to develop as males at high density. Methods Using a novel approach to treat plants with leachate from pots containing males or hermaphrodites of M. annua, the hypothesis that individuals assess their mating opportunities, and adjust their sex expression accordingly, was tested through an exchange of chemical cues through the soil. Key Results For the population under study, from Morocco, no evidence was found for soil-signal-dependent sex expression: neither sex ratios nor sex allocation differed among experimental treatments. Conclusions The results imply either that the Moroccan population under study behaves differently from that previously studied in Spain (pointing to potential geographical variation in plasticity for sex expression), or that our method failed to capture the signals used by M. annua for adjustment of sex expression. PMID:22899829

Multiple Phenotypic and Genotypic Artemisinin Sensitivity Evaluation of Malian Plasmodium falciparum Isolates.

PubMed

Niaré, Karamoko; Paloque, Lucie; Ménard, Sandie; Tor, Pety; Ramadani, Arba P; Augereau, Jean-Michel; Dara, Antoine; Berry, Antoine; Benoit-Vical, Françoise; Doumbo, Ogobara K

2018-04-01

We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1-200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA 0-3 h ) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA 0-3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lincoln, D.E.

Preliminary analysis of two populations of Artemisia tridentata compared leaf chemical and physiological characteristics which influence herbivores. The proportion of sixteen of the volatile compounds differed significantly between the two populations; however, total yield of volatiles did not. This initial survey established the reliability of the procedure to quantitatively monitor plant responses to CO/sub 2/ enrichment and suggests that test samples be restricted to a single population. Four sesquiterpene lactones have been selected for the experimental quantitative HPLC analysis; all peaks have been assigned identities and have demonstrated high degree of reproducibility. Growth of Artemisia under high and low lightmore » at three CO/sub 2/ levels demonstrated that this species also undergoes a ''dilution'' of the leaf carbon content and is useful as test species for herbivory response to CO/sub 2/ induced effects. The initial experiment also showed that high irradiance is a necessary growth condition. 10 refs.« less

Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.

PubMed

Wang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C Y; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S W; Lin, Qingsong

2015-12-22

The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.

Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum

PubMed Central

Wang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, Qingsong

2015-01-01

The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing. PMID:26694030

Unexpected Preferential Dehydration of Artemisinin in Ionic Liquids

NASA Astrophysics Data System (ADS)

Sanders, Marc W.; Wright, Lawrence; Tate, Lauren; Fairless, Gayle; Crowhurst, Lorna; Bruce, Neil C.; Walker, Adam J.; Hembury, Guy A.; Shimizu, Seishi

2009-09-01

Thermodynamic measurements (at 298 K) reveal that a crucial step in the extraction process of the key antimalarial drug artemisinin by ionic liquids (ILs), namely, precipitation through the addition of water, is driven by artemisinin dehydration due to the differences in the water's interaction with the bulk ILs, rather than with the artemisinin itself.

Artemisinin nanoformulation suitable for intravenous injection: Preparation, characterization and antimalarial activities.

PubMed

Ibrahim, Nehal; Ibrahim, Hany; Sabater, Alicia Moreno; Mazier, Dominique; Valentin, Alexis; Nepveu, Françoise

2015-11-30

More than 40 years after its discovery, artemisinin has become the most promising antimalarial agent. However, no intravenous formulation is available due to its poor aqueous solubility. Here, we report the preparation, characterization, and in vitro and in vivo biological evaluation of biodegradable albumin-bound artemisinin nanoparticles. The nanoparticles were prepared by a combination of a bottom-up and a top-down processes and characterized by different spectroscopic techniques. The preparation process was optimized to develop a nanoformulation with the smallest possible diameter and good homogeneity suitable for intravenous injection enabling direct contact of artemisinin with infected erythrocytes. Chemically and physically stable artemisinin nanoparticles were obtained with excellent entrapment efficiency. In in vitro experiments, the artemisinin nanoformulation was interestingly more effective than non-formulated artemisinin. In Plasmodiumm falciparum-infected 'humanized' mice, the nanoparticles proved to be highly effective with 96% parasitemia inhibition at 10mg/kg/day, prolonging mean survival time without recrudescence. This nanoparticulate albumin-bound system allows the intravenous administration of artemisinin for the first time without harsh organic solvents or cosolvents with 100% bioavailability. Copyright © 2015 Elsevier B.V. All rights reserved.

Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion

PubMed Central

Klonis, Nectarios; Crespo-Ortiz, Maria P.; Bottova, Iveta; Abu-Bakar, Nurhidanatasha; Kenny, Shannon; Rosenthal, Philip J.; Tilley, Leann

2011-01-01

Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance. PMID:21709259

Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents.

PubMed

Magoulas, George E; Tsigkou, Tzoanna; Skondra, Lina; Lamprou, Margarita; Tsoukala, Panagiota; Kokkinogouli, Vassiliki; Pantazaka, Evangelia; Papaioannou, Dionissios; Athanassopoulos, Constantinos M; Papadimitriou, Evangelia

2017-07-15

The natural product artemisinin and derivatives thereof are currently considered as the drugs of choice for the treatment of malaria. At the same time, a significant number of such drugs have also shown interesting anticancer activity. In the context of the present research work, artemisinin was structurally modified and anchored to naturally occurring polyamines to afford new artemisinin dimeric conjugates whose potential anticancer activity was evaluated. All artemisinin conjugates tested were more effective than artemisinin itself in decreasing the number of MCF7 breast cancer cells. The effect required conjugation and was not due to the artemisinin analogue or the polyamine, alone or in combination. To elucidate potential mechanism of action, we used the most effective conjugates 6, 7, 9 and 12 and found that they decreased expression and secretion of the angiogenic growth factor pleiotrophin by the cancer cells themselves, and inhibited angiogenesis in vivo and endothelial cell growth in vitro. These data suggest that the new artemisinin dimers are good candidates for the development of effective anticancer agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

Artemisinin-resistant malaria: research challenges, opportunities, and public health implications.

PubMed

Fairhurst, Rick M; Nayyar, Gaurvika M L; Breman, Joel G; Hallett, Rachel; Vennerstrom, Jonathan L; Duong, Socheat; Ringwald, Pascal; Wellems, Thomas E; Plowe, Christopher V; Dondorp, Arjen M

2012-08-01

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance.

A new approach for the delivery of artemisinin: formulation, characterization, and ex-vivo antileishmanial studies.

PubMed

Want, Muzamil Yaqub; Islamuddin, Mohammad; Chouhan, Garima; Dasgupta, Anjan Kumar; Chattopadhyay, Asoke Prasun; Afrin, Farhat

2014-10-15

Artemisinin, a potential antileishmanial compound with poor bioavailability and stability has limited efficacy in visceral leishmaniasis. Encapsulating artemisinin into poly lactic-co glycolic nanoparticles may improve its effectiveness and reduce toxicity. Artemisinin-loaded nanoparticles were prepared, optimized (using Box-Behnken design) and characterized by dynamic light scattering technique, Atomic force microscopy (AFM), Transmission electron microscopy (TEM) and Fourier Transform-Infra Red spectroscopy. Release kinetics of artemisinin from optimized nanoformulation was studied by dialysis method at pH 7.4 and 5.5. Cytotoxicity and antileishmanial activity of these nanoparticles was tested on murine macrophages by MTT assay and macrophage-infested Leishmania donovani amastigotes ex vivo, respectively. Artemisinin-loaded nanoparticles were 221±14nm in diameter, with polydispersity index, zeta potential, drug loading and entrapment efficiency of 0.1±0.015, -9.07±0.69mV, 28.03±1.14 and 68.48±1.97, respectively. AFM and TEM studies indicated that the particles were spherical in shape. These colloidal particles showed a sustained release pattern in vitro. Treatment with artemisinin-loaded nanoparticles significantly reduced the number of amastigotes per macrophage and percent infected macrophages ex vivo compared to free artemisinin. These nanoparticles were also non-toxic to macrophages compared to artemisinin alone. Copyright © 2014 Elsevier Inc. All rights reserved.

Selection and Spread of Artemisinin-Resistant Alleles in Thailand Prior to the Global Artemisinin Resistance Containment Campaign

PubMed Central

Talundzic, Eldin; Okoth, Sheila Akinyi; Congpuong, Kanungnit; Plucinski, Mateusz M.; Morton, Lindsay; Goldman, Ira F.; Kachur, Patrick S.; Wongsrichanalai, Chansuda; Satimai, Wichai; Barnwell, John W.; Udhayakumar, Venkatachalam

2015-01-01

The recent emergence of artemisinin resistance in the Greater Mekong Subregion poses a major threat to the global effort to control malaria. Tracking the spread and evolution of artemisinin-resistant parasites is critical in aiding efforts to contain the spread of resistance. A total of 417 patient samples from the year 2007, collected during malaria surveillance studies across ten provinces in Thailand, were genotyped for the candidate Plasmodium falciparum molecular marker of artemisinin resistance K13. Parasite genotypes were examined for K13 propeller mutations associated with artemisinin resistance, signatures of positive selection, and for evidence of whether artemisinin-resistant alleles arose independently across Thailand. A total of seven K13 mutant alleles were found (N458Y, R539T, E556D, P574L, R575K, C580Y, S621F). Notably, the R575K and S621F mutations have previously not been reported in Thailand. The most prevalent artemisinin resistance-associated K13 mutation, C580Y, carried two distinct haplotype profiles that were separated based on geography, along the Thai-Cambodia and Thai-Myanmar borders. It appears these two haplotypes may have independent evolutionary origins. In summary, parasites with K13 propeller mutations associated with artemisinin resistance were widely present along the Thai-Cambodia and Thai-Myanmar borders prior to the implementation of the artemisinin resistance containment project in the region. PMID:25836766

Using supply side evidence to inform oral artemisinin monotherapy replacement in Myanmar: a case study.

PubMed

Khin, Hnin Su Su; Aung, Tin; Aung, Moe; Thi, Aung; Boxshall, Matt; White, Chris

2016-08-18

In 2012, alarmingly high rates of oral artemisinin monotherapy availability and use were detected along Eastern Myanmar, threatening efforts to halt the spread of artemisinin resistance in the Greater Mekong Subregion (GMS), and globally. The aim of this paper is to exemplify how the use of supply side evidence generated through the ACTwatch project shaped the artemisinin monotherapy replacement malaria (AMTR) project's design and interventions to rapidly displace oral artemisinin monotherapy with subsidized, quality-assured ACT in the private sector. The AMTR project was implemented as part of the Myanmar artemisinin resistance containment (MARC) framework along Eastern Myanmar. Guided by outlet survey and supply chain evidence, the project implemented a high-level subsidy, including negotiations with a main anti-malarial distributor, with the aim of squeezing oral artemisinin monotherapy out of the market through price competition and increased availability of quality-assured artemisinin-based combinations. This was complemented with a plethora of demand-creation activities targeting anti-malarial providers and consumers. Priority outlet types responsible for the distribution of oral artemisinin monotherapy were identified by the outlet survey, and this evidence was used to target the AMTR project's supporting interventions. The widespread availability and use of oral artemisinin monotherapy in Myanmar has been a serious threat to malaria control and elimination in the country and across the region. Practical anti-malarial market evidence was rapidly generated and used to inform private sector approaches to address these threats. The program design approach outlined in this paper is illustrative of the type of evidence generation and use that will be required to ensure effective containment of artemisinin drug resistance and progress toward regional and global malaria elimination goals.

Protective effect of artemisinin on chronic alcohol induced-liver damage in mice.

PubMed

Zhao, Xiaoyan; Wang, Liqing; Zhang, Hao; Zhang, Duoduo; Zhang, Zhihao; Zhang, Jie

2017-06-01

The liver disease related to chronic alcohol consumption is one of the leading causes of death for alcoholics. The efficient drug to ameliorate the alcoholic liver injury was needed urgently. The present study was performed to investigate whether artemisinin possessed the protective effect against chronic alcohol consumption. 50 male Kunming mice were divided into 5 groups: control group (C): 10ml/kg saline+10ml/kg saline, alcohol group (A): 10ml/kg 56%(v/v) alcohol+10ml/kg saline, low dose group of artemisinin (L): 10ml/kg 56%(v/v) alcohol+30mg/kg/day artemisinin, medium dose group of artemisinin (M): 10ml/kg 56%(v/v) alcohol+60mg/kg/day artemisinin, high dose group of artemisinin (H): 10ml/kg 56%(v/v) alcohol+120mg/kg/day artemisinin. Drugs were given orally every day. The general state of mice was observed and the levels of serum activities of AST and ALT were detected after treatment with drugs for 30days. Besides, the liver weight index was calculated and histopathological analysis was performed. We successfully demonstrated that treatment with high dose of artemisinin significantly decreased the elevated levels of AST (p<0.05) and ALT (p<0.01) in plasma, as well as the liver weight index (p<0.01). The loss of body weight, tissue injury, oedema and inflammatory cell infiltration in the hepatocytes were found in the A group. These symptoms were remarkably alleviated in animals treated with artemisinin. Artemisinin can inhibit the activation of NF-кB and the expression of inflammatory cytokines inducible nitric oxide synthase. Besides, it can also enhance the stability of liver cell membrane, and reduce the damage of liver cell membrane and liver cell. Artemisinin showed a protective effect against chronic alcohol poisoning and it has a great potential for the clinical application to treat the liver injury induced by alcohol. Copyright © 2017 Elsevier B.V. All rights reserved.

Fitness of artemisinin-resistant Plasmodium falciparum in vitro.

PubMed

Hott, Amanda; Tucker, Matthew S; Casandra, Debora; Sparks, Kansas; Kyle, Dennis E

2015-10-01

Drug resistance confers a fitness advantage to parasites exposed to frequent drug pressure, yet these mutations also may incur a fitness cost. We assessed fitness advantages and costs of artemisinin resistance in Plasmodium falciparum in vitro to understand how drug resistance will spread and evolve in a competitive environment. Genotyping of SNPs, drug susceptibility assays and copy number determination were used to assess the impact of artemisinin resistance on parasite fitness. An artemisinin-resistant clone (C9) selected in vitro from an isogenic parental clone (D6) was used to conduct competitive growth studies to assess fitness of artemisinin resistance. The resistant and susceptible clones were mixed or grown alone in the presence and absence of drug pressure (dihydroartemisinin or pyrimethamine) to quantify the rate at which artemisinin resistance was gained or lost. We experimentally demonstrate for the first time that artemisinin resistance provides a fitness advantage that is selected for with infrequent exposure to drug, but is lost in the absence of exposure to artemisinin drugs. The best correlations with artemisinin resistance were decreased in vitro drug susceptibility to artemisinin derivatives, increased copy number of Pf3D7_1030100 and an SNP in Pf3D7_0307600. An SNP conferring an E208K mutation in the kelch gene (Pf3D7_1343700) was not associated with resistance. Furthermore, we observed second-cycle ring-stage dormancy induced by pyrimethamine, suggesting that dormancy is a fitness trait that provides an advantage for survival from antimalarial drug stress. Artemisinin-resistant P. falciparum have a fitness advantage to survive and predominate in the population even in the face of infrequent exposure to artemisinin drugs. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

[Artemisinin inhibits proliferation of gallbladder cancer cell lines through triggering cell cycle arrest and apoptosis].

PubMed

Jia, J G; Zhang, L G; Guo, C X; Wang, Y G; Chen, B L; Wang, Y M; Qian, J

2016-03-01

To evaluate the effects of artemisinin on proliferation, cell cycle and apoptosis of gallbladder cancer cells. Gallbladder carcinoma cell lines(GBC-SD and NOZ)were cultured in vitro. The effects of artemisinin in different concentration on proliferation of the two cell lines in vitro were examined using MTT assay. The cell cycle distribution of GBC-SD and NOZ cells 24 h after treatments with artemisinin(20 μmol/L) were examined using flow cytometry. The apoptosis of GBC-SD and NOZ cells 24 h after treatments with artemisinin (20 μmol/L) were examined using Annexin V/PI staining.The expressions of p-ERK1/2, CDK4, cyclin D1, p16, cytochrome C and caspase-3 were examined by Western blot assay. t-test and one way ANOVA were used to evaluate the differences between two groups and more than two groups, respectively. The cell proliferation was significantly inhibited by artemisinin, the IC50 of artemisinin against GBC-SD and NOZ cells were 14.05 μmol/L and 12.42 μmol/L, respectively.Artemisinin induced cycle arrest, and G1 population of GBC-SD and NOZ cells increased to 74.60% and 78.86%. Cell apoptosis and apoptotic population of GBC-SD and NOZ cells were increased to 15.67% and 16.51% after dealt with artemisinin, respectively. In addition, expression of p16 was increased, and expressions of p-ERK1/2, CDK4 and cyclin D1 were down-regulated by artemisinin(all P<0.05). Cytochrome C was released from mitochondria to cytoplasm leading to the activation of caspase-3 and PARP after dealt with artemisinin(P<0.05). The inhibition effect of artemisinin on the proliferation gallbladder cancer cells is accompanied by down-regulation of ERK1/2 signaling pathway, G1 phase arrest and triggering caspase-3-mediate apoptosis.

Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: relationship with flavoenzyme function and antimalarial mechanism of action.

PubMed

Haynes, Richard K; Chan, Wing-Chi; Wong, Ho-Ning; Li, Ka-Yan; Wu, Wai-Keung; Fan, Kit-Man; Sung, Herman H Y; Williams, Ian D; Prosperi, Davide; Melato, Sergio; Coghi, Paolo; Monti, Diego

2010-08-02

The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH(2) initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH(2) for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N-benzyldihydronicotinamide (BNAH) in situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA-MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of two-electron reduction products from the artemisinins; regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is enhanced by artemisinins, especially under aerobic conditions. Recombinant human GR is not affected. Artemisinins thus may act as antimalarial drugs by perturbing the redox balance within the malaria parasite, both by oxidising FADH(2) in parasite GR or other parasite flavoenzymes, and by initiating autoxidation of the dihydroflavin by oxygen with generation of ROS. Reduction of the artemisinin is proposed to occur via hydride transfer from LMB or the dihydroflavin to O1 of the peroxide. This hitherto unrecorded reactivity profile conforms with known structure-activity relationships of artemisinins, is consistent with their known ability to generate ROS in vivo, and explains the synergism between artemisinins and redox-active antimalarial drugs such as MB and doxorubicin. As the artemisinins appear to be relatively inert towards human GR, a putative model that accounts for the selective potency of artemisinins towards the malaria parasite also becomes apparent. Decisively, ferrous iron or carbon-centered free radicals cannot be involved, and the reactivity described herein reconciles disparate observations that are incompatible with the ferrous iron-carbon radical hypothesis for antimalarial mechanism of action. Finally, the urgent enquiry into the emerging resistance of the malaria parasite to artemisinins may now in one part address the possibilities either of structural changes taking place in parasite flavoenzymes that render the flavin cofactor less accessible to artemisinins or of an enhancement in the ability to use intra-erythrocytic human disulfide reductases required for maintenance of parasite redox balance.

Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs.

PubMed

Classen, W; Altmann, B; Gretener, P; Souppart, C; Skelton-Stroud, P; Krinke, G

1999-11-01

Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Previous animal safety studies with Qinghaosu derivatives revealed dose-dependent neurotoxicity with movement disturbances and neuropathic changes in the hindbrain of intramuscularly treated dogs, rats and monkeys. Such effects have not been seen in man. The objective of our present studies was to compare the effects of high levels of AM administered to dogs p.o. versus i.m. In a pilot study 20 mg/kg/day of AM was given i.m. to groups of 3 male Beagle dogs for 5 and 30 days, respectively. Clinical signs of neurotoxicity were noted in some individual dogs from test day 23 on. One dog had to be sacrificed pre-term. Hematologic findings indicated a hypochromic, microcytic anemia. Microscopic examination demonstrated neuropathic changes only at 30 days, but not at 5 days. The animals had neuronal and secondary axonal damage, most prominent in the cerebellar roof, pontine and vestibular nuclei, and in the raphe/paralemniscal region. The affected neurons showed loss of Nissl substance, cytoplasmic eosinophilia, shrinkage of the nucleus and in advanced stages scavenging by microglia. In a subsequent experiment, AM was administered to groups of 4 male and 4 female dogs, respectively, at 8 daily doses of 0, 20, 40 and 80 mg/kg i.m., or 0, 50, 150 and 600 mg/kg p.o. Neurologic signs were seen at high i.m. doses only. In most animals they were inconspicuous and consisted of reduced activity with convulsions seen in single dogs shortly before death. Neuronal damage occurred in all animals at 40 and 80 mg/kg following i.m. treatment. At 20 mg/kg minimal effects occurred in 5/8 dogs only, indicating that this level was close to tolerated exposure. No comparable lesions were observed after oral administration. Both i.m. and p.o. exposure at high dose levels was associated with a prolongation of mean QT interval of ECG, suggesting slowing of repolarization of the myocardium. Individual data indicated that in 1 of 4 females at 80 mg/kg i.m. this prolongation was above the 25% level considered as threshold for concern. After intramuscular administration pharmacokinetics indicated peak plasma levels of AM at 2 to 4 hours post-dose, slow elimination and a tendency to accumulate after repeated administration. Only low levels of the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the cerebrospinal fluid (CSF) were < 10% of plasma levels. After oral administration AM concentrations were considerably lower than after i.m. administration. The concentration of DHA was high on day 1 but almost nil on day 7 indicating its fast inactivation in dogs. Two hours after the 8th oral administration neither AM nor DHA was detected in CSF which may explain the absence of neurotoxicity in dogs after oral administration of AM.

Preparation and Characterization of Micronized Artemisinin via a Rapid Expansion of Supercritical Solutions (RESS) Method

PubMed Central

Yu, Huimin; Zhao, Xiuhua; Zu, Yuangang; Zhang, Xinjuan; Zu, Baishi; Zhang, Xiaonan

2012-01-01

The particle sizes of pharmaceutical substances are important for their bioavailability. Bioavailability can be improved by reducing the particle size of the drug. In this study, artemisinin was micronized by the rapid expansion of supercritical solutions (RESS). The particle size of the unprocessed white needle-like artemisinin particles was 30 to 1200 μm. The optimum micronization conditions are determined as follows: extraction temperature of 62 °C, extraction pressure of 25 MPa, precipitation temperature 45 °C and nozzle diameter of 1000 μm. Under the optimum conditions, micronized artemisinin with a (mean particle size) MPS of 550 nm is obtained. By analysis of variance (ANOVA), extraction temperature and pressure have significant effects on the MPS of the micronized artemisinin. The particle size of micronized artemisinin decreased with increasing extraction temperature and pressure. Moreover, the SEM, LC-MS, FTIR, DSC and XRD allowed the comparison between the crystalline initial state and the micronization particles obtained after the RESS process. The results showed that RESS process has not induced degradation of artemisinin and that processed artemisinin particles have lower crystallinity and melting point. The bulk density of artemisinin was determined before and after RESS process and the obtained results showed that it passes from an initial density of 0.554 to 0.128 g·cm−3 after the processing. The decrease in bulk density of the micronized powder can increase the liquidity of drug particles when they are applied for medicinal preparations. These results suggest micronized powder of artemisinin can be of great potential in drug delivery systems. PMID:22606030

Artemisinin induces hormonal imbalance and oxidative damage in the erythrocytes and uterus but not in the ovary of rats.

PubMed

Farombi, E O; Abolaji, A O; Adedara, I A; Maduako, I; Omodanisi, I

2015-01-01

Artemisinin is an antimalarial drug previously reported to induce neurotoxicity and embryotoxicity in animal models. This study investigated the erythrocytes and reproductive toxicity potentials of artemisinin in female rats. Animals were randomly divided into four study groups of eight rats each. The control group (group I) received corn oil, the vehicle, while groups II-IV were orally exposed to 7, 35 and 70 mg kg(-1) day(-1) of artemisinin, respectively, by gastric intubation for 7 consecutive days. Subsequently, we evaluated the impact of artemisinin on the endocrine environment and selected markers of oxidative damage and antioxidant status of the erythrocytes, ovary and uterus. Artemisinin significantly increased hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels and decreased catalase, glutathione peroxidase and superoxide dismutase activities in erythrocytes and uterus of rats compared with control group (p < 0.05). However, artemisinin did not alter ovarian MDA, H2O2, glutathione levels and catalase activity, while ovarian and uterine histological assessment revealed absence of visible lesions. Moreover, artemisinin significantly decreased follicle-stimulating hormone and increased progesterone levels compared with control (p < 0.05). Thus, these data suggest that in the absence of malarial parasite infection, artemisinin induced hormonal imbalance and oxidative damage in the erythrocytes and uterus but spared the ovary of rats. © The Author(s) 2014.

Artemisinin-Resistant Malaria: Research Challenges, Opportunities, and Public Health Implications

PubMed Central

Fairhurst, Rick M.; Nayyar, Gaurvika M. L.; Breman, Joel G.; Hallett, Rachel; Vennerstrom, Jonathan L.; Duong, Socheat; Ringwald, Pascal; Wellems, Thomas E.; Plowe, Christopher V.; Dondorp, Arjen M.

2012-01-01

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance. PMID:22855752

Sexual dimorphism in a dioecious population of the wind-pollinated herb Mercurialis annua: the interactive effects of resource availability and competition.

PubMed

Hesse, Elze; Pannell, John R

2011-05-01

Male-biased sex allocation commonly occurs in wind-pollinated hermaphroditic plants, and is often positively associated with size, notably in terms of height. Currently, it is not well established whether a corresponding pattern holds for dioecious plants: do males of wind-pollinated species exhibit greater reproductive allocation than females? Here, sexual dimorphism is investigated in terms of life history trade-offs in a dioecious population of the wind-pollinated ruderal herb Mercurialis annua. The allocation strategies of males and females grown under different soil nutrient availability and competitive (i.e. no, male or female competitor) regimes were compared. Male reproductive allocation increased disproportionately with biomass, and was greater than that of females when grown in rich soils. Sexual morphs differentially adjusted their reproductive allocation in response to local environmental conditions. In particular, males reduced their reproductive allocation in poor soils, whereas females increased theirs, especially when competing with another female rather than growing alone. Finally, males displayed smaller above-ground vegetative sizes than females, but neither nutrient availability nor competition had a strong independent effect on relative size disparities between the sexes. Selection appears to favour plasticity in reproductive allocation in dioecious M. annua, thereby maintaining a relatively constant size hierarchy between sexual morphs. In common with other dioecious species, there seems to be little divergence in the niches occupied by males and females of M. annua.

Sexual dimorphism in a dioecious population of the wind-pollinated herb Mercurialis annua: the interactive effects of resource availability and competition

PubMed Central

Hesse, Elze; Pannell, John R.

2011-01-01

Background and Aims Male-biased sex allocation commonly occurs in wind-pollinated hermaphroditic plants, and is often positively associated with size, notably in terms of height. Currently, it is not well established whether a corresponding pattern holds for dioecious plants: do males of wind-pollinated species exhibit greater reproductive allocation than females? Here, sexual dimorphism is investigated in terms of life history trade-offs in a dioecious population of the wind-pollinated ruderal herb Mercurialis annua. Methods The allocation strategies of males and females grown under different soil nutrient availability and competitive (i.e. no, male or female competitor) regimes were compared. Key Results Male reproductive allocation increased disproportionately with biomass, and was greater than that of females when grown in rich soils. Sexual morphs differentially adjusted their reproductive allocation in response to local environmental conditions. In particular, males reduced their reproductive allocation in poor soils, whereas females increased theirs, especially when competing with another female rather than growing alone. Finally, males displayed smaller above-ground vegetative sizes than females, but neither nutrient availability nor competition had a strong independent effect on relative size disparities between the sexes. Conclusions Selection appears to favour plasticity in reproductive allocation in dioecious M. annua, thereby maintaining a relatively constant size hierarchy between sexual morphs. In common with other dioecious species, there seems to be little divergence in the niches occupied by males and females of M. annua. PMID:21385775

A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

NASA Astrophysics Data System (ADS)

Ariey, Frédéric; Witkowski, Benoit; Amaratunga, Chanaki; Beghain, Johann; Langlois, Anne-Claire; Khim, Nimol; Kim, Saorin; Duru, Valentine; Bouchier, Christiane; Ma, Laurence; Lim, Pharath; Leang, Rithea; Duong, Socheat; Sreng, Sokunthea; Suon, Seila; Chuor, Char Meng; Bout, Denis Mey; Ménard, Sandie; Rogers, William O.; Genton, Blaise; Fandeur, Thierry; Miotto, Olivo; Ringwald, Pascal; Le Bras, Jacques; Berry, Antoine; Barale, Jean-Christophe; Fairhurst, Rick M.; Benoit-Vical, Françoise; Mercereau-Puijalon, Odile; Ménard, Didier

2014-01-01

Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (`K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

PubMed Central

Ariey, Frédéric; Witkowski, Benoit; Amaratunga, Chanaki; Beghain, Johann; Langlois, Anne-Claire; Khim, Nimol; Kim, Saorin; Duru, Valentine; Bouchier, Christiane; Ma, Laurence; Lim, Pharath; Leang, Rithea; Duong, Socheat; Sreng, Sokunthea; Suon, Seila; Chuor, Char Meng; Bout, Denis Mey; Ménard, Sandie; Rogers, William O.; Genton, Blaise; Fandeur, Thierry; Miotto, Olivo; Ringwald, Pascal; Le Bras, Jacques; Berry, Antoine; Barale, Jean-Christophe; Fairhurst, Rick M.; Benoit-Vical, Françoise; Mercereau-Puijalon, Odile; Ménard, Didier

2016-01-01

Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (‘K13-propeller’) with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread. PMID:24352242

Taxonomic and nomenclatural rearrangements in Artemisia subgen. Tridentatae, including a redefinition of Sphaeromeria (Asteraceae, Anthemideae)

Treesearch

Sonia Garcia; Teresa Garnatje; E. Durant McArthur; Jaume Pellicer; Stewart C. Sanderson; Joan Valles

2011-01-01

A recent molecular phylogenetic study of all members of Artemisia subgenus Tridentatae, as well as most of the other New World endemic Artemisia and the allied genera Sphaeromeria and Picrothamnus, raised the necessity of revising the taxonomic framework of the North American endemic Artemisia. Composition of the subgenus Tridentatae is enlarged to accommodate other...

Allergenicity of Artemisia contained in bee pollen is proportional to its mass.

PubMed

Nonotte-Varly, C

2015-11-01

Bee product mugwort is identified as being at the origin of allergic accidents but the biological potency of Artemisia contained in bee pollen is not well known. In this experiment, Artemisia mass was identified in bee pollen mass and after having calculated the proportion of Artemisia using the bee pollen melissopalynology spectrum. Skin reactivity to Artemisia was assessed by measuring wheal diameters (W) from skin prick tests using three serial dilutions of bee pollen on 11 allergic patients to Artemisia, in order to calculate the relationship between Artemisia mass (Massartemisia) in bee pollen and skin reactivity. The dose-response power regression curve (Wartemisia)=3.328 (Massartemisia)0.297 (R2=0.9947) and the linear function Log10 (Wartemisia)=0.297 (Log10 (Massartemisia)+0.520 (R=0.9974)) were established using a bee pollen sample with 0.246 mg of Artemisia pollen per mg. Mugwort allergens seem to be little or not altered by bee secretions and bee pollen retains its allergenic capacity. To our knowledge this is the first time it has been shown that skin reactivity of patients allergic to mugwort is proportional to the absolute mugwort mass contained in the bee pollen.

Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

PubMed Central

2011-01-01

Background The World Health Organization has urged all member states to deploy artemisinin-based combination therapy and progressively withdraw oral artemisinin monotherapies from the market due to their high recrudescence rates and to reduce the risk of drug resistance. Prescription practices by physicians and the availability of oral artemisinin monotherapies with pharmacists directly affect the pattern of their use. Thus, treatment practices for malaria, with special reference to artemisinin monotherapy prescription, in selected states of India were evaluated. Methods Structured, tested questionnaires were used to conduct convenience surveys of physicians and pharmacists in eleven purposively selected districts across six states in 2008. In addition, exit interviews of patients with a diagnosis of uncomplicated malaria or a prescription for an anti-malarial drug were also performed. Logistic regression was used to determine patient clinical care, and institutional factors associated with artemisinin monotherapy prescription. Results Five hundred and eleven physicians from 196 health facilities, 530 pharmacists, and 1, 832 patients were interviewed. Artemisinin monotherapy was available in 72.6% of pharmacies and was prescribed by physicians for uncomplicated malaria in all study states. Exit interviews among patients confirmed the high rate of use of artemisinin monotherapy with 14.8% receiving such a prescription. Case management, i.e. method of diagnosis and overall treatment, varied by state and public or private sector. Treatment in the private sector (OR 8.0, 95%CI: 3.8, 17) was the strongest predictor of artemisinin monotherapy prescription when accounting for other factors. Use of the combination therapy recommended by the national drug policy, artesunate + sulphadoxine-pyrimethamine, was minimal (4.9%), with the exception of one state. Conclusions Artemisinin monotherapy use was widespread across India in 2008. The accessible sale of oral artemisinin monotherapy in retail market and an inadequate supply of recommended drugs in the public sector health facilities promoted its prescription. This study resulted in notifications to all state drug controllers in India to withdraw the oral artemisinin formulations from the market. In 2010, artesunate + sulphadoxine-pyrimethamine became the universal first-line treatment for confirmed Plasmodium falciparum malaria and was deployed at full scale. PMID:22166073

Artemisinin derivatives for treating severe malaria.

PubMed

McIntosh, H M; Olliaro, P

2000-01-01

Artemisinin derivatives may have advantages over quinoline drugs for treating severe malaria since they are fast acting and effective against quinine resistant malaria parasites. The objective of this review was to assess the effects of artemisinin drugs for severe and complicated falciparum malaria in adults and children. We searched the Cochrane Infectious Diseases Group trials register, Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, Lilacs, African Index Medicus, conference abstracts and reference lists of articles. We contacted organisations, researchers in the field and drug companies. Randomised and pseudo-randomised trials comparing artemisinin drugs (rectal, intramuscular or intravenous) with standard treatment, or comparisons between artemisinin derivatives in adults or children with severe or complicated falciparum malaria. Eligibility, trial quality assessment and data extraction were done independently by two reviewers. Study authors were contacted for additional information. Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from the blood and similar adverse effects. The evidence suggests that artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria. No artemisinin derivative appears to be better than the others.

Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation.

PubMed

Long, Huibao; Xu, Bincan; Luo, Yanling; Luo, Keqin

2016-05-01

NLRP3 inflammasome activation is recently reported to be linked to the pathogenesis of sepsis. Artemisinin is shown to play beneficial effects in sepsis. However, the impacts of artemisinin on burn sepsis have not been investigated. This study is designed to investigate the role of artemisinin in burn sepsis and the involvement of NLRP3 inflammasome activation. Male BALB/c mice were randomly divided into sham burn, burn, burn sepsis, and artemisinin treated groups. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Adhesion molecules and neutrophil infiltration in lung and heart were detected by real-time polymerase chain reaction. Mortality rates were monitored. Artemisinin was added to Raw 264.7 cells that were stimulated with burn sepsis serum in the presence/absence of an inhibitor of NLRP3 inflammasome, 3, 4-methylenedioxy-β-nitrostyrene. Interleukin (IL) 1β and IL-18 messenger RNA expression as well as NLRP3 and caspase 1 protein were measured. Production of inflammatory cytokines in serum, levels of adhesion molecules and neutrophil infiltration in lung and heart, and mortality rate of burn septic mice were significantly higher than those of control. These effects were attenuated by artemisinin. Artemisinin down-regulated protein levels of NLRP3 and caspase 1 and inhibited the increases of IL-1β and IL-18 messenger RNA expression from Raw 264.7 cells that were stimulated with burn sepsis serum. These effects of artemisinin were not further strengthened in the presence of 4-methylenedioxy-β-nitrostyrene. Artemisinin protects mice from burn sepsis by attenuating the inflammatory response and alleviating inflammatory infiltration in vital organs, likely through inhibiting the activation of NLRP3 inflammasome. Copyright © 2016 Elsevier Inc. All rights reserved.

Evidence for the contribution of the hemozoin synthesis pathway of the murine Plasmodium yoelii to the resistance to artemisinin-related drugs.

PubMed

Witkowski, Benoit; Lelièvre, Joel; Nicolau-Travers, Marie-Laure; Iriart, Xavier; Njomnang Soh, Patrice; Bousejra-Elgarah, Fatima; Meunier, Bernard; Berry, Antoine; Benoit-Vical, Françoise

2012-01-01

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia.

Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

PubMed Central

Nicolau-Travers, Marie-Laure; Iriart, Xavier; Njomnang Soh, Patrice; Bousejra-ElGarah, Fatima; Meunier, Bernard; Berry, Antoine; Benoit-Vical, Françoise

2012-01-01

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia. PMID:22403683

Mechanism of artemisinin phytotoxicity action: induction of reactive oxygen species and cell death in lettuce seedlings.

PubMed

Yan, Zhi-Qiang; Wang, Dan-Dan; Ding, Lan; Cui, Hai-Yan; Jin, Hui; Yang, Xiao-Yan; Yang, Jian-She; Qin, Bo

2015-03-01

Artemisinin has been recognized as an allelochemical that inhibits growth of several plant species. However, its mode of action is not well clarified. In this study, the mechanism of artemisinin phytotoxicity on lettuce seedlings was investigated. Root and shoot elongation of lettuce seedlings were inhibited by artemisinin in a concentration-dependent manner. The compound effectively arrested cell division and caused loss of cell viability in root tips of lettuce. Overproduction of reactive oxygen species (ROS) was induced by artemisinin. Lipid peroxidation, proline overproduction and reduction of chlorophyll content in lettuce seedlings were found after treatments. These results suggested that artemisinin could induce ROS overproduction, which caused membrane lipids peroxidation and cell death, and impacted mitosis and physiological processes, resulting in growth inhibition of receptor plants. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Neuroprotective effects of artemisinin against isoflurane-induced cognitive impairments and neuronal cell death involve JNK/ERK1/2 signalling and improved hippocampal histone acetylation in neonatal rats.

PubMed

Xu, Guang; Huang, Yun-Li; Li, Ping-le; Guo, Hai-Ming; Han, Xue-Ping

2017-06-01

This study was performed to assess the effect of artemisinin against isoflurane-induced neuronal apoptosis and cognitive impairment in neonatal rats. Artemisinin (50, 100 or 200 mg/kg b.wt/day; oral gavage) was administered to separate groups of neonatal rats starting from postnatal day 3 (P3) to postnatal day 21 (P21). On postnatal day 7 (P7), animals were exposed to inhalation anaesthetic isoflurane (0.75%) for 6 h. Neuronal apoptosis following anaesthetic exposure was significantly reduced by artemisinin. Isoflurane-induced upregulated cleaved caspase-3, Bax and Bad expression were downregulated. Western blotting analysis revealed that treatment with artemisinin significantly enhanced the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, xIAP and survivin). Artemisinin increased the acetylation of H3K9 and H4K12 while reducing the expression of histone deacetlyases (HDACs) - HDAC-2 and HDAC-3. Isoflurane-induced activation of JNK signalling and downregulated ERK1/2 expression was effectively modulated by artemisinin. General behaviour of the animals in open-field and T-maze test were improved. Morris water maze test and object recognition test revealed better learning, working memory and also better memory retention on artemisinin treatment. Artemisinin effectively inhibited neuronal apoptosis and improved cognition and memory via regulating histone acetylation and JNK/ERK1/2 signalling. © 2017 Royal Pharmaceutical Society.

The Case for Development of 11-Aza-artemisinins for Malaria.

PubMed

Harmse, Rozanne; Wong, Ho Ning; Smit, Frans; Haynes, Richard K; N'Da, David D

2015-01-01

The current treatment regimens for uncomplicated malaria comprise an artemisinin in combination with another drug (ACT). However, the recent emergence of resistance to ACTs in South East Asia dramatically emphasizes the need for new artemisinins. The current artemisinins have been in use since the late 1970s and have relatively poor thermal, chemical and metabolic stabilities - all are metabolized or hydrolyzed in vivo to dihydroartemisinin (DHA) that itself undergoes facile decomposition in vivo. The current artemisinins possess neurotoxicity as demonstrated in animal models, an issue that mandates increased vigilance in view of trends to use of protracted treatment regimens involving sequential administration of different ACTs against the resistant disease. As artemisinins induce the most rapid reduction in parasitaemia of any drug, common sense dictates that any new artemisinin derivative, selected on the bases of more robust chemical and thermal stability, metabolic stability with respect to the generation of DHA in vivo, and relatively benign neurotoxicity should be used in any new ACT whose components are rationally chosen in order to counter resistant malaria and inhibit transmission. 11-Azaartemisinin and its N-substituted derivatives attract because of overall ease of preparation from artemisinin. Some derivatives also possess notable thermal stabilities and although metabolic pathways of the derivatives are as yet unknown, none can provide DHA. The azaartemisinins synthesized over the past 20 years are critically discussed on the basis of their synthetic accessibility and biological activities with the view to assessing suitability to serve as new artemisinin derivatives for treatment of malaria.

Sperm characteristics, antioxidant status and hormonal profile in rats treated with artemisinin.

PubMed

Farombi, E O; Adedara, I A; Abolaji, A O; Anamelechi, J P; Sangodele, J O

2014-10-01

The indiscriminate use, abuse and patients' noncompliance to normal prescription of artemisinin and its derivatives are a common practice during the treatment for drug-resistant malaria parasites in most developing countries. This study investigated the influence of artemisinin on the testicular and epididymal sperm antioxidant systems as well as on the plasma levels of hormones from the pituitary and thyroid components of the brain-pituitary-testicular axis. Oral exposure of rats to 0, 7 and 35 mg kg(-1) artemisinin for 7 days showed that the testicular antioxidant status at both therapeutic dose (7 mg kg(-1) ) and overdose (35 mg kg(-1) ), and the sperm antioxidant status at therapeutic dose of artemisinin remained unaffected compared with control. However, increased hydrogen peroxide and lipid peroxidation levels were accompanied by a concomitant decrease in glutathione peroxidase and glutathione-S-transferase activities as well as glutathione level in spermatozoon of rats administered with overdose of artemisinin. While plasma levels of all the hormones investigated remained unaffected, severe epididymal degeneration with concomitant decrease in sperm quantity and quality was observed in rats treated with overdose of artemisinin compared with control. Overall, induction of oxidative stress in the epididymis, but not in the testes, could cause reproductive deficits in individuals unduly undergoing artemisinin therapy. © 2013 Blackwell Verlag GmbH.

Cross-sensitization to Artemisia and Ambrosia pollen allergens in an area located outside of the current distribution range of Ambrosia.

PubMed

Grewling, Łukasz; Jenerowicz, Dorota; Bogawski, Paweł; Smith, Matt; Nowak, Małgorzata; Frątczak, Agata; Czarnecka-Operacz, Magdalena

2018-02-01

The role of long-distance transported (LDT) Ambrosia pollen in inducing new sensitization and affecting sensitization rates in Artemisia -sensitized patients is unclear. The aim of this study was to estimate the degree of cross-sensitization to Ambrosia/Artemisi a allergens in citizens of Poznan (Western Poland). This area is covered by extensive Artemisia populations but does not currently have local Ambrosia populations. Sera of 119 patients were tested by fluoroenzyme immunoassay (CAP-FEIA system) against pollen allergen extracts of Artemisia vulgaris and Ambrosia artemisiifolia , an allergenic component of A. vulgaris ( nArt v 1 ), and an allergenic component of A. artemisiifolia ( nAmb a 1 ). Skin prick tests (SPTs, n = 86) were performed with pollen allergen extracts of A. vulgaris and A. artemisiifolia . Artemisia and Ambrosia pollen in ambient air was collected (1996-2013) by a Hirst type volumetric trap sited at roof level (33 m). The SPT showed that the prevalence of sensitization to Ambrosia and Artemisia pollen exceeded 3.5%, and 10.5%, respectively. The measurements of IgE in blood serum (CAP-FEIA) revealed that among Ambrosia -sensitized patients 90.1% (20/22 patients) were concomitantly sensitized to Artemisia . 59.1% (13/22) of these patients reacted to nArt v 1 , suggesting primary sensitization to Artemisia pollen. Only 2 (9.1%) patients were mono-sensitized to Ambrosia pollen extract, but surprisingly not to nAmb a 1 . The LDT Ambrosia pollen had a negligible effect on the rate of sensitization to Ambrosia allergens in Poznan and did not increase the prevalence of sensitization to Artemisia pollen in this region. However, the majority of patients showing hypersensitization to Artemisia pollen might also present symptoms during elevated episodes of LDT of Ambrosia pollen.

Distribution and integrated assessment of lead in an abandoned lead-acid battery site in Southwest China before redevelopment.

PubMed

Wang, Mei; Zhang, Chao; Zhang, Zhuo; Li, Fasheng; Guo, Guanlin

2016-06-01

Lead-acid battery sites have contributed enormous amounts of lead to the environment, significantly affecting its global biogeochemical cycle and leaving the potential risks to human health. An abandoned lead-acid battery site prepared for redevelopment was selected in order to study the distribution of lead in soils, plants, rhizosphere soils and soil solutions. In total, 197 samples from 77 boreholes were collected and analyzed. Single extractions by acetic acid (HOAc) were conducted to assess the bioavailability and speciation of lead in soils for comparison with the parts of the plants that are aboveground. Health risks for future residential development were evaluated by the integrated exposure uptake biokinetic (IEUBK) model. The results indicated that lead concentrations in 83% of the soil samples exceeded the Chinese Environmental Quality Standard for soil (350 mg/kg for Pb) and mainly occurred at depths between 0 and 1.5 m while accumulating at the surface of demolished construction waste and miscellaneous fill. Lead concentrations in soil solutions and HOAc extraction leachates were linked closely to the contents of aboveground Broussonetia papyrifera and Artemisia annua, two main types of local plants that were found at the site. The probability density of lead in blood (PbB) in excess of 10 µg/dL could overtake the 99% mark in the residential scenario. The findings provided a relatively integrated method to illustrate the onsite investigations and assessment for similar sites before remediation and future development from more comprehensive aspects. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular phylogeny of Subtribe Artemisiinae (Asteraceae), including Artemisia and its allied and segregate genera

PubMed Central

Watson, Linda E; Bates, Paul L; Evans, Timothy M; Unwin, Matthew M; Estes, James R

2002-01-01

Background Subtribe Artemisiinae of Tribe Anthemideae (Asteraceae) is composed of 18 largely Asian genera that include the sagebrushes and mugworts. The subtribe includes the large cosmopolitan, wind-pollinated genus Artemisia, as well as several smaller genera and Seriphidium, that altogether comprise the Artemisia-group. Circumscription and taxonomic boundaries of Artemisia and the placements of these small segregate genera is currently unresolved. Results We constructed a molecular phylogeny for the subtribe using the internal transcribed spacers (ITS) of nuclear ribosomal DNA analyzed with parsimony, likelihood, and Bayesian criteria. The resulting tree is comprised of three major clades that correspond to the radiate genera (e.g., Arctanthemum and Dendranthema), and two clades of Artemisia species. All three clades have allied and segregate genera embedded within each. Conclusions The data support a broad concept of Artemisia s.l. that includes Neopallasia, Crossostephium, Filifolium, Seriphidium, and Sphaeromeria. However, the phylogeny excludes Elachanthemum, Kaschgaria, and Stilnolepis from the Artemisia-group. Additionally, the monophyly of the four subgenera of Artemisia is also not supported, with the exception of subg. Dracunculus. Homogamous, discoid capitula appear to have arisen in parallel four to seven times, with the loss of ray florets. Thus capitular morphology is not a reliable taxonomic character, which traditionally has been one of the defining characters. PMID:12350234

Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

PubMed Central

Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D.; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M.; Onwujekwe, Obinna

2015-01-01

Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained. PMID:26018221

The Screening and Evaluation of Experimental Antiparasitic Drugs

DTIC Science & Technology

1990-03-01

exhibited better activity than 5 analogs of artemisinin and only 2 of the 4 different 5-fluoropyrimidine analogs were active. Neither verapamil, diltiazem...Dietary Studies 17 Table III Artemisinin , Artelinic Acid, and Arteether in a 6-Day Suppressive Test 18 Table IV Artemisinin and Related Analogs in a 3...indicate antagnism. 3-DOSE MODIFIED MM TEST A series of artemisinin analogs were administered on days 3, 4 and 5 after inoculation with a regular MM

Re-evaluation of how artemisinins work in light of emerging evidence of in vitro resistance

PubMed Central

Krishna, Sanjeev; Woodrow, Charles J.; Staines, Henry M.; Haynes, Richard K.; Mercereau-Puijalon, Odile

2006-01-01

There are more than half a billion cases of malaria every year. Combinations of an artemisinin with other antimalarial drugs are now recommended treatments for Plasmodium falciparum malaria in most endemic areas. These treatment regimens act rapidly to relieve symptoms and effect cure. There is considerable controversy on how artemisinins work and over emerging indications of resistance to this class of antimalarial drugs. Several individual molecules have been proposed as targets for artemisinins, in addition to the idea that artemisinins might have many targets at the same time. Our suggestion that artemisinins inhibit the parasite-encoded sarco–endoplasmic reticulum Ca2+-ATPase (SERCA) PfATP6 has gained support from recent observations that a polymorphism in the gene encoding PfATP6 is associated with in vitro resistance to artemether in field isolates of P. falciparum. PMID:16616639

Visible-light-sensitive titanium dioxide nanoplatform for tumor-responsive Fe2+ liberating and artemisinin delivery

PubMed Central

Zhang, Huijuan; Zhang, Hongling; Zhu, Xing; Zhang, Xiaoge; Chen, Qianqian; Chen, Jianjiao; Hou, Lin; Zhang, Zhenzhong

2017-01-01

Artemisinin is a kind of Fe2+-dependent drugs. Artemisinin and Fe2+ co-transport systems can improve its anti-tumor effect. In this study, a visible light-sensitive nanoplatform (HA-TiO2-IONPs/ART) was developed. Detailed investigation demonstrated that HA-TiO2-IONPs/ART could realize Fe2+ and artemisinin synchronous co-delivery and tumor-responsive release. This feature enhanced the anti-tumor efficiency of artemisinin significantly. In vitro results proved that hyaluronic acid modification could improve the biocompatibility, dispersion stability and cytophagy ability of nanocarriers. Furthermore, this drug delivery system could generate reactive oxygen species under visual light irradiation. In vitro and in vivo experiments demonstrated that HA-TiO2-IONPs/ART combining with laser irradiation displayed the best anti-tumor efficacy. This study affords a promising idea to improve the curative efficiency of artemisinin analogs for cancer therapy. PMID:28938592

In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin.

PubMed

Njokah, Muturi J; Kang'ethe, Joseph N; Kinyua, Johnson; Kariuki, Daniel; Kimani, Francis T

2016-07-22

Anti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programmes. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance. Here, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clinically relevant concentrations in vivo, and the molecular haplotypes investigated. Genomic DNA was extracted using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by standard bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast. Exposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with standard methods was noticeably less than expected for parasite lines recovered from 50 µg/ml 48 h drug pressure. The change in parasite susceptibility was associated with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72-76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene. This data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivatives in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria. Artemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivatives together with the parasite's ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clinical concentrations. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.

Artemisinin resistance in rodent malaria - mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking

PubMed Central

2013-01-01

Background The control of malaria, caused by Plasmodium falciparum, is hampered by the relentless evolution of drug resistance. Because artemisinin derivatives are now used in the most effective anti-malarial therapy, resistance to artemisinin would be catastrophic. Indeed, studies suggest that artemisinin resistance has already appeared in natural infections. Understanding the mechanisms of resistance would help to prolong the effective lifetime of these drugs. Genetic markers of resistance are therefore required urgently. Previously, a mutation in a de-ubiquitinating enzyme was shown to confer artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi. Methods Here, for a mutant P. chabaudi malaria parasite and its immediate progenitor, the in vivo artemisinin resistance phenotypes and the mutations arising using Illumina whole-genome re-sequencing were compared. Results An increased artemisinin resistance phenotype is accompanied by one non-synonymous substitution. The mutated gene encodes the μ-chain of the AP2 adaptor complex, a component of the endocytic machinery. Homology models indicate that the mutated residue interacts with a cargo recognition sequence. In natural infections of the human malaria parasite P. falciparum, 12 polymorphisms (nine SNPs and three indels) were identified in the orthologous gene. Conclusion An increased artemisinin-resistant phenotype occurs along with a mutation in a functional element of the AP2 adaptor protein complex. This suggests that endocytosis and trafficking of membrane proteins may be involved, generating new insights into possible mechanisms of resistance. The genotypes of this adaptor protein can be evaluated for its role in artemisinin responses in human infections of P. falciparum. PMID:23561245

Artemisinin Represses Telomerase Subunits and Induces Apoptosis in HPV-39 Infected Human Cervical Cancer Cells.

PubMed

Mondal, Anushree; Chatterji, Urmi

2015-09-01

Artemisinin, a plant-derived antimalarial drug with relatively low toxicity on normal cells in humans, has selective anticancer activities in various types of cancers, both in vitro and in vivo. In the present study, we have investigated the anticancer effects of artemisinin in human cervical cancer cells, with special emphasis on its role in inducing apoptosis and repressing cell proliferation by inhibiting the telomerase subunits, ERα which is essential for maintenance of the cervix, and downstream components like VEGF, which is known to activate angiogenesis. Effects of artemisinin on apoptosis of ME-180 cells were measured by flow cytometry, DAPI, and annexin V staining. Expression of genes and proteins related to cell proliferation and apoptosis was quantified both at the transcriptional and translational levels by semi-quantitative RT-PCR and western blot analysis, respectively. Our findings demonstrated that artemisinin significantly downregulated the expression of ERα and its downstream component, VEGF. Antiproliferative activity was also supported by decreased telomerase activity and reduced expression of hTR and hTERT subunits. Additionally, artemisinin reduced the expression of the HPV-39 viral E6 and E7 components. Artemisinin-induced apoptosis was confirmed by FACS, nuclear chromatin condensation, annexin V staining. Increased expression of p53 with concomitant decrease in expression of the p53 inhibitor Mdm2 further supported that artemisinin-induced apoptosis was p53-dependent. The results clearly indicate that artemisinin induces antiproliferative and proapoptotic effects in HPV-39-infected ME-180 cells, and warrants further trial as an effective anticancer drug. © 2015 Wiley Periodicals, Inc.

Quality of Artemisinin-based Combination Therapy for malaria found in Ghanaian markets and public health implications of their use.

PubMed

Tivura, Mathilda; Asante, Isaac; van Wyk, Albert; Gyaase, Stephaney; Malik, Naiela; Mahama, Emmanuel; Hostetler, Dana M; Fernandez, Facundo M; Asante, Kwaku Poku; Kaur, Harparkash; Owusu-Agyei, Seth

2016-10-28

Ghana changed their antimalarial drug policy from monotherapies to Artemisinin-based Combination Therapies in 2004 in order to provide more efficacious medicines for treatment of malaria. The policy change can be eroded if poor quality Artemisinin-based Combination Therapies are allowed to remain on the Ghanaian market unchecked by regulatory bodies and law enforcement agencies. The presence and prevalence of substandard and counterfeit Artemisinin-based Combination Therapies need to be determined on open markets in Ghana; a review of the current policy; identifying any gaps and making recommendations on actions to be taken in addressing gaps identified are essential as the data provided and recommendations made will help in ensuring effective control of malaria in Ghana. A field survey of antimalarial drugs was conducted in the central part of Ghana. The amount of active pharmaceutical ingredient in each Artemisinin-based Combination Therapy sample identified in the survey was measured using high performance liquid chromatographic analyses. Active pharmaceutical ingredient within the range of 85-115 % was considered as standard and active pharmaceutical ingredient results out of the range were considered as substandard. All samples were screened to confirm stated active pharmaceutical ingredient presence using mass spectrometry. A total of 256 Artemisinin-based Combination Therapies were purchased from known medicine outlets, including market stalls, hospitals/clinics, pharmacies, drug stores. Artemether lumefantrine (52.5 %) and artesunate amodiaquine (43.2 %) were the predominant Artemisinin-based Combination Therapies purchased. Of the 256 Artemisinin-based Combination Therapies purchased, 254 were tested, excluding two samples of Artesunate-SP. About 35 % of Artemisinin-based Combination Therapies were found to be substandard. Nine percent of Artemisinin-based Combination Therapies purchased were past their expiry date; no counterfeit (falsified) medicine samples were detected by either high performance liquid chromatographic or mass spectrometry. A high proportion of Artemisinin-based Combination Therapies sold in central Ghana were found to be substandard. Manufacturing of medicines that do not adhere to good manufacturing practices may have contributed to the poor quality of the Artemisinin-based Combination Therapies procured. A strict law enforcement and quality monitoring systems is recommended to ensure effective malaria case management as part of malaria control.

Intravenous Artesunate: The New Generation of Lifesaving Treatment for Severe Malaria in the Warfighter

DTIC Science & Technology

2006-11-01

certain electrocardiac disturbances and may soon cease to be available in the U.S. Artemisinins are antimalarials derived from the Chinese herb... artemisinins have been used in much of the world and represent an improvement in efficacy and safety for severe malaria. There are currently no FDA...approved intravenous artemisinin products available in the U.S. The Walter Reed Army Institute of Research has a long history with the artemisinins

Absence of Putative Artemisinin Resistance Mutations Among Plasmodium falciparum in Sub-Saharan Africa: A Molecular Epidemiologic Study

PubMed Central

Taylor, Steve M.; Parobek, Christian M.; DeConti, Derrick K.; Kayentao, Kassoum; Coulibaly, Sheick Oumar; Greenwood, Brian M.; Tagbor, Harry; Williams, John; Bojang, Kalifa; Njie, Fanta; Desai, Meghna; Kariuki, Simon; Gutman, Julie; Mathanga, Don P.; Mårtensson, Andreas; Ngasala, Billy; Conrad, Melissa D.; Rosenthal, Philip J.; Tshefu, Antoinette K.; Moormann, Ann M.; Vulule, John M.; Doumbo, Ogobara K.; ter Kuile, Feiko O.; Meshnick, Steven R.; Bailey, Jeffrey A.; Juliano, Jonathan J.

2015-01-01

Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance. PMID:25180240

Isolation and quantitative analysis of peroxynitrite scavengers from Artemisia princeps var. orientalis.

PubMed

Nugroho, Agung; Lee, Kang Ro; Alam, Md Badrul; Choi, Jae Sue; Park, Hee-Juhn

2010-05-01

Young and mature Artemisia princeps var. orientalis (APO, Compositae) are used as a health food and a medicinal plant, respectively, in Korea. Here, we identified the in vitro potent peroxynitrite (ONOO(-))-scavenging effect (IC(50), 0.26 microg/mL) of the components from the EtOAc fraction. Octadecylsilane column chromatography on the EtOAc fraction yielded two caffeoylquinic acid compounds, 3,5-di-O-caffeoyl-muco-quinic acid (1) and methyl 4,5-di-O-caffeoylquinate (2) by NMR spectroscopic data, which have not been reported before from APO. The IC(50) values of compounds 1 and 2 were 0.18 +/- 0.01 microg/mL and 0.12 +/- 0.00 microg/mL, respectively, lower than that of the positive control (L-penicillamine). HPLC data indicated that young APO (1: 30.3 mg/g dried weight, 2: 27.7 mg/g) contained considerably higher quantities of the two caffeoylquinic acids than mature APO (1: 1.77 mg/g dried weight, 2: 4.10 mg/g).

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy.

PubMed

Karl, Stephan; Laman, Moses; Moore, Brioni R; Benjamin, John; Koleala, Tamarah; Ibam, Clemencia; Kasian, Bernadine; Siba, Peter M; Waltmann, Andreea; Mueller, Ivo; Woodward, Robert C; St Pierre, Timothy G; Davis, Timothy M E

2015-08-01

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway.

PubMed

Zeng, Zhiwen; Xu, Jinying; Zheng, Wenhua

2017-08-01

Accumulating evidence displays that an abnormal deposition of amyloid beta-peptide (Aβ) is the primary cause of the pathogenesis of Alzheimer's disease (AD). And therefore the elimination of Aβ is regarded as an important strategy for AD treatment. The discovery of drug candidates using culture neuronal cells against Aβ peptide toxicity is believed to be an effective approach to develop drug for the treatment of AD patients. We have previously showed that artemisinin, a FDA-approved anti-malaria drug, has neuroprotective effects recently. In the present study, we aimed to investigate the effects and potential mechanism of artemisinin in protecting neuronal PC12 cells from toxicity of β amyloid peptide. Our studies revealed that artemisinin, in clinical relevant concentration, protected and rescued PC12 cells from Aβ25-35-induced cell death. Further study showed that artemisinin significantly ameliorated cell death due to Aβ25-35 insult by restoring abnormal changes in nuclear morphology, lactate dehydrogenase, intracellular ROS, mitochondrial membrane potential and activity of apoptotic caspase. Western blotting analysis demonstrated that artemisinin activated extracellular regulated kinase ERK1/2 but not Akt survival signaling. Consistent with the role of ERK1/2, preincubation of cells with ERK1/2 pathway inhibitor PD98059 blocked the effect of artemisinin while PI3K inhibitor LY294002 has no effect. Moreover, Aβ1-42 also caused cells death of PC12 cells while artemisinin suppressed Aβ1-42 cytotoxicity in PC12 cells. Taken together, these results, at the first time, suggest that artemisinin is a potential protectant against β amyloid insult through activation of the ERK1/2 pathway. Our finding provides a potential application of artemisinin in prevention and treatment of AD. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Development of SCAR marker for discrimination of Artemisia princeps and A. argyi from other Artemisia herbs.

PubMed

Lee, Mi Young; Doh, Eui Jeong; Park, Chae Haeng; Kim, Young Hwa; Kim, Eung Soo; Ko, Byong Seob; Oh, Seung-Eun

2006-04-01

Some Artemisia herbs are used for medicinal purposes. In particular, A. princeps and A. argyi are classified as 'Aeyup' and are used as important medicinal material in traditional Korean medicine. On the other hand, A. capillaris and A. iwayomogi, which are classified as 'Injinho' and 'Haninjin', respectively, are used for other purposes distinct from those of 'Aeyup'. However, sometimes 'Aeyup' is not clearly discriminated from 'Injinho' and/or 'Haninjin'. Furthermore, Artemisia capillaris and/or A. iwayomogi have been used in place of A. princeps and A. argyi. In this study, we developed an efficient method to discriminate A. argyi and A. princeps from other Artemisia plants. The RAPD (random amplified polymorphic DNA) method efficiently discriminated various Artemisia herbs. In particular, non-specific primer 329 (5'-GCG AAC CTC C-3'), which shows polymorphism among Artemisia herbs, amplified 838 bp products, which are specific to A. princeps and A. argyi only. Based on nucleotide sequence of the primer 329 product, we designed a Fb (5'-CAT CAA CCA TGG CTT ATC CT-3') and R7 (5'-GCG AAC CTC CCC ATT CCA-3') primer-set to amplify a 254 bp sized SCAR (sequence characterized amplified regions) marker, through which A. princeps and A. argyi can be efficiently discriminated from other Artemisia herbs, particularly, A. capillaris and A. iwayomogi.

Quality Testing of Artemisinin-Based Antimalarial Drugs in Myanmar.

PubMed

Guo, Suqin; Kyaw, Myat Phone; He, Lishan; Min, Myo; Ning, Xiangxue; Zhang, Wei; Wang, Baomin; Cui, Liwang

2017-10-01

Artemisinin-based combination therapies are the frontline treatment of Plasmodium falciparum malaria. The circulation of falsified and substandard artemisinin-based antimalarials in Southeast Asia has been a major predicament for the malaria elimination campaign. To provide an update of this situation, we purchased 153 artemisinin-containing antimalarials, as convenience samples, in private drug stores from different regions of Myanmar. The quality of these drugs in terms of their artemisinin derivative content was tested using specific dipsticks for these artemisinin derivatives, as point-of-care devices. A subset of these samples was further tested by high-performance liquid chromatography (HPLC). This survey identified that > 35% of the collected drugs were oral artesunate and artemether monotherapies. When tested with the dipsticks, all but one sample passed the assays, indicating that the detected artemisinin derivative content corresponded approximately to the labeled contents. However, one artesunate injection sample was found to contain no active ingredient at all by the dipstick assay and subsequent HPLC analysis. The continued circulation of oral monotherapies and the description, for the first time, of falsified parenteral artesunate provides a worrisome picture of the antimalarial drug quality in Myanmar during the malaria elimination phase, a situation that deserves more oversight from regulatory authorities.

Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors.

PubMed

Hosoya, Kenji; Couto, C Guillermo; London, Cheryl A; Kisseberth, William C; Phelps, Mitchell A; Dalton, James T

2014-01-01

To evaluate the clinical toxicity and activity of orally administered artemisinin in dogs with spontaneous tumors, 24 client-owned dogs were randomly divided into two groups and received either low-continuous dose (3 mg/kg q 24 hr) or high-dose intermittent (three doses of 45 mg/kg q 6 hr repeated q 1 wk) of artemisinin per os. Treatment was continued for 21 days. Dogs were evaluated weekly for clinical effect and at the end of the treatment for hematologic and biochemical adverse events. Whole blood concentrations of artemisinin and dihydroartemisinin were measured by liquid chromatography/tandem mass spectrometry after the first dose of artemisinin in three dogs in each group. Blood concentrations of artemisinin and dihydroartemisinin were <0.1 μM at all time points, and there was no difference in blood concentration between the two dosing groups. The most frequent adverse event was anorexia, which was observed in 11% of the low-dose group and 29% of the high-dose group. Oral artemisinin, both in low-dose continuous and high-dose intermittent, is well tolerated in dogs but results in low bioavailability. Parenteral administration should be considered for future studies.

Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

PubMed Central

Hott, Amanda; Casandra, Debora; Sparks, Kansas N.; Morton, Lindsay C.; Castanares, Geocel-Grace; Rutter, Amanda

2015-01-01

Artemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yet in vitro phenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistant Plasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novel in vitro delayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-life in vivo as well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistant P. falciparum has evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance in P. falciparum and new tools for monitoring the spread of artemisinin resistance. PMID:25779582

Stereoselective Total Synthesis of Radiolabeled Artemisinin (Qinghaosu).

DTIC Science & Technology

Our previous total synthesis of (+)- artemisinin has been optimized from 18 to 11 steps. The final two steps in the sequence are: 1) alkylation of a...product (+)- artemisinin . The first step was repeated utilizing carbon-14 methyl iodide and the sequence completed as before to afford the desired...carbon-14labeled (+)- artemisinin . The label resides in the methyl group pendant from the lactone ring (ring D), the position of attachment being C-9, the carbon atom being C-16. Keywords: Antimalarials. (aw)

Putting the genie back in the bottle? Availability and presentation of oral artemisinin compounds at retail pharmacies in urban Dar-es-Salaam

PubMed Central

Kachur, S Patrick; Black, Carolyn; Abdulla, Salim; Goodman, Catherine

2006-01-01

Background Recently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments. Methods This paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005. Results Nineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug. Conclusion The findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies. PMID:16569252

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

PubMed Central

Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V.; Rizk, Shahir; Njimoh, Dieudonne L.; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M.; Wiest, Olaf; Haldar, Kasturi

2015-01-01

Artemisinins are the corner stone of anti-malarial drugs1. Emergence and spread of resistance to them2–4 raises risk of wiping out recent gains achieved in reducing world-wide malaria burden and threatens future malaria control and elimination on a global level. Genome wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance5–10. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase as well as its lipid product phosphatidylinositol 3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signaling, where transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination. PMID:25874676

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.

PubMed

Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V; Rizk, Shahir S; Njimoh, Dieudonne L; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M; Wiest, Olaf; Haldar, Kasturi

2015-04-30

Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

Artemisinin Protects Retinal Neuronal Cells against Oxidative Stress and Restores Rat Retinal Physiological Function from Light Exposed Damage.

PubMed

Yan, Fengxia; Wang, Haitao; Gao, Yang; Xu, Jiangping; Zheng, Wenhua

2017-08-16

Oxidative stress plays a key role in the pathogenesis of age-related macular degeneration (AMD), a leading cause of severe visual loss and blindness in the aging population which lacks any effective treatments currently. In this study, artemisinin, a well-known antimalarial drug was found to suppress hydrogen peroxide (H 2 O 2 )-induced cell death in retinal neuronal RGC-5 cells. Artemisinin, in the therapeutically relevant dosage, concentration-dependently attenuated the accumulation of intracellular reactive oxygen species (ROS), increased mitochondrial membrane potential and decreased cell apoptosis in RGC-5 cells induced by H 2 O 2 . Western blot analysis showed that artemisinin upregulated the phosphorylation of p38 and extracellular signal-regulated kinases1/2 (ERK1/2) and reversed the inhibitory effect of H 2 O 2 on the phosphorylation of these two kinases. Moreover, protective effect of artemisinin was blocked by the p38 kinase inhibitor PD169316 or ERK1/2 kinase pathway inhibitor PD98059, respectively. In contrast, c-Jun N-terminal kinase inhibitor and rapamycin had no effect in the protective effect of artemisinin. Taken together, these results demonstrated that artemisinin promoted the survival of RGC-5 cells from H 2 O 2 toxicity via the activation of the p38 and ERK1/2 pathways. Interestingly, intravitreous injection of artimisinin, concentration-dependently reversed light exposed-damage (a dry AMD animal model) of rat retinal physiological function detected by flash electroretinogram. These results indicate that artemisinin can protect retinal neuronal functions from H 2 O 2 -induced damage in vitro and in vivo and suggest the potential application of artemisinin as a new drug in the treatment of retinal disorders like AMD.

Decomposition mechanism of an artemisinin-type compound via hemin-electrocatalysis.

PubMed

Chen, H Y; Chen, Y; Zhu, S M; Bian, N S; Shan, F; Li, Y

1999-01-01

The interaction between a typical derivative of artemisinin and hemin was investigated by electrochemical and spectroelectrochemical methods. This derivative can be reduced via hemin-catalysis at the glassy carbon electrode, the cathodic overpotential is decreased by ca. 650 mV. A HPLC method for separating the products of the catalytic reaction was established. They were identified either in H(2)O-CH(3)CN solution or in tetrahydrofuran, respectively. The structures of these products show that the hemin-catalyzed decomposition of an artemisinin-type compound on the glassy carbon or reticulated vitreous carbon electrode can be achieved by both electrochemical reduction and rearrangement. The conclusion that the reaction of artemisinin with hemin is a critical step in the antimalarial mechanism of artemisinin can be drawn.

Hypocholesterolemic and antiatherosclerotic effect of artemisia aucheri in hypercholesterolemic rabbits.

PubMed

Dinani, N Jafari; Asgary, Asgary; Madani, H; Naderi, Gh; Mahzoni, P

2010-07-01

Atherosclerosis which results from gradual deposition of lipids in arteries is a leading cause of mortality worldwide. Diet is one of the most important factors underlying atherosclerosis. High-cholesterol diets enhance atherosclerosis and vegetarian diets are known to slow down the process. Artemisia aucheri is an herb of the Composite family. Many species of Artemisia have proven hypolipidemic and antioxidant properties. This study determine the effects of Artemisia aucheri on lipoproteins and atherosclerosis in hypercholesterolemic rabbits. Fifteen male rabbits were randomly divided into three groups. Normal diet group, high-cholesterol diet group (1% cholesterol) and Artemisia aucheri group (1% cholesterol diet supplemented with 100 mg/kg body weight the Artemisi aucheri every other day). Biochemical factors were measured at the start, end of the first and second months of the study. At the end of the study, the aorta were removed for assessment of atherosclerotic plaques. The results indicate that Artemisia aucheri significantly reduced the level of total cholesterol, LDL cholesterol and triglycerids and increased HDL cholesterol. The degree of atherosclerotic thickness was significantly reduced in the treated group. Therefore, Artemisia aucheri is one of the useful herbal medicine for preventation of atherosclerosis and more studies in this regard is recommended.

Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study.

PubMed

Taylor, Steve M; Parobek, Christian M; DeConti, Derrick K; Kayentao, Kassoum; Coulibaly, Sheick Oumar; Greenwood, Brian M; Tagbor, Harry; Williams, John; Bojang, Kalifa; Njie, Fanta; Desai, Meghna; Kariuki, Simon; Gutman, Julie; Mathanga, Don P; Mårtensson, Andreas; Ngasala, Billy; Conrad, Melissa D; Rosenthal, Philip J; Tshefu, Antoinette K; Moormann, Ann M; Vulule, John M; Doumbo, Ogobara K; Ter Kuile, Feiko O; Meshnick, Steven R; Bailey, Jeffrey A; Juliano, Jonathan J

2015-03-01

Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cytogeography and chromosome evolution of subgenus Tridentatae of Artemisia (Asteraceae)

Treesearch

E. Durant McArthur; Stewart C. Sanderson

1999-01-01

The subgenus Tridentatae of Artemisia (Asteraceae: Anthemideae) is composed of 11 species of various taxonomic and geographic complexities. It is centered on Artemisia tridentata with its three widespread common subspecies and two more geographically confined ones. Meiotic chromosome counts on pollen mother cells...

Size and Content of the Sex-Determining Region of the Y Chromosome in Dioecious Mercurialis annua, a Plant with Homomorphic Sex Chromosomes.

PubMed

Veltsos, Paris; Cossard, Guillaume; Beaudoing, Emmanuel; Beydon, Genséric; Savova Bianchi, Dessislava; Roux, Camille; C González-Martínez, Santiago; R Pannell, John

2018-05-29

Dioecious plants vary in whether their sex chromosomes are heteromorphic or homomorphic, but even homomorphic sex chromosomes may show divergence between homologues in the non-recombining, sex-determining region (SDR). Very little is known about the SDR of these species, which might represent particularly early stages of sex-chromosome evolution. Here, we assess the size and content of the SDR of the diploid dioecious herb Mercurialis annua , a species with homomorphic sex chromosomes and mild Y-chromosome degeneration. We used RNA sequencing (RNAseq) to identify new Y-linked markers for M. annua. Twelve of 24 transcripts showing male-specific expression in a previous experiment could be amplified by polymerase chain reaction (PCR) only from males, and are thus likely to be Y-linked. Analysis of genome-capture data from multiple populations of M. annua pointed to an additional six male-limited (and thus Y-linked) sequences. We used these markers to identify and sequence 17 sex-linked bacterial artificial chromosomes (BACs), which form 11 groups of non-overlapping sequences, covering a total sequence length of about 1.5 Mb. Content analysis of this region suggests that it is enriched for repeats, has low gene density, and contains few candidate sex-determining genes. The BACs map to a subset of the sex-linked region of the genetic map, which we estimate to be at least 14.5 Mb. This is substantially larger than estimates for other dioecious plants with homomorphic sex chromosomes, both in absolute terms and relative to their genome sizes. Our data provide a rare, high-resolution view of the homomorphic Y chromosome of a dioecious plant.

The Global Fund to Fight AIDS, Tuberculosis, and Malaria: Progress Report and Issues for Congress

DTIC Science & Technology

2006-04-25

artemisinin -based combination drug treatments (ACT). Artemisinin -based treatments have been found to be effective in dealing with drug-resistant...and have no observable resistance are considerably more expensive. The new drugs called, “ artemisinin -based combination therapies” (ACTs) cost about

Molecular Evidence of Drug Resistance in Asymptomatic Malaria Infections, Myanmar, 2015.

PubMed

Nyunt, Myat Htut; Shein, Thinzar; Zaw, Ni Ni; Han, Soe Soe; Muh, Fauzi; Lee, Seong-Kyun; Han, Jin-Hee; Thant, Kyaw Zin; Han, Eun-Taek; Kyaw, Myat Phone

2017-03-01

Artemisinin resistance containment in Myanmar was initiated in 2011 after artemisinin-resistant Plasmodium falciparum malaria was reported. Molecular evidence suggests that asymptomatic malaria infections harboring drug resistance genes are present among residents of the Myanmar artemisinin resistance containment zone. This evidence supports efforts to eliminate these hidden infections.

Novel spirobicyclic artemisinin analogues (artemalogues): Synthesis and antitumor activities.

PubMed

Liu, Gang; Song, Shanshan; Shu, Shiqi; Miao, Zehong; Zhang, Ao; Ding, Chunyong

2015-10-20

The sesquiterpene lactone framework of artemisinin was used as a drug repositioning prototype for the development of novel antitumor drugs. Several series of novel artemisinin analogues (artemalogues) were designed and synthesized through 1,3-dipolar cycloaddition of artemisitene with nitrile oxides or nitrones. The isoxazolidine-containing spirobicyclic artemalogue 11b turns out to be the most potent with low micromolar IC₅₀ values against all three tumor cells, which were at least 4- to 14-fold more potent than the parent artemisinin. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

More insights into the pharmacological effects of artemisinin.

PubMed

Zyad, Abdelmajid; Tilaoui, Mounir; Jaafari, Abdeslam; Oukerrou, Moulay Ali; Mouse, Hassan Ait

2018-02-01

Artemisinin is one of the most widely prescribed drugs against malaria and has recently received increased attention because of its other potential biological effects. The aim of this review is to summarize recent discoveries of the pharmaceutical effects of artemisinin in basic science along with its mechanistic action, as well as the intriguing results of recent clinical studies, with a focus on its antitumor activity. Scientific evidence indicates that artemisinin exerts its biological activity by generating reactive oxygen species that damage the DNA, mitochondrial depolarization, and cell death. In the present article review, scientific evidence suggests that artemisinin is a potential therapeutic agent for various diseases. Thus, this review is expected to encourage interested scientists to conduct further preclinical and clinical studies to evaluate these biological activities. Copyright © 2017 John Wiley & Sons, Ltd.

Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins.

PubMed

Konziase, Benetode

2015-08-01

We studied the target proteins of artemisinin in Trypanosoma brucei brucei using the affinity-labeling method. We designed and synthesized four biotinylated probes of artemisinin for use as molecular tools. Their in vitro trypanocidal activities (data not shown) proved that they mimicked the biological action of artemisinin. We assessed the chemical stability for all of the probes in the parasite culture medium and lysate using reversed-phase high-performance liquid chromatography (HPLC). After 3-h incubations, the probes remained undecomposed in a range of 40 to 65% in the parasite culture medium, whereas approximately 80% of the probes remained stable in the parasite lysate. Using liquid chromatography mass spectrometry (LC-MS), we demonstrated that, with respect to all of the probes, uptakes into the parasite ranging from 81 to 96% occurred after 30-min incubations. In a competitive binding assay between artemisinin and the four biotinylated probes, we searched for the trypanosomal target protein of artemisinin. Consequently, we observed that only the diazirine-free probe 5 could provide the desired result with high affinity-labeling efficiency. Using the horseradish peroxidase-tagged streptavidin-biotin method, we showed that artemisinin could specifically bind to candidate target proteins of approximately 60, 40, and 39 kDa. Copyright © 2015 Elsevier Inc. All rights reserved.

Studies of a new hybrid taxon in the Artemisia tridentata (Asteraceae: Anthemideae) complex

Treesearch

Heather D. Garrison; Leila M. Shultz; E. Durant McArthur

2013-01-01

Members of the Artemisia tridentata complex (ASTERACEAE: Anthemideae: Artemisia subgen. Tridentatae) have adapted to changing environmental conditions through geographic migration, introgression, and hybridization. These processes have resulted in morphologic and genetic variation. A presumed hybrid ("Bonneville" big sagebrush) of the complex occurs in the...

Transport pathway and source area for Artemisia pollen in Beijing, China

NASA Astrophysics Data System (ADS)

Qin, Xiaoxin; Li, Yiyin; Sun, Xu; Meng, Ling; Wang, Xiaoke

2017-12-01

Artemisia pollen is an important allergen responsible for allergic rhinitis in Beijing, China. To explore the transport pathways and source areas of Artemisia pollen, we used Burkard 7-day traps to monitor daily pollen concentrations in 2016 in an urban and suburban locality. Backward trajectories of 24- and 96-h and their cluster analysis were performed to identify transport pathways of Artemisia pollen using the HYSPLIT model on 0.5° × 0.5° GADS meteorological data. The potential source contribution function (PSCF) and concentration weighted trajectory (CWT) were calculated to further identify the major potential source areas at local, regional, and long-range scales. Our results showed significant differences in Artemisia pollen concentration between urban and suburban areas, attributed to differences in plant distribution and altitude of the sampling locality. Such differences arisen from both pollen emission and air mass movements, hence pollen dispersal. At local or regional scales, source area of northwestern parts of Beijing City, Hebei Province and northern and northwestern parts of Inner Mongolia influenced the major transport pathways of Artemisia pollen. Transport pathway at a long-range scale and its corresponding source area extended to northwestern parts of Mongolia. The regional-scale transport affected by wind and altitude is more profound for Artemisia pollen at the suburban than at the urban station.

Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

PubMed

Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Okell, Lucy C

2016-01-06

Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

PubMed Central

Gomes, Melba; Ribeiro, Isabela; Warsame, Marian; Karunajeewa, Harin; Petzold, Max

2008-01-01

Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy. PMID:18373841

Artemisinin-resistant Plasmodium falciparum malaria

PubMed Central

Fairhurst, Rick M.; Dondorp, Arjen M.

2016-01-01

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins – the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs) – the first-line treatments for malaria – are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in-vitro, genomics, and transcriptomics studies in SEA have defined in-vivo and in-vitro phenotypes of artemisinin resistance; identified its causal genetic determinant; explored its molecular mechanism; and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's ‘K13’ gene; is associated with an upregulated “unfolded protein response” pathway that may antagonize the pro-oxidant activity of artemisinins; and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent; test whether new combinations of currently-available drugs cure ACT failures; and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to Sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest. PMID:27337450

Artemisinin-Resistant Plasmodium falciparum Malaria.

PubMed

Fairhurst, Rick M; Dondorp, Arjen M

2016-06-01

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

Synthesis of novel ring-contracted artemisinin dimers with potent anticancer activities.

PubMed

Zhang, Ning; Yu, Zhimei; Yang, Xiaohong; Hu, Ping; He, Yun

2018-04-25

Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC 50 value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Organism-like formation of Schistosoma hemozoin and its function suggest a mechanism for anti-malarial action of artemisinin

PubMed Central

Sun, Jun; Li, Chen; Wang, Suwen

2016-01-01

The current theories of antimalarial mechanism of artemisinin are inadequate to fully explain the observed effects. In our study, “organism-like” formation of Schistosoma hemozoin granules by attaching to and utilizing erythrocytes to form new ones was observed. This indicates that heme iron is transferred from erythrocytes to hemozoin granules during their formation. However, as a disposal product of heme detoxification, these granules are not completely expelled from the Schistosoma gut, but decomposed again between microvilli in the posterior portion of the gut to transfer iron to eggs. Based on the function of iron transport supported by our observation of the unique process of Schistosoma hemozoin formation, here we propose a new viewpoint of antimalarial mechanism of artemisinin, which emphasizes the final outcome, i.e., interference of iron utilization in parasites by artemisinin, instead of focusing on the mode of interaction between artemisinin and heme or hemozoin. This suggests that artemisinin and its endoperoxides derivatives likely hit the Achilles’ heel of hemozoin-producing and iron-dependent organisms. PMID:27694940

How "resistant" is artemisinin resistant malaria? - The risks of ambiguity using the term "resistant" malaria.

PubMed

Hanscheid, Thomas; Hardisty, David W

2018-04-30

In scientific discourse, few would consider the widely used term resistance as ambiguous. The definition and usage of the term antimicrobial resistance revolves around the concept that microorganisms change in ways that render antimicrobial medications clinically ineffective. Because artemisinins have become the cornerstone for antimalarial therapy, the widely used term artemisinin resistance in scientific literature is highly alarming. Naturally, many people will assume that artemisinin resistance must essentially be the same as antimicrobial resistance, which means it is clinically ineffective. However, this is incorrect, and the WHO defines artemisinin resistance differently to antimicrobial resistance as "partial/relative resistance". This means that parasite clearance times are increased but does not automatically mean that artemisinins have become clinically inefficacious. Is the ambiguous use of the term resistance justified and appropriate, although it might be misleading biomedical researchers, the media, policy makers and possibly attending physicians? Science is also about clear and unambiguous use of terminology, so that a message is accurately communicated and understood. Ambiguity can lead to misunderstandings, and misunderstandings can cause wrong actions; unnecessarily so. Copyright © 2018 Elsevier Ltd. All rights reserved.

Influence of Mowing Artemisia tridentata ssp. wyomingensis on Winter Habitat for Wildlife

NASA Astrophysics Data System (ADS)

Davies, Kirk W.; Bates, Jonathan D.; Johnson, Dustin D.; Nafus, Aleta M.

2009-07-01

Mowing is commonly implemented to Artemisia tridentata ssp. wyomingensis (Beetle & A. Young) S.L. Welsh (Wyoming big sagebrush) plant communities to improve wildlife habitat, increase forage production for livestock, and create fuel breaks for fire suppression. However, information detailing the influence of mowing on winter habitat for wildlife is lacking. This information is crucial because many wildlife species depended on A. tridentata spp. wyomingensis plant communities for winter habitat and consume significant quantities of Artemisia during this time . Furthermore, information is generally limited describing the recovery of A. tridentata spp. wyomingensis to mowing and the impacts of mowing on stand structure. Stand characteristics and Artemisia leaf tissue crude protein (CP), acid detergent fiber (ADF), and neutral detergent fiber (NDF) concentrations were measured in midwinter on 0-, 2-, 4-, and 6-year-old fall-applied mechanical (mowed at 20 cm height) treatments and compared to adjacent untreated (control) areas. Mowing compared to the control decreased Artemisia cover, density, canopy volume, canopy elliptical area, and height ( P < 0.05), but all characteristics were recovering ( P < 0.05). Mowing A. tridentata spp. wyomingensis plant communities slightly increases the nutritional quality of Artemisia leaves ( P < 0.05), but it simultaneously results in up to 20 years of decrease in Artemisia structural characteristics. Because of the large reduction in A. tridentata spp. wyomingensis for potentially 20 years following mowing, mowing should not be applied in Artemisia facultative and obligate wildlife winter habitat. Considering the decline in A. tridentata spp. wyomingensis-dominated landscapes, we caution against mowing these communities.

The production and exportation of artemisinin-derived drugs in China: current status and existing challenges.

PubMed

Huang, Yangmu; Li, Hui; Peng, Danlu; Wang, Yu; Ren, Qiaomeng; Guo, Yan

2016-07-15

As the discoverer and a major manufacturer of artemisinin, China has made valuable contributions to malaria control and the global market of artemisinin-derived drugs. This study aims to explore the production and export status of artemisinin-derived drugs in China during 2011 and 2014 to provide a clear understanding of China's participation in this field and also to provide guidance for its future role on global malaria control. Production and exportation data were obtained from the Ministry of Industry and Information Technology (MIIT) database of the People's Republic China and monthly reports of the General Administration of Customs of China, respectively. The production volume, export volume, export value, and export area of artemisinin and its derivatives (artemether, artesunate, dihydroartemisinin), including both active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs), were descripted and analysed by Microsoft Excel. Between 2011 and 2013, the total production volume of artemisinin-derived APIs and FPPs reached 543.41 metric tons (MT) and 14.79 MT, respectively. The total export value and volume of artemisinin-derived APIs during 2012 and 2014 was US$ 211.39 million and 338.53 MT; the total export value and volume of FPPs was US$ 227.17 million and 4401.44 MT. Compared with the sharply decreasing trend of API exports each year, the export value of FPPs kept at a more stable level, with 14.66 % increase in 2013 and 5.31 % decrease in 2014. As for exportation areas, India was the largest purchaser of APIs, accounting for nearly a half of the total amount, while FPPs mainly exported to African countries. Exports of artemisinin derivatives for China have been transforming from API-dominated to FPP-dominated. However, the exportation of artemisinin-derived drugs in China still face the challenges of small market share in the global FPP market and indirect sale of FPPs through a third country due to the deficiency in obtaining relevant certification into global market.

Mountain big sagebrush (Artemisia tridentata spp vaseyana) seed production

Treesearch

Melissa L. Landeen

2015-01-01

Big sagebrush (Artemisia tridentata Nutt.) is the most widespread and common shrub in the sagebrush biome of western North America. Of the three most common subspecies of big sagebrush (Artemisia tridentata), mountain big sagebrush (ssp. vaseyana; MBS) is the most resilient to disturbance, but still requires favorable climactic conditions and a viable post-...

Endophytic Fungi in Species of Artemisia.

PubMed

Cosoveanu, Andreea; Cabrera, Raimundo

2018-05-01

The genus Artemisia , a collection of ~400 hardy herbaceous plant and shrub species, is an important resource contributing to chemistry, medicine, agriculture, industry, and ecology. Its communities of endophytic fungi have only recently begun to be explored. Summarized from studies conducted on the fungal endophytes in Artemisia species, both fungal phylogenetic diversity and the associated bioactivity was examined. Isolations from 14 species of Artemisia have led to 51 genera of fungal endophytes, 28 families, and 18 orders. Endophytes belonged mainly to Ascomycota , except for two taxa of Cantharellales and Sporidiobolales , one taxon of Mucoromycota , and one species of Oomycota . The mostly common families were Pleosporaceae , Trichocomaceae , Leptosphaeriaceae , and Botryosphaeriaceae (relative abundance = 14.89, 8.51, 7.14 and 6.38, respectively). In the search for bioactive metabolites, 27 novel compounds were characterized and 22 metabolites were isolated between 2006 and 2017. The first study on endophytic fungi isolated from species of Artemisia was published but 18 years ago. This summary of recently acquired data illustrates the considerable diversity of biological purposes addressed by fungal endophytes of Artemisia spp.

Understanding artemisinin-resistant malaria: what a difference a year makes

PubMed Central

Fairhurst, Rick M.

2015-01-01

Purpose of review The emergence of artemisinin resistance in Southeast Asia, where artemisinin combination therapies (ACTs) are beginning to fail, threatens global endeavors to control and eliminate Plasmodium falciparum malaria. Future efforts to prevent the spread of this calamity to Africa will benefit from last year’s tremendous progress in understanding artemisinin resistance. Recent findings Multiple international collaborations have established that artemisinin resistance is associated with slow parasite clearance in patients; increased survival of early ring-stage parasites in vitro; single-nucleotide polymorphisms (SNPs) in the parasite’s ‘K13’ gene; parasite ‘founder’ populations sharing a genetic background of four additional SNPs; parasite transcriptional profiles reflecting an “unfolded protein response” and decelerated parasite development; and elevated parasite phosphatidylinositol-3-kinase activity. In Western Cambodia, where the K13 C580Y mutation is approaching fixation, the frontline ACT is failing to cure nearly half of patients, likely due to partner drug resistance. In Africa, where dozens of K13 mutations have been detected at low frequency, there is no evidence yet of artemisinin resistance. Summary In Southeast Asia, clinical and epidemiological investigations are urgently needed to stop the further spread of artemisinin resistance; monitor ACT efficacy where K13 mutations are prevalent; identify currently-available drug regimens that cure ACT failures; and rapidly advance new antimalarial compounds through clinical trials. PMID:26237549

Declining Transmission and Immunity to Malaria and Emerging Artemisinin Resistance in Thailand: A Longitudinal Study.

PubMed

Ataíde, Ricardo; Powell, Rosanna; Moore, Kerryn; McLean, Alistair; Phyo, Aung Pyae; Nair, Shalini; White, Marina; Anderson, Tim J; Beeson, James G; Simpson, Julie A; Nosten, Francois; Fowkes, Freya J I

2017-09-15

Reductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time. Antibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time. Immunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001). Understanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

PubMed Central

Henrich, Philipp P.; O'Brien, Connor; Sáenz, Fabián E.; Cremers, Serge; Kyle, Dennis E.

2014-01-01

The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria. PMID:24145526

Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination.

PubMed

Ouji, Manel; Augereau, Jean-Michel; Paloque, Lucie; Benoit-Vical, Françoise

2018-01-01

The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions. © M. Ouji et al., published by EDP Sciences, 2018.

Co-occurrence of Artemisia and Ambrosia pollen seasons against the background of the synoptic situations in Poland.

PubMed

Stępalska, Danuta; Myszkowska, Dorota; Katarzyna, Leśkiewicz; Katarzyna, Piotrowicz; Katarzyna, Borycka; Kazimiera, Chłopek; Łukasz, Grewling; Idalia, Kasprzyk; Barbara, Majkowska-Wojciechowska; Małgorzata, Malkiewicz; Małgorzata, Nowak; Krystyna, Piotrowska-Weryszko; Małgorzata, Puc; Elżbieta, Weryszko-Chmielewska

2017-04-01

The Asteraceae family is one of the largest families, comprising 67 genera and 264 species in Poland. However, only a few genera, including Artemisia and Ambrosia are potential allergenic sources. The aim of the study was to estimate how often and to what degree Artemisia and Ambrosia pollen seasons co-occur intensifying human health risk, and how synoptic situations influence frequency of days with high pollen concentrations of both taxa. Artemisia and Ambrosia pollen data were collected, using the volumetric method, at 8 sites in Poland. Daily concentrations of Artemisia pollen equal to 30 grains or more and Ambrosia pollen equal to 10 grains or more were accepted as high values. Concentrations of more than 10 pollen grains were defined as high in the case of Ambrosia because its allergenicity is considered higher. High concentrations were confronted with synoptic situations. Analysis was performed on the basis of two calendars on circulation types of atmosphere in Poland (Niedźwiedź, 2006, 2015). Co-occurrence of Artemisia and Ambrosia pollen seasons is being found most often, when Ambrosia pollen season starts in the first half of August. If it happens in the last 10 days of August high pollen concentrations of Artemisia and Ambrosia do not occur at the same days. At three sites (Sosnowiec, Rzeszów, Lublin) high Ambrosia pollen concentrations during the Artemisia pollen season appear more often than in other sites under question. The high Artemisia pollen concentrations occur, when continental or polar maritime old air masses inflow into Poland. The impact of air masses on high Ambrosia pollen concentrations depends on site localizations. It is likely, that in the south-eastern part of Poland high Ambrosia pollen concentrations result from the pollen transport from east-south-south-westerly directions and the local sources. Co-occurrence of both taxa pollen seasons depends on the air masses inflow and appears more often in a south-eastern part of Poland.

Co-occurrence of Artemisia and Ambrosia pollen seasons against the background of the synoptic situations in Poland

NASA Astrophysics Data System (ADS)

Stępalska, Danuta; Myszkowska, Dorota; Katarzyna, Leśkiewicz; Katarzyna, Piotrowicz; Katarzyna, Borycka; Kazimiera, Chłopek; Łukasz, Grewling; Idalia, Kasprzyk; Barbara, Majkowska-Wojciechowska; Małgorzata, Malkiewicz; Małgorzata, Nowak; Krystyna, Piotrowska-Weryszko; Małgorzata, Puc; Elżbieta, Weryszko-Chmielewska

2017-04-01

The Asteraceae family is one of the largest families, comprising 67 genera and 264 species in Poland. However, only a few genera, including Artemisia and Ambrosia are potential allergenic sources. The aim of the study was to estimate how often and to what degree Artemisia and Ambrosia pollen seasons co-occur intensifying human health risk, and how synoptic situations influence frequency of days with high pollen concentrations of both taxa. Artemisia and Ambrosia pollen data were collected, using the volumetric method, at 8 sites in Poland. Daily concentrations of Artemisia pollen equal to 30 grains or more and Ambrosia pollen equal to 10 grains or more were accepted as high values. Concentrations of more than 10 pollen grains were defined as high in the case of Ambrosia because its allergenicity is considered higher. High concentrations were confronted with synoptic situations. Analysis was performed on the basis of two calendars on circulation types of atmosphere in Poland (Niedźwiedź, 2006, 2015). Co-occurrence of Artemisia and Ambrosia pollen seasons is being found most often, when Ambrosia pollen season starts in the first half of August. If it happens in the last 10 days of August high pollen concentrations of Artemisia and Ambrosia do not occur at the same days. At three sites (Sosnowiec, Rzeszów, Lublin) high Ambrosia pollen concentrations during the Artemisia pollen season appear more often than in other sites under question. The high Artemisia pollen concentrations occur, when continental or polar maritime old air masses inflow into Poland. The impact of air masses on high Ambrosia pollen concentrations depends on site localizations. It is likely, that in the south-eastern part of Poland high Ambrosia pollen concentrations result from the pollen transport from east-south-south-westerly directions and the local sources. Co-occurrence of both taxa pollen seasons depends on the air masses inflow and appears more often in a south-eastern part of Poland.

Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1

PubMed Central

Sagar, S.M.; Yance, D.; Wong, R.K.

2006-01-01

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies. PMID:17576437

Chemotherapy of Rodent Malaria. Part 1

DTIC Science & Technology

1987-10-01

to produce exaggerated resistance factors (I 90 values). For example, the ED of chloroquine against the artemisinin 90 resistant ART strain...primaquine, quinine, cinchonine, quinidine, mefloquine, halofantrine, artemisinin , pyronaridine, mepacrine and Mannich bases (such as WR 228258). It is...RC. It is markedly resistant to primaquine and possesses slight cross-resistance to quinidine, mefloquine, artemisinin . There is also a marked cross

Preparation of Chemicals and Bulk Drug Substances for the U.S. Army Drug Development Program.

DTIC Science & Technology

1997-12-01

4(R)-rio (,) -dihydroartemisininoxy]-; artemisinin ; dihydroartemisinin; artelinic acid, methyl ester; artelinic acid. -I- TABLE OF CONTENTS I...acid, 4-(4-chloro- phenyl) -4(R) -[10(P) -dihydro- artemisininoxy]-......................... 49 10. Artemisinin ................................. 58 11...dihydroartemisininoxy]-; artemisinin ; dihydroartemisinin; artelinic acid, methyl ester; artelinic acid. -V- II FOREWORD opinions, interpretations, conclusions and

Quantitative structure-activity relationship and molecular docking of artemisinin derivatives to vascular endothelial growth factor receptor 1.

PubMed

Saeed, Mohamed E M; Kadioglu, Onat; Seo, Ean-Jeong; Greten, Henry Johannes; Brenk, Ruth; Efferth, Thomas

2015-04-01

The antimalarial drug artemisinin has been shown to exert anticancer activity through anti-angiogenic effects. For further drug development, it may be useful to have derivatives with improved anti-angiogenic properties. We performed molecular docking of 52 artemisinin derivatives to vascular endothelial growth factor receptors (VEGFR1, VEGFR2), and VEGFA ligand using Autodock4 and AutodockTools-1.5.7.rc1 using the Lamarckian genetic algorithm. Quantitative structure-activity relationship (QSAR) analyses of the compounds prepared by Corina Molecular Networks were performed using the Molecular Operating Environment MOE 2012.10. A statistically significant inverse relationship was obtained between in silico binding energies to VEGFR1 and anti-angiogenic activity in vivo of a test-set of artemisinin derivatives (R=-0.843; p=0.035). This served as a control experiment to validate molecular docking predicting anti-angiogenc effects. Furthermore, 52 artemisinin derivatives were docked to VEGFR1 and in selected examples also to VEGFR2 and VEGFA. Higher binding affinities were calculated for receptors than for the ligand. The best binding affinities to VEGFR1 were found for an artemisinin dimer, 10-dihydroartemisinyl-2-propylpentanoate, and dihydroartemisinin α-hemisuccinate sodium salt. QSAR analyses revealed significant relationships between VEGFR1 binding energies and defined molecular descriptors of 35 artemisinins assigned to the training set (R=0.0848, p<0.0001) and 17 derivatives assigned to the test set (R=0.761, p<0.001). Molecular docking and QSAR calculations can be used to identify novel artemisinin derivatives with anti-angiogenic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms

PubMed Central

Burk, O; Piedade, R; Ghebreghiorghis, L; Fait, JT; Nussler, AK; Gil, JP; Windshügel, B; Schwab, M

2012-01-01

BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug–drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug–drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered. PMID:22577882

Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro.

PubMed

Tjahjani, Susy

2017-02-28

Malaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro. Dry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC 50 ). Analysis of the parasite growth in vitro indicated that IC 50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were <1. This study demonstrated a promising antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.

Availability and quality of anti-malarials among private sector outlets in Myanmar in 2012: results from a large, community-based, cross-sectional survey before a large-scale intervention.

PubMed

Khin, Hnin Su Su; Chen, Ingrid; White, Chris; Sudhinaraset, May; McFarland, Willi; Littrell, Megan; Montagu, Dominic; Aung, Tin

2015-07-14

Global malaria control efforts are threatened by the spread and emergence of artemisinin-resistant Plasmodium falciparum parasites. In 2012, the widespread sale of partial courses of artemisinin-based monotherapy was suspected to take place in the highly accessed, weakly regulated private sector in Myanmar, posing potentially major threats to drug resistance. This study investigated the presence of artemisinin-based monotherapies in the Myanmar private sector, particularly as partial courses of therapy, to inform the targeting of future interventions to stop artemisinin resistance. A large cross-sectional survey comprised of a screening questionnaire was conducted across 26 townships in Myanmar between March and May, 2012. For outlets that stocked anti-malarials at the time of survey, a stock audit was conducted, and for outlets that stocked anti-malarials within 3 months of the survey, a provider survey was conducted. A total of 3,658 outlets were screened, 83% were retailers (pharmacies, itinerant drug vendors and general retailers) and 17% were healthcare providers (private facilities and health workers). Of the 3,658 outlets screened, 1,359 outlets (32%) stocked at least one anti-malarial at the time of study. Oral artemisinin-based monotherapy comprised of 33% of self-reported anti-malarials dispensing volumes found. The vast majority of artemisinin-based monotherapy was sold by retailers, where 63% confirmed that they sold partial courses of therapy by cutting blister packets. Very few retailers (5%) had malaria rapid diagnostic tests available, and quality-assured artemisinin-based combination therapy was virtually nonexistent among retailers. Informal private pharmacies, itinerant drug vendors and general retailers should be targeted for interventions to improve malaria treatment practices in Myanmar, particularly those that threaten the emergence and spread of artemisinin resistance.

Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions.

PubMed

Van Nijlen, T; Brennan, K; Van den Mooter, G; Blaton, N; Kinget, R; Augustijns, P

2003-03-26

The purpose of this study was to enhance the dissolution rate of artemisinin in order to improve the intestinal absorption characteristics. The effect of: (1) micronisation and (2) formation of solid dispersions with PVPK25 was assessed in an in vitro dissolution system [dissolution medium: water (90%), ethanol (10%) and sodium lauryl sulphate (0.1%)]. Coulter counter analysis was used to measure particle size. X-ray diffraction and DSC were used to analyse the physical state of the powders. Micronisation by means of a jet mill and supercritical fluid technology resulted in a significant decrease in particle size as compared to untreated artemisinin. All powders appeared to be crystalline. The dissolution rate of the micronised forms improved in comparison to the untreated form, but showed no difference in comparison to mechanically ground artemisinin. Solid dispersions of artemisinin with PVPK25 as a carrier were prepared by the solvent method. Both X-ray diffraction and DSC showed that the amorphous state was reached when the amount of PVPK25 was increased to 67%. The dissolution rate of solid dispersions with at least 67% of PVPK25 was significantly improved in comparison to untreated and mechanically ground artemisinin. Modulation of the dissolution rate of artemisinin was obtained by both particle size reduction and formation of solid dispersions. The effect of particle size reduction on the dissolution rate was limited. Solid dispersions could be prepared by using a relatively small amount of PVPK25. The formation of solid dispersions with PVPK25 as a carrier appears to be a promising method to improve the intestinal absorption characteristics of artemisinin. Copyright 2003 Elsevier Science B.V.

Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

PubMed Central

Miotto, Olivo; Almagro-Garcia, Jacob; Manske, Magnus; MacInnis, Bronwyn; Campino, Susana; Rockett, Kirk A; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Duong, Socheat; Nguon, Chea; Chuor, Char Meng; Saunders, David; Se, Youry; Lon, Chantap; Fukuda, Mark M; Amenga-Etego, Lucas; Hodgson, Abraham VO; Asoala, Victor; Imwong, Mallika; Takala-Harrison, Shannon; Nosten, Francois; Su, Xin-zhuan; Ringwald, Pascal; Ariey, Frédéric; Dolecek, Christiane; Hien, Tran Tinh; Boni, Maciej F; Thai, Cao Quang; Amambua-Ngwa, Alfred; Conway, David J; Djimdé, Abdoulaye A; Doumbo, Ogobara K; Zongo, Issaka; Ouedraogo, Jean-Bosco; Alcock, Daniel; Drury, Eleanor; Auburn, Sarah; Koch, Oliver; Sanders, Mandy; Hubbart, Christina; Maslen, Gareth; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Miles, Alistair; O’Brien, John; Gamble, Chris; Oyola, Samuel O; Rayner, Julian C; Newbold, Chris I; Berriman, Matthew; Spencer, Chris CA; McVean, Gilean; Day, Nicholas P; White, Nicholas J; Bethell, Delia; Dondorp, Arjen M; Plowe, Christopher V; Fairhurst, Rick M; Kwiatkowski, Dominic P

2013-01-01

We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination. PMID:23624527

Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa

PubMed Central

St. Laurent, Brandyce; Miller, Becky; Burton, Timothy A.; Amaratunga, Chanaki; Men, Sary; Sovannaroth, Siv; Fay, Michael P.; Miotto, Olivo; Gwadz, Robert W.; Anderson, Jennifer M.; Fairhurst, Rick M.

2015-01-01

Artemisinin-resistant Plasmodium falciparum parasites are rapidly spreading in Southeast Asia, yet nothing is known about their transmission. This knowledge gap and the possibility that these parasites will spread to Africa endanger global efforts to eliminate malaria. Here we produce gametocytes from parasite clinical isolates that displayed artemisinin resistance in patients and in vitro, and use them to infect native and non-native mosquito vectors. We show that contemporary artemisinin-resistant isolates from Cambodia develop and produce sporozoites in two Southeast Asian vectors, Anopheles dirus and Anopheles minimus, and the major African vector, Anopheles coluzzii (formerly Anopheles gambiae M). The ability of artemisinin-resistant parasites to infect such highly diverse Anopheles species, combined with their higher gametocyte prevalence in patients, may explain the rapid expansion of these parasites in Cambodia and neighbouring countries, and further compromise efforts to prevent their global spread. PMID:26485448

Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa.

PubMed

St Laurent, Brandyce; Miller, Becky; Burton, Timothy A; Amaratunga, Chanaki; Men, Sary; Sovannaroth, Siv; Fay, Michael P; Miotto, Olivo; Gwadz, Robert W; Anderson, Jennifer M; Fairhurst, Rick M

2015-10-20

Artemisinin-resistant Plasmodium falciparum parasites are rapidly spreading in Southeast Asia, yet nothing is known about their transmission. This knowledge gap and the possibility that these parasites will spread to Africa endanger global efforts to eliminate malaria. Here we produce gametocytes from parasite clinical isolates that displayed artemisinin resistance in patients and in vitro, and use them to infect native and non-native mosquito vectors. We show that contemporary artemisinin-resistant isolates from Cambodia develop and produce sporozoites in two Southeast Asian vectors, Anopheles dirus and Anopheles minimus, and the major African vector, Anopheles coluzzii (formerly Anopheles gambiae M). The ability of artemisinin-resistant parasites to infect such highly diverse Anopheles species, combined with their higher gametocyte prevalence in patients, may explain the rapid expansion of these parasites in Cambodia and neighbouring countries, and further compromise efforts to prevent their global spread.

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus Are Absent in Plasmodium falciparum Isolates from Haiti

PubMed Central

Carter, Tamar E.; Boulter, Alexis; Existe, Alexandre; Romain, Jean R.; St. Victor, Jean Yves; Mulligan, Connie J.; Okech, Bernard A.

2015-01-01

Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations. PMID:25646258

[Chemical studies on essential oils from 6 Artemisia species].

PubMed

Pan, J G; Xu, Z L; Ji, L

1992-12-01

The constituents of the essential oils obtained from the leaves of Artemisia argyi, A. argyi cv.qiai, A. lavandulaefolia, A. mongolica, A. princeps and A. argyi var. gracilis were analysed by GC-MS. 96 compounds including alpha-thujene, 1,8-cineole, camphor and artemisia alcohol, etc. were identified. Their percentages in the oils were given.

Artemisia systematics and phylogeny: Cytogenetic and molecular insights

Treesearch

Joan Valles; E. Durant McArthur

2001-01-01

The genus Artemisia (Asteraceae, Anthemideae, Artemisiinae) is a large genus, one of the largest genera in its family. It is comprised of about 500 taxa at the specific or subspecific level, distributed in 5 sections or subgenera. Most species are perennial and many are landscape dominants of arid or semiarid regions. Artemisia is widely distributed in the Northern...

Climate drives adaptive genetic responses associated with survival in big sagebrush (Artemisia tridentata)

Treesearch

Lindsay Chaney; Bryce A. Richardson; Matthew J. Germino

2016-01-01

A genecological approach was used to explore genetic variation for survival in Artemisia tridentata (big sagebrush). Artemisia tridentata is a widespread and foundational shrub species in western North America. This species has become extremely fragmented, to the detriment of dependent wildlife, and efforts to restore it are now a land management priority. Common-...

Chemical composition and biological effects of Artemisia maritima and Artemisia nilagirica essential oils from wild plant of Western Himalaya

USDA-ARS?s Scientific Manuscript database

Artemisia species possess pharmacological properties that are used for medical purposes worldwide. In this paper, the essential oils from the aerial parts of A. nilagirica and A. maritima from the western Indian Himalaya region are described. The main compounds analyzed by simultaneous GC/MS and GC/...

Study of two-stage ohmic hydro-extraction of essential oil from Artemisia aucheri Boiss.: Antioxidant and antimicrobial characteristics.

PubMed

Mojtahed Zadeh Asl, Rozita; Niakousari, Mehrdad; Hashemi Gahruie, Hadi; Saharkhiz, Mohammad Jamal; Mousavi Khaneghah, Amin

2018-05-01

The effect of two-stage ohmic-assisted hydrodistillation (TSOH) on the extraction and characteristics of essential oils (EOs) from the Artemisia aucheri Boiss. was studied, and the results were compared to conventional hydrodistillation (HD). According to the results, the yield of EOs obtained through TSOH was almost 30% higher than those extracted by HD in nearly one-quarter of a time used by the HD. Scanning electron micrographs of A. aucheri leaves showed almost complete eruption of EO glands and their surrounding area in TSOH extraction method, hence achieving higher yield. The components of the EOs obtained through TSOH were only slightly different from those of HD. GC/MS analysis indicated some differences in the quantity of the main components, too. The main components of EOs were identified as Thymol, Linalool, Geraniol, Camphor, and 1, 8-Cineole, Davana ether and Cis-Davanone. Thymol (~17%) and Cis-Davanone (~23%) were the highest quantity in the EOs extracted from TSOH and HD, respectively. The variation of antioxidant and antimicrobial activities of the EOs may be attributed to these differences in the percentage of the main components. The radical scavenging activity of the EOs obtained by TSOH was almost twice that of HD. Based on antimicrobial activity assays, the EOs were efficient against S. aureus (a Gram-positive), E. coli (a Gram-negative), and S. cerevisiae (yeast). However, the efficacy was higher in gram-positive than gram-negative bacteria and yeast. The results indicate TSOH has a potential to produce EOs from herbal plants at a faster rate, higher yield, being probably more efficient in terms of energy although having similar antimicrobial and antioxidant efficacy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Inhibitory Activity of Eleven Artemisia Species from Iran against Leishmania Major Parasites

PubMed Central

Emami, Seyed Ahmad; Zamanai Taghizadeh Rabe, Shahrzad; Ahi, Ali; Mahmoudi, Mahmoud

2012-01-01

Objective(s) Annual incidence of cutaneous leishmaniasis is increasingly growing and development of the alternative drugs against it is a major concern. Artemisia genus is a traditional medicinal plant in Iran. The aim of this study was to examine the leishmanicidal activity of various Iranian Artemisia species extracts. Materials and Methods Different extracts were gathered from eleven Iranian Artemisia species. Their leishmanicidal activities against the growth of Leishmania major (L. major) promastigotes were examined as the half maximal inhibitory concentration (IC50) using MTT assay. Results Obtained results showed that ethanol extracts especially those taken from A. ciniformis, A. santolina and A. kulbadica have the strongest effects. Conclusion Looking for the effective leishmanicidal agents from natural resources in Iran, we found that the ethanol extract of collected Artemisia species had significant effect on in vitro leishmanicidal activity and may be suitable candidates in the treatment of leishmaniasis. PMID:23493354

Electron Microscopy to Correlate Cell Structure and Biochemical Activity

DTIC Science & Technology

1993-03-10

prevent and/or cure cerebral malaria. d) Morphological effects of artemisinin in Plasmodium falciparum In collaboration with Dr. Milhous of WRAR...uitrastructural changes induced in jPlasmodium falciparum, by artemisinin were studied in vitro. Two hours after administration, changes were...Electron microscope autoradiography was performed after [5H]-dihydroartemisinin and [uC]- artemisinin were administered to infected erythrocytes in

Natural polyhydroxyalkanoate-gold nanocomposite based biosensor for detection of antimalarial drug artemisinin.

PubMed

Phukon, Pinkee; Radhapyari, Keisham; Konwar, Bolin Kumar; Khan, Raju

2014-04-01

The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate-gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate-gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01-0.08μg mL(-1)) with sensitivity of 0.26μAμg mL(-1). The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035μg mL(-1) and 0.0036μg mL(-1) in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Molecular Epidemiology of Malaria in Cameroon and Côte d'Ivoire. XXXI. Kelch 13 Propeller Sequences in Plasmodium falciparum Isolates before and after Implementation of Artemisinin-Based Combination Therapy.

PubMed

Djaman, Joseph Allico; Olefongo, Dagnogo; Ako, Aristide Berenger; Roman, Jocelyne; Ngane, Vincent Foumane; Basco, Leonardo K; Tahar, Rachida

2017-07-01

Artemisinin-resistant malaria has not been reported from Africa, but resistance can possibly spread from Asia or arise independently in Africa. The emergence of artemisinin resistance in Africa can be monitored by molecular assay of Kelch 13 (K13) propeller sequences. A total of 251 archived DNA samples of Plasmodium falciparum isolates collected in 2002, 2003, and 2006 in Yaounde, Cameroon, and 47 samples collected in 2006 and 2013 in Abidjan, Côte d'Ivoire, were analyzed for K13-propeller sequence polymorphism. Only one isolate carried a mutant K13-propeller allele (E602D). None of the isolates carried the key mutant alleles (Y493H, R539T, I543T, and C580Y) associated with artemisinin resistance in Cambodia. The presence of the mutant allele was not correlated with in vitro response to dihydroartemisinin determined by the classical hypoxanthine incorporation assay. There was no evidence of K13 mutations associated with artemisinin resistance before and soon after the introduction of artemisinin-based combination therapies in Cameroon and Côte d'Ivoire.

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

PubMed

Avery, Mitchell A; Muraleedharan, Kannoth M; Desai, Prashant V; Bandyopadhyaya, Achintya K; Furtado, Marise M; Tekwani, Babu L

2003-09-25

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis.

PubMed

Kovacs, Stephanie D; van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S; Emerson, Scott; Steketee, Richard; Ter Kuile, Feiko O; Stergachis, Andy

2016-01-01

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24-0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31-1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27-3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77-1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79-1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37-1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy.

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

PubMed Central

van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S.; Emerson, Scott; Steketee, Richard; ter Kuile, Feiko O.; Stergachis, Andy

2016-01-01

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy. PMID:27824884

Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach

NASA Astrophysics Data System (ADS)

Nagasundaram, N.; George Priya Doss, C.; Chakraborty, Chiranjib; Karthick, V.; Thirumal Kumar, D.; Balaji, V.; Siva, R.; Lu, Aiping; Ge, Zhang; Zhu, Hailong

2016-07-01

Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs.

Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia.

PubMed

Dwivedi, Ankit; Khim, Nimol; Reynes, Christelle; Ravel, Patrice; Ma, Laurence; Tichit, Magali; Bourchier, Christiane; Kim, Saorin; Dourng, Dany; Khean, Chanra; Chim, Pheaktra; Siv, Sovannaroth; Frutos, Roger; Lek, Dysoley; Mercereau-Puijalon, Odile; Ariey, Frédéric; Menard, Didier; Cornillot, Emmanuel

2016-06-14

Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential. To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia. Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance. The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.

Environmental Compliance Assessment and Management System Program (ECAMP). U.S. Air Force European Economic Community (EEC)

DTIC Science & Technology

1993-09-01

alboranensis Anthemis glabemrma Artemisia granatensis Artemisia laciniata Aster pyrenacus Aster sibiricus Centaurea heldreichii Centaurea horrida Centaurea...kalambakensi s Centaurea lactiflora Centaurea Iinaresii Centaurea megarensis Centaurea niederi Centaurea peucedanifolia Centaurea princeps Crepis...50 Table 448 (continued) COMIPOSrrAE Anthemis glaberrima (Rech. f.) Greuter Artemisia granatensis Boiss. Aster pyrenacus Desf. ex DC. Aster sorrentinil

Fractionation and Characterization of Biologically-active Polysaccharides from Artemisia tripartita

PubMed Central

Xie, Gang; Schepetkin, Igor A.; Siemsen, Daniel W.; Kirpotina, Liliya N.; Wiley, James A.; Quinn, Mark T.

2008-01-01

The leaves of Artemisia species have been traditionally used for prevention and treatment of a number of diseases. In this study, five polysaccharide fractions (designated A-I to A-V) were isolated from the leaves of Artemisia tripartita Rydb. by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, and chromatography. The homogeneity and average molecular weight of each fraction were determined by high performance size-exclusion chromatography. Sugar composition analysis revealed that Artemisia polysaccharides consisted primarily of xylose, glucose, arabinose, galactose, and galactosamine. Moreover, all fractions contained at least 3.4% sulfate, and fractions A-II through A-V contained an arabinogalactan type II structure. All fractions exhibited macrophage-activating activity, enhancing production of intracellular reactive oxygen species and release of nitric oxide, interleukin 6, interleukin 10, tumor necrosis factor α, and monocyte chemotactic protein-1. In addition, all fractions exhibited scavenging activity for reactive oxygen species generated enzymatically or produced extracellularly by human neutrophils. Finally, fractions A-I and A-V exhibited complement-fixing activity. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Artemisia extracts, and suggest the possibility of using Artemisia polysaccharides as an immunotherapeutic adjuvant. PMID:18325553

Artemisinin anti-malarial drugs in China

PubMed Central

Guo, Zongru

2016-01-01

Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the “whole nation” system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements. PMID:27006895

Range 74 Target Complexes, Environmental Assessment, Nevada Test and Training Range, Nevada

DTIC Science & Technology

2007-07-01

Sagebrush-Grass Community The sagebrush-grass community (Photograph 3-3) is primarily dominated by big sagebrush ( Artemisia tridentata), but other...sagebrush species, such as black sagebrush ( Artemisia nova) can also be dominant. This community is often located in areas with greater...Sagebrush-Grass Community The sagebrush-grass community is primarily dominated by big sagebrush ( Artemisia tridentata), but other sagebrush species

Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

PubMed Central

Ménard, Sandie; Ben Haddou, Tanila; Ramadani, Arba Pramundita; Ariey, Frédéric; Iriart, Xavier; Beghain, Johann; Bouchier, Christiane; Witkowski, Benoit; Berry, Antoine; Mercereau-Puijalon, Odile

2015-01-01

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy. PMID:26401601

Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties

PubMed Central

Soomro, Shahid; Langenberg, Tobias; Mahringer, Anne; Konkimalla, V Badireenath; Horwedel, Cindy; Holenya, Pavlo; Brand, Almut; Cetin, Canan; Fricker, Gert; Dewerchin, Mieke; Carmeliet, Peter; Conway, Edward M; Jansen, Herwig; Efferth, Thomas

2011-01-01

Abstract Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer. PMID:20629994

Heme Mediates Cytotoxicity from Artemisinin and Serves as a General Anti-Proliferation Target

PubMed Central

Zhang, Shiming; Gerhard, Glenn S.

2009-01-01

Heme (Fe2+ protoporphyrin IX) is an essential molecule that has been implicated the potent antimalarial action of artemisinin and its derivatives, although the source and nature of the heme remain controversial. Artemisinins also exhibit selective cytotoxicity against cancer cells in vitro and in vivo. We demonstrate that intracellular heme is the physiologically relevant mediator of the cytotoxic effects of artemisinins. Increasing intracellular heme synthesis through the addition of aminolevulinic acid, protoporphyrin IX, or transferrin-bound iron increased the cytotoxicity of dihydroartemisinin, while decreasing heme synthesis through the addition of succinyl acetone decreased its cytotoxic activity. A simple and robust high throughput assay was developed to screen chemical compounds that were capable of interacting with heme. A natural products library was screened which identified the compound coralyne, in addition to artemisinin, as a heme interacting compound with heme synthesis dependent cytotoxic activity. These results indicate that cellular heme may serve a general target for the development of both anti-parasitic and anti-cancer therapeutics. PMID:19862332

Artemisinin resistance-associated polymorphisms at the K13-propeller locus are absent in Plasmodium falciparum isolates from Haiti.

PubMed

Carter, Tamar E; Boulter, Alexis; Existe, Alexandre; Romain, Jean R; St Victor, Jean Yves; Mulligan, Connie J; Okech, Bernard A

2015-03-01

Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations. © The American Society of Tropical Medicine and Hygiene.

Genetic architecture of artemisinin-resistant Plasmodium falciparum

PubMed Central

Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I; Onyamboko, Marie; Mokuolu, Olugbenga A; Jacob, Christopher G; Takala-Harrison, Shannon; Plowe, Christopher V; Day, Nicholas P; Dondorp, Arjen M; Spencer, Chris C A; McVean, Gilean; Fairhurst, Rick M; White, Nicholas J; Kwiatkowski, Dominic P

2015-01-01

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population. PMID:25599401

Pilot testing of dipsticks as point-of-care assays for rapid diagnosis of poor-quality artemisinin drugs in endemic settings.

PubMed

Guo, Suqin; He, Lishan; Tisch, Daniel J; Kazura, James; Mharakurwa, Sungano; Mahanta, Jagadish; Herrera, Sócrates; Wang, Baomin; Cui, Liwang

2016-01-01

Good-quality artemisinin drugs are essential for malaria treatment, but increasing prevalence of poor-quality artemisinin drugs in many endemic countries hinders effective management of malaria cases. To develop a point-of-care assay for rapid identification of counterfeit and substandard artemisinin drugs for resource-limited areas, we used specific monoclonal antibodies against artesunate and artemether, and developed prototypes of lateral flow dipstick assays. In this pilot test, we evaluated the feasibility of these dipsticks under different endemic settings and their performance in the hands of untrained personnel. The results showed that the dipstick tests can be successfully performed by different investigators with the included instruction sheet. None of the artemether and artesunate drugs collected from public pharmacies in different endemic countries failed the test. It is possible that the simple dipstick assays, with future optimization of test conditions and sensitivity, can be used as a qualitative and semi-quantitative assay for rapid screening of counterfeit artemisinin drugs in endemic settings.

In vitro antibacterial and antitumor activities of some medicinal plant extracts, growing in Turkey.

PubMed

Yildirim, Arzu Birinci; Karakas, Fatma Pehlivan; Turker, Arzu Ucar

2013-08-01

To investigate antibacterial and antitumor activities of 51 different extracts prepared with 3 types of solvents (water, ethanol and methanol) of 16 different plant species (Ajuga reptans (A. reptans) L., Phlomis pungens (P. pungens) Willd., Marrubium astracanicum (M. astracanicum) Jacq., Nepeta nuda (N. nuda) L., Stachys annua (S. annua) L., Genista lydia (G. lydia) Boiss., Nuphar lutea (N. lutea) L., Nymphaea alba (N. alba) L., Vinca minor (V. minor) L., Stellaria media (S. media) L., Capsella bursa-pastoris (C. bursa-pastoris) L., Galium spurium (G. spurium) L., Onosma heterophyllum (O. heterophyllum) Griseb., Reseda luteola (R. luteola) L., Viburnum lantana (V. lantana) L. and Mercurialis annua (M. annua) L.) grown in Turkey was conducted. Antibacterial activity was evaluated with 10 bacteria including Streptococcus pyogenes (S. pyogenes), Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), Escheria coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Salmonella typhimurium (S. typhimurium), Serratia marcescens (S. marcescens), Proteus vulgaris (P. vulgaris), Enterobacter cloacae (E. cloacea), and Klebsiella pneumoniae (K. pneumoniae) by using disc diffusion method. Antitumor activity was evaluated with Agrobacterium tumefaciens (A. tumefaciens)-induced potato disc tumor assay. Best antibacterial activity was obtained with ethanolic extract of P. pungens against S. pyogenes. Ethanolic and methanolic extract of N. alba and ethanolic extract of G. lydia also showed strong antibacterial activities. Results indicated that alcoholic extracts especially ethanolic extracts exhibited strong antibacterial activity against both gram-positive and gram-negative bacteria. Best antitumor activity was obtained with methanolic extracts of N. alba and V. lantana (100% tumor inhibition). Ethanolic extract of N. alba, alcoholic extracts of N. lutea, A. reptans and V. minor flowers, methanolic extracts of G. lydia and O. heterophyllum and ethanolic extract of V. lantana and aqueous extract of V. minor leaves exhibited strong tumor inhibitions. In near future works, identification of active components can be studied for plant extracts having strong bioactivity. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Potentiation of Artemisinin Activity against Chloroquine-Resistant Plasmodium falciparum Strains by Using Heme Models

PubMed Central

Benoit-Vical, Françoise; Robert, Anne; Meunier, Bernard

1999-01-01

The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of Plasmodium falciparum (FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of meso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both Plasmodium strains. PMID:10508044

Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

PubMed Central

O’Brien, Connor; Henrich, Philipp P.; Passi, Neha; Fidock, David A.

2012-01-01

Purpose of review Artemisinin-based combination therapies (ACTs) have been deployed globally with remarkable success for more than 10 years without having lost their malaria treatment efficacy. However, recent reports from the Thai–Cambodian border reveal evidence of emerging resistance to artemisinins. The latest published clinical and molecular findings are summarized herein. Recent findings Clinical studies have identified delayed parasite clearance time as the most robust marker of artemisinin resistance. Resistance has only been documented from Southeast Asia and has been observed in isolates that show no significant decrease in drug susceptibility in vitro. Genetic investigations have yet to uncover robust molecular markers. In-vitro studies have identified parasite quiescence or dormancy mechanisms that protect early ‘ring-stage’ intra-erythrocytic parasites against short-term artemisinin exposure. This might be achieved by reducing the rate of hemoglobin degradation, important for artemisinin bioactivation. Summary Should ACTs fail, no suitable alternatives exist as first-line treatments of P. falciparum malaria. Intensified efforts are essential to monitor the spread of resistance, define therapeutic and operational strategies to counter its impact, and understand its molecular basis. Success in these areas is critical to ensuring that recent gains in reducing the burden of malaria are not lost. PMID:22001944

Unique and Highly Selective Anticytomegalovirus Activities of Artemisinin-Derived Dimer Diphenyl Phosphate Stem from Combination of Dimer Unit and a Diphenyl Phosphate Moiety

PubMed Central

He, Ran; Forman, Michael; Mott, Bryan T.; Venkatadri, Rajkumar; Posner, Gary H.

2013-01-01

We report that the artemisinin-derived dimer diphenyl phosphate (DPP; dimer 838) is the most selective inhibitor of human cytomegalovirus (CMV) replication among a series of artemisinin-derived monomers and dimers. Dimer 838 was also unique in being an irreversible CMV inhibitor. The peroxide unit within artemisinins' chemical structures is critical to their activities, and its absence results in loss of anti-CMV activities. Surprisingly, the deoxy dimer of 838 retained modest anti-CMV activity, suggesting that the DPP moiety of dimer 838 contributes to its anti-CMV activities. DPP alone did not inhibit CMV replication, but triphenyl phosphate (TPP) had modest CMV inhibition, although its selectivity index was low. Artemisinin DPP derivatives dimer 838 and monomer diphenyl phosphate (compound 558) showed stronger CMV inhibition and a higher selectivity index than their analogs lacking the DPP unit. An add-on and removal assay revealed that removing DPP derivatives (compounds 558 and 838) but not the non-DPP backbones (artesunate and compound 606) at 24 h postinfection (hpi) already resulted in dominant CMV inhibition. CMV inhibition was fully irreversible with 838 and partially irreversible with 558, while non-DPP artemisinins were reversible inhibitors. While all artemisinin derivatives and TPP reduced the expression of the CMV immediate early 2 (IE2), UL44, and pp65 proteins at or after 48 hpi, only TPP inhibited the expression of both IE1 and IE2. Combination of a non-DPP dimer (compound 606) with TPP was synergistic in CMV inhibition, while ganciclovir and TPP were additive. Although TPP shared structural similarity with monomer DPP (compound 558) and dimer DPP (compound 838), its pattern of CMV inhibition was significantly different from the patterns of the artemisinins. These findings demonstrate that the DPP group contributes to the unique activities of compound 838. PMID:23774439

Artemisia supplementation differentially affects the mucosal and luminal ileal microbiota of diet-induced obese mice

PubMed Central

Shawna, Wicks; M., Taylor Christopher; Meng, Luo; Eugene, Blanchard IV; David, Ribnicky; T., Cefalu William; L., Mynatt Randall; A., Welsh David

2014-01-01

Objective The gut microbiome has been implicated in obesity and metabolic syndrome; however, most studies have focused on fecal or colonic samples. Several species of Artemisia have been reported to ameliorate insulin signaling both in vitro and in vivo. The aim of this study was to characterize the mucosal and luminal bacterial populations in the terminal ileum with or without supplementation with Artemisia extracts. Materials/Methods Following 4 weeks of supplementation with different Artemisia extracts (PMI 5011, Santa or Scopa), diet-induced obese mice were sacrificed and luminal and mucosal samples of terminal ileum were used to evaluate microbial community composition by pyrosequencing of 16S rDNA hypervariable regions. Results Significant differences in community structure and membership were observed between luminal and mucosal samples, irrespective of diet group. All Artemisia extracts increased the Bacteroidetes:Firmicutes ratio in mucosal samples. This effect was not observed in the luminal compartment. There was high inter-individual variability in the phylogenetic assessments of the ileal microbiota, limiting the statistical power of this pilot investigation. Conclusions Marked differences in bacterial communities exist dependent upon the biogeographic compartment in the terminal ileum. Future studies testing the effects of Artemisia or other botanical supplements require larger sample sizes for adequate statistical power. PMID:24985102

[Essential oil from Artemisia lavandulaefolia induces apoptosis and necrosis of HeLa cells].

PubMed

Zhang, Lu-min; Lv, Xue-wei; Shao, Lin-xiang; Ma, Yan-fang; Cheng, Wen-zhao; Gao, Hai-tao

2013-12-01

To investigate the effects of Artemisia lavandulaefolia essential oil on apoptosis and necrosis of HeLa cells. Cell viability was assayed using MTT method. The morphological and structure alterations in HeLa cells were observed by microscopy. Furthermore, cell apoptosis was measured by DNA Ladder and flow cytometry. DNA damage was measured by comet assay, and the protein expression was examined by Western blot analysis. MTT assay displayed essential oil from Artemisia lavandulaefolia could inhibit the proliferation of HeLa cells in a dose-dependent manner. After treated with essential oil of Artemisia lavadulaefolia for 24 h, HeLa cells in 100 and 200 microg/mL experiment groups exhibited the typical morphology changes of undergoing apoptosis, such as cell shrinkage and nucleus chromatin condensed. However, the cells in the 400 microg/mL group showed the necrotic morphology changes including cytomembrane rupture and cytoplasm spillover. In addition, DNA Ladder could be demonstrated by DNA electrophoresis in each experiment group. Apoptosis peak was also evident in flow cytometry in each experiment group. After treating the HeLa cells with essential oil of Artemisia lavadulaefolia for 6 h, comet tail was detected by comet assay. Moreover, western blotting analysis showed that caspase-3 was activated and the cleavage of PARP was inactivated. Essential oil from Artemisia lavadulaefolia can inhibit the proliferation of HeLa cells in vitro. Low concentration of essential oil from Artemisia lavadulaefolia can induce apoptosis, whereas high concentration of the compounds result in necrosis of HeLa cells. And,the mechanism may be related to the caspase-3-mediated-PARP apoptotic signal pathway.

Application of the multiplex PCR method for discrimination of Artemisia iwayomogi from other Artemisia herbs.

PubMed

Lee, Mi Young; Doh, Eui Jeong; Kim, Eung Soo; Kim, Young Wha; Ko, Byong Seob; Oh, Seung-Eun

2008-04-01

Some plants classified in the genus Artemisia are used for medicinal purposes. In particular, A. iwayomogi, which is referred to as 'Haninjin,' is used as an important medicinal material in traditional Korean medicine. However, A. capillaris, and both A. argyi and A. princeps, referred to as 'Injinho' and 'Aeyup,' respectively, are used for purposes other than those for which 'Haninjin' is utilized. However, it is occasionally difficult to differentiate 'Haninjin' from 'Injinho' and/or 'Aeyup' on the basis of their morphological features, particularly when in the dried and/or sliced form. Therefore, the development of a reliable method by which to discriminate 'Haninjin' from other Artemisia herbs, especially 'Injinho' and 'Aeyup,' is clearly necessary. We recently determined that the RAPD (random amplified polymorphic DNA) technique can be used to discriminate efficiently between some Artemisia herbs. In particular, when applied to RAPD, the non-specific UBC primer 391 (5'-GCG AAC CTC G-3') was demonstrated to amplify PCR products specific to A. iwayomogi. Based on the nucleotide sequences of the PCR product, we designed a 2F1 (5'-ACC TCG GAC CTA AAT ACA-3')/ 2F3 (5'-TTA TGA TTC ATG TTC AAT TC-3') primer set to amplify a SCAR (sequence-characterized amplified region) marker of A. iwayomogi. Employing this primer set, along with two other primer sets amplifying SCAR markers of 'Aeyup' (A. argyi and A. princeps) and both 'Injinho' (A. capillaris) and A. japonica, which are classified into the same subgroup in a phenogram constructed from RAPD analysis, we developed a multiplex PCR method by which A. iwayomogi could be discriminated with certainty from other Artemisia herbs. Via this method, we determined not only whether the tested Artemisia herb was A. iwayomogi, but also which Artemisia herbs were tested concurrently with A. iwayomogi.

Stress Response and Artemisinin Resistance in Malaria Parasite

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-16-1-0241 TITLE: Stress Response and Artemisinin Resistance in Malaria Parasite PRINCIPAL INVESTIGATOR: Juan C. Pizarro...SUBTITLE Stress Response and Artemisinin Resistance in Malaria Parasite 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0241 5c. PROGRAM ELEMENT...explored the role of GRP78, a protein chaperone from the stress response, in arteminisin resistant parasites. The GRP78 expression at the mRNA and

Archaeological Test Excavations. Phase II Testing at the Hagerman National Fish Hatchery, Hagerman Valley, Idaho,

DTIC Science & Technology

1981-02-01

horizons, a surface horizon or hori- zons not significantly darkened by humus , and absence of deep, wide cracks . . . the Aridisols have no "available...constituents or the frequencies of the various species present, as opposed to an area like the Hagerman locale which is characterized by a complex... species along with the Agropyron, stiff sagebrush (Artemisia rigida), threetip sagebrush (Artemisia tripartita) or low sagebrush (Artemisia arbuscula

Generation of ROS mediated by mechanical waves (ultrasound) and its possible applications.

PubMed

Duco, Walter; Grosso, Viviana; Zaccari, Daniel; Soltermann, Arnaldo T

2016-10-15

The thermal decomposition of 9,10 diphenylanthracene peroxide (DPAO 2 ) generates DPA and a mix of triplet and singlet molecular oxygen. For DPAO 2 the efficiency to produce singlet molecular oxygen is 0.35. On the other hand, it has shown that many thermal reactions can be carried out through the interaction of molecules with ultrasound. Ultrasound irradiation can create hydrodynamic stress (sonomechanical process), inertial cavitation (pyrolitic process) and long range effects mediated by radicals or ROS. Sonochemical reactions can be originated by pyrolytic like process, shock mechanical waves, thermal reactions and radical and ROS mediated reactions. Sonolysis of pure water can yield hydrogen or hydroxyl radicals and hydrogen peroxide (ROS). When DPAO 2 in 1,4 dioxane solution is treated with 20 or 24kHz and different power intensity the production of molecular singlet oxygen is observed. Specific scavengers like tetracyclone (TC) are used to demonstrate it. The efficiency now is 0.85 showing that the sonochemical process is much more efficient that the thermal one. Another endoperoxide, artemisinin was also studied. Unlike the concept of photosensitizer of photodynamic therapy, in spite of large amount of reported results in literature, the term sonosensitizer and the sonosensitization process are not well defined. We define sonosensitized reaction as one in which a chemical species decompose as consequence of cavitation phenomena producing ROS or other radicals and some other target species does undergo a chemical reaction. The concept could be reach rapidly other peroxides which are now under experimental studies. For artemisinin, an important antimalarian and anticancer drug, was established that ultrasound irradiation increases the effectiveness of the treatment but without any explanation. We show that artemisinin is an endoperoxide and behaves as a sonosensitizer in the sense of our definition. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular surveillance of artemisinin resistance falciparum malaria among migrant goldmine workers in Myanmar.

PubMed

Nyunt, Myat Htut; Wang, Bo; Aye, Khin Myo; Aye, Kyin Hla; Han, Jin-Hee; Lee, Seong-Kyun; Han, Kay Thwe; Htut, Ye; Han, Eun-Taek

2017-03-01

Artemisinin resistance has been reported in Greater Mekong Sub-region countries, including Myanmar. After discovery of artemisinin resistance marker (K13), molecular surveillance on artemisinin resistance in endemic regions have been conducted. As the migrant population represents a high percentage of malaria cases, molecular surveillance of artemisinin resistance among migrant workers is of great concern. A cross-sectional survey was conducted in Shwegyin Township, where migrants work in the goldmines. Blood samples were collected from uncomplicated Plasmodium falciparum-infected migrant workers by active and passive cases screening with rapid diagnostic testing (RDT) and microscopy. Amplification and sequence analysis of artemisinin resistance molecular markers, such as k13, pfarps10, pffd, pfmdr2, pfmrp1, pfrad5, and pfcnbp, were carried out and pfmdr1 copy number analysis was conducted by real-time PCR. Among the 100 falciparum-infected patients, most were male (90%), of working age (20-40 years) with median parasite density of 11,166 parasites/µL (range 270-110,472 parasites/µL). Artemisinin resistance molecular marker, k13 mutations were detected in (21/100, 21.0%) in which composed of a validated marker, C580Y (9/21, 42.9%) and candidate markers such as P574L (5/21, 23.8%), P667T (5/21, 23.8%) and M476I (2/21, 9.5%). Underlying genetic markers predisposing to become k13 mutants were found as V127M of pfarps10 (41/100, 41.0%), D153Y of pffd (64/100, 64.0%), T484I of pfmdr2 (58/100, 58.0%) and F1390I of pfmrp1 (24/100, 24.0%). The pfmdr1 copy number analysis revealed six copy numbers (1/100, 1.0%), three (2/100, 2.0%), two (8/100, 8.0%) and only one copy number (89/100, 89.0%). Only one sample showed both k13 mutation (P667T) and multiple copy number of pfmdr1. High mutant rate of artemisinin resistance markers and relatively high pfmdr1 copy number among isolates collected from migrant goldmine workers alert the importance of containment measures among this target population. Clinical and molecular surveillance of artemisinin resistance among migrants should be scaled up.

Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy.

PubMed

Huang, Bo; Deng, Changsheng; Yang, Tao; Xue, Linlu; Wang, Qi; Huang, Shiguang; Su, Xin-zhuan; Liu, Yajun; Zheng, Shaoqin; Guan, Yezhi; Xu, Qin; Zhou, Jiuyao; Yuan, Jie; Bacar, Afane; Abdallah, Kamal Said; Attoumane, Rachad; Mliva, Ahamada M S A; Zhong, Yanchun; Lu, Fangli; Song, Jianping

2015-12-15

Plasmodium falciparum malaria is a significant public health problem in Comoros, and artemisinin combination therapy (ACT) remains the first choice for treating acute uncomplicated P. falciparum. The emergence and spread of artemisinin-resistant P. falciparum in Southeast Asia, associated with mutations in K13-propeller gene, poses a potential threat to ACT efficacy. Detection of mutations in the P. falciparum K13-propeller gene may provide the first-hand information on changes in parasite susceptibility to artemisinin. The objective of this study is to determinate the prevalence of mutant K13-propeller gene among the P. falciparum isolates collected from Grande Comore Island, Union of Comoros, where ACT has been in use since 2004. A total of 207 P. falciparum clinical isolates were collected from the island during March 2006 and October 2007 (n = 118) and March 2013 and December 2014 (n = 89). All isolates were analysed for single nucleotide polymorphisms (SNPs) and haplotypes in the K13-propeller gene using nested PCR and DNA sequencing. Only three 2006-2007 samples carried SNPs in the K13-propeller gene, one having a synonymous (G538G) and the other having two non-synonymous (S477Y and D584E) substitutions leading to two mutated haplotypes (2.2%, 2/95). Three synonymous mutations (R471R, Y500Y, and G538G) (5.9%, 5/85) and 7 non-synonymous substitutions (21.2%, 18/85) with nine mutated haplotypes (18.8%, 16/85) were found in isolates from 2013 to 2014. However, none of the polymorphisms associated with artemisinin-resistance in Southeast Asia was detected from any of the parasites examined. This study showed increased K13-propeller gene diversity among P. falciparum populations on the Island over the course of 8 years (2006-2014). Nevertheless, none of the polymorphisms known to be associated with artemisinin resistance in Asia was detected in the parasite populations examined. Our data suggest that P. falciparum populations in Grande Comore are still effectively susceptible to artemisinin. Our results provide insights into P. falciparum populations regarding mutations in the gene associated with artemisinin resistance and will be useful for developing and updating anti-malarial guidance in Comoros.

Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013).

PubMed

Nyunt, Myat Htut; Soe, Myat Thu; Myint, Hla Win; Oo, Htet Wai; Aye, Moe Moe; Han, Soe Soe; Zaw, Ni Ni; Cho, Cho; Aung, Phyo Zaw; Kyaw, Khin Thiri; Aye, Thin Thin; San, Naychi Aung; Ortega, Leonard; Thimasarn, Krongthong; Bustos, Maria Dorina G; Galit, Sherwin; Hoque, Mohammad Rafiul; Ringwald, Pascal; Han, Eun-Taek; Kyaw, Myat Phone

2017-08-14

Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.

Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene.

PubMed

Wang, Zenglei; Wang, Yingna; Cabrera, Mynthia; Zhang, Yanmei; Gupta, Bhavna; Wu, Yanrui; Kemirembe, Karen; Hu, Yue; Liang, Xiaoying; Brashear, Awtum; Shrestha, Sony; Li, Xiaolian; Miao, Jun; Sun, Xiaodong; Yang, Zhaoqing; Cui, Liwang

2015-11-01

Artemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95% and day 3 parasite-positive rates of 6.3 to 23.1%. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and -negative cases, respectively) identified nine point mutations in 38 (66.7%) samples, of which F446I (49.1%) and an N-terminal NN insertion (86.0%) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ∼10 times higher ring survival rates than day 3 parasite-negative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread

PubMed Central

Woodrow, Charles J.; White, Nicholas J.

2017-01-01

Abstract Artemisinins are the most rapidly acting of currently available antimalarial drugs. Artesunate has become the treatment of choice for severe malaria, and artemisinin-based combination therapies (ACTs) are the foundation of modern falciparum malaria treatment globally. Their safety and tolerability profile is excellent. Unfortunately, Plasmodium falciparum infections with mutations in the ‘K13’ gene, with reduced ring-stage susceptibility to artemisinins, and slow parasite clearance in patients treated with ACTs, are now widespread in Southeast Asia. We review clinical efficacy data from the region (2000–2015) that provides strong evidence that the loss of first-line ACTs in western Cambodia, first artesunate-mefloquine and then DHA-piperaquine, can be attributed primarily to K13 mutated parasites. The ring-stage activity of artemisinins is therefore critical for the sustained efficacy of ACTs; once it is lost, rapid selection of partner drug resistance and ACT failure are inevitable consequences. Consensus methods for monitoring artemisinin resistance are now available. Despite increased investment in regional control activities, ACTs are failing across an expanding area of the Greater Mekong subregion. Although multiple K13 mutations have arisen independently, successful multidrug-resistant parasite genotypes are taking over and threaten to spread to India and Africa. Stronger containment efforts and new approaches to sustaining long-term efficacy of antimalarial regimens are needed to prevent a global malaria emergency. PMID:27613271

Multi-omics Based Identification of Specific Biochemical Changes Associated With PfKelch13-Mutant Artemisinin-Resistant Plasmodium falciparum.

PubMed

Siddiqui, Ghizal; Srivastava, Anubhav; Russell, Adrian S; Creek, Darren J

2017-05-01

The emergence of artemisinin resistance in the malaria parasite Plasmodium falciparum poses a major threat to the control and elimination of malaria. Certain point mutations in the propeller domain of PfKelch13 are associated with resistance, but PfKelch13 mutations do not always result in clinical resistance. The underlying mechanisms associated with artemisinin resistance are poorly understood, and the impact of PfKelch13 mutations on cellular biochemistry is not defined. This study aimed to identify global biochemical differences between PfKelch13-mutant artemisinin-resistant and -sensitive strains of P. falciparum by combining liquid chromatography-mass spectrometry (LC-MS)-based proteomics, peptidomics, and metabolomics. Proteomics analysis found both PfKelch13 mutations examined to be specifically associated with decreased abundance of PfKelch13 protein. Metabolomics analysis demonstrated accumulation of glutathione and its precursor, gamma-glutamylcysteine, and significant depletion of 1 other putative metabolite in resistant strains. Peptidomics analysis revealed lower abundance of several endogenous peptides derived from hemoglobin (HBα and HBβ) in the artemisinin-resistant strains. PfKelch13 mutations associated with artemisinin resistance lead to decreased abundance of PfKelch13 protein, decreased hemoglobin digestion, and enhanced glutathione production. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Artemisinin conferred ERK mediated neuroprotection to PC12 cells and cortical neurons exposed to sodium nitroprusside-induced oxidative insult.

PubMed

Zheng, Wenhua; Chong, Cheong-Meng; Wang, Haitao; Zhou, Xuanhe; Zhang, Lang; Wang, Rikang; Meng, Qian; Lazarovici, Philip; Fang, Jiankang

2016-08-01

The production of nitric oxide (NO) is one of the primary mediators of ischemic damage, glutamate neurotoxicity and neurodegeneration and therefore inhibition of NO-induced neurotoxicity may be considered a therapeutic target for reducing neuronal cell death (neuroprotection). In this study, artemisinin, a well-known anti-malaria drug was found to suppress sodium nitroprusside (SNP, a nitric oxide donor)-induced cell death in the PC12 cells and brain primary cortical neuronal cultures. Pretreatment of PC12 cells with artemisinin significantly suppressed SNP-induced cell death by decreasing the extent of oxidation, preventing the decline of mitochondrial membrane potential, restoring abnormal changes in nuclear morphology and reducing lactate dehydrogenase release and inhibiting caspase 3/7 activities. Western blotting analysis revealed that artemisinin was able to activate extracellular regulated protein kinases (ERK) pathway. Furthermore, the ERK inhibitor PD98059 blocked the neuroprotective effect of artemisinin whereas the PI3K inhibitor LY294002 had no effect. Cumulatively these findings support the notion that artemisinin confers neuroprotection from SNP-induce neuronal cell death insult, a phenomenon coincidentally related to activation of ERK phosphorylation. This SNP-induced oxidative insult in PC12 cell culture model may be useful to investigate molecular mechanisms of NO-induced neurotoxicity and drug-induced neuroprotection, and to generate novel therapeutic concepts for ischemic disease treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.

PubMed

Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

2007-07-01

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.

Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites§

PubMed Central

Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

2007-01-01

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed. PMID:17581118

Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paeshuyse, Jan; Coelmont, Lotte; Vliegen, Inge

2006-09-15

We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC{sub 5}) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 {+-} 21 {mu}M. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivatesmore » the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 {mu}M) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.« less

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

PubMed

Ramharter, Michael; Noedl, Harald; Thimasarn, Krongthong; Wiedermann, Gerhard; Wernsdorfer, Gunther; Wernsdorfer, Walther H

2002-07-01

Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

Progress in the development of peroxide-based anti-parasitic agents.

PubMed

Muraleedharan, K M; Avery, Mitchell A

2009-08-01

Progress made in the past decade pertaining to the development of anti-parasitic agents based on artemisinin is presented. Apart from discussions on important derivatives obtained through functionalization at the C-3, C-9, C-10 and O-11 positions of artemisinin, an outline on its seco analogs and artemisinin bundles are given for a broader perspective on structure-activity relationships. Success with synthetic peroxides, drug-hybrid approaches, broad-spectrum anti-infective properties of peroxide compounds and a survey on peroxide-containing natural products other than artemisinin with available biological data are included to highlight recent trends and avenues for future research. A supplementary material with details on the biological properties of a larger collection of molecules belonging to the above structural classes is also given for reference.

Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance.

PubMed

von Seidlein, Lorenz; Dondorp, Arjen

2015-06-01

The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured.

Identification and partial purification of pollen allergens from Artemisia princeps.

PubMed

Park, H S; Hong, C S; Choi, H J; Hahm, K S

1989-12-01

The pollen of Artemisia has been considered as the main late summer-autumn allergen source in this country. To identify its allergenic components, Artemisia princeps pollen extracts were separated by 10% sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), and transferred to nitrocellulose membrane, where IgE binding components were detected by the reaction with sera of twenty Artemisia-allergic patients and 125I-anti-human IgE, sixteen components in the molecular range of 10,000 and 85,000 daltons were detected. Twelve bands bound to IgE from 50% of the sera tested, and two bands (37,000, 23,000 daltons) showed the highest (85%) frequency of IgE-binding in twenty sera tested. When the gel of SDS-PAGE with Artemisia pollen extracts was sliced into 11 allergenic groups (AG) and the protein of each AG was obtained by the gel elution method, the wormwool-RAST inhibition test showed that the AG 10 demonstrated to be the most potent, and the AG 7 was the next. Six AGs showed significant responses (more than 100% of wheal size to histamine, 1 mg/ml) on the skin prick test in more than 50% of the patients tested. It is suggested that electrophoretic transfer analysis with SDS-PAGE may be a valuable method for Artemisia allergen identification, and the possibility of partial purification of allergens by employing gel elution is discussed.

EFFECT OF-GYMNEMA SYLVESTRE, CITRULLUS COLOCYNTHIS AND ARTEMISIA ABSINTHIUM ON BLOOD GLUCOSE AND LIPID PROFILE IN DIABETIC HUMAN.

PubMed

Li, Youshan; Zheng, Min; Zhai, Xing; Huang, Youliang; Khalid, Anwar; Malik, Aneela; Shah, Pervaiz; Karim, Sabiha; Azhar, Saira; Hou, Xiaobing

2015-01-01

The aim of this study was to manage diabetes with medicinal plants (Gymnema sylvestre, Artemisia absinthium and Citillus colocynthis) in human patients with type II diabetes. Thirty two patients of type II diabetes from both sexes of 30-60 years age were registered for this study and distributed them into four groups, each having 8 patients. Capsules of each, Gymnema sylvestre, Artemisia absinthium and Citrullus colocynthis were given to patients twice a day for 30 days in 1 g per day dosage and investigated for glucose, triglyceride (TGL) and cholesterol level. Gymnema sylvestre reduced 37% glucose, 5% TGL, 13% cholesterol and 19% low desity lipoproteins (LDL) level in diabetic individuals. Citrullus colocynth reduced glucose, cholesterol and TGL and HDL-cholesterol level by 35, 6, 6, and 5%, respectively. Artemisia absinthium reduced 3% high desity lipoproteins (HDL) and 6% LDL level. From results, it can be concluded that the powdered Gymnema sylvestre, Citrulus colocynthis, and Artemisia absinthium possess good anti-diabetic features, however these herbal products had no significant effect on lipid profiles of the diabetic human.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halvorson, J.J.; Bolton, H. Jr.; Smith, J.L.

Artemisia tridentata is a prominent shrub of cool deserts that affects the soil in which it grows. We sampled adjacent burned and unburned sites to see if resource islands persisted in locations where shrubs had been removed by fire. The concentrations of soil variables near the location of burned Artemisia tridentata were smaller than under live Artemisia tridentata and did not vary as much with distance away from the plant axis. However, the patterns of soil variables in these remnant resource islands were still substantial. Significantly higher concentrations of total N and soil microbial C, and significantly higher electrical conductivitymore » were observed at the location of a burned Artemisia tridentata stem than at distances further away. The differences between burned and unburned soil were greatest in samples collected near the plant. In contrast, samples of burned or unburned soil were not distinguishable from each other at locations greater than about 50 cm away from a live Artemisia tridentata axis or a burned stump indicating that the resource island effect was most affected by removal of the plant and not by the fire.« less

Artemisinin, a miracle of traditional Chinese medicine.

PubMed

Kong, Ling Yi; Tan, Ren Xiang

2015-12-19

The 2015 Nobel Prize in Physiology or Medicine, shared by Professor Youyou Tu, focused worldwide attention on artemisinin, a natural product antimalarial drug inspired by traditional Chinese medicine (TCM). This is the first Nobel Prize in natural sciences presented to a Chinese scientist for her impactful research work in China in collaboration with other Chinese scientists. We are delighted to provide the background and implications of the discovery of artemisinin, along with our personal viewpoints toward the affordability of modern medicines from natural products.

Efficacy and Tolerability of Artesunate Plus Sulfadoxine-Pyrimethamine and Sulfadoxine-Pyrimethamine Alone for the Treatment of Uncomplicated Plasmodium Falciparium Malaria in Peru

DTIC Science & Technology

2005-01-01

Combinations of artemisinin drugs with mefloquine have al- ready proven to be highly efficacious in Southeast Asia and there is suggestive evidence...4 Artemisinin and its derivatives produce more rapid resolution of fever and parasitemia than any other antima- larial agent due to their rapid...virtue of their activity against the gametocyte stage of the parasite.6 Other promising candidates for combination therapy with an artemisinin drug

Ultrasound-assisted extraction of polysaccharides from Artemisia selengensis Turcz and its antioxidant and anticancer activities.

PubMed

Wang, Juan; Lu, He Dong; Muḥammad, Umair; Han, Jin Zhi; Wei, Zhao Hui; Lu, Zhao Xin; Bie, Xiao Mei; Lu, Feng Xia

2016-02-01

Artemisia selengensis Turcz (AST) is a perennial herb with therapeutic and economic applications in China. The effects of ultrasound-assisted extraction (UAE) parameters upon extraction yield (EY%), antioxidant and antitumor activities of the polysaccharides extracts were studied by using a factorial design and response surface methodology. The optimal conditions determined were as: ultrasonic power 146 W, extraction time 14.5 min. and extraction temperature 60 °C. The average molecular weights of two homogeneous polysaccharides (APS1 and APS2) purified by DEAE cellulose-52 and Sephadex G-100 column chromatography were 125.4 and 184.1 kDa, respectively. Monosaccharide analysis showed that APS1 and APS2 were composed of five common monomers i.e., galactose, mannose, arabinose, xylose and rhamnose and one different monomer glucose and galacturonic acid respectively, with a most abundant part in molar % of APS1 and APS2 were glucose (83.01 %) and galacturonic acid (48.87 %) while least were xylose (0.80 %) and mannose (1.73 %) respectively. The antioxidant properties were determined by evaluating DPPH, hydroxyl radical scavenging activity and reducing power which indicated both APS1 and APS2 showed strong scavenging activities and anticancer activities on HT-29, BGC823 and antitumor activity on HepG-2. As UAE improved the polysaccharides yield than CSE, meanwhile, no significant difference of polysaccharides chemical compositions. Therefore, the present study suggests that the consumption of AST leaves may beneficial for the treatment of many diseases.

HPTLC Determination of Artemisinin and Its Derivatives in Bulk and Pharmaceutical Dosage

NASA Astrophysics Data System (ADS)

Agarwal, Suraj P.; Ahuja, Shipra

A simple, selective, accurate, and precise high-performance thin-layer chromatographic (HPTLC) method has been established and validated for the analysis of artemisinin and its derivatives (artesunate, artemether, and arteether) in the bulk drugs and formulations. The artemisinin, artesunate, artemether, and arteether were separated on aluminum-backed silica gel 60 F254 plates with toluene:ethyl acetate (10:1), toluene: ethyl acetate: acetic acid (2:8:0.2), toluene:butanol (10:1), and toluene:dichloro methane (0.5:10) mobile phase, respectively. The linear detector response for concentrations between 100 and 600 ng/spot showed good linear relationship with r value 0.9967, 0.9989, 0.9981 and 0.9989 for artemisinin, artesunate, artemether, and arteether, respectively. Statistical analysis proves that the method is precise, accurate, and reproducible and hence can be employed for the routine analysis.

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum.

PubMed

De Lucia, Serena; Tsamesidis, Ioannis; Pau, Maria Carmina; Kesely, Kristina R; Pantaleo, Antonella; Turrini, Francesco

2018-01-01

Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

Lack of artemisinin resistance in Plasmodium falciparum in northwest Benin after 10 years of use of artemisinin-based combination therapy.

PubMed

Ogouyèmi-Hounto, Aurore; Damien, Georgia; Deme, Awa Bineta; Ndam, Nicaise T; Assohou, Constance; Tchonlin, Didier; Mama, Atika; Hounkpe, Virgile Olivier; Moutouama, Jules Doumitou; Remoué, Franck; Ndiaye, Daouda; Gazard, Dorothée Kinde

2016-01-01

In Benin, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment for uncomplicated Plasmodium falciparum malaria since 2004. The emergence in Southeast Asia of parasites that are resistant to artemisinins poses a serious threat to global control of this disease. The presence of artemisinin resistance genotypes in parasite populations in Benin is currently unknown. The present study investigated the prevalence of relevant K13-propeller gene polymorphisms in parasite isolates from the north-western region of Benin. Plasmodium falciparum isolates were collected from children with a confirmed diagnosis of malaria aged 6 months to 5 years in two towns, Cobly and Djougou, in the north-western part of Benin. The study was conducted during the rainy season from July to November 2014 in local health facilities. The K13-propeller gene was amplified in parasite isolates using nested PCR and subsequently sequenced. A total of 108 children were recruited into the study. The efficiency of amplification reactions was 72% (78/108). The propeller domain of the K13 gene was successfully sequenced in 78 P. falciparum isolates; all of them were wild type with no polymorphisms detectable. The absence of mutations in the K13 gene indicates that P. falciparum parasite populations in the study area are still fully susceptible to artemisinins. © A. Ogouyèmi-Hounto et al., published by EDP Sciences, 2016.

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum.

PubMed

Lobo, Lis; Cabral, Lília I L; Sena, Maria Inês; Guerreiro, Bruno; Rodrigues, António Sebastião; de Andrade-Neto, Valter Ferreira; Cristiano, Maria L S; Nogueira, Fatima

2018-04-03

The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC 50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.

Effect of artemisinin on neuropathic pain mediated by P2X4 receptor in dorsal root ganglia.

PubMed

Ying, Mofeng; Liu, Hui; Zhang, Tengling; Jiang, Chenxu; Gong, Yingxin; Wu, Bing; Zou, Lifang; Yi, Zhihua; Rao, Shenqiang; Li, Guilin; Zhang, Chunping; Jia, Tianyu; Zhao, Shanhong; Yuan, Huilong; Shi, Liran; Li, Lin; Liang, Shangdong; Liu, Shuangmei

2017-09-01

Neuropathic pain is a type of chronic pain caused by nervous system damage and dysfunction. The pathogenesis of chronic pain is complicated, and there are no effective therapies for neuropathic pain. Studies show that the P2X 4 receptor expressed in the satellite glial cells (SGCs) of dorsal root ganglia (DRG) is related to neuropathic pain. Artemisinin is a monomeric component extracted from traditional Chinese medicine and has a variety of important pharmacological effects and potential applications. This study observed the effect of artemisinin on neuropathic pain and delineated its possible mechanism. The chronic constriction injury (CCI) rat model was used in this study. The results demonstrated that artemisinin relieved pain behaviors in the CCI rats, inhibited the expression of P2X 4 receptor in the DRG, and decreased the ATP-activated currents in HEK293 cells transfected with P2X 4 plasmid. Dual-labeling immunofluorescence showed that the coexpression of P2X 4 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to control rats. After CCI rats were treated with artemisinin, the coexpression of P2X 4 receptor and GFAP in the DRG was significantly decreased compared to the CCI group. This finding suggested that artemisinin could inhibit the nociceptive transmission mediated by P2X 4 receptor in the DRG SGCs and thus relieve pain behaviors in the CCI rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Access to artemisinin-based combination therapies and other anti-malarial drugs in Kinshasa.

PubMed

Nkoli Mandoko, P; Sinou, V; Moke Mbongi, D; Ngoyi Mumba, D; Kahunu Mesia, G; Losimba Likwela, J; Bi Shamamba Karhemere, S; Muepu Tshilolo, L; Tamfum Muyembe, J-J; Parzy, D

2018-06-01

Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa. We performed a cross-sectional survey of 404 pharmacies. Anti-malarial drugs were stocked in all surveyed pharmacies. Non-artemisinin-based anti-malarial therapies such as quinine or sulfadoxine-pyrimethamine, were the most frequently stocked drugs (93.8% of pharmacies). Artemisinin-based combination therapies were stocked in 88% of pharmacies. Artemether-lumefantrine combinations were the most frequently dispensed drugs (93% of pharmacies), but less than 3% were quality-assured products. Other non-officially recommended artemisinin-based therapies including oral monotherapies were widely available. Artemisinin-based combination therapies were widely available in the private pharmacies of Kinshasa. However, the private sector does not guarantee the use of nationally recommended anti-malarial drugs nor does it give priority to quality-assured anti-malarial drugs. These practices contribute to the risk of emergence and spread of resistance to anti-malarial drugs and to increasing treatment costs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

[The advantages and disadvantages of Artemisia princeps and A. montana].

PubMed

Oda, R

2000-01-01

In Japan, Moxa is made from Artemisia princeps and A. montana P. which are plants of the composiae family. Evaluations of the superiority or inferiority of these raw materials for Moxa have been confusing. The judgement of superiority or inferiority is roughly based on the strenght of the fragrance and somewhat of down. When I investigated 14 kinds of documents from the Edo period to the Showa period, 10 of the documents gave good evaluations for Artemisia princeps. On the other hand the remaining four gave good evaluations for A. montana P. But there is quite an opposite opinion, because the four deemed good for Artemisia princeps were misunderstood regarding the discrimination of Artemisia princeps and A. montana P. Since correcting them, each material has seven good evaluations, tying the score. Therefore, I researched the contents of the principal ingredient, Cineole, using an important evaluation index and the fragrances were compared measuring both materials, which were collected from different places. The results to examining six kinds of Artemisia princeps, and eight kinds of A. montana P. (14 kinds in total) are as follows: The A. montana P. contents Cineole was more abundant than the other on average. However, it is from three to five times the change by the growing both ground, and superiority or inferiority cannot be decided indiscriminately. When quality is evaluated, it is necessary to clarify the materials orgin. Generally speaking, the fragrance of A. montana P. is stronger than the other.

Nrf2-mediated mucoprotective and anti-inflammatory actions of Artemisia extracts led to attenuate stress related mucosal damages

PubMed Central

Park, Jong-Min; Han, Young-Min; Lee, Jin-Seok; Ko, Kwang Hyun; Hong, Sung-Pyo; Kim, Eun-Hee; Hahm, Ki-Baik

2015-01-01

The aim of this study was to compare biological actions between isopropanol and ethanol extracts of Artemisia including antioxidant, anti-inflammatory, and cytoprotective actions. Antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and confocal microscopy on lipopolysaccharide-induced RGM1 cells, cytoprotection effects evaluated by detecting heme oxygenase-1 (HO-1), Nf-E2 related factor2 (Nrf2) and heat shock protein 70 (HSP70), and anti-inflammatory effects investigated by measuring inflammatory mediators. Water immersion restraint stress was imposed to provoke stress related mucosal damages (SRMD) in rats. Isopropanol extracts of Artemisia showed the higher DPPH radical scavenging activity and lesser LPS-induced reactive oxygen species productions and increased HO-1 expression through increased nuclear translocation of Nrf2 transcription factor compared to ethanol extracts. The increased expression of HSP70 and decreased expression of endothelin-1 were only increased with isopropanol extracts. A concentration-dependent inhibition of LPS-induced COX-2 and iNOS even at a rather lower concentration than ethanol extract was achieved with isopropanol extracts. Cytokine protein array revealed Artemisia extracts significantly attenuated the levels of CXCL-1, CXCL-16, and MCP-1. These orchestrated actions led to significant rescue from SRMD. Conclusively, Artemisia extracts imposed significant antioxidant and anti-inflammatory activity against SRMD and isopropanol extracts were superior to ethanol extracts in these beneficiary actions of Artemisia. PMID:25759519

Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector—Results from a Nationally Representative Outlet Survey

PubMed Central

2015-01-01

Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85–115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. PMID:25897065

Allelopathic Potential of Invasive Plantago virginica on Four Lawn Species.

PubMed

Wang, Huatian; Zhou, Yumei; Chen, Yang; Wang, Quanxi; Jiang, Lifen; Luo, Yiqi

2015-01-01

Plantago virginica L. has invaded many lawn ecosystems in the Eastern part of China. The invasion has incurred an economic cost to remove them. In order to prevent the invasion, it is critical to understand the invasive mechanisms of this species. However, few studies have been conducted on the allelopathic mechanisms of its invasion. In this study, we examined allelopathic effects of P. virginica on germination of seeds and growth of seedlings of four widely used lawn species. We found extensive allelopathic potential of P. virginica on other lawn species, which varied with species and developmental stage. While most effects of the extracts of P. virginica were inhibitory, some variables in some species were promoted by the addition of the extracts. The extracts of P. virginica significantly inhibited seed germination of Agrostis matsumurae. While the overall differences in seed germination rate of Poa annua were significant among treatments, difference between control and any of the treatments was not significant. The height of seedlings of A. matsumurae and Cynodon dactylon was significantly lower under the treatments of adding extracts of P. virginica. In contrast, growth of seedlings of Festuca elata and P. annua did not show significant differences among treatments. The root length of A. matsumurae, C. dactylon and P. annua was suppressed by the extracts of P. virginica whereas root length of F. elata was not affected. Aboveground biomass of A. matsumurae and F. elata was significantly higher than control, except for F. elata at the concentration of 50mg/mL, whereas aboveground biomass of C. dactylon and P. annua was reduced at higher concentrations of the extracts. Except for A. matsumurae, root biomass of the other three lawn species declined under the treatments with the extracts of P. virginica. Our results revealed that P. virginica had allelopathic potential on four lawn species and supported the theory of "novel weapons hypothesis". Invasion by P. virginica in lawn can be moderated by selecting those species that are not affected or promotionally affected by it.

Allelopathic Potential of Invasive Plantago virginica on Four Lawn Species

PubMed Central

Wang, Huatian; Zhou, Yumei; Chen, Yang; Wang, Quanxi; Jiang, Lifen; Luo, Yiqi

2015-01-01

Plantago virginica L. has invaded many lawn ecosystems in the Eastern part of China. The invasion has incurred an economic cost to remove them. In order to prevent the invasion, it is critical to understand the invasive mechanisms of this species. However, few studies have been conducted on the allelopathic mechanisms of its invasion. In this study, we examined allelopathic effects of P. virginica on germination of seeds and growth of seedlings of four widely used lawn species. We found extensive allelopathic potential of P. virginica on other lawn species, which varied with species and developmental stage. While most effects of the extracts of P. virginica were inhibitory, some variables in some species were promoted by the addition of the extracts. The extracts of P. virginica significantly inhibited seed germination of Agrostis matsumurae. While the overall differences in seed germination rate of Poa annua were significant among treatments, difference between control and any of the treatments was not significant. The height of seedlings of A. matsumurae and Cynodon dactylon was significantly lower under the treatments of adding extracts of P. virginica. In contrast, growth of seedlings of Festuca elata and P. annua did not show significant differences among treatments. The root length of A. matsumurae, C. dactylon and P. annua was suppressed by the extracts of P. virginica whereas root length of F. elata was not affected. Aboveground biomass of A. matsumurae and F. elata was significantly higher than control, except for F. elata at the concentration of 50mg/mL, whereas aboveground biomass of C. dactylon and P. annua was reduced at higher concentrations of the extracts. Except for A. matsumurae, root biomass of the other three lawn species declined under the treatments with the extracts of P. virginica. Our results revealed that P. virginica had allelopathic potential on four lawn species and supported the theory of “novel weapons hypothesis”. Invasion by P. virginica in lawn can be moderated by selecting those species that are not affected or promotionally affected by it. PMID:25915515

Chemical Polymorphism of Essential Oils of Artemisia vulgaris Growing Wild in Lithuania.

PubMed

Judzentiene, Asta; Budiene, Jurga

2018-02-01

Compositional variability of mugwort (Artemisia vulgaris L.) essential oils has been investigated in the study. Plant material (over ground parts at full flowering stage) was collected from forty-four wild populations in Lithuania. The oils from aerial parts were obtained by hydrodistillation and analyzed by GC(FID) and GC/MS. In total, up to 111 components were determined in the oils. As the major constituents were found: sabinene, 1,8-cineole, artemisia ketone, both thujone isomers, camphor, cis-chrysanthenyl acetate, davanone and davanone B. The compositional data were subjected to statistical analysis. The application of PCA (Principal Component Analysis) and AHC (Agglomerative Hierarchical Clustering) allowed grouping the oils into six clusters. AHC permitted to distinguish an artemisia ketone chemotype, which, to the best of our knowledge, is very scarce. Additionally, two rare cis-chrysanthenyl acetate and sabinene oil types were determined for the plants growing in Lithuania. Besides, davanone was found for the first time as a principal component in mugwort oils. The performed study revealed significant chemical polymorphism of essential oils in mugwort plants native to Lithuania; it has expanded our chemotaxonomic knowledge both of A. vulgaris species and Artemisia genus. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

The Genus Artemisia: A 2012–2017 Literature Review on Chemical Composition, Antimicrobial, Insecticidal and Antioxidant Activities of Essential Oils

PubMed Central

Singh, Pooja

2017-01-01

Essential oils of aromatic and medicinal plants generally have a diverse range of activities because they possess several active constituents that work through several modes of action. The genus Artemisia includes the largest genus of family Asteraceae has several medicinal uses in human and plant diseases aliments. Extensive investigations on essential oil composition, antimicrobial, insecticidal and antioxidant studies have been conducted for various species of this genus. In this review, we have compiled data of recent literature (2012–2017) on essential oil composition, antimicrobial, insecticidal and antioxidant activities of different species of the genus Artemisia. Regarding the antimicrobial and insecticidal properties we have only described here efficacy of essential oils against plant pathogens and insect pests. The literature revealed that 1, 8-cineole, beta-pinene, thujone, artemisia ketone, camphor, caryophyllene, camphene and germacrene D are the major components in most of the essential oils of this plant species. Oils from different species of genus Artemisia exhibited strong antimicrobial activity against plant pathogens and insecticidal activity against insect pests. However, only few species have been explored for antioxidant activity. PMID:28930281

Interactive Effects of Moss-Dominated Crusts and Artemisia ordosica on Wind Erosion and Soil Moisture in Mu Us Sandland, China

PubMed Central

Yang, Yongsheng; Bu, Chongfeng; Mu, Xingmin; Shao, Hongbo; Zhang, Kankan

2014-01-01

To better understand the effects of biological soil crusts (BSCs) on soil moisture and wind erosion and study the necessity and feasibility of disturbance of BSCs in the Mu Us sandland, the effects of four treatments, including moss-dominated crusts alone, Artemisia ordosica alone, bare sand, and Artemisia ordosica combined with moss-dominated crusts, on rainwater infiltration, soil moisture, and annual wind erosion were observed. The major results are as follows. (1) The development of moss-dominated crusts exacerbated soil moisture consumption and had negative effects on soil moisture in the Mu Us sandland. (2) Moss-dominated crusts significantly increased soil resistance to wind erosion, and when combined with Artemisia ordosica, this effect became more significant. The contribution of moss-dominated crusts under Artemisia ordosica was significantly lower than that of moss-dominated crusts alone in sites where vegetative coverage > 50%. (3) Finally, an appropriate disturbance of moss-dominated crusts in the rainy season in sites with high vegetative coverage improved soil water environment and vegetation succession, but disturbance in sites with little or no vegetative cover should be prohibited to avoid the exacerbation of wind erosion. PMID:24982973

Interactive effects of moss-dominated crusts and Artemisia ordosica on wind erosion and soil moisture in Mu Us sandland, China.

PubMed

Yang, Yongsheng; Bu, Chongfeng; Mu, Xingmin; Shao, Hongbo; Zhang, Kankan

2014-01-01

To better understand the effects of biological soil crusts (BSCs) on soil moisture and wind erosion and study the necessity and feasibility of disturbance of BSCs in the Mu Us sandland, the effects of four treatments, including moss-dominated crusts alone, Artemisia ordosica alone, bare sand, and Artemisia ordosica combined with moss-dominated crusts, on rainwater infiltration, soil moisture, and annual wind erosion were observed. The major results are as follows. (1) The development of moss-dominated crusts exacerbated soil moisture consumption and had negative effects on soil moisture in the Mu Us sandland. (2) Moss-dominated crusts significantly increased soil resistance to wind erosion, and when combined with Artemisia ordosica, this effect became more significant. The contribution of moss-dominated crusts under Artemisia ordosica was significantly lower than that of moss-dominated crusts alone in sites where vegetative coverage > 50%. (3) Finally, an appropriate disturbance of moss-dominated crusts in the rainy season in sites with high vegetative coverage improved soil water environment and vegetation succession, but disturbance in sites with little or no vegetative cover should be prohibited to avoid the exacerbation of wind erosion.

Fire tolerance of a resprouting Artemisia (Asteraceae) shrub

USGS Publications Warehouse

Winter, S.L.; Fuhlendorf, S.D.; Goad, C.L.; Davis, C.A.; Hickman, K.R.; Leslie, David M.

2011-01-01

In North America, most Artemisia (Asteraceae) shrub species lack the ability to resprout after disturbances that remove aboveground biomass. We studied the response of one of the few resprouting Artemisia shrubs, Artemisia filifolia (sand sagebrush), to the effects of prescribed fires. We collected data on A. filifolia density and structural characteristics (height, canopy area, and canopy volume) in an A. filifolia shrubland in the southern Great Plains of North America. Our study sites included areas that had not been treated with prescribed fire, areas that had been treated with only one prescribed fire within the previous 5 years, and areas that had been treated with two prescribed fires within the previous 10 years. Our data were collected at time periods ranging from 1/2 to 5 years after the prescribed fires. Density of A. filifolia was not affected by one or two fires. Structural characteristics, although initially altered by prescribed fire, recovered to levels characteristic of unburned areas in 3-4 years after those fires. In contrast to most non-sprouting North American Artemisia shrub species, our research suggested that the resprouting A. filifolia is highly tolerant to the effects of fire. ?? 2011 Springer Science+Business Media B.V.

Artemisia Extract Improves Insulin Sensitivity in Women With Gestational Diabetes Mellitus by Up-Regulating Adiponectin.

PubMed

Sun, Xia; Sun, Hong; Zhang, Jing; Ji, Xianghong

2016-12-01

Gestational diabetes mellitus (GDM) has affected a great number of pregnant women worldwide. Artemisia extracts have been found to exhibit a potent antidiabetic effect in the treatment of type 2 diabetes mellitus. We aimed to examine the effects of Artemisia extract on insulin resistance and lipid profiles in pregnant GDM patients. Patients in their second trimester were randomly assigned to the Artemisia extract group (AE) or to a placebo group (PO). They were instructed to consume either AE or PO daily for a period of 10 weeks. Glucose and insulin profiles and adiponectin level were assessed at baseline (week 0) and after the treatment (week 10). Compared to the PO group, fasting plasma glucose, serum insulin levels, homeostasis model of assessment of insulin resistance (HOMA-IR), and β-cell function (HOMA-B) were significantly reduced in the AE group participants. Moreover, levels of circulating adiponectin were also significantly up-regulated in the AE group, which also positively contributed to improved insulin sensitivity. Daily administration of Artemisia extract improves insulin sensitivity by up-regulating adiponectin in women with gestational diabetes mellitus. © 2016, The American College of Clinical Pharmacology.

Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia.

PubMed

Mukherjee, Angana; Bopp, Selina; Magistrado, Pamela; Wong, Wesley; Daniels, Rachel; Demas, Allison; Schaffner, Stephen; Amaratunga, Chanaki; Lim, Pharath; Dhorda, Mehul; Miotto, Olivo; Woodrow, Charles; Ashley, Elizabeth A; Dondorp, Arjen M; White, Nicholas J; Wirth, Dyann; Fairhurst, Rick; Volkman, Sarah K

2017-05-12

Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin-piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA 0-3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA 0-3h  = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine resistance and development of strategies to prevent or overcome anti-malarial resistance.

Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis.

PubMed

Want, Muzamil Y; Islammudin, Mohammad; Chouhan, Garima; Ozbak, Hani A; Hemeg, Hassan A; Chattopadhyay, Asoke P; Afrin, Farhat

2017-01-01

Visceral leishmaniasis (VL) is a fatal, vector-borne disease caused by the intracellular protozoa of the genus Leishmania . Most of the therapeutics for VL are toxic, expensive, or ineffective. Sesquiterpenes are a new class of drugs with proven antimicrobial and antiviral activities. Artemisinin is a sesquiterpene lactone with potent antileishmanial activity, but with limited access to infected cells, being a highly lipophilic molecule. Association of artemisinin with liposome is a desirable strategy to circumvent the problem of poor accessibility, thereby improving its efficacy, as demonstrated in a murine model of experimental VL. Nanoliposomal artemisinin (NLA) was prepared by thin-film hydration method and optimized using Box-Behnken design with a mean particle diameter of 83±16 nm, polydispersity index of 0.2±0.03, zeta potential of -27.4±5.7 mV, and drug loading of 33.2%±2.1%. Morphological study of these nanoliposomes by microscopy showed a smooth and spherical surface. The mechanism of release of artemisinin from the liposomes followed the Higuchi model in vitro. NLA was free from concomitant signs of toxicity, both ex vivo in murine macrophages and in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of Leishmania donovani amastigotes and the number of infected macrophages ex vivo with an IC 50 of 6.0±1.4 µg/mL and 5.1±0.9 µg/mL, respectively. Following treatment in a murine model of VL, NLA demonstrated superior efficacy compared to artemisinin with a percentage inhibition of 82.4%±3.8% in the liver and 77.6%±5.5% in spleen at the highest dose of 20 mg/kg body weight with modulation of cell-mediated immunity towards protective Th1 type. This study is the first report on the use of a liposomal drug delivery system for artemisinin as a promising alternative intervention against VL.

Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis.

PubMed

Want, Muzamil Yaqub; Islamuddin, Mohammad; Chouhan, Garima; Ozbak, Hani A; Hemeg, Hassan A; Dasgupta, Anjan Kumar; Chattopadhyay, Asoke Prasun; Afrin, Farhat

2015-06-01

Visceral leishmaniasis (VL) is a fatal vector-borne parasitic syndrome attributable to the protozoa of the Leishmania donovani complex. The available chemotherapeutic options are not ideal due to their potential toxicity, high cost and prolonged treatment schedule. In the present study, we conjectured the use of nano drug delivery systems for plant-derived secondary metabolite; artemisinin as an alternative strategy for the treatment of experimental VL. Artemisinin-loaded poly lactic co-glycolic acid (ALPLGA) nanoparticles prepared were spherical in shape with a particle size of 220.0±15.0 nm, 29.2±2.0% drug loading and 69.0±3.3% encapsulation efficiency. ALPLGA nanoparticles administered at doses of 10 and 20mg/kg body weight showed superior antileishmanial efficacy compared with free artemisinin in BALB/c model of VL. There was a significant reduction in hepatosplenomegaly as well as in parasite load in the liver (85.0±5.4%) and spleen (82.0±2.4%) with ALPLGA nanoparticles treatment at 20mg/kg body weight compared to free artemisinin (70.3±0.6% in liver and 62.7±3.7% in spleen). In addition, ALPLGA nanoparticle treatment restored the defective host immune response in mice with established VL infection. The protection was associated with a Th1-biased immune response as evident from a positive delayed-type hypersensitivity reaction, escalated IgG2a levels, augmented lymphoproliferation and enhancement in proinflammatory cytokines (IFN-γ and IL-2) with significant suppression of Th2 cytokines (IL-10 and IL-4) after in vitro recall, compared to infected control and free artemisinin treatment. In conclusion, our results advocate superior efficacy of ALPLGA nanoparticles over free artemisinin, which was coupled with restoration of suppressed cell-mediated immunity in animal models of VL. Copyright © 2015 Elsevier B.V. All rights reserved.

Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis

PubMed Central

Want, Muzamil Y; Islammudin, Mohammad; Chouhan, Garima; Ozbak, Hani A; Hemeg, Hassan A; Chattopadhyay, Asoke P; Afrin, Farhat

2017-01-01

Visceral leishmaniasis (VL) is a fatal, vector-borne disease caused by the intracellular protozoa of the genus Leishmania. Most of the therapeutics for VL are toxic, expensive, or ineffective. Sesquiterpenes are a new class of drugs with proven antimicrobial and antiviral activities. Artemisinin is a sesquiterpene lactone with potent antileishmanial activity, but with limited access to infected cells, being a highly lipophilic molecule. Association of artemisinin with liposome is a desirable strategy to circumvent the problem of poor accessibility, thereby improving its efficacy, as demonstrated in a murine model of experimental VL. Nanoliposomal artemisinin (NLA) was prepared by thin-film hydration method and optimized using Box–Behnken design with a mean particle diameter of 83±16 nm, polydispersity index of 0.2±0.03, zeta potential of −27.4±5.7 mV, and drug loading of 33.2%±2.1%. Morphological study of these nanoliposomes by microscopy showed a smooth and spherical surface. The mechanism of release of artemisinin from the liposomes followed the Higuchi model in vitro. NLA was free from concomitant signs of toxicity, both ex vivo in murine macrophages and in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of Leishmania donovani amastigotes and the number of infected macrophages ex vivo with an IC50 of 6.0±1.4 µg/mL and 5.1±0.9 µg/mL, respectively. Following treatment in a murine model of VL, NLA demonstrated superior efficacy compared to artemisinin with a percentage inhibition of 82.4%±3.8% in the liver and 77.6%±5.5% in spleen at the highest dose of 20 mg/kg body weight with modulation of cell-mediated immunity towards protective Th1 type. This study is the first report on the use of a liposomal drug delivery system for artemisinin as a promising alternative intervention against VL. PMID:28356736

Phenotypic and genotypic characterization of Thai isolates of Plasmodium falciparum after an artemisinin resistance containment project.

PubMed

Thita, Thunyapit; Jadsri, Pimrat; Thamkhantho, Jarupatr; Ruang-Areerate, Toon; Suwandittakul, Nantana; Sitthichot, Naruemon; Mahotorn, Kittiya; Tan-Ariya, Peerapan; Mungthin, Mathirut

2018-05-15

In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone ® , a combination of atovaquone-proguanil (ATQ-PG), has been used to cease artemisinin pressure in some areas along Thai-Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before. One hundred and nine of P. falciparum isolates collected from Thai-Cambodia border from Chanthaburi and Trat provinces during 1988-2016 were used in this study. Of these, 58 isolates were collected after the containment. These parasite isolates were characterized for in vitro antimalarial sensitivities including chloroquine (CQ), quinine (QN), mefloquine (MQ), piperaquine (PPQ), artesunate (AS), dihydroartemisinin (DHA), ATQ and PG and genetic markers for drug resistance including the Kelch13 (k13), Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1) and cytochrome b (cytb) genes. Mean CQ, QN, MQ, PPQ and AS IC 50 s of the parasite isolates collected from 2009 to 2016 exhibited significantly higher than those of parasites collected before 2009. Approximately 57% exhibited in vitro MQ resistance. Approximately 94% of the isolates collected from 2009 to 2016 contained the pfmdr1 184F allele. Mutations of the k13 gene were detected in approximately 90% of the parasites collected from 2009 to 2016 which were significantly higher than the parasite isolates collected before. No ATQ-resistant genotype and phenotype of P. falciparum were found among the isolates collected after the containment project. Although the containment project had been implemented in this area, the expansion of artemisinin-resistant parasites did not decline. In addition, reduced sensitivity of the partner drugs of ACT including MQ and PPQ were identified.

K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates

PubMed Central

Straimer, Judith; Gnädig, Nina F.; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D.; Urnov, Fyodor D.; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M.; Ménard, Didier; Fidock, David A.

2015-01-01

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. PMID:25502314

Relative stability of radicals derived from artemisinin: A semiempirical and DFT study

NASA Astrophysics Data System (ADS)

Arantes, C.; de Araujo, M. T.; Taranto, A. G.; de M. Carneiro, J. W.

The semiempirical AM1 and PM3 methods, as well as the density functional (DFT/B3LYP) approach using the 6-31g(d) basis set, were employed to calculate the relative stability of intermediate radicals derived from artemisinin, a sesquiterpene lactone having an endoperoxide bridge that is essential for its antimalarial activity. The compounds studied have their nonperoxidic oxygen atom of the trioxane ring and/or the carbonyl group replaced by a CH2 unit. Relative stabilities were calculated by means of isodesmic equations using artemisinin as reference. It was found that replacement of oxygen atoms decreases the relative stability of the anionic radical intermediates. In contrast, for compounds with inverted stereochemistry the intermediate radicals were found to be more stable than those with the artemisinin-like stereochemistry. These relative stabilities may modulate the antimalarial potency. Radicals centered on carbon are always more stable than the corresponding radicals centered on oxygen.

Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia.

PubMed

Grist, Eric P M; Flegg, Jennifer A; Humphreys, Georgina; Mas, Ignacio Suay; Anderson, Tim J C; Ashley, Elizabeth A; Day, Nicholas P J; Dhorda, Mehul; Dondorp, Arjen M; Faiz, M Abul; Gething, Peter W; Hien, Tran T; Hlaing, Tin M; Imwong, Mallika; Kindermans, Jean-Marie; Maude, Richard J; Mayxay, Mayfong; McDew-White, Marina; Menard, Didier; Nair, Shalini; Nosten, Francois; Newton, Paul N; Price, Ric N; Pukrittayakamee, Sasithon; Takala-Harrison, Shannon; Smithuis, Frank; Nguyen, Nhien T; Tun, Kyaw M; White, Nicholas J; Witkowski, Benoit; Woodrow, Charles J; Fairhurst, Rick M; Sibley, Carol Hopkins; Guerin, Philippe J

2016-10-24

Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caldwell, M.M.; Eissenstat, D.M.; Richards, J.H.

Two species of Agropyron grass differed strikingly in their capacity to compete for phosphate in soil interspaces shared with a common competitor, the sagebrush Artemisia tridentata. Of the total phosphorus-32 and -33 absorbed by Artemisia, 86% was from the interspace shared with Agropyron spicatum and only 14% from that shared with Agropyron desertorum. Actively absorbing mycorrhizal roots of Agropyron and Artemisia were present in both interspaces, where competition for the labeled phosphate occurred. The results have important implications about the way in which plants compete for resources below ground in both natural plant communities and agricultural intercropping systems.

A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment.

PubMed

Huang, Fang; Takala-Harrison, Shannon; Jacob, Christopher G; Liu, Hui; Sun, Xiaodong; Yang, Henglin; Nyunt, Myaing M; Adams, Matthew; Zhou, Shuisen; Xia, Zhigui; Ringwald, Pascal; Bustos, Maria Dorina; Tang, Linhua; Plowe, Christopher V

2015-11-15

Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and poses a threat to malaria control and elimination. Mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 have been associated with delayed parasite clearance following artemisinin treatment elsewhere in the region, but not yet in China. Therapeutic efficacy studies of artesunate and dihydroartemisinin-piperaquine were conducted from 2009 to 2012 in the Yunnan Province of China near the border with Myanmar. K13 mutations were genotyped by capillary sequencing of DNA extracted from dried blood spots collected in these clinical trials and in routine surveillance. Associations between K13 mutations and delayed parasite clearance were tested using regression models. Parasite clearance half-lives were prolonged after artemisinin treatment, with 44% of infections having half-lives >5 hours (n = 109). Fourteen mutations in K13 were observed, with an overall prevalence of 47.7% (n = 329). A single mutation, F446I, predominated, with a prevalence of 36.5%. Infections with F446I were significantly associated with parasitemia on day 3 following artemisinin treatment and with longer clearance half-lives. Plasmodium falciparum infections in southern China displayed markedly delayed clearance following artemisinin treatment. F446I was the predominant K13 mutation and was associated with delayed parasite clearance. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Prevalence of K13 mutation and Day-3 positive parasitaemia in artemisinin-resistant malaria endemic area of Cambodia: a cross-sectional study.

PubMed

Kheang, Soy Ty; Sovannaroth, Siv; Ek, Sovann; Chy, Say; Chhun, Phally; Mao, Sokkieng; Nguon, Sokomar; Lek, Dy Soley; Menard, Didier; Kak, Neeraj

2017-09-13

The presence of artemisinin-resistant malaria parasites was confirmed in western Cambodia in 2009. In 2013, mutations in the propeller domain of the kelch protein K13 was found to be associated with artemisinin resistance. A cross-sectional study was conducted to determine the prevalence of Day-3 parasitaemia, estimate the frequency of k13 molecular marker and assess their relationship in the context of operational research. Blood smears and filter paper blood spots were collected from febrile patients in Kravanh District, Pursat Province. The blood smears were examined by microscopy, and blood spots by a k13 mutation assay. Data from 92 patients were analysed. Only one was positive for Day-3 parasitaemia. Results of the k13 assay were interpretable for 76 of the 92 samples. The findings were: wild type: 9 (12%), C580Y: 64 (84%), Y493H: 3 (4%). Therefore, despite the high prevalence of k13 mutants (67/76: 88%), only 1 of the 92 patients remained blood smear positive for Plasmodium falciparum on Day-3. These preliminary findings suggest good potency of artemisinin despite the dominance of k13 mutation in Kravanh, but the result is not necessarily representative of the western part of Cambodia. Further investigation should be made to determine if k13 marker remains useful as a tool for tracking artemisinin resistance and predicting the trend of the efficacy of artemisinin combination therapy once the mutant alleles have been well established in the population.

A survey on anticancer effects of artemisinin, iron, miconazole, and butyric acid on 5637 (bladder cancer) and 4T1 (Breast cancer) cell lines.

PubMed

Shahbazfar, Amir Ali; Zare, Payman; Ranjbaran, Mehrdad; Tayefi-Nasrabadi, Hossein; Fakhri, Omid; Farshi, Yashar; Shadi, Sahar; Khoshkerdar, Afsaneh

2014-01-01

Anticancer properties of artemisinin and its derivatives have been shown in many experiments. Addition of butyric acid, miconazole, and iron to this traditional drug has been done in order to enhance its anticancer potency. Cell lines 5637 and 4T1, were cultivated and classified into 13 groups of three each. Different doses of artemisinin with constant doses of iron, miconazole and butyric acid, were added to the cultures. At the end of exposure pathological and enzymatic studies were performed. In four groups treated with different doses of artemisinin and iron, dose-dependent changes were observed. These changes included apoptosis and necrosis with dominance of apoptosis. The supernatant lactate dehydrogenase (LDH) level was increased in a dose-dependent manner, but there was no significant increase in the cell fraction of malonyldialdehyde (MDA) or LDH. In four other groups, which received miconazole, butyric acid and iron in addition to different doses of artemisinin, necrosis was more prominent than apoptosis, and the MDA level did not show any significant change, but LDH was increased. The groups treated with miconazole showed identical changes, with less severity compared to combination therapy groups. In butyric acid-treated groups, the only detectable changes were, mild cell swelling, few apoptosis, and rare necrosis. A combination therapy with artemisinin can be more effective against cancer cells than monotherapy with that. Butyric acid was not effective on cancer cells. Miconazole deviated the nature of cell death from apoptosis to necrosis and it must be used under caution.

Resistance screening and trend analysis of imported falciparum malaria in NSW, Australia (2010 to 2016).

PubMed

Prosser, Christiane; Meyer, Wieland; Ellis, John; Lee, Rogan

2018-01-01

The World Health Organization currently recommends artemisinin (along with a partner drug) as the global frontline treatment for Plasmodium falciparum malaria. Artemisinin resistant P. falciparum are now found throughout the greater Mekong subregion of South East Asia. Several polymorphisms in the parasite's kelch gene have been demonstrated to confer artemisinin resistance. While genotypes within the greater Mekong subregion are thoroughly examined in the literature, P. falciparum populations within several areas that do not (yet) have endemic resistance are underrepresented. This investigation characterised the Pfkelch13 propeller domains from 153 blood samples of 140 imported cases of P. falciparum malaria in New South Wales from 2010 to 2016. A low level of propeller domain diversity was observed, including the C580Y coding mutation most strongly associated with artemisinin resistance in South East Asia. The resistance genotype was found in a sample originating in Papua New Guinea, where this mutation, or artemisinin treatment failure, have not been previously reported. Sequencing a panel of geographically informative polymorphisms within the organellar genomes identified the C580Y parasite as having Oceanic origins. Patient data analysis revealed that New South Wales, Australia, P. falciparum malaria cases often originated from regions with limited drug resistance screening. The C580Y finding from outside of the greater Mekong subregion supports the consensus to upscale molecular surveillance of artemisinin resistance outside of South East Asia. The genetic screening results identify a risk of importing resistant falciparum malaria to Australia, supporting an ongoing surveillance protocol to pre-empt treatment failure and contribute to global data gathering.

Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study

PubMed Central

Moore, Kerryn A; Simpson, Julie A; Paw, Moo Kho; Pimanpanarak, MuPawJay; Wiladphaingern, Jacher; Rijken, Marcus J; Jittamala, Podjanee; White, Nicholas J; Fowkes, Freya J I; Nosten, François; McGready, Rose

2016-01-01

Summary Background Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations. Methods In this observational study, we assessed data from antenatal clinics on the Thai–Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures. Findings Of 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32–1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24–4·68; p<0·0001), and 2·44-fold (1·01–5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45–1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22–6·47] versus eight (1%) of 641 [0·54–2·44], respectively). Interpretation First-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations. Funding The Wellcome Trust and The Bill & Melinda Gates Foundation. PMID:26869377

Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study

PubMed Central

Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Dek, Dalin; Try, Vorleak; Amato, Roberto; Blessborn, Daniel; Song, Lijiang; Tullo, Gregory S; Fay, Michael P; Anderson, Jennifer M; Tarning, Joel; Fairhurst, Rick M

2016-01-01

Background Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin–piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. Methods In this prospective cohort study, we enrolled patients aged 2–65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin–piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Findings Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory concentration (IC50) values, and lower mefloquine IC50 values; none had multiple pfmdr1 copies, a genetic marker of mefloquine resistance. Interpretation Dihydroartemisinin–piperaquine failures are caused by both artemisinin and piperaquine resistance, and commonly occur in places where dihydroartemisinin–piperaquine has been used in the private sector. In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin–piperaquine failures, and a more effective first-line ACT in areas where dihydroartemisinin–piperaquine failures are common. The use of single low-dose primaquine to eliminate circulating gametocytes is needed in areas where artemisinin and ACT resistance is prevalent. Funding National Institute of Allergy and Infectious Diseases. PMID:26774243

Seeding considerations in restoring big sagebrush habitat

Treesearch

Scott M. Lambert

2005-01-01

This paper describes methods of managing or seeding to restore big sagebrush communities for wildlife habitat. The focus is on three big sagebrush subspecies, Wyoming big sagebrush (Artemisia tridentata ssp. wyomingensis), basin big sagebrush (Artemisia tridentata ssp. tridentata), and mountain...

Sagebrush systematics and distribution

Treesearch

E. Durant McArthur

2000-01-01

In this paper on sagebrush systematics and distribution, it is appropriate to begin by defining a few terms. Sagebrush, under my definition, are woody North American Artemisia of the subgenus Tridentatae. Tridentatae are one of four subgenera in Artemisia. Tridentatae or true...

Phytotoxic Lignans from Artemisia arborescens

USDA-ARS?s Scientific Manuscript database

A systematic bioassay-guided fractionation of methylene chloride extracts of the aerial part of Artemisia arborescens was performed in order to identify its phytotoxic compounds. Two lignans were isolated, sesamin and ashantin, that inhibited growth of Agrostis stolonifera (bentgrass), a monocot, a...

In vitro activity of anti-malarial ozonides against an artemisinin-resistant isolate.

PubMed

Baumgärtner, Fabian; Jourdan, Joëlle; Scheurer, Christian; Blasco, Benjamin; Campo, Brice; Mäser, Pascal; Wittlin, Sergio

2017-01-25

Recently published data suggest that artemisinin derivatives and synthetic peroxides, such as the ozonides OZ277 and OZ439, have a similar mode of action. Here the cross-resistance of OZ277 and OZ439 and four additional next-generation ozonides was probed against the artemisinin-resistant clinical isolate Plasmodium falciparum Cam3.I, which carries the K13-propeller mutation R539T (Cam3.I R539T ). The previously described in vitro ring-stage survival assay (RSA 0-3h ) was employed and a simplified variation of the original protocol was developed. At the pharmacologically relevant concentration of 700 nM, all six ozonides were highly effective against the dihydroartemisinin-resistant P. falciparum Cam3.I R539T parasites, showing a per cent survival ranging from <0.01 to 1.83%. A simplified version of the original RSA 0-3h method was developed and gave similar results, thus providing a practical drug discovery tool for further optimization of next-generation anti-malarial peroxides. The absence of in vitro cross-resistance against the artemisinin-resistant clinical isolate Cam3.I R539T suggests that ozonides could be effective against artemisinin-resistant P. falciparum. How this will translate to the human situation in clinical settings remains to be investigated.

Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali.

PubMed

Ouattara, Amed; Kone, Aminatou; Adams, Matthew; Fofana, Bakary; Maiga, Amelia Walling; Hampton, Shay; Coulibaly, Drissa; Thera, Mahamadou A; Diallo, Nouhoum; Dara, Antoine; Sagara, Issaka; Gil, Jose Pedro; Bjorkman, Anders; Takala-Harrison, Shannon; Doumbo, Ogobara K; Plowe, Christopher V; Djimde, Abdoulaye A

2015-06-01

Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non-synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin-sensitive parasites and that they preceded the wide use of ACTs in Mali. © The American Society of Tropical Medicine and Hygiene.

Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector--Results from a Nationally Representative Outlet Survey.

PubMed

Act Consortium Drug Quality Project Team And The Impact Study Team

2015-06-01

Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. © The American Society of Tropical Medicine and Hygiene.

Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo.

PubMed

Mvumbi, Dieudonné Makaba; Bobanga, Thierry Lengu; Kayembe, Jean-Marie Ntumba; Mvumbi, Georges Lelo; Situakibanza, Hippolyte Nani-Tuma; Benoit-Vical, Françoise; Melin, Pierrette; De Mol, Patrick; Hayette, Marie-Pierre

2017-01-01

Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.

Application of 3D printing to prototype and develop novel plant tissue culture systems.

PubMed

Shukla, Mukund R; Singh, Amritpal S; Piunno, Kevin; Saxena, Praveen K; Jones, A Maxwell P

2017-01-01

Due to the complex process of designing and manufacturing new plant tissue culture vessels through conventional means there have been limited efforts to innovate improved designs. Further, development and availability of low cost, energy efficient LEDs of various spectra has made it a promising light source for plant growth in controlled environments. However, direct replacement of conventional lighting sources with LEDs does not address problems with uniformity, spectral control, or the challenges in conducting statistically valid experiments to assess the effects of light. Prototyping using 3D printing and LED based light sources could help overcome these limitations and lead to improved culture systems. A modular culture vessel design in which the fluence rate and spectrum of light are independently controlled was designed, prototyped using 3D printing, and evaluated for plant growth. This design is compatible with semi-solid and liquid based culture systems. Observations on morphology, chlorophyll content, and chlorophyll fluorescence based stress parameters from in vitro plants cultured under different light spectra with similar overall fluence rate indicated different responses in Nicotiana tabacum and Artemisia annua plantlets. This experiment validates the utility of 3D printing to design and test functional vessels and demonstrated that optimal light spectra for in vitro plant growth is species-specific. 3D printing was successfully used to prototype novel culture vessels with independently controlled variable fluence rate/spectra LED lighting. This system addresses several limitations associated with current lighting systems, providing more uniform lighting and allowing proper replication/randomization for experimental plant biology while increasing energy efficiency. A complete procedure including the design and prototyping of a culture vessel using 3D printing, commercial scale injection molding of the prototype, and conducting a properly replicated experiment are discussed. This open source design has the scope for further improvement and adaptation and demonstrates the power of 3D printing to improve the design of culture systems.

Absence of association between polymorphisms in the K13 gene and the presence of Plasmodium falciparum parasites at day 3 after treatment with artemisinin derivatives in Senegal.

PubMed

Madamet, Marylin; Kounta, Mame Bou; Wade, Khalifa Ababacar; Lo, Gora; Diawara, Silman; Fall, Mansour; Bercion, Raymond; Nakoulima, Aminata; Fall, Khadidiatou Ba; Benoit, Nicolas; Gueye, Mamadou Wague; Fall, Bécaye; Diatta, Bakary; Pradines, Bruno

2017-06-01

In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy as first-line treatment for uncomplicated malaria. In addition, intravenous (i.v.) injection of artesunate and artemether has gradually replaced quinine for the treatment of severe malaria. Mutations in the propeller domain of the Kelch 13 gene (K13-propeller, PF3D71343700), such as Y493H, R539T, I543T and C580Y, were recently associated with in vivo and in vitro resistance to artemisinin in Southeast Asia. However, these mutations were not identified in Africa. In total, 181 isolates of Plasmodium falciparum from 161 patients from Dakar, Senegal, were collected between August 2015 and January 2016. The K13-propeller gene of the isolates was sequenced. A search for non-synonymous mutations in the propeller region of K13 was performed in the 181 isolates collected from Dakar from 2015 to 2016. Three synonymous mutations were detected (D464D, C469C and R471R). Of 119 patients treated with i.v. artesunate or intramuscular artemether followed by artemether/lumefantrine, 9 patients were still parasitaemic on Day 3. Parasites from these nine patients were wild-type for K13-propeller. None of the polymorphisms known to be involved in artemisinin resistance in Asia were detected. These results suggest that K13 is not the best predictive marker for artemisinin resistance in Africa. More isolates from clinical failure cases or patients with delayed parasite clearance after treatment with artemisinin derivatives are necessary to identify new molecular markers. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

PubMed Central

2011-01-01

Background Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. Results In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC). In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. Conclusions The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis of pathogens with drug resistance phenotypes in vivo. PMID:21810278

Phenotypic and Genotypic Analysis of In Vitro-Selected Artemisinin-Resistant Progeny of Plasmodium falciparum

PubMed Central

Tucker, Matthew S.; Mutka, Tina; Sparks, Kansas; Patel, Janus

2012-01-01

Emergence of artemisinin resistance in Cambodia highlights the importance of characterizing resistance to this class of drugs. Previously, intermediate levels of resistance in Plasmodium falciparum were generated in vitro for artelinic acid (AL) and artemisinin (QHS). Here we expanded on earlier selection efforts to produce levels of clinically relevant concentrations, and the resulting lines were characterized genotypically and phenotypically. Recrudescence assays determined the ability of resistant and parent lines to recover following exposure to clinically relevant levels of drugs. Interestingly, the parent clone (D6) tolerated up to 1,500 ng/ml QHS, but the resistant parasite, D6.QHS340×3, recovered following exposure to 2,400 ng/ml QHS. Resistant D6, W2, and TM91c235 parasites all exhibited elevated 50% inhibitory concentrations (IC50s) to multiple artemisinin drugs, with >3-fold resistance to QHS and AL; however, the degree of resistance obtained with standard methods was remarkably less than expected for parasite lines that recovered from 2,400-ng/ml drug pressure. A novel assay format with radiolabeled hypoxanthine demonstrated a greater degree of resistance in vitro than the standard SYBR green method. Analysis of merozoite number in resistant parasites found D6 and TM91c235 resistant progeny had significantly fewer merozoites than parent strains, whereas W2 resistant progeny had significantly more. Amplification of pfmdr1 increased proportionately to the increased drug levels tolerated by W2 and TM91c235, but not in resistant D6. In summary, we define the artemisinin resistance phenotype as a decrease in susceptibility to artemisinins along with the ability to recover from drug-induced dormancy following supraclinical concentrations of the drug. PMID:22083467

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

PubMed Central

Copple, Ian M; Mercer, Amy E; Firman, James; Donegan, Gail; Herpers, Bram; Wong, Michael HL; Chadwick, James; Bringela, Andreia D; Cristiano, Maria LS; van de Water, Bob; Ward, Stephen A; O’Neill, Paul M; Park, B Kevin

2012-01-01

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria. PMID:22669474

Artemisia tridenata seed bank densities following wildfires

USDA-ARS?s Scientific Manuscript database

Big sagebrush (Artemisia spp.) is a critical shrub to such sagebrush obligate species as sage grouse, (Centocercus urophasianus), mule deer (Odocoileus hemionus), and pygmy rabbit (Brachylagus idahoensis). Big sagebrush do not sprout after wildfires and big sagebrush seed is generally short-lived a...

Solvent effects on the relative stability of radicals derived from artemisinin: DFT study using the PCM/COSMO approach

NASA Astrophysics Data System (ADS)

Araujo, M. T. De; Carneiro, J. W. De M.; Taranto, A. G.

The PCM/COSMO approach was employed to calculate the relative stability of radicals derived from the antimalarial artemisinin. The calculations were performed in polar (water) and apolar (THF) solvent at the density functional level [B3LYP/6-31g(d)]. Relative stabilities were calculated by means of isodesmic equations using artemisinin as reference. Replacement of oxygen atoms by CH2 unities was found to decrease the relative stability of the anionic radical intermediates. The degree of destabilization is reduced in the presence of solvent, being less in water than in THF. The dipole moment and the corresponding solvation free energies of these species modulate this effect. Derivatives with inverted stereochemistry are more stable than those with the artemisinin-like stereochemistry, although the solvent attenuates this stabilization effect. As was found in the in vacuo calculations, the radicals centered on carbon are always more stable than the corresponding radicals centered on oxygen.

Studies of protonated and anionic artemisinin in the gas-phase by infrared multi-photon dissociation and by negative ion photoelectron spectroscopies

NASA Astrophysics Data System (ADS)

Seydou, M.; Gillet, J. C.; Li, X.; Wang, H.; Posner, G. H.; Grégoire, G.; Schermann, J. P.; Bowen, K. H.; Desfrançois, C.

2007-12-01

Protonated and anionic artemisinin in the gas phase have respectively been studied by infrared multi-photon dissociation (IRMPD) spectroscopy and by anion photoelectron spectroscopy. Comparison of the measured IRMPD spectrum with calculated spectra of various conformations showed that the two lowest-energy protonated structures, both corresponding to protonation at the C dbnd O 14 carbonyl site, were observed experimentally. The calculations also indicated that the peroxide bridge in artemisinin is only slightly modified by protonation. Additionally, stable, intact (parent) artemisinin radical anions have been obtained for the first time in the gas phase and the photoelectron spectrum supports the computational finding that the excess electron is mainly localized on the σ ∗ orbital of the peroxide bond. The vertical detachment energy and adiabatic electron affinity, calculated at the MP2/6-31+G ∗ level, are in good agreement with the experimental data and the O-O distance is calculated to be stretched by more than 50% in the anion.

Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

PubMed

Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A

2015-01-23

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. Copyright © 2015, American Association for the Advancement of Science.

A new synthetic biology approach allows transfer of an entire metabolic pathway from a medicinal plant to a biomass crop.

PubMed

Fuentes, Paulina; Zhou, Fei; Erban, Alexander; Karcher, Daniel; Kopka, Joachim; Bock, Ralph

2016-06-14

Artemisinin-based therapies are the only effective treatment for malaria, the most devastating disease in human history. To meet the growing demand for artemisinin and make it accessible to the poorest, an inexpensive and rapidly scalable production platform is urgently needed. Here we have developed a new synthetic biology approach, combinatorial supertransformation of transplastomic recipient lines (COSTREL), and applied it to introduce the complete pathway for artemisinic acid, the precursor of artemisinin, into the high-biomass crop tobacco. We first introduced the core pathway of artemisinic acid biosynthesis into the chloroplast genome. The transplastomic plants were then combinatorially supertransformed with cassettes for all additional enzymes known to affect flux through the artemisinin pathway. By screening large populations of COSTREL lines, we isolated plants that produce more than 120 milligram artemisinic acid per kilogram biomass. Our work provides an efficient strategy for engineering complex biochemical pathways into plants and optimizing the metabolic output.

Current perspectives on the mechanism of action of artemisinins.

PubMed

Golenser, Jacob; Waknine, Judith H; Krugliak, Miriam; Hunt, Nicholas H; Grau, Georges E

2006-12-01

Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.

The solid-state fermentation of Artemisia capillaris leaves with Ganoderma lucidum enhances the anti-inflammatory effects in a model of atopic dermatitis

PubMed Central

Son, Hyeong-U; Lee, Seul; Heo, Jin-Chul; Lee, Sang-Han

2017-01-01

Artemisia capillaris, which belongs to the Asteraceae family and the genus Artemisia, has been reported to exert inhibitory effects on diabetes, cancer and inflammation. In this study, in order to enhance the bioactivity potential of the leaves of Artemisia by Ganoderma lucidum mycelium, we prepared aqueous samples of Artemisia capillaris (Ac) leaves, Ganoderma lucidum (Gl) and aqueous fractions produced by the solid fermentation of Ganoderma lucidum on Artemisia capillaris leaves (afAc/Gl). Thereafter, we evaluated whether these samples have potential to attenuate inflammation-related symptoms in an amimal model of 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis. We found that afAc/Gl exhibited enhanced anti-inflamamatory activity following the solid fermentation process when compared with Ac or Gl on ear thickness, ear epidermal thickness and eosinophil infiltration in the skin tissues. The expression of nitric oxide (NO) synthases (NOSs) was measured by immunohistochemical staining. The results revealed that afAc/Gl decreased endothelial NOS and inducible NOS expression compared with the DNFB group, while neuronal NOS expression was not altered. By comparing NO production, we found that as opposed to Ac, afAc/Gl has potential to inhibit atopic dermatitis-related symptoms during the inflammatory event. As regards matrix metalloproteinase (MMP) expression patterns, afAc/Gl exerted potent inhibitory activity on the mRNA expression of MMP-2, -7, -9, -12, -14 and -19. Taken together, these results suggest that the solid state fermentation of Ac by Gl is an effective strategy to obtaining useful ingredients which are converted into valuable compounds during an atopic inflammatory insult. PMID:28393198

The solid-state fermentation of Artemisia capillaris leaves with Ganoderma lucidum enhances the anti-inflammatory effects in a model of atopic dermatitis.

PubMed

Son, Hyeong-U; Lee, Seul; Heo, Jin-Chul; Lee, Sang-Han

2017-05-01

Artemisia capillaris, which belongs to the Asteraceae family and the genus Artemisia, has been reported to exert inhibitory effects on diabetes, cancer and inflammation. In this study, in order to enhance the bioactivity potential of the leaves of Artemisia by Ganoderma lucidum mycelium, we prepared aqueous samples of Artemisia capillaris (Ac) leaves, Ganoderma lucidum (Gl) and aqueous fractions produced by the solid fermentation of Ganoderma lucidum on Artemisia capillaris leaves (afAc/Gl). Thereafter, we evaluated whether these samples have potential to attenuate inflammation-related symptoms in an amimal model of 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis. We found that afAc/Gl exhibited enhanced anti-inflamamatory activity following the solid fermentation process when compared with Ac or Gl on ear thickness, ear epidermal thickness and eosinophil infiltration in the skin tissues. The expression of nitric oxide (NO) synthases (NOSs) was measured by immunohistochemical staining. The results revealed that afAc/Gl decreased endothelial NOS and inducible NOS expression compared with the DNFB group, while neuronal NOS expression was not altered. By comparing NO production, we found that as opposed to Ac, afAc/Gl has potential to inhibit atopic dermatitis-related symptoms during the inflammatory event. As regards matrix metalloproteinase (MMP) expression patterns, afAc/Gl exerted potent inhibitory activity on the mRNA expression of MMP-2, -7, -9, -12, -14 and -19. Taken together, these results suggest that the solid state fermentation of Ac by Gl is an effective strategy to obtaining useful ingredients which are converted into valuable compounds during an atopic inflammatory insult.

Artemisinin resistance--modelling the potential human and economic costs.

PubMed

Lubell, Yoel; Dondorp, Arjen; Guérin, Philippe J; Drake, Tom; Meek, Sylvia; Ashley, Elizabeth; Day, Nicholas P J; White, Nicholas J; White, Lisa J

2014-11-23

Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified. This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool. Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment. These 'ballpark' figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world.

Orally Formulated Artemisinin in Healthy Fasting Vietnamese Male Subjects: A Randomized, Four-Sequence, Open-Label, Pharmacokinetic Crossover Study

PubMed Central

Hien, Tran Tinh; Hanpithakpong, Warunee; Truong, Nguyen Thanh; Dung, Nguyen Thi; Toi, Pham Van; Farrar, Jeremy; Lindegardh, Niklas; Tarning, Joel; Ashton, Michael

2011-01-01

Background Artemisinin derivatives are used in antimalarial drug combination therapy. Artemisinin and piperaquine have recently been proven to be prospective candidates for combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. Objective The goal of this study was to evaluate the relative bioavailability and to characterize the pharmacokinetic properties of a new micronized powder formulation of artemisinin against the previous standard Vietnamese formulation when administered as a single oral dose or in combination with piperaquine. Methods This was a single-center, randomized, 4-sequence, open-label, crossover study conducted in 15 healthy male Vietnamese volunteers under fasting conditions with a washout period of 3 weeks between study visits. A single oral dose of 160 or 500 mg of artemisinin was administered alone or in combination with piperaquine. Potential adverse events were monitored daily by the clinician and by using laboratory test results. Frequent blood samples were drawn for 12 hours after dose. Artemisinin was quantified in plasma using LC-MS/MS. Pharmacokinetic parameters were computed from the plasma concentration–time profiles using a noncompartmental analysis method. Results Pharmacokinetic parameters Tmax, Cmax, AUC0-∞, Vd/F, CL/F, and t1/2 (mean [SD]) for the new formulation of artemisinin were 1.83 (0.88) hours, 178 (97) ng/mL, 504 (210) h × ng/mL, 1270 (780) L, 401 (260) L/h, and 2.21 (0.29) hours, respectively. The mean percentage of the test/reference formulation ratio for the logarithmically transformed values of Cmax, AUC0–last, and AUC0–∞ were 121% (90% CI, 92.5–158), 122% (90% CI, 101–148), and 120% (90% CI, 98.0–146), respectively. Conclusions This single-dose study found that the dose-normalized Cmax, AUC0–last, and AUC0–∞ mean geometric differences between the test and reference formulations were relatively small (<40%) and will probably not have a clinical impact in the treatment of malaria infections. PMID:21665048

Reflections on the Nobel Prize for Medicine 2015--The Public Health Legacy and Impact of Avermectin and Artemisinin.

PubMed

Molyneux, David H; Ward, Steve A

2015-12-01

The award of the Nobel Prize to Dr Bill Campbell and Professor Satoshi Ōmura for their role in the discovery of avermectin and Professor Youyou Tu for her work on the development of artemisinin has been universally welcomed by the International Health community for what the Nobel Committee described as 'The discoveries of Avermectin and Artemisinin have revolutionized therapy for patients suffering from devastating parasitic diseases. Campbell, Ōmura and Tu have transformed the treatment of parasitic diseases. The global impact of their discoveries and the resulting benefit to mankind are immeasurable'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug.

PubMed

Kulkarni, C; Kelly, A L; Gough, T; Jadhav, V; Singh, K K; Paradkar, A

2018-02-01

Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus ® , a low T g amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110 °C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC 0-24h ) and peak plasma concentration (C max ) were four times higher for the modified solid dispersion compared to that of pure artemisinin.

78 FR 48925 - Culturally Significant Object Imported for Exhibition Determinations: “Violence and Virtue...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-12

... DEPARTMENT OF STATE [Public Notice 8417] Culturally Significant Object Imported for Exhibition Determinations: ``Violence and Virtue: Artemisia Gentileschi's Judith Slaying Holofernes'' SUMMARY: Notice is... object to be included in the exhibition ``Violence and Virtue: Artemisia Gentileschi's Judith Slaying...

Evaluation of Drug and Vaccine Candidates in the Human Malaria/Aotus Monkey Model

DTIC Science & Technology

1998-03-01

parasitemia, resulting in infection cure without retreatment (10). Evaluation of two oil-soluble derivatives of artemisinin , artemether and arteether...Artelinic acid in Aotus. Artelinic acid an Artemisinin derivative is known to possess in vitro and in vivo antimalarial activity against strains of

Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study.

PubMed

Moore, Kerryn A; Simpson, Julie A; Paw, Moo Kho; Pimanpanarak, MuPawJay; Wiladphaingern, Jacher; Rijken, Marcus J; Jittamala, Podjanee; White, Nicholas J; Fowkes, Freya J I; Nosten, François; McGready, Rose

2016-05-01

Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations. In this observational study, we assessed data from antenatal clinics on the Thai-Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures. Of 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32-1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24-4·68; p<0·0001), and 2·44-fold (1·01-5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45-1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22-6·47] versus eight (1%) of 641 [0·54-2·44], respectively). First-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations. The Wellcome Trust and The Bill & Melinda Gates Foundation. Copyright © 2016 Moore et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

An artemisinin-mediated ROS evolving and dual protease light-up nanocapsule for real-time imaging of lysosomal tumor cell death.

PubMed

Huang, Liwei; Luo, Yingping; Sun, Xian; Ju, Huangxian; Tian, Jiangwei; Yu, Bo-Yang

2017-06-15

Lysosomes are critical organelles for cellular homeostasis and can be used as potential targets to kill tumor cells from inside. Many photo-therapeutic methods have been developed to overproduce reactive oxygen species (ROS) to trigger lysosomal membrane permeabilization (LMP)-associated cell death pathway. However, these technologies rely on extra irradiation to activate the photosensitizers, which limits the applications in treating deep seated tumors and widespread metastatic lesions. This work reports a multifunctional nanocapsule to achieve targeted lysosomal tumor cell death without irradiation and real-time monitoring of drug effect through encapsulating artemisinin and dual protease light-up nanoprobe in a folate-functionalized liposome. The nanocapsule can be specifically uptaken by tumor cells via folate receptor-mediated endocytosis to enter lysosomes, in which artemisinin reacts with ferrous to generate ROS for LMP-associated cell death. By virtue of confocal fluorescence imaging, the artemisinin location in lysosome, ROS-triggered LMP and ultimate cell apoptosis can be visualized with the cathepsin B and caspase-3 activatable nanoprobe. Notably, the artemisinin-mediated ROS evolving for tumor therapy and real-time therapeutic monitoring were successfully implemented by living imaging in tumor-bearing mice, which broaden the nanocapsule for in vivo theranostics and may offer new opportunities for precise medicine. Copyright © 2016 Elsevier B.V. All rights reserved.

Correlation between Cyclin Dependent Kinases and Artemisinin-Induced Dormancy in Plasmodium falciparum In Vitro

PubMed Central

Gray, Karen-Ann; Gresty, Karryn J.; Chen, Nanhua; Zhang, Veronica; Gutteridge, Clare E.; Peatey, Christopher L.; Chavchich, Marina; Waters, Norman C.; Cheng, Qin

2016-01-01

Background Artemisinin-induced dormancy provides a plausible explanation for recrudescence following artemisinin monotherapy. This phenomenon shares similarities with cell cycle arrest where cyclin dependent kinases (CDKs) and cyclins play an important role. Methods Transcription profiles of Plasmodium falciparum CDKs and cyclins before and after dihydroartemisinin (DHA) treatment in three parasite lines, and the effect of CDK inhibitors on parasite recovery from DHA-induced dormancy were investigated. Results After DHA treatment, parasites enter a dormancy phase followed by a recovery phase. During the dormancy phase parasites up-regulate pfcrk1, pfcrk4, pfcyc2 and pfcyc4, and down-regulate pfmrk, pfpk5, pfpk6, pfcrk3, pfcyc1 and pfcyc3. When entering the recovery phase parasites immediately up-regulate all CDK and cyclin genes. Three CDK inhibitors, olomoucine, WR636638 and roscovitine, produced distinct effects on different phases of DHA-induced dormancy, blocking parasites recovery. Conclusions The up-regulation of PfCRK1 and PfCRK4, and down regulation of other CDKs and cyclins correlate with parasite survival in the dormant state. Changes in CDK expression are likely to negatively regulate parasite progression from G1 to S phase. These findings provide new insights into the mechanism of artemisinin-induced dormancy and cell cycle regulation of P. falciparum, opening new opportunities for preventing recrudescence following artemisinin treatment. PMID:27326764

Novel Polymorphisms in Plasmodium falciparum ABC Transporter Genes Are Associated with Major ACT Antimalarial Drug Resistance

PubMed Central

Veiga, Maria Isabel; Ferreira, Pedro Eduardo; Jörnhagen, Louise; Malmberg, Maja; Kone, Aminatou; Schmidt, Berit Aydin; Petzold, Max; Björkman, Anders; Nosten, Francois; Gil, Jose Pedro

2011-01-01

Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions. PMID:21633513

Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance.

PubMed

Veiga, Maria Isabel; Ferreira, Pedro Eduardo; Jörnhagen, Louise; Malmberg, Maja; Kone, Aminatou; Schmidt, Berit Aydin; Petzold, Max; Björkman, Anders; Nosten, Francois; Gil, Jose Pedro

2011-01-01

Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

pH-Responsive Artemisinin Derivatives and Lipid Nanoparticle Formulations Inhibit Growth of Breast Cancer Cells In Vitro and Induce Down-Regulation of HER Family Members

PubMed Central

Zhang, Yitong J.; Gallis, Byron; Taya, Michio; Wang, Shusheng; Ho, Rodney J. Y.; Sasaki, Tomikazu

2013-01-01

Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives. PMID:23516601

Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells.

PubMed

Nam, Woong; Tak, Jungae; Ryu, Ju-Kyoung; Jung, Mankil; Yook, Jong-In; Kim, Hyung-Jun; Cha, In-Ho

2007-04-01

Artemisinin is of special biological interest because of its outstanding antimalarial activity. Recently, it was reported that artemisinin has antitumor activity. Its derivatives, artesunate, arteether, and artemeter, also have antitumor activity against melanoma, breast, ovarian, prostate, CNS, and renal cancer cell lines. Recently, monomer, dimer, and trimer derivatives were synthesized from deoxoartemisinin, and the dimers and the trimers were found to have much more potent antitumor activity than the monomers. We evaluated the antitumor activity of artemisinin and its various derivatives (dihydroartemisinin, dihydroartemisinin 12-benzoate, 12-(2'-hydroxyethyl) deoxoartemisinin, 12-(2'-ethylthio) deoxoartemisinin dimer, deoxoartemisinin trimer) in comparison with paclitaxel (Taxol), 5-fluorouracil (5-FU), cisplatin in vitro. In this study, the deoxoartemisinin trimer had the most potent antitumor effect (IC(50) = 6.0 microM), even better than paclitaxel (IC(50) = 13.1 microM), on oral cancer cell line (YD-10B). In addition, it induced apoptosis through a caspase-3-dependent mechanism. The deoxoartemisinin trimer was found to have greater antitumor effect on tumor cells than other commonly used chemotherapeutic drugs, such as 5-FU, cisplatin, and paclitaxel. Furthermore, the ability of artemisinin and its derivatives to induce apoptosis highlights their potential as chemotherapeutic agents, for many anticancer drugs achieve their antitumor effects by inducing apoptosis in tumor cells. (c) 2006 Wiley Periodicals, Inc.

Annotations on Artemisia.

PubMed

Gedo, John E

2013-10-01

To demonstrate the relevance of an artist's biography to the understanding of her creations, no instance is more persuasive than the career of the 17th-century Italian painter Artemisia Gentileschi. Numerous scholars have attempted to correlate the nature of her subject matter with the more dramatic events of her picaresque private life. A psychoanalytic effort to make such a correlation needs to go beyond discrete incidents, to reconstruct her personality and its development. Artemisia's oeuvre is tightly focused on a fantasy system of sexual irrestibility, probably based on the interactions of this motherless child with a delinquent father. Hypotheses that the artist became a vengeful victim overtook her strength, resilience, and affability.

Attempting to restore mountain big sagebrush (Artemisia tridentata ssp. vaseyana) four years after fire

USDA-ARS?s Scientific Manuscript database

Restoration of shrubs is increasingly needed throughout the world because of altered fire regimes, anthropogenic disturbance, and over-utilization. The native shrub mountain big sagebrush (Artemisia tridentata Nutt. ssp. vaseyana (Rydb.) Beetle) is a restoration priority in western North America be...

In vitro antiprotozoal activity of the leaves of Artemisia ludoviciana.

PubMed

Said Fernández, Salvador; Ramos Guerra, Monica Celina; Mata Cárdenas, Benito David; Vargas Villarreal, Javier; Villarreal Treviño, Licet

2005-07-01

The inhabitants of Northeast of Mexico use an infusion of leaves from Artemisia ludoviciana as an antidiarrheal remedy. The aqueous, methanol, acetone and hexane leaf extracts from mature plants were found to be active in vitro against the parasitic protozoa Entamoeba histolytica and Giardia lamblia.

Growth-inhibiting effects of seco-tanapartholides identified in Artemisia princeps var. orientalis whole plant on human intestinal bacteria.

PubMed

Cho, S-H; Na, Y-E; Ahn, Y-J

2003-01-01

The present work aimed at isolating antibacterial constituents from the whole plant of Artemisia princeps var. orientalis active towards nine human intestinal bacteria. The growth-inhibiting activities of materials derived from the Artemisia whole plant towards test bacteria were examined using an impregnated paper disc method. The biologically active constituents of the Artemisia whole plant were characterized as the sesquiterpene lactones seco-tanapartholides A and B by spectroscopic analysis. In a test using 1 mg per disc, seco-tanapartholides A and B produced a clear inhibitory effect against Clostridium perfringens, Bacteroides fragilis and Staphylococcus aureus. These compounds did not affect the growth of test lactic acid-producing bacteria (Bifidobacterium adolescentis, Bif. breve, Lactobacillus acidophilus and Lact. casei) and Escherichia coli, whereas weak growth inhibition towards Bif. bifidum was observed. At 0.5 mg per disc, seco-tanapartholides A and B exhibited moderate growth inhibition towards Cl. perfringens but weak growth inhibition towards Bact. fragilis and Staph. aureus. Inhibitory action of seco-tanapartholides A and B towards specific bacteria without any adverse effects on lactic acid-producing bacteria may be an indication of at least one of the pharmacological actions of A. princeps var. orientalis whole plant. These naturally occurring Artemisia whole plant-derived materials could be useful as a new preventive agent against various diseases caused by harmful intestinal bacteria such as clostridia.

CHEMICAL AND BIOLOGICAL STABILITY OF ARTEMISININ IN COW RUMEN FLUID AND ITS KINETICS IN GOATS (CAPRA HIRCUS)

USDA-ARS?s Scientific Manuscript database

There is a pressing need to develop alternative, natural anthelmintics to control widespread drug-resistant gastrointestinal nematodes in ruminants, such as Haemonchus contortus. Artemisinin and its semi-synthetic derivatives are widely used against drug-resistant Plasmodium falciparum, but their r...

Update LADOTD policy on pile driving vibration management : tech summary.

DOT National Transportation Integrated Search

2012-02-01

Piles have often been used to transfer heavy loads to stronger soil strata or temporarily retain earth or water in highway and bridge : construction. The Louisiana Department of Transportation and Development (LADOTD) spends millions of dollars annua...

Total synthesis of rupestine G and its epimers

PubMed Central

Yusuf, Abdullah; Zhao, Jiangyu; Wang, Bianlin; Aibibula, Paruke; Aisa, Haji Akber

2018-01-01

Rupestine G is a guaipyridine sesquiterpene alkaloid isolated from Artemisia rupestris L. The total synthesis of rupestine G and its epimers was accomplished employing a Suzuki reaction to build a terminal diene moiety. The diene was further elaborated into the desired guaipyridine structure by a ring-closing metathesis reaction. Over all, rupestine G and its three epimers were obtained as a mixture in a sequence of nine linear steps with 18.9% yield. Rupestine G and its optically pure isomers were isolated by chiral preparative HPLC and fully characterized by 1H ,13C NMR, HRMS, optical rotation value, and experimental and calculated electronic circular dichroism spectroscopy. PMID:29657802

Sagebrush identification, ecology, and palatability relative to sage-grouse

Treesearch

Roger Rosentreter

2005-01-01

Basic identification keys and comparison tables for 23 low and big sagebrush (Artemisia) taxa are presented. Differences in sagebrush ecology, soil temperature regimes, geographic range, palatability, mineralogy, and chemistry are discussed. Coumarin, a chemical produced in the glands of some Artemisia species, causes UV-light fluorescence of the...

Big sagebrush (Artemisia tridentata) communities: Ecology, importance and restoration potential

Treesearch

Stephen B. Monsen; Nancy L. Shaw

2000-01-01

Big sagebrush (Artemisia tridentata Nutt.) is the most common and widespread sagebrush species in the Intermountain region. Climatic patterns, elevation gradients, soil characteristics and fire are among the factors regulating the distribution of its three major subspecies. Each of these subspecies is considered a topographic climax dominant....

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

PubMed

Agarwal, Drishti; Sharma, Manish; Dixit, Sandeep K; Dutta, Roshan K; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

2015-02-05

Emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT). Fluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters' four-day suppressive test. Promising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW). In vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives.

PubMed

de Lange, Christo; Coertzen, Dina; Smit, Frans J; Wentzel, Johannes F; Wong, Ho Ning; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

2017-12-26

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC 50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells. Copyright © 2017. Published by Elsevier Ltd.

A new synthetic biology approach allows transfer of an entire metabolic pathway from a medicinal plant to a biomass crop

PubMed Central

Fuentes, Paulina; Zhou, Fei; Erban, Alexander; Karcher, Daniel; Kopka, Joachim; Bock, Ralph

2016-01-01

Artemisinin-based therapies are the only effective treatment for malaria, the most devastating disease in human history. To meet the growing demand for artemisinin and make it accessible to the poorest, an inexpensive and rapidly scalable production platform is urgently needed. Here we have developed a new synthetic biology approach, combinatorial supertransformation of transplastomic recipient lines (COSTREL), and applied it to introduce the complete pathway for artemisinic acid, the precursor of artemisinin, into the high-biomass crop tobacco. We first introduced the core pathway of artemisinic acid biosynthesis into the chloroplast genome. The transplastomic plants were then combinatorially supertransformed with cassettes for all additional enzymes known to affect flux through the artemisinin pathway. By screening large populations of COSTREL lines, we isolated plants that produce more than 120 milligram artemisinic acid per kilogram biomass. Our work provides an efficient strategy for engineering complex biochemical pathways into plants and optimizing the metabolic output. DOI: http://dx.doi.org/10.7554/eLife.13664.001 PMID:27296645

Stabilizing supply of artemisinin and artemisinin-based combination therapy in an era of wide-spread scale-up.

PubMed

Shretta, Rima; Yadav, Prashant

2012-12-02

The global demand for artemisinin-based combination therapy (ACT) has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure appropriate purchasing and sales practices as well as minimum quality and ethical standards could help stabilize the artemisinin market in the long term.

Stabilizing supply of artemisinin and artemisinin-based combination therapy in an era of wide-spread scale-up

PubMed Central

2012-01-01

The global demand for artemisinin-based combination therapy (ACT) has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure appropriate purchasing and sales practices as well as minimum quality and ethical standards could help stabilize the artemisinin market in the long term. PMID:23198961

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

PubMed Central

2011-01-01

Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems. PMID:22152094

Spread of artemisinin resistance in Plasmodium falciparum malaria.

PubMed

Ashley, Elizabeth A; Dhorda, Mehul; Fairhurst, Rick M; Amaratunga, Chanaki; Lim, Parath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Mao, Sivanna; Sam, Baramey; Sopha, Chantha; Chuor, Char Meng; Nguon, Chea; Sovannaroth, Siv; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chotivanich, Kesinee; Chutasmit, Kitipumi; Suchatsoonthorn, Chaiyaporn; Runcharoen, Ratchadaporn; Hien, Tran Tinh; Thuy-Nhien, Nguyen Thanh; Thanh, Ngo Viet; Phu, Nguyen Hoan; Htut, Ye; Han, Kay-Thwe; Aye, Kyin Hla; Mokuolu, Olugbenga A; Olaosebikan, Rasaq R; Folaranmi, Olaleke O; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Newton, Paul N; Onyamboko, Marie A; Fanello, Caterina I; Tshefu, Antoinette K; Mishra, Neelima; Valecha, Neena; Phyo, Aung Pyae; Nosten, Francois; Yi, Poravuth; Tripura, Rupam; Borrmann, Steffen; Bashraheil, Mahfudh; Peshu, Judy; Faiz, M Abul; Ghose, Aniruddha; Hossain, M Amir; Samad, Rasheda; Rahman, M Ridwanur; Hasan, M Mahtabuddin; Islam, Akhterul; Miotto, Olivo; Amato, Roberto; MacInnis, Bronwyn; Stalker, Jim; Kwiatkowski, Dominic P; Bozdech, Zbynek; Jeeyapant, Atthanee; Cheah, Phaik Yeong; Sakulthaew, Tharisara; Chalk, Jeremy; Intharabut, Benjamas; Silamut, Kamolrat; Lee, Sue J; Vihokhern, Benchawan; Kunasol, Chanon; Imwong, Mallika; Tarning, Joel; Taylor, Walter J; Yeung, Shunmay; Woodrow, Charles J; Flegg, Jennifer A; Das, Debashish; Smith, Jeffery; Venkatesan, Meera; Plowe, Christopher V; Stepniewska, Kasia; Guerin, Philippe J; Dondorp, Arjen M; Day, Nicholas P; White, Nicholas J

2014-07-31

Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.

PubMed

Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

2015-04-01

Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. Copyright © 2015 Tun et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

PubMed Central

Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

2015-01-01

Summary Background Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. PMID:25704894

Big sagebrush response to one-way and two-way chaining in Southeastern Utah

Treesearch

John A. Fairchild; James N. Davis; Jack D. Brotherson

2005-01-01

A decadent, mixed stand of Wyoming big sagebrush, Artemisia tridentata wyomingensis, and mountain big sagebrush, Artemisia tridentata vaseyana, located north of Cisco, Utah, was subjected to one-way and two-way chaining treatments in November 1987. The effect of the treatments on plant community characteristics and shrub vigor was...

Chemical and biological diversity of the volatiles of five Artemisia species from far east of Russia

USDA-ARS?s Scientific Manuscript database

Aim of the present study was to investigate the chemical composition and biological activity of essential oils from aerial parts of Artemisia argyi, A. feddei, A. gmelinii, A. manshurica, A. olgensis (Asteraceae). Plants were collected in the Far East region (Primorski Krai) of the Russian Federatio...

Spectrophotometry of Artemisia tridentata to quantitatively determine subspecies

Treesearch

Bryce A. Richardson; Alicia A. Boyd; Tanner Tobiasson; Matthew J. Germino

2018-01-01

Ecological restoration is predicated on our abilities to discern plant taxa. Taxonomic identification is a first step in ensuring that plants are appropriately adapted to the site. An example of the need to identify taxonomic differences comes from big sagebrush (Artemisia tridentata). This species is composed of three predominant subspecies occupying distinct...

Artemisia L.: sagebrush

Treesearch

Susan E. Meyer

2008-01-01

Sagebrush - Artemisia L. - species are probably the most common shrubs in western North America. Big sagebrush alone occupies an estimated 60 million ha as a landscape dominant or codominant in the semiarid interior, and related species of the subgenus Tridentatae are estimated to occupy an additional 50 million ha (Beetle 1960; McArthur and Stevens in press)....

Volatile chemicals identified in extracts from leaves of Japanese mugwort (Artemisia princeps pamp.).

PubMed

Umano, K; Hagi, Y; Nakahara, K; Shoji, A; Shibamoto, T

2000-08-01

Extracts from leaves of Japanese mugwort (Artemisia princeps Pamp.) were obtained using two methods: steam distillation under reduced pressure followed by dichloromethane extraction (DRP) and simultaneous purging and extraction (SPSE). A total of 192 volatile chemicals were identified in the extracts obtained by both methods using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). They included 47 monoterpenoids (oxygenated monoterpenes), 26 aromatic compounds, 19 aliphatic esters, 18 aliphatic alcohols, 17 monoterpenes (hydrocarbon monoterpenes), 17 sesquiterpenes (hydrocarbon sesquiterpenes), 13 sesquiterpenoids (oxygenated sesquiterpenes), 12 aliphatic aldehydes, 8 aliphatic hydrocarbons, 7 aliphatic ketones, and 9 miscellaneous compounds. The major volatile constituents of the extract by DRP were borneol (10.27 ppm), alpha-thujone (3.49 ppm), artemisia alcohol (2.17 ppm), verbenone (1.85 ppm), yomogi alcohol (1.50 ppm), and germacren-4-ol (1.43 ppm). The major volatile constituents of the extract by SPSE were 1,8-cineole (8.12 ppm), artemisia acetate (4.22 ppm), alpha-thujone (3.20 ppm), beta-caryophyllene (2.39 ppm), bornyl acetate (2.05 ppm), borneol (1.80 ppm), and trans-beta-farnesene (1. 78 ppm).

Impact of retreatment with an artemisinin-based combination on malaria incidence and its potential selection of resistant strains: study protocol for a randomized controlled clinical trial

PubMed Central

2013-01-01

Background Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains. Design We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection. Trial registration NCT01374581 and PACTR201203000351114 PMID:24059911

Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

PubMed Central

Laman, Moses; Moore, Brioni R.; Benjamin, John M.; Yadi, Gumul; Bona, Cathy; Warrel, Jonathan; Kattenberg, Johanna H.; Koleala, Tamarah; Manning, Laurens; Kasian, Bernadine; Robinson, Leanne J.; Sambale, Naomi; Lorry, Lina; Karl, Stephan; Davis, Wendy A.; Rosanas-Urgell, Anna; Mueller, Ivo; Siba, Peter M.; Betuela, Inoni; Davis, Timothy M. E.

2014-01-01

Background Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y. Methods and Findings An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing. Conclusions Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000913077 Please see later in the article for the Editors' Summary PMID:25549086

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

PubMed

Dellicour, Stephanie; Sevene, Esperança; McGready, Rose; Tinto, Halidou; Mosha, Dominic; Manyando, Christine; Rulisa, Stephen; Desai, Meghna; Ouma, Peter; Oneko, Martina; Vala, Anifa; Rupérez, Maria; Macete, Eusébio; Menéndez, Clara; Nakanabo-Diallo, Seydou; Kazienga, Adama; Valéa, Innocent; Calip, Gregory; Augusto, Orvalho; Genton, Blaise; Njunju, Eric M; Moore, Kerryn A; d'Alessandro, Umberto; Nosten, Francois; Ter Kuile, Feiko; Stergachis, Andy

2017-05-01

Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. PROSPERO CRD42015032371.

Allergy to foods in patients monosensitized to Artemisia pollen.

PubMed

Garcia Ortiz, J C; Cosmes, P M; Lopez-Asunsolo, A

1996-12-01

It is known that patients with pollinosis may display clinical characteristics caused by allergy to certain fruits and vegetables, but subjects allergic to Artemisia seem to show particularly peculiar characteristics. The clinical features of 84 patients with rhinitis, asthma, urticaria, and/or anaphylaxis whose inhalant allergy was exclusively to Artemisia vulgaris were studied and compared with a control group of 50 patients monosensitized to grass pollen. The mean age for the beginning of symptoms was 30.2 years, and this was higher than in the control group (P < 0.05). We found the main incidence to be in women (70.2%). Some 42.3% had family history of atopia, lower than in the control group (P < 0.05), while the prevalence of asthma and urticaria was significantly higher (P < 0.05). Food hypersensitivity was reported by 23 patients (27.3%) allergic to Artemisia. The foods responsible (with respective numbers of cases) were honey (14), sunflower seeds (11), camomile (four), pistachio (three), hazelnut (two), lettuce (two), pollen (two), beer (two), almond (one), peanut (one), other nuts (one), carrot (one), and apple (one). None of the patients monosensitized to grass had food allergy. CAP inhibition experiments were carried out on a single patient. Results showed the existence of common antigenic epitopes in pistachio and Artemisia pollen for this patient. We concluded that mugwort hay fever can be associated with the Compositae family of foods, but that it is not normally associated with other foods.

Deceleration efficiencies of shrub windbreaks in a wind tunnel

NASA Astrophysics Data System (ADS)

Wu, Xiaoxu; Zou, Xueyong; Zhou, Na; Zhang, Chunlai; Shi, Sha

2015-03-01

Artemisia and Salix are dominant shrub species for windbreaks in arid areas of China, and they show similar features to shrubs in other arid areas of the world. We compared the mean velocity fields and shelter effects of two shrub windbreaks with different layouts. For a single plant of Artemisia, the higher the free airflow velocity is, the more the wind velocity around two sides of the plant increases. The velocity gradient around a single plant of Salix is smaller than that around an Artemisia plant due to the difference in the plant shapes. Seven new velocity zones in the horizontal direction appear when airflow passes through an Artemisia windbreak, including four deceleration zones and three acceleration zones. The mean velocity field that is affected by a Salix windbreak can be divided into a deceleration zone in the front, an acceleration zone above, a vortex zone behind and a restoration zone downwind of the vortex zone. Shelter effects of the shrub windbreaks vary with the wind velocity and are influenced by the construct of the windbreaks. Shrub windbreaks that have a complex construction have better shelter effects than simple ones. The shelter effects of plant windbreaks are also influenced by the growth features of the plants. Considering the plant characteristics and the shelter effects of Salix and Artemisia windbreaks, it is optimal to plant these two windbreaks together in a sand-control system. This research is intended to be useful for sand movement control in arid areas.

Effect of andrographolide on phosphatases activity and cytotoxicity against Spodoptera litura

USDA-ARS?s Scientific Manuscript database

Development of biorational insecticides from plant extracts, holds promise for many farmers in developing countries as an affordable alternative to commercially available pesticides. The chemical andrographolide was isolated using ethanol extraction of the leaves of Andrographis paniculata, an annua...

[Flavonoids of Artemisia campestris, ssp. glutinosa].

PubMed

Hurabielle, M; Eberle, J; Paris, M

1982-10-01

Four flavanones (pinostrobin, pinocembrin, sakuranetin and naringenin), one dihydroflavonol (7-methyl aromadendrin) and one flavone (hispidulin) have been isolated from Artemisia campestris L. ssp. glutinosa Gay and identified by spectroscopic methods. Artemisia campestris L. sous-espèce glutinosa Gay est une Composée Anthémidée largement répandue sur les sables du littoral méditerranéean et abondante dans certaines régions d'Espagne et d'Italie. Dans le cadre d'une étude chimiotaxonomique du genre Artemisia Tourn., nous nous sommes intéressés à l'analyse des flavonoïdes, composés jamais décrits, à notre connaissance, dans cette espèce d' Artemisia. Les sommités fleuries d' Artemisia campestris sous-espèce glutinosa, séchées et pulvérisées, sont dégraissées à l'ether de pétrole et épuisées par le chloroforme. Le fractionnement de l'extrait chloroformique, par chromatographie sur colonne de silice, et la purification de certaines fractions conduisent à l'isolement de six génines flavoniques, à l'etat pur. L' étude des spectres UV, des spectres de masse et des spectres de RMN [1,2] et la comparaison avec des échantillons authentiques permettent de proposer, pour ces flavonoïdes, les structures de la pinostrobine [3], de la pinocembrine [4], de la sakuranétine, de la naringénine [5] (flavanones), de la méthyl-7-aromadendrine, [6, 7] (dihydroflavonol) et de l'hispiduline [8, 9] (flavone); quatre de ces génines sont méthylées. Parmi ces flavonoïdes, la pinostrobine n'a jamais été décrite, à notre connaissance, dans la famille des Composées; la pinocembrine, la sakuranétine et la naringénine ont déjà été signalées chez quelques Astéracées et Eupatoriées [10], et l'hispiduline dans la tribu des Anthémidées ( Santolina chamaecyparissus L.) [8]. Seule, la méthyl-7-aromadendrine semble décrite, à ce jour, dans le genre Artemisia Tourn. [7].

Artemisinins from folklore to modern medicine--transforming an herbal extract to life-saving drugs.

PubMed

Weina, P J

2008-06-01

The history of the artemisinins from Ge Hong in China during the 4th century, to the re-discovery of the qing hao derivatives in the 1970s, to the explosion of artemisinin derivatives and combinations throughout the world today is a fascinating story. The central and underappreciated role of the United States Army's 'drug company' known as the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research is a story worth relating. From being the first group outside China to extract the active component of qing hao, to leading the work on neurotoxicity of the class in animals, to bringing a Good Manufacturing Practices intravenous formulation to the worldwide market is traced.

Global thermal niche models of two European grasses show high invasion risks in Antarctica.

PubMed

Pertierra, Luis R; Aragón, Pedro; Shaw, Justine D; Bergstrom, Dana M; Terauds, Aleks; Olalla-Tárraga, Miguel Ángel

2017-07-01

The two non-native grasses that have established long-term populations in Antarctica (Poa pratensis and Poa annua) were studied from a global multidimensional thermal niche perspective to address the biological invasion risk to Antarctica. These two species exhibit contrasting introduction histories and reproductive strategies and represent two referential case studies of biological invasion processes. We used a multistep process with a range of species distribution modelling techniques (ecological niche factor analysis, multidimensional envelopes, distance/entropy algorithms) together with a suite of thermoclimatic variables, to characterize the potential ranges of these species. Their native bioclimatic thermal envelopes in Eurasia, together with the different naturalized populations across continents, were compared next. The potential niche of P. pratensis was wider at the cold extremes; however, P. annua life history attributes enable it to be a more successful colonizer. We observe that particularly cold summers are a key aspect of the unique Antarctic environment. In consequence, ruderals such as P. annua can quickly expand under such harsh conditions, whereas the more stress-tolerant P. pratensis endures and persist through steady growth. Compiled data on human pressure at the Antarctic Peninsula allowed us to provide site-specific biosecurity risk indicators. We conclude that several areas across the region are vulnerable to invasions from these and other similar species. This can only be visualized in species distribution models (SDMs) when accounting for founder populations that reveal nonanalogous conditions. Results reinforce the need for strict management practices to minimize introductions. Furthermore, our novel set of temperature-based bioclimatic GIS layers for ice-free terrestrial Antarctica provide a mechanism for regional and global species distribution models to be built for other potentially invasive species. © 2017 John Wiley & Sons Ltd.

Model System to Define Pharmacokinetic Requirements for Antimalarial Drug Efficacy

PubMed Central

Bakshi, Rahul P.; Nenortas, Elizabeth; Tripathi, Abhai K.; Sullivan, David J.; Shapiro, Theresa A.

2013-01-01

Malaria presents a tremendous public health burden and new therapies are needed. Massive compound libraries screened against Plasmodium falciparum have yielded thousands of lead compounds, resulting in an acute need for rational criteria to select the best candidates for development. We reasoned that, akin to antibacterials, antimalarials might have an essential pharmacokinetic requirement for efficacy: action governed either by total exposure or peak concentration (AUC/CMAX), or by duration above a defined minimum concentration (Time above Minimum Inhibitory Concentration, TMIC). We devised an in vitro system for P. falciparum, capable of mimicking the dynamic fluctuations of a drug in vivo. Utilizing this apparatus, we find that chloroquine is TMIC-dependent while the efficacy of artemisinin is driven by CMAX. The latter was confirmed in a mouse model of malaria. These characteristics can explain the clinical success of two antimalarial drugs with widely different kinetics in humans. Chloroquine, which persists for weeks, is ideally suited for its TMIC mechanism, whereas great efficacy despite short exposure (t1/2 in blood 3 h or less) is attained by CMAX-driven artemisinins. This validated preclinical model system can be used to select those antimalarial lead compounds whose CMAX or TMIC requirement for efficacy match pharmacokinetics obtained in vivo. The apparatus can also be used to explore the kinetic-dependence of other pharmacodynamic endpoints in parasites. PMID:24089407

Essential oils of aromatic Egyptian plants repel nymphs of the tick Ixodes ricinus (Acari: Ixodidae).

PubMed

El-Seedi, Hesham R; Azeem, Muhammad; Khalil, Nasr S; Sakr, Hanem H; Khalifa, Shaden A M; Awang, Khalijah; Saeed, Aamer; Farag, Mohamed A; AlAjmi, Mohamed F; Pålsson, Katinka; Borg-Karlson, Anna-Karin

2017-09-01

Due to the role of Ixodes ricinus (L.) (Acari: Ixodidae) in the transmission of many serious pathogens, personal protection against bites of this tick is essential. In the present study the essential oils from 11 aromatic Egyptian plants were isolated and their repellent activity against I. ricinus nymphs was evaluated Three oils (i.e. Conyza dioscoridis L., Artemisia herba-alba Asso and Calendula officinalis L.) elicited high repellent activity in vitro of 94, 84.2 and 82%, respectively. The most active essential oil (C. dioscoridis) was applied in the field at a concentration of 6.5 µg/cm 2 and elicited a significant repellent activity against I. ricinus nymphs by 61.1%. The most repellent plants C. dioscoridis, C. officinalis and A. herba-alba yielded essential oils by 0.17, 0.11 and 0.14%, respectively. These oils were further investigated using gas chromatography-mass spectrometry analysis. α-Cadinol (10.7%) and hexadecanoic acid (10.5%) were the major components of C. dioscoridis whereas in C. officinalis, α-cadinol (21.2%) and carvone (18.2%) were major components. Artemisia herba-alba contained piperitone (26.5%), ethyl cinnamate (9.5%), camphor (7.7%) and hexadecanoic acid (6.9%). Essential oils of these three plants have a potential to be used for personal protection against tick bites.

Artemisia communities in arid zones of Uzbekistan (Central Asia)

Treesearch

Lyubov A. Kapustina; Montserrat Torrell; Joan Valles

2001-01-01

Central Asia, and particularly the former Soviet Middle Asian countries, with more than 180 taxa (45 endemics), is one of the centers of origin and speciation of the genus Artemisia L. (Asteraceae, Anthemideae). Several species of this genus, mainly belonging to subgenus Seriphidium (Besser) Rouy, are shrubs that dominate the landscape and form large communities in...

Abiotic and biotic influences on Bromus tectoreum invasion and Artemisia tridentata recovery after fire

Treesearch

Lea Condon; Peter J. Weisberg; Jeanne C. Chambers

2011-01-01

Native sagebrush ecosystems in the Great Basin (western USA) are often invaded following fire by exotic Bromus tectorum (cheatgrass), a highly flammable annual grass. Once B. tectorum is established, higher fire frequencies can lead to local extirpation of Artemisia tridentata ssp. vaseyana (mountain big sagebrush) and have cascading effects on sagebrush ecosystems and...

Seed production estimation for mountain big sagebrush (Artemisia tridentata ssp. vaseyana)

Treesearch

Melissa L. Landeen; Loreen Allphin; Stanley G. Kitchen; Steven L. Petersen

2017-01-01

Seed production is an essential component of postdisturbance recovery for mountain big sagebrush (Artemisia tridentata Nutt. ssp vaseyana [Rydb] Beetle; MBS). We tested a method for rapid estimation of MBS seed production using measurements of inflorescence morphology. We measured total stem length, stem length from first branchlet to stem tip, stem diameter, fresh...

Big sagebrush (Artemisia tridentata) in a shifting climate context: Assessment of seedling responses to climate

Treesearch

Martha A. Brabec

2014-01-01

The loss of big sagebrush (Artemisia tridentata) throughout the Great Basin Desert has motivated efforts to restore it because of fire and other disturbance effects on sagebrush-dependent wildlife and ecosystem function. Initial establishment is the first challenge to restoration, and appropriateness of seeds, climate, and weather variability are factors that may...

A molecular phylogenetic approach to western North America endemic Artemisia and allies (Asteraceae): Untangling the sagebrushes

Treesearch

Sonia Garcia; E. Durant McArthur; Jaume Pellicer; Stewart C. Sanderson; Joan Valles; Teresa Garnatje

2011-01-01

Premise of the study: Artemisia subgenus Tridentatae plants characterize the North American Intermountain West. These are landscape-dominant constituents of important ecological communities and habitats for endemic wildlife. Together with allied species and genera (Picrothamnus and Sphaeromeria), they make up an intricate series of taxa whose limits are uncertain,...

Seed germination of five Poa species at negative water potentials

USDA-ARS?s Scientific Manuscript database

Under field conditions water is often inadequate for satisfactory seed germination. An experiment was conducted to determine the effects of simulated dry conditions on germination and seedling growth of five bluegrass (Poa) species including: Texas, P. arachnifera Torr.; annual, P. annua L.; mutto...

Master Regulatory Genes, Auxin Levels, and Sexual Organogeneses in the Dioecious Plant Mercurialis annua

PubMed Central

Hamdi, Saïd; Teller, Gerard; Louis, Jean-Paul

1987-01-01

In Mercurialis annua L. (2n = 16) genes for sex determination are considered as major regulator genes controlling stamen and ovary development and sexual phenotypes. After stamen induction, sterility determinants control sporogenous tissue and pollen formation. Moreover, exogenous auxins are able to induce male flowers on female plants. In order to verify if sex and sterility genes have an effect on indole-3-acetic acid (IAA) contents of these plants, various wild or genetically constructed strains were assayed. The IAA levels of their apices were determined by HPLC followed by gas chromatography, selected ion monitoring, mass spectrometry. Results show that high auxin levels are linked to male phenotypes. The genes inducing maleness and the determinants of restored male fertility appear to control and modulate the IAA content. Close correspondence between the number of these dominant genes and IAA levels was established. A final hypothesis about the control of sexual specialization by phytohormones induced by the presence of these genes is discussed. Images Fig. 4 PMID:16665709

Artemisinin dimer anti-cancer activity correlates with heme-catalyzed ROS generation and ER stress induction

PubMed Central

Stockwin, Luke H.; Han, Bingnan; Yu, Sherry X.; Hollingshead, Melinda G.; ElSohly, Mahmoud A.; Gul, Waseem; Slade, Desmond; Galal, Ahmed M.; Newton, Dianne L.

2009-01-01

Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anti-cancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the anti-oxidant L-NAC, the iron chelator desferroxamine, and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity while inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage; iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian ER-resident SERCA Ca2+-ATPases. A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity. PMID:19533749

Methylene Homologues of Artemisone: An Unexpected Structure-Activity Relationship and a Possible Implication for the Design of C10-Substituted Artemisinins.

PubMed

Wu, Yuet; Wu, Ronald Wai Kung; Cheu, Kwan Wing; Williams, Ian D; Krishna, Sanjeev; Slavic, Ksenija; Gravett, Andrew M; Liu, Wai M; Wong, Ho Ning; Haynes, Richard K

2016-07-05

We sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Artemisone and artemiside - potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages.

PubMed

Coertzen, Dina; Reader, Janette; van der Watt, Mariëtte; Nondaba, Sindisiwe H; Gibhard, Liezl; Wiesner, Lubbe; Smith, Peter; D'Alessandro, Sarah; Taramelli, Donatella; Ning Wong, Ho; du Preez, Jan L; Wu, Ronald Wai Keung; Birkholtz, Lyn-Marie; Haynes, Richard K

2018-06-04

The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives towards the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes in the low nM range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displays notable synergism. These data suggest that modulation of redox-homeostasis likely is an important druggable process, particularly in gametocytes, and thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control. Copyright © 2018 American Society for Microbiology.

Artemisinin and Chinese Medicine as Tu Science.

PubMed

Fu, Jia-Chen

2017-09-01

The story of discovery of artemisinin highlights the diversity of scientific values across time and space. Resituating artemisinin research within a broader temporal framework allows us to understand how Chinese drugs like qinghao came to articulate a space for scientific experimentation and innovation through its embodiment of alternating clusters of meanings associated with tu and yang within scientific discourse. Tu science, which was associated with terms like native, Chinese, local, rustic, mass, and crude, articulated a radical vision of science in the service of socialist revolutionary ideals. Yang science, which signified foreign, Western, elite, and professional, tended to bear the hallmarks of professionalism, transnational networks in education and training, and an emphasis on basic or foundational research. With respect to medical research, the case of artemisinin highlights how the constitution of socialist science as an interplay of tu and yang engendered different scientific values and parameters for scientific endeavor. Modern medical research in Maoist China could harness the productive energies of mass participation to technical expertise in its investigations of Chinese drugs, and under the banner of tu science, it became possible and scientifically legitimate to research Chinese drugs in ways that had previously provoked resistance and controversy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evolutionary and ecological implications of genome size in the North American endemic sagebrushes and allies (Artemisia, Asteraceae)

Treesearch

Sonia Garcia; Miguel A. Canela; Teresa Garnatje; E. Durant McArthur; Jaume Pellicer; Stewart C. Sanderson; Joan Valles

2008-01-01

The genome size of 51 populations of 20 species of the North American endemic sagebrushes (subgenus Tridentatae), related species, and some hybrid taxa were assessed by flow cytometry, and were analysed in a phylogenetic framework. Results were similar for most Tridentatae species, with the exception of three taxonomically conflictive species: Artemisia bigelovii Gray...

Flowering branches cause injuries to second-year main stems of Artemisia tridentata nutt. subspecies tridentata

Treesearch

Lance S. Evans; Angela Citta; Stewart C. Sanderson

2012-01-01

Eccentricity of stems of Artemisia tridentata Nutt. (big sagebrush) has been reported previously. Analysis of samples observed over 2 years documented that each stem terminal produces about 8-10 branches each year, and during second-year growth, 3-8 of these develop into short, flowering, determinate branches. Each flowering branch produces hundreds of seeds and then...

Transcriptome characterization and polymorphism detection between subspecies of big sagebrush (Artemisia tridentata)

Treesearch

Prabin Bajgain; Bryce A. Richardson; Jared C. Price; Richard C. Cronn; Joshua A. Udall

2011-01-01

Big sagebrush (Artemisia tridentata) is one of the most widely distributed and ecologically important shrub species in western North America. This species serves as a critical habitat and food resource for many animals and invertebrates. Habitat loss due to a combination of disturbances followed by establishment of invasive plant species is a serious threat to big...

Ribosomal DNA, heterochromatin, and correlation with genome size in diploid and polyploid North American endemic sagebrushes (Artemisia, Asteraceae)

Treesearch

Sonia Garcia; Teresa Garnatje; Jaume Pellicer; E. Durant McArthur; Sonja Siljak-Yakovlev; Joan Valles

2009-01-01

Subgenus Tridentatae (Artemisia, Asteraceae) can be considered a polyploid complex. Both polyploidy and hybridization have been documented in the Tridentatae. Fluorescent in situ hybridization (FISH) and fluorochrome banding were used to detect and analyze ribosomal DNA changes linked to polyploidization in this group by studying four diploidpolyploid species pairs. In...

Deep sequencing of amplicons reveals widespread intraspecific hybridization and multiple origins of polyploidy in big sagebrush (Artemisia tridentata, Asteraceae)

Treesearch

Bryce A. Richardson; Justin T. Page; Prabin Bajgain; Stewart C. Sanderson; Joshua A. Udall

2012-01-01

Premise of the study: Hybridization has played an important role in the evolution and ecological adaptation of diploid and polyploid plants. Artemisia tridentata (Asteraceae) tetraploids are extremely widespread and of great ecological importance. These tetraploids are often taxonomically identified as A. tridentata subsp. wyomingensis or as autotetraploids of diploid...

Inhibitory effect of eupatilin and jaceosidin isolated from Artemisia princeps on carrageenan-induced inflammation in mice.

PubMed

Min, Sung-Won; Kim, Nam-Jae; Baek, Nam-In; Kim, Dong-Hyun

2009-09-25

Artemisia princeps Pampanini (family Asteraceae) is an herbal medicine widely used as a hepatoprotective, antioxidative, anti-inflammatory, and antibacterial agent in Korea, China, and Japan. This study aimed to elucidate the anti-inflammatory effect of the main constituents, eupatilin and jaceosidin, isolated from Artemisia princeps. We used carrageenan-induced inflammation in an air pouch on the back of mice and carrageenan-induced hind paw edema in rats to determine the anti-inflammatory effects of eupatilin and jaceosidin. Inflammatory makers, such as expression of pro-inflammatory cytokines and cyclooxygenase (COX)-2, and activation of nuclear factor-kappa B (NF-kappaB), were measured by enzyme-linked immunosorbent assays and immunoblot analyses. Eupatilin and jaceosidin blocked carrageenan-induced increase in leukocyte number and protein levels in air pouch exudates. Eupatilin and jaceosidin inhibited COX-2 expression and NF-kappaB activation, and markedly reduced TNF-alpha, IL-1beta, and prostaglandin E2 (PGE(2)) levels. They also inhibited hind paw edema induced by carrageenan. Eupatilin and jaceosidin had similar activity. These findings suggest that eupatilin and jaceosidin may reduce inflammation by inhibiting NF-kappaB activation, and that Artemisia princeps inhibits inflammation because of these constituents.

Chemical composition and antiprolifrative activity of Artemisia persica Boiss. and Artemisia turcomanica Gand. essential oils

PubMed Central

Nikbakht, M.R.; Sharifi, S.; Emami, S.A.; Khodaie, L.

2014-01-01

Essential oils obtained from aerial parts of Artemisia persica and Artemisia turcomanica were analyzed by GC/MS. While 28 components representing 91.01 % of A. persica were identified, the identity of 50 components, constituting 81.93 % of the total oil, was confirmed in A. turcomanica. β-thujone was the main compound (75.23%) in A. persica while the major identified phytochemicals in A. turcomanica were 1,8-cineol (19.23%), camphor (15.55%) and filifolone (15.53%). Both of the essential oils were predominantly made up of monoterpenes. Time- and dose-dependent cytotoxic effects of A. persica and A. turcomanica on MCF-7 cell line evaluated by MTT assay at 24, 48 and 72 h, showed that the highest cytotoxic effect of A. persica and A. turcomanica were appeared at 72 h incubation. At that incubation period, CI50 of A. persica was found to be 0.15 μg/ml, while that of A. turcomanica was 0.1 μg/ml. Thus, cytotoxicity of A. turcomanica was slightly higher than A. persica which could be attributed to the higher content of sesquiterpene present in A. turcomanica. As a conclusion, these volatile oils could have chemotherapeutic potentials. PMID:25657784

Chemical composition and antiprolifrative activity of Artemisia persica Boiss. and Artemisia turcomanica Gand. essential oils.

PubMed

Nikbakht, M R; Sharifi, S; Emami, S A; Khodaie, L

2014-01-01

Essential oils obtained from aerial parts of Artemisia persica and Artemisia turcomanica were analyzed by GC/MS. While 28 components representing 91.01 % of A. persica were identified, the identity of 50 components, constituting 81.93 % of the total oil, was confirmed in A. turcomanica. β-thujone was the main compound (75.23%) in A. persica while the major identified phytochemicals in A. turcomanica were 1,8-cineol (19.23%), camphor (15.55%) and filifolone (15.53%). Both of the essential oils were predominantly made up of monoterpenes. Time- and dose-dependent cytotoxic effects of A. persica and A. turcomanica on MCF-7 cell line evaluated by MTT assay at 24, 48 and 72 h, showed that the highest cytotoxic effect of A. persica and A. turcomanica were appeared at 72 h incubation. At that incubation period, CI50 of A. persica was found to be 0.15 μg/ml, while that of A. turcomanica was 0.1 μg/ml. Thus, cytotoxicity of A. turcomanica was slightly higher than A. persica which could be attributed to the higher content of sesquiterpene present in A. turcomanica. As a conclusion, these volatile oils could have chemotherapeutic potentials.

The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review.

PubMed

Burger, Renée J; Visser, Benjamin J; Grobusch, Martin P; van Vugt, Michèle

2016-02-18

Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy (ACT). However, small sample sizes make it difficult to draw strong conclusions based on individual pharmacokinetic studies. The aim of this review is to summarize the evidence of the influence of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. A PROSPERO-registered systematic review to identify clinical trials that investigated the influence of pregnancy on the pharmacokinetic properties of different forms of ACT was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2015. The following components of ACT that are currently recommend by the World Health Organization as first-line treatment of malaria in pregnancy were reviewed: artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil. The literature search identified 121 reports, 27 original studies were included. 829 pregnant women were included in the analysis. Comparison of the available studies showed lower maximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the active metabolite of all artemisinin derivatives, after oral administration of artemether, artesunate and dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seen in lumefantrine studies, indicating a low exposure and possibly reduced efficacy. The influence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant. Sulfadoxine plasma concentration was significantly reduced and clearance rates were higher in pregnancy, while pyrimethamine and mefloquine need more research as no general conclusion can be drawn based on the available evidence. For atovaquone, the available data showed a lower maximum concentration and exposure. Finally, the maximum concentration of cycloguanil, the active metabolite of proguanil, was significantly lower, possibly compromising the efficacy. These findings suggest that reassessment of the dose of the artemisinin derivate and some components of ACT are necessary to ensure the highest possible efficacy of malaria treatment in pregnant women. However, for most components of ACT, data were insufficient and extensive research with larger sample sizes will be necessary to identify the exact influences of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. In addition, different clinical studies used diverse study designs with various reported relevant outcomes. Future pharmacokinetic studies could benefit from more uniform designs, in order to increase quality, robustness and effectiveness. CRD42015023756 (PROSPERO).

Regional Supplement to the Corps of Engineers Wetland Delineation Manual: Great Plains Region (Version 2.0)

DTIC Science & Technology

2010-03-01

Dominant? Panicum virgatum Ambrosia artemisiifolia Iva annua Cardiospermum halicacabum Xanthium strumarium FACW FACU− FAC FAC FAC− 40 15 15...Xanthium strumarium Toxicodendron radicans3 15 12 8 6 4 45 3 135 FACU species Ambrosia artemisiifolia 15 15 4 60

Role of plant volatiles in host plant recognition by Listronotus maculicollis (Coleoptera: Curculionidae)

USDA-ARS?s Scientific Manuscript database

The annual bluegrass weevil (ABW), Listronotus maculicollis Kirby, is an economically important pest of short cut turfgrass. ABW females prefer annual bluegrass, Poa annua L., for oviposition, and this grass species is a more suitable host for larvae compared to bentgrasses (Agrostis spp.). We inves...

Seasonal soil CO2 flux under big sagebrush (Artemisia tridentata Nutt.)

Treesearch

Michael C. Amacher; Cheryl L. Mackowiak

2011-01-01

Soil respiration is a major contributor to atmospheric CO2, but accurate landscape-scale estimates of soil CO2 flux for many ecosystems including shrublands have yet to be established. We began a project to measure, with high spatial and temporal resolution, soil CO2 flux in a stand (11 x 25 m area) of big sagebrush (Artemisia tridentata Nutt.) at the Logan, Utah,...

Vegetation Resources of Rocky Mountain Arsenal, Adams County, Colorado

DTIC Science & Technology

1989-10-01

BE I Verbesina encelioides Cow-pen Daisy AF N 1’anthium strumarium Cocklebur AF A-4 Native/ Family/Species Common Name Life Form2 Introduced 3... strumarium Cocklebur Compositae SEMI-SHRUBS OR HALF-SHRUBS Artemisia dracunculus Green Sage Compositae Artomisia frigida Fringed Sagewort Compositae SHRUBS...Speedwell, Scrophulariaceae Xanthlum strumarium Cocklebur Coupos itae SEMI-SHRUBS OR HALF-SHRUBS Artemisia trigida. Fringed Sagewort Compositae ,.a

Projections of contemporary and future climate niche for Wyoming big sagebrush (Artemisia tridentate subsp. wyomingensis): A guide for restoration

Treesearch

Shannon M. Still; Bryce A. Richardson

2015-01-01

Big sagebrush (Artemisia tridentata) is one of the most widespread and abundant plant species in the intermountain regions of western North America. This species occupies an extremely wide ecological niche ranging from the semi-arid basins to the subalpine. Within this large niche, three widespread subspecies are recognized. Montane ecoregions are occupied by...

Narrow hybrid zone between two subspecies of big sagebrush (Artemisia tridentata: Asteraceae): XI. Plant-insect interactions in reciprocal transplant gardens

Treesearch

John H. Graham; E. Durant McArthur; D. Carl Freeman

2001-01-01

Basin big sagebrush (Artemisia tridentata ssp. tridentata) and mountain big sagebrush (A. t. ssp. vaseyana) hybridize in a narrow zone near Salt Creek, Utah. Reciprocal transplant experiments in this hybrid zone demonstrate that hybrids are more fit than either parental subspecies, but only in the hybrid zone. Do hybrids experience greater, or lesser, use by...

Antibacterial Action of Essential Oils of Artemisia as an Ecological Factor

PubMed Central

Nagy, Julius G.; Tengerdy, Robert P.

1967-01-01

Bacterial response to increasing amounts of the volatile oils varies significantly according to species of bacteria tested. Among the four species examined, Escherichia coli was the most resistant to the oils, followed by Neisseria sicca, Bacillus subtilis, and Staphylococcus aureus. The oils of Artemisia tridentata seem to have the same degree of antibacterial action as oils obtained from A. nova. PMID:4963443

Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester.

PubMed

Clark, Robert L

2017-08-15

The World Health Organization currently recommends quinine+clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing = 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine+pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine+pyrimethamine and artemether+lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios ≤2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above. Birth Defects Research 109:1075-1126, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites

PubMed Central

2010-01-01

Background Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum. Results A lineage of isogenic in vivo drug-selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (Illumina® Solexa) defined the point mutations, insertions, deletions and copy-number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme. Conclusions This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. PMID:20846421

Plasmodium falciparum Genetic Diversity in Continental Equatorial Guinea before and after Introduction of Artemisinin-Based Combination Therapy

PubMed Central

Guerra, Mónica; Neres, Rita; Salgueiro, Patrícia; Mendes, Cristina; Ndong-Mabale, Nicolas; Berzosa, Pedro; de Sousa, Bruno

2016-01-01

ABSTRACT Efforts to control malaria may affect malaria parasite genetic variability and drug resistance, the latter of which is associated with genetic events that promote mechanisms to escape drug action. The worldwide spread of drug resistance has been a major obstacle to controlling Plasmodium falciparum malaria, and thus the study of the origin and spread of associated mutations may provide some insights into the prevention of its emergence. This study reports an analysis of P. falciparum genetic diversity, focusing on antimalarial resistance-associated molecular markers in two socioeconomically different villages in mainland Equatorial Guinea. The present study took place 8 years after a previous one, allowing the analysis of results before and after the introduction of an artemisinin-based combination therapy (ACT), i.e., artesunate plus amodiaquine. Genetic diversity was assessed by analysis of the Pfmsp2 gene and neutral microsatellite loci. Pfdhps and Pfdhfr alleles associated with sulfadoxine-pyrimethamine (SP) resistance and flanking microsatellite loci were investigated, and the prevalences of drug resistance-associated point mutations of the Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps genes were estimated. Further, to monitor the use of ACT, we provide the baseline prevalences of K13 propeller mutations and Pfmdr1 copy numbers. After 8 years, noticeable differences occurred in the distribution of genotypes conferring resistance to chloroquine and SP, and the spread of mutated genotypes differed according to the setting. Regarding artemisinin resistance, although mutations reported as being linked to artemisinin resistance were not present at the time, several single nucleotide polymorphisms (SNPs) were observed in the K13 gene, suggesting that closer monitoring should be maintained to prevent the possible spread of artemisinin resistance in Africa. PMID:27795385