Статті в журналах: "Artemisinin activity"

1

Bai, Jennifer, Xiaochun Chen, and Curt I. Civin. "Nrf2 Regulates Sensitivity of Leukemias to Artemisinins." Blood 128, no. 22 (December 2, 2016): 2324. http://dx.doi.org/10.1182/blood.v128.22.2324.2324.

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Abstract The artemisinins are a class of drugs widely used to treat severe malaria due to their potency and few adverse effects. In addition to antimalarial activity, artemisinins have been shown to have potent anti-cancer activity, specifically in leukemia. Therefore, artesunate (AS), the WHO-recommended treatment for severe malaria, and a new dimeric artemisinin derivative (ART-838) are promising agents to repurpose for leukemia treatment. Reactive oxygen species (ROS) have been implicated in the mechanism of artemisinin activity in both malaria and cancer; however, the full mechanisms of artemisinin activity in cancer have not yet been elucidated. In 2014, Ariey et al, published a paper on malaria identifying the Kelch (K13) propeller domain as a molecular marker for artemisinin resistance. Since Keap1 ̶ the human homolog of K13 ̶ is involved in ROS regulation, it may also play a role in artemisinin action in cancer. To investigate the role of Keap1-Nrf2 signaling cascades in mediating artemisinin action and resistance in leukemia, qPCRs and Western blots were performed to quantify endogenous levels of selected Keap1 pathway molecules (Keap1, Nrf2, Nqo1, and Gsta1) in 23 human acute leukemia cell lines. However no significant correlation was observed between the levels of these molecules (mRNA or protein) and AS/ART-838 sensitivity. Using an antioxidant response element (ARE) luciferase reporter that can be activated by Nrf2, a significant increase in ARE activity was observed in K562 cells upon AS or ART-838 treatment. In addition to increased transcription upon drug treatment, the ARE downstream proteins Nqo1 and Gsta1 were upregulated upon AS or ART-838 treatment. K562 cell lines with Keap1 and Nrf2 stably knocked down (KD) were generated. The Nrf2 KD K562 cell line had increased sensitivity to AS and ART-838. In contrast, KD of Keap1 did not result in a substantial change in drug sensitivity to either artemisinin. In conclusion, these studies suggest involvement of Nrf2 in human leukemia cell resistance to artemisinins. Further studies on Nrf2 may help us better understand the molecular actions of the artemisinins in order to optimize their efficacy as single agents or in drug combinations for leukemia treatment. Disclosures No relevant conflicts of interest to declare.

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KANNAN, Rangiah, Krishan KUMAR, Dinkar SAHAL, Shrikant KUKRETI, and Virander S. CHAUHAN. "Reaction of artemisinin with haemoglobin: implications for antimalarial activity." Biochemical Journal 385, no. 2 (January 7, 2005): 409–18. http://dx.doi.org/10.1042/bj20041170.

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Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These ‘haemarts’ bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from ‘haemartoglobins’ may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.

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Mishina, Yuliya V., Sanjeev Krishna, Richard K. Haynes, and John C. Meade. "Artemisinins Inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense In Vitro Growth." Antimicrobial Agents and Chemotherapy 51, no. 5 (March 5, 2007): 1852–54. http://dx.doi.org/10.1128/aac.01544-06.

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ABSTRACT Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.

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Zhelyazkova, Margarita Y., Nadya G. Hristova-Avakumova, and Georgi Tsv Momekov. "Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells." Folia Medica 63, no. 4 (August 31, 2021): 488–95. http://dx.doi.org/10.3897/folmed.63.e55938.

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Aim: We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to  influence iron-induced oxidative damage of biologically relevant molecules. Materials and methods: MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose. Results: Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation. Conclusions: This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors.

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Teoh, Keat H., Devin R. Polichuk, Darwin W. Reed, and Patrick S. Covello. "Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annuaThis paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, no. 6 (June 2009): 635–42. http://dx.doi.org/10.1139/b09-032.

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Limitations in the supply of the antimalarial compound artemisinin from Artemisia annua L. have led to an interest in understanding its biosynthesis and enhancing its production. Recent biochemical and molecular genetic data have implicated dihydroartemisinic aldehyde as a precursor to the corresponding acid, which is then converted to artemisinin. Thus, it is important to understand the enzyme or enzymes involved in dihydroartemisinic aldehyde oxidation. Given its activity on artemisinic aldehyde, the cytochrome P450 CYP71AV1 was investigated for its ability to oxidize dihydroartemisinic aldehyde. However, no net activity was detected. In a search for alternative enzymes that could catalyze the oxidation, an expressed sequence tag (EST) collection from A. annua was investigated for relevant cDNAs. This led to the isolation of a full-length cDNA encoding an aldehyde dehydrogenase homologue, named Aldh1, which is highly expressed in trichomes. Expression of the cDNA in E. coli and characterization of the purified recombinant enzyme revealed that the gene product catalyses the NAD(P)-dependent oxidation of the putative artemisinin precursors, artemisinic and dihydroartemsinic aldehydes, and a limited range of other aldehydes. The observed enzyme activity of Aldh1 and the expression pattern of the corresponding gene suggest a role in artemisinin biosynthesis in the glandular secretory trichomes of A. annua.

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Zhu, Pan, and Bing Zhou. "The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum." Molecules 27, no. 6 (March 8, 2022): 1755. http://dx.doi.org/10.3390/molecules27061755.

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The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC50 values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug.

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Rosenberg, Alex, Madeline R. Luth, Elizabeth A. Winzeler, Michael Behnke, and L. David Sibley. "Evolution of resistance in vitro reveals mechanisms of artemisinin activity inToxoplasma gondii." Proceedings of the National Academy of Sciences 116, no. 52 (December 5, 2019): 26881–91. http://dx.doi.org/10.1073/pnas.1914732116.

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Artemisinins are effective against a variety of parasites and provide the first line of treatment for malaria. Laboratory studies have identified several mechanisms for artemisinin resistance inPlasmodium falciparum, including mutations in Kelch13 that are associated with delayed clearance in some clinical isolates, although other mechanisms are likely involved. To explore other potential mechanisms of resistance in parasites, we took advantage of the genetic tractability ofToxoplasma gondii, a related parasite that shows moderate sensitivity to artemisinin. Resistant populations ofT. gondiiwere selected by culture in increasing concentrations and whole-genome sequencing identified several nonconservative point mutations that emerged in the population and were fixed over time. Genome editing using CRISPR/Cas9 was used to introduce point mutations conferring amino acid changes in a serine protease homologous to DegP and a serine/threonine protein kinase of unknown function. Single and double mutations conferred a competitive advantage over wild-type parasites in the presence of drug, despite not changing EC50values. Additionally, the evolved resistant lines showed dramatic amplification of the mitochondria genome, including genes encoding cytochromeband cytochromecoxidase I. Prior studies in yeast and mammalian tumor cells implicate the mitochondrion as a target of artemisinins, and treatment of wild-type parasites with high concentrations of drug decreased mitochondrial membrane potential, a phenotype that was stably altered in the resistant parasites. These findings extend the repertoire of mutations associated with artemisinin resistance and suggest that the mitochondrion may be an important target of inhibition of resistance inT. gondii.

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Crespo-Ortiz, Maria P., and Ming Q. Wei. "Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug." Journal of Biomedicine and Biotechnology 2012 (2012): 1–18. http://dx.doi.org/10.1155/2012/247597.

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Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

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Nagamune, Kisaburo, Wandy L. Beatty, and L. David Sibley. "Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite Toxoplasma gondii." Eukaryotic Cell 6, no. 11 (August 31, 2007): 2147–56. http://dx.doi.org/10.1128/ec.00262-07.

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ABSTRACT Intracellular calcium controls several crucial cellular events in apicomplexan parasites, including protein secretion, motility, and invasion into and egress from host cells. The plant compound thapsigargin inhibits the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA), resulting in elevated calcium and induction of protein secretion in Toxoplasma gondii. Artemisinins are natural products that show potent and selective activity against parasites, making them useful for the treatment of malaria. While the mechanism of action is uncertain, previous studies have suggested that artemisinin may inhibit SERCA, thus disrupting calcium homeostasis. We cloned the single-copy gene encoding SERCA in T. gondii (TgSERCA) and demonstrate that the protein localizes to the endoplasmic reticulum in the parasite. In extracellular parasites, TgSERCA partially relocalized to the apical pole, a highly active site for regulated secretion of micronemes. TgSERCA complemented a calcium ATPase-defective yeast mutant, and this activity was inhibited by either thapsigargin or artemisinin. Treatment of T. gondii with artemisinin triggered calcium-dependent secretion of microneme proteins, similar to the SERCA inhibitor thapsigargin. Artemisinin treatment also altered intracellular calcium in parasites by increasing the periodicity of calcium oscillations and inducing recurrent, strong calcium spikes, as imaged using Fluo-4 labeling. Collectively, these results demonstrate that artemisinin perturbs calcium homeostasis in T. gondii, supporting the idea that Ca2+-ATPases are potential drug targets in parasites.

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Smeilus, Toni, Farnoush Mousavizadeh, Johannes Krieger, Xingzhao Tu, Marcel Kaiser, and Athanassios Giannis. "Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin." Beilstein Journal of Organic Chemistry 15 (February 27, 2019): 567–70. http://dx.doi.org/10.3762/bjoc.15.51.

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Herein, we describe a biomimetic entry to (+)-3-hydroxymethylartemisinin (2) as well as to the artemisinin derivatives (+)-3-hydroxymethyl-9-desmethylartemisinin (16) and (+)-3-hydroxymethyl-9-epi-artemisinin (18), starting from the known and readily available chiral aldehyde 3 and alkyne 4. Subsequently, the synthesized compounds have been evaluated for their antimalarial activity against the drug-sensitive P. falciparum NF54 strain. All of them were inactive. In addition, they did not show any toxicity against L6 cells (a primary cell line derived from rat skeletal myoblasts). These results contribute to a better understanding of artemisinins mechanism of action.

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Reyser, Thibaud, Lucie Paloque, Manel Ouji, Michel Nguyen, Sandie Ménard, Benoit Witkowski, Jean-Michel Augereau, and Françoise Benoit-Vical. "Identification of compounds active against quiescent artemisinin-resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA)." Journal of Antimicrobial Chemotherapy 75, no. 10 (July 12, 2020): 2826–34. http://dx.doi.org/10.1093/jac/dkaa250.

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Abstract Background Quiescence is an unconventional mechanism of Plasmodium survival, mediating artemisinin resistance. This phenomenon increases the risk of clinical failures following artemisinin-based combination therapies (ACTs) by slowing parasite clearance and allowing the selection of parasites resistant to partner drugs. Objectives To thwart this multiresistance, the quiescent state of artemisinin-resistant parasites must be taken into consideration from the very early stages of the drug discovery process. Methods We designed a novel phenotypic assay we have named the quiescent-stage survival assay (QSA) to assess the antiplasmodial activity of drugs on quiescent parasites. This assay was first validated on quiescent forms from different artemisinin-resistant parasite lines (laboratory strain and field isolates), using two reference drugs with different mechanisms of action: chloroquine and atovaquone. Furthermore, the efficacies of different partner drugs of artemisinins used in ACTs were investigated against both laboratory strains and field isolates from Cambodia. Results Our results highlight that because of the mechanism of quiescence and the respective pharmacological targets of drugs, drug efficacies on artemisinin-resistant parasites may be different between quiescent parasites and their proliferating forms. Conclusions These data confirm the high relevance of adding the chemosensitivity evaluation of quiescent parasites by the specific in vitro QSA to the antiplasmodial drug development process in the current worrisome context of artemisinin resistance.

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Domokos, Erzsébet, Béla Bíró-Janka, János Bálint, Katalin Molnár, Csaba Fazakas, László Jakab-Farkas, József Domokos, Csilla Albert, Gyöngyvér Mara, and Adalbert Balog. "Arbuscular Mycorrhizal Fungus Rhizophagus irregularis Influences Artemisia annua Plant Parameters and Artemisinin Content under Different Soil Types and Cultivation Methods." Microorganisms 8, no. 6 (June 15, 2020): 899. http://dx.doi.org/10.3390/microorganisms8060899.

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Artemisinin extracted from Artemisia annua has been used efficiently in malaria treatment since 2005. In this study, the variations in plant parameters (plant biomass, glandular trichome density, essential oil total chemical content, artemisinin production, and polyphenol oxidase (PPO) activity) were tested under different soil types (Luvisol, Gleysol, Anthrosol and sterile peat) and cultivation conditions (potted plants in semi-open field, and open field experiments) for plants inoculated with arbuscular mycorrhizal fungus (AMF) Rizophagus irregularis. Under semi-open field conditions, the AMF colonization of A. annua plant roots varied, and presented the highest percentage in Luvisol and sterile peat. The increase in the root colonization rate positively influenced some plant parameters (biomass, glandular trichome density, artemisinin concentration, essential oil quantity and composition), but no effects on PPO enzyme activity were detected. AMF fungus R. irregularis significantly increased the artemisinin content and essential oil yield of plants cultivated in Luvisol, Gleysol, Anthrosol and in peat. These soil types can offer appropriate conditions for A. annua cultivation and artemisinin production even on a smaller scale. Under open field conditions, low (about 5%) AMF colonization was observed. No differences in artemisin contents were detected, but essential oil yield significantly increased compared to control plants. AMF treatment increased beta-farnesene and germacrene D concentrations in Artemisia plants in the open field experiment.

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Fügi, Matthias A., Sergio Wittlin, Yuxiang Dong, and Jonathan L. Vennerstrom. "Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals." Antimicrobial Agents and Chemotherapy 54, no. 3 (December 22, 2009): 1042–46. http://dx.doi.org/10.1128/aac.01305-09.

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ABSTRACT Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions, resulting in a lower proportion of radicals available for subsequent chemical reactions such as the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets.

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Li, Yue, Xiaoyan Zhou, Jiali Liu, Xiaohong Yuan, and Qian He. "Therapeutic Potentials and Mechanisms of Artemisinin and its Derivatives for Tumorigenesis and Metastasis." Anti-Cancer Agents in Medicinal Chemistry 20, no. 5 (May 28, 2020): 520–35. http://dx.doi.org/10.2174/1871520620666200120100252.

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Background: Tumor recurrence and metastasis are still leading causes of cancer mortality worldwide. The influence of traditional treatment strategies against metastatic tumors may still be limited. To search for novel and powerful agents against tumors has become a major research focus. In this study, Artemisinin (ARM), a natural compound isolated from herbs, Artemisia annua L., proceeding from drug repurposing methods, attracts more attention due to its good efficacy and tolerance in antimalarial practices, as well as newly confirmed anticancer activity. Methods: We have searched and reviewed the literatures about ARM and its derivatives (ARMs) for cancer using keywords "artemisinin" until May 2019. Results: In preclinical studies, ARMs can induce cell cycle arrest and cell death by apoptosis etc., to inhibit the progression of tumors, and suppress EMT and angiogenesis to inhibit the metastasis of tumors. Notably, the complex relationships of ARMs and autophagy are worth exploring. Inspired by the limitations of its antimalarial applications and the mechanical studies of artemisinin and cancer, people are also committed to develop safer and more potent ARM-based modified compounds (ARMs) or combination therapy, such as artemisinin dimers/ trimers, artemisinin-derived hybrids. Some clinical trials support artemisinins as promising candidates for cancer therapy. Conclusion: ARMs show potent therapeutic potentials against carcinoma including metastatic tumors. Novel compounds derived from artemisinin and relevant combination therapies are supposed to be promising treatment strategies for tumors, as the important future research directions.

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He, Ran, Michael Forman, Bryan T. Mott, Rajkumar Venkatadri, Gary H. Posner, and Ravit Arav-Boger. "Unique and Highly Selective Anticytomegalovirus Activities of Artemisinin-Derived Dimer Diphenyl Phosphate Stem from Combination of Dimer Unit and a Diphenyl Phosphate Moiety." Antimicrobial Agents and Chemotherapy 57, no. 9 (June 17, 2013): 4208–14. http://dx.doi.org/10.1128/aac.00893-13.

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ABSTRACTWe 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.

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Galal, Ahmed M., Samir A. Ross, Melissa Jacob, and Mahmoud A. ElSohly. "Antifungal Activity of Artemisinin Derivatives." Journal of Natural Products 68, no. 8 (August 2005): 1274–76. http://dx.doi.org/10.1021/np050074u.

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Yang, Tuo, Stanley C. Xie, Pengxing Cao, Carlo Giannangelo, James McCaw, Darren J. Creek, Susan A. Charman, Nectarios Klonis, and Leann Tilley. "Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains." Antimicrobial Agents and Chemotherapy 60, no. 8 (May 9, 2016): 4501–10. http://dx.doi.org/10.1128/aac.00574-16.

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ABSTRACTFully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of thein vitroresponses ofPlasmodium falciparumto the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to theirin vivoexposure, the ozonide antimalarials were markedly more effective.

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Tjahjani, Susy, Yonathan Biantoro, and Rita Tjokropranoto. "Ethyl acetate Fraction of Garcinia Mangostana L Rind Study as Antimalaria and Antioxidant in Plasmodium berghei Inoculated Mice." Open Access Macedonian Journal of Medical Sciences 7, no. 12 (July 7, 2019): 1935–39. http://dx.doi.org/10.3889/oamjms.2019.480.

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BACKGROUND: Drug resistance to malaria is still a problem in various regions, and there have even been developments in resistance to the ACTs (artemisinin-based combination therapies) as standard antimalarial drugs included to artemisinin’s partner drugs. Ethyl acetate fraction of G. mangostana L rind, containing xanthones as an antioxidant, has antimalarial activity in vitro which has a synergistic effect with artemisinin. That’s why the activities of this fraction are needed to be studied in vivo. AIM: To explore the antimalarial and antioxidant activity of ethyl acetate fraction of Garcinia mangostana L rind in mice. METHODS: This was a complete randomised design true experimental study. Six groups of mice: a healthy mice group and 5 groups of Plasmodium berghei inoculated mice treated with various doses of the sample for 3 days compared to artemisinin. Parasitemia and total antioxidant status were examined and analysed using ANOVA, and probit analysis were done.RESULTS: The parasitemia level in all of the treatment groups were lower than the positive control group without treatment (p < 0.01) and the parasitemia level was the lowest in artemisinin group which was not significantly different from the 100 mg/kg body weight dose group (p > 0.05). The parasitemia level in 20 and 4 mg/kg body weight dose groups were higher than the artemisinin group (p < 0.01). Parasite growth inhibition rate from the highest to the lowest consecutively was: artemisinin, 100 mg/kg body weight, 20 mg/kg body weight, 4 mg/kg body weight, and positive control group (p < 0.05) and ED50 was 3.396 mg/kg body weight. Total antioxidant status was the highest in 20 mg/ kg body weight dose and higher than the negative control group (p < 0.05) while the lowest total antioxidant status was in the positive control group. CONCLUSION: Ethyl acetate fraction of G. mangostana L rind potentially showed antimalarial and antioxidant activity in vivo. Further study is needed to explore the detail of its mechanism of action and its quantitative phytochemical analysis to find the leading compound in it.

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Lydon, John, John R. Teasdale, and Peter K. Chen. "Allelopathic activity of annual wormwood (Artemisia annua) and the role of artemisinin." Weed Science 45, no. 6 (December 1997): 807–11. http://dx.doi.org/10.1017/s0043174500089001.

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Leaf tissue and leaf-tissue extracts from annual wormwood and pure artemisinin were evaluated for their effects on plant growth when incorporated into sandy loam soil. Dried leaf tissue was successively extracted with methylene chloride (MeCl2), ethanol (EtOH), and water, and the extracts and residue were reduced to dryness and stored at −20 C. Leaf tissue was incorporated in soil at rates equivalent to 0, 0.37, 0.73, or 1.1% (w/w) based on soil dry weight. Peat moss treated with extracts or artemisinin was incorporated into soil at a rate equivalent to the 0.73% (w/w) treatment. Inhibition of growth was species-specific; estimated reduction of dry weight by 0.73% (w/w) leaf tissue was 82, 49, 25, and 9% for redroot pigweed, common lambsquarters, soybean, and corn, respectively. The effects of the MeCl2extract, which contained all of the extractable artemisinin, on germination and growth of redroot pigweed were similar to that of leaf tissue. Annual wormwood leaf tissue and MeCl2-extract treatments were the only treatments that resulted in a reduction in seedling survival. Artemisinin at levels equivalent to that contained in the MeCl2extract and leaf-tissue treatments had significantly less effect on seedling survival, germination, and growth of redroot pigweed than the MeCl2extract. Furthermore, the aqueous extract, which did not contain artemisinin, and the extract residue had activities similar to that of the artemisinin treatment. Thus, the allelopathic effects of annual wormwood can not be attributed to artemisinin alone.

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20

Nagelschmitz, Johannes, Barbara Voith, Georg Wensing, Axel Roemer, Burkhard Fugmann, Richard K. Haynes, Barbara M. Kotecka, Karl H. Rieckmann, and Michael D. Edstein. "First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 16, 2008): 3085–91. http://dx.doi.org/10.1128/aac.01585-07.

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ABSTRACT In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.

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21

Bilia, Anna Rita, Marcel Kaiser, Franco Francesco Vincieri, and Deniz Tasdemir. "Antitrypanosomal and Antileishmanial Activities of Organic and Aqueous Extracts of Artemisia Annua." Natural Product Communications 3, no. 12 (December 2008): 1934578X0800301. http://dx.doi.org/10.1177/1934578x0800301204.

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Artemisia annua is an herbal drug with profound antimalarial activity, which can be ascribed to the sesquiterpene lactone artemisinin. Artemisinin also shows efficacy against other parasitic protozoan species, such as Trypanosoma and Leishmania, however trypanocidal and leishmanicidal effects of A. annua extracts have not been reported so far. In the current study, we evaluated the in vitro growth inhibitory activity of a number of organic and aqueous A. annua extracts, including tinctures, infusions and decoctions against three parasitic protozoa, T. brucei rhodesiense, T. cruzi and L. donovani. Artemisinin content of these extracts was determined by HPLC/DAD/MS. Artemisinin was also evaluated for its antiparasitic activity for comparison. Among the tested extracts, the acetone- and the n-hexane-solubles of A. annua were the most potent against T. b. rhodesiense with IC50 values of 0.30 and 0.455 μg/mL, respectively, whereas the other extracts were ten- to fifty-fold less potent. Neither of the extracts nor artemisinin had trypanocidal activity against T. cruzi (IC50 > 30 μg/mL). Only the organic extracts of A. annua arrested the growth of L. donovani with modest IC50 values (5.1 to 9.0 μg/mL) comparable to that of artemisinin (IC50 8.8 μg/mL). This study highlights significant variations in the artemisinin content of A. annua extracts and underlines the potential of A. annua extracts and artemisinin in the treatment of trypanosomal and leishmanial infections.

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Posner, Gary H., John D’Angelo, Paul M O’Neill, and Amy Mercer. "Anticancer activity of artemisinin-derived trioxanes." Expert Opinion on Therapeutic Patents 16, no. 12 (November 22, 2006): 1665–72. http://dx.doi.org/10.1517/13543776.16.12.1665.

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23

Kalra, Sourav, Gaurav Joshi, Raj Kumar, and Anjana Munshi. "Role of 2-Dimensional Autocorrelation Descriptors in Predicting Antimalarial Activity of Artemisinin and its Aanalogues: A QSAR Study." Current Topics in Medicinal Chemistry 18, no. 31 (February 22, 2019): 2720–30. http://dx.doi.org/10.2174/1568026619666190119143838.

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Background: Malaria, one of the World’s biggest billers’ is on the schedule for biomedical research and public health policies. The introduction of the artemisinin, a Chinese traditional drug from Artemisia annua is a revolution in the treatment of malaria. Artemisinin-based combination treatment (ACT) is considered to be the best strategy for uncomplicated Falciparum malaria. The presence of 1,2,4-trioxane system in artemisinin is responsible for its antimalarial activity. Methods: In this study, twenty-nine analogues of artemisinin were taken into account for QSAR studies along with artemisinin. The most active analogue of artemisinin 21 was energy minimized. All the structures were prepared from the active conformer 21 and energy was minimized to the stable state using MMFF94 force field using ChemBioDraw-12. Genetic Algorithm is used to decide the descriptors best required for the model generation. The test set and training set division were done by using hierarchal clustering module available with NCSS statistical software. Results and Conclusion: The antimalarial activity of the artemisinin and its substituted analogues has been analyzed through the multiple linear regression (MLR) using various physiochemical and structural descriptors obtained from PADEL software. The models were prepared using the Sigma Plot version 11. The calculated 2D autocorrelation descriptors and the MLR model suggest that artemisinin and its analogues hold the scope in the optimization of antimalarial activity.

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Lezama-Dávila, Claudio M., Abhay R. Satoskar, Mirna Úc-Encalada, Ricardo Isaac-Márquez, and Angélica P. Isaac-Márquez. "Leishmanicidal Activity of Artemisinin, Deoxoartemisinin, Artemether and Arteether." Natural Product Communications 2, no. 1 (January 2007): 1934578X0700200. http://dx.doi.org/10.1177/1934578x0700200101.

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In this work we studied the in vitro toxicity of artemisinin and its chemical derivatives deoxoartemisinin, artemether and arteether against stationary phase promastigotes of Leishmania (L) mexicana. Results presented in this work include dramatic changes in parasite morphology when they were cultured in the presence of these chemicals. These changes were accompanied by the parasite's lost of mobility and eventual death after four days of culturing. We also observed that parasite growth was much more effectively reduced in cultures carried out in the presence of either artemisinin or its semi-synthetic derivatives than the reference drug N-methyl meglumine (Glucantime™, Rhone Poulenc, France). The compounds tested in this work were not toxic to Hela cells cultured in vitro. This is the first report describing the promising potential use of Qinghaosu (artemisinin) and related chemical analogues to treat L (L) mexicana infections.

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Roy, Sujayita, Arun Kapoor, Fei Zhu, Rupkatha Mukhopadhyay, Ayan Kumar Ghosh, Hyun Lee, Jennifer Mazzone, Gary H. Posner, and Ravit Arav-Boger. "Artemisinins target the intermediate filament protein vimentin for human cytomegalovirus inhibition." Journal of Biological Chemistry 295, no. 44 (August 27, 2020): 15013–28. http://dx.doi.org/10.1074/jbc.ra120.014116.

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The antimalarial agents artemisinins inhibit cytomegalovirus (CMV) in vitro and in vivo, but their target(s) has been elusive. Using a biotin-labeled artemisinin, we identified the intermediate filament protein vimentin as an artemisinin target, validated by detailed biochemical and biological assays. We provide insights into the dynamic and unique modulation of vimentin, depending on the stage of human CMV (HCMV) replication. In vitro, HCMV entry and viral progeny are reduced in vimentin-deficient fibroblasts, compared with control cells. Similarly, mouse CMV (MCMV) replication in vimentin knockout mice is significantly reduced compared with controls in vivo, confirming the requirement of vimentin for establishment of infection. Early after HCMV infection of human foreskin fibroblasts vimentin level is stable, but as infection proceeds, vimentin is destabilized, concurrent with its phosphorylation and virus-induced calpain activity. Intriguingly, in vimentin-overexpressing cells, HCMV infection is reduced compared with control cells. Binding of artesunate, an artemisinin monomer, to vimentin prevents virus-induced vimentin degradation, decreasing vimentin phosphorylation at Ser-55 and Ser-83 and resisting calpain digestion. In vimentin-deficient fibroblasts, the anti-HCMV activity of artesunate is reduced compared with controls. In summary, an intact and stable vimentin network is important for the initiation of HCMV replication but hinders its completion. Artesunate binding to vimentin early during infection stabilizes it and antagonizes subsequent HCMV-mediated vimentin destabilization, thus suppressing HCMV replication. Our target discovery should enable the identification of vimentin-binding sites and compound moieties for binding.

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26

Luo, Jiaer, Rebecca Mobley, Sian Woodfine, Falko Drijfhout, Paul Horrocks, Xiao-Dong Ren, and Wen-Wu Li. "Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger." Applied Microbiology and Biotechnology 106, no. 7 (March 31, 2022): 2433–44. http://dx.doi.org/10.1007/s00253-022-11888-0.

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Abstract Artemisinin is a component part of current frontline medicines for the treatment of malaria. The aim of this study is to make analogues of artemisinin using microbial transformation and evaluate their in vitro antimalarial activity. A panel of microorganisms were screened for biotransformation of artemisinin (1). The biotransformation products were extracted, purified and isolated using silica gel column chromatography and semi-preparative HPLC. Spectroscopic methods including LC-HRMS, GC–MS, FT-IR, 1D and 2D NMR were used to elucidate the structure of the artemisinin metabolites.1H NMR spectroscopy was further used to study the time-course biotransformation. The antiplasmodial activity (IC50) of the biotransformation products of 1 against intraerythrocytic cultures of Plasmodium falciparum were determined using bioluminescence assays. A filamentous fungus Aspergillus niger CICC 2487 was found to possess the best efficiency to convert artemisinin (1) to a novel derivative, 4-methoxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (2) via ring rearrangement and further degradation, along with three known derivatives, compound (3), deoxyartemisinin (4) and 3-hydroxy-deoxyartemisinin (5). Kinetic study of the biotransformation of artemisinin indicated the formation of artemisinin G as a key intermediate which could be hydrolyzed and methylated to form the new compound 2. Our study shows that the anti-plasmodial potency of compounds 2, 3, 4 and 5 were ablated compared to 1, which attributed to the loss of the unique peroxide bridge in artemisinin (1). This is the first report of microbial degradation and ring rearrangement of artemisinin with subsequent hydrolysis and methoxylation by A.niger. Key points • Aspergillus niger CICC 2487 was found to be efficient for biotransformation of artemisinin • A novel and unusual artemisinin derivative was isolated and elucidated • The peroxide bridge in artemisinin is crucial for its high antimalarial potency • The pathway of biotransformation involves the formation of artemisinin G as a key intermediate

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Shi, Henan, Zhuqing Wang, Fujie Xu, Jialin Li, Jing Li, and Manyuan Wang. "A Discovery-Based Metabolomic Approach Using UPLC-Q-TOF-MS/MS Reveals Potential Antimalarial Compounds Present in Artemisia annua L." International Journal of Molecular Sciences 23, no. 23 (November 28, 2022): 14903. http://dx.doi.org/10.3390/ijms232314903.

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In 1972, Nobel laureate Youyou Tu’s research team conducted clinical trials on the dried material of Artemisia annua L. from Beijing extracted by ether and then treated with alkali (called “ether neutral dry”), which showed that artemisinin was not the only antimalarial component contained. The biosynthesis of sesquiterpenoids in A. annua has increased exponentially after unremitting cultivation efforts, and the plant resources are now quite different from those in the 1970s. In consideration of emerging artemisinin resistance, it is of great theoretical and practical value to further study the antimalarial activity of A. annua and explore its causes. The purpose of this study is to clarify scientific questions, such as “What ingredients are synergistic with artemisinin in A. annua?”, and “Are there non-artemisinin antimalarial ingredients in A. annua?”. In this paper, Beijing wild A. annua was used as a control and two representative cultivation species of A. annua were selected to evaluate the antimalarial activity of the herbal medicine. The antimalarial activity of different extracts on mice was studied using the Peters’ four-day suppressive test. UPLC-Q-TOF-MS was used to obtain mass spectrum data for all samples, and a UNIFI platform was used for identification. A multivariate statistical method was used to screen the different compounds with positive correlations. The antimalarial activity of different components from the ether extract and alkali treatments was determined and antimalarial components other than artemisinin were obtained. A total of 24 flavonoids, 68 sesquiterpenoids and 21 other compounds were identified. Compounds associated with differential antimalarial activity were identified. The material basis for the antimalarial activity of A. annua was clarified. The antimalarial components of A. annua include two categories: first, artemisinin and non-artemisinin antimalarial active components, of which the non-artemisinin antimalarial active components may include 5α-hydroperoxy-eudesma-4(15),11-diene; second, several antimalarial synergistic ingredients in A. annua, including arteanniun B, arteanniun B analogues and polymethoxy flavonoids.

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Kumar, Maushmi S., Tanuja T. Yadav, Rohan R. Khair, Godefridus J. Peters, and Mayur C. Yergeri. "Combination Therapies of Artemisinin and its Derivatives as a Viable Approach for Future Cancer Treatment." Current Pharmaceutical Design 25, no. 31 (November 14, 2019): 3323–38. http://dx.doi.org/10.2174/1381612825666190902155957.

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Background: Many anticancer drugs have been developed for clinical usage till now, but the major problem is the development of drug-resistance over a period of time in the treatment of cancer. Anticancer drugs produce huge adverse effects, ultimately leading to death of the patient. Researchers have been focusing on the development of novel molecules with higher efficacy and lower toxicity; the anti-malarial drug artemisinin and its derivatives have exhibited cytotoxic effects. Methods: We have done extensive literature search for artemisinin for its new role as anti-cancer agent for future treatment. Last two decades papers were referred for deep understanding to strengthen its role. Results: Literature shows changes at 9, 10 position in the artemisinin structure produces anticancer activity. Artemisinin shows anticancer activity in leukemia, hepatocellular carcinoma, colorectal and breast cancer cell lines. Artemisinin and its derivatives have been studied as combination therapy with several synthetic compounds, RNA interfaces, recombinant proteins and antibodies etc., for synergizing the effect of these drugs. They produce an anticancer effect by causing cell cycle arrest, regulating signaling in apoptosis, angiogenesis and cytotoxicity activity on the steroid receptors. Many novel formulations of artemisinin are being developed in the form of carbon nanotubes, polymer-coated drug particles, etc., for delivering artemisinin, since it has poor water/ oil solubility and is chemically unstable. Conclusion: We have summarize the combination therapies of artemisinin and its derivatives with other anticancer drugs and also focussed on recent developments of different drug delivery systems in the last 10 years. Various reports and clinical trials of artemisinin type drugs indicated selective cytotoxicity along with minimal toxicity thus projecting them as promising anti-cancer agents in future cancer therapies.

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Ponnusamy, Chandrasekar, Abimanyu Sugumaran, Venkateshwaran Krishnaswami, Rajaguru Palanichamy, Ravichandiran Velayutham, and Subramanian Natesan. "Development and Evaluation of Polyvinylpyrrolidone K90 and Poloxamer 407 Self-Assembled Nanomicelles: Enhanced Topical Ocular Delivery of Artemisinin." Polymers 13, no. 18 (September 8, 2021): 3038. http://dx.doi.org/10.3390/polym13183038.

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Age-related macular degeneration is a multifactorial disease affecting the posterior segment of the eye and is characterized by aberrant nascent blood vessels that leak blood and fluid. It ends with vision loss. In the present study, artemisinin which is poorly water-soluble and has potent anti-angiogenic and anti-inflammatory properties was formulated into nanomicelles and characterized for its ocular application and anti-angiogenic activity using a CAM assay. Artemisinin-loaded nanomicelles were prepared by varying the concentrations of PVP k90 and poloxamer 407 at different ratios and showed spherical shape particles in the size range of 41–51 nm. The transparency and cloud point of the developed artemisinin-loaded nanomicelles was found to be 99–94% and 68–70 °C, respectively. The in vitro release of artemisinin from the nanomicelles was found to be 96.0–99.0% within 8 h. The trans-corneal permeation studies exhibited a 1.717–2.169 µg permeation of the artemisinin from nanomicelles through the excised rabbit eye cornea for 2 h. Drug-free nanomicelles did not exhibit noticeable DNA damage and showed an acceptable level of hemolytic potential. Artemisinin-loaded nanomicelles exhibited remarkable anti-angiogenic activity compared to artemisinin suspension. Hence, the formulated artemisinin-loaded nanomicelles might have the potential for the treatment of AMD.

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Lv, Zongyou, Zhiying Guo, Lida Zhang, Fangyuan Zhang, Weimin Jiang, Qian Shen, Xueqing Fu, et al. "Interaction of bZIP transcription factor TGA6 with salicylic acid signaling modulates artemisinin biosynthesis in Artemisia annua." Journal of Experimental Botany 70, no. 15 (April 11, 2019): 3969–79. http://dx.doi.org/10.1093/jxb/erz166.

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Abstract Artemisinin is a sesquiterpene lactone produced by the Chinese traditional herb Artemisia annua and is used for the treatment of malaria. It is known that salicylic acid (SA) can enhance artemisinin content but the mechanism by which it does so is not known. In this study, we systematically investigated a basic leucine zipper family transcription factor, AaTGA6, involved in SA signaling to regulate artemisinin biosynthesis. We found specific in vivo and in vitro binding of the AaTGA6 protein to a ‘TGACG’ element in the AaERF1 promoter. Moreover, we demonstrated that AaNPR1 can interact with AaTGA6 and enhance its DNA-binding activity to its cognate promoter element ‘TGACG’ in the promoter of AaERF1, thus enhancing artemisinin biosynthesis. The artemisinin contents in AaTGA6-overexpressing and RNAi transgenic plants were increased by 90–120% and decreased by 20–60%, respectively, indicating that AaTGA6 plays a positive role in artemisinin biosynthesis. Importantly, heterodimerization with AaTGA3 significantly inhibits the DNA-binding activity of AaTGA6 and plays a negative role in target gene activation. In conclusion, we demonstrate that binding of AaTGA6 to the promoter of the artemisinin-regulatory gene AaERF1 is enhanced by AaNPR1 and inhibited by AaTGA3. Based on these findings, AaTGA6 has potential value in the genetic engineering of artemisinin production.

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Muangphrom, Paskorn, Munenori Suzuki, Hikaru Seki, Ery Odette Fukushima, and Toshiya Muranaka. "Functional analysis of orthologous artemisinic aldehyde Δ11(13)-reductase reveals potential artemisinin-producing activity in non-artemisinin-producing Artemisia absinthium." Plant Biotechnology 31, no. 5 (2014): 483–91. http://dx.doi.org/10.5511/plantbiotechnology.14.0807a.

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Arav-Boger, Ravit, Ran He, Chuang-Jiun Chiou, Jianyong Liu, Lauren Woodard, Andrew Rosenthal, Lorraine Jones-Brando, Michael Forman, and Gary Posner. "Artemisinin-Derived Dimers Have Greatly Improved Anti-Cytomegalovirus Activity Compared to Artemisinin Monomers." PLoS ONE 5, no. 4 (April 28, 2010): e10370. http://dx.doi.org/10.1371/journal.pone.0010370.

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Mawlood, Mawlood K., Ali A. Dawood, and Noor E. Abdul-Razzaq. "Identification of Flavonoids in Artemisia annua L. by High-performance Liquid Chromatography and Evaluate the Antioxidant Activity." INTERNATIONAL JOURNAL OF DRUG DELIVERY TECHNOLOGY 12, no. 04 (December 25, 2022): 1820–24. http://dx.doi.org/10.25258/ijddt.12.4.55.

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Анотація:

The study aimed to isolate and identify flavonoids in the Artemisia plant, results obtained from the high-performance liquid chromatography (HPLC) analysis indicated that Artemisia plant contains different concentrations of flavonoids, which include 0.995 μg/g (0.58%) artemisinic acid, 3.96 μg/g (2.33%) artemisitene, 10.36 μg/g (6.09%) dihydroartemisinin, 152.25 μg/g (89.6%) artemisinin and 2.318 μg/g (1.36%) deoxyartemisinin. The identification of all types of flavonoids in flavonoids isolated from Artemisia indicates the efficiency of the method for isolating flavonoids from Artemisia, as well as evaluation of flavonoid concentration in Artemisia extract and isolated flavonoids by measurement of the antioxidant effect) in three methods.

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Kamarullah, William, Erika Indrajaya, and Janice Emmanuella. "POTENCY OF LUTEOLIN WITH SOLID LIPID NANOPARTICLE (SLN)-POLYETHYLENE GLYCOL (PEG) MODIFICATION FOR ARTEMISININ-RESISTANT PLASMODIUM FALCIPARUM INFECTION." Indonesian Journal of Tropical and Infectious Disease 7, no. 3 (October 31, 2018): 80. http://dx.doi.org/10.20473/ijtid.v7i3.6726.

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Falciparum malaria is still considered as one of the important global health problems and its causal agent (Plasmodium falciparum) is reported to be the third most common factor for contributing the number of deaths in the world. As we all know, Artemisinins arethe most rapidly acting of currently available antimalarial drugs. Along with Artesunate, these two combining drugs, the so-called Artemisinin-based combination therapies (ACTs) has become the foundation of modern falciparum malaria treatment globally. Nowadays, however, there have been reports about intricate cases of resistance against Artemisinin in various Southeast Asian countries and it is predicted to spread over several other countries, including Indonesia. Therefore, adjuvant therapy is required along with first-line therapy administration to help eradicate both Artemisinin-sensitive and resistant P. falciparum. Luteolin in vitro has a prospective inhibitory activity (IC50<50 μg) in inhibiting the development of parasite’s life cycle. Nonetheless, its poor bioavailability and pharmacokinetics restrict clinical application. The low bioavailability of luteolin requires encapsulation using solid lipid nanoparticle (SLN) and polyethylene glycol (PEG). SLN is useful for improving the bioavailability of luteolin in the body, whereas PEG is needed in order to prevent the destruction of luteolin-SLN substance by the reticuloendothelial system. Here in this literature review, we’re trying to demonstrate the benefits, potential, way of constructions, pharmacokinetics, and pharmacodynamics of luteolin encapsulated with SLN with PEG modification. Thus, it is hoped that the results of this literature study may encourage further research in assisting the development of adjuvant therapy for cases of Artemisinin-resistant P. falciparum infection.

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Bilia, Anna Rita, Caterina Gabriele, Maria Camilla Bergonzi, Pedro Melillo de Malgalhaes, and Franco Francesco Vincieri. "Variation in Artemisinin and Flavonoid Content in Different Extracts of Artemisia annua L." Natural Product Communications 1, no. 12 (December 2006): 1934578X0600101. http://dx.doi.org/10.1177/1934578x0600101208.

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Анотація:

Artemisia annua L. is a promising and potent antimalarial drug. This activity has been ascribed to its content of artemisinin, a sesquiterpene lactone that is stage specific and very effective against drug-resistant Plasmodium species and which has low toxicity. The in vitro antiplasmodial activity of artemisinin is enhanced by the flavonoids of the extract, as recently proposed by the authors. Different extracts (tinctures, infusions and decoctions), obtained from a cultivar selected by the University of Campinas (0.52% artemisinin), were analyzed in order to prove the selectivity of the solvents to obtain high yields of both artemisinin and flavonoids. Tinctures 40 and 60% v/v showed a greater power of extraction in comparison with infusions and decoctions. The best performance was obtained using 60% v/v tincture. The extraction efficiency for artemisinin was 40% and for flavonoids was 29.5%. Among aqueous extracts, the best results were obtained by preparing an infusion with boiling water, left to cool for 15 minutes before filtration. The extraction efficiency for artemisinin was 57.5% and for flavonoids was 8.2%. If leaves are boiled for several minutes the artemisinin concentration is decreased, probably due to the heat instability of this constituent. Also microwave could represent a valid alternative method to extract the phytocomplex, the extraction efficiency for artemisinin was 41.0% and that for flavonoids was 7.7%.

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Randrianarivo, Saholinirina, Claudine Rasolohery, Sitraka Rafanomezantsoa, Heriniaina Randriamampionona, Liti Haramaty, Roger Marie Rafanomezantsoa, and Eric H. Andrianasolo. "(−)-6-epi-Artemisinin, a Natural Stereoisomer of (+)-Artemisinin in the Opposite Enantiomeric Series, from the Endemic Madagascar Plant Saldinia proboscidea, an Atypical Source." Molecules 26, no. 18 (September 12, 2021): 5540. http://dx.doi.org/10.3390/molecules26185540.

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Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (−)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (−)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua.

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Kang, Jong Soon, Ki Hwan Park, Hyunju Lee, Sang-Bae Han, Kiho Lee, Song-Kyu Park та Hwan Mook Kim. "Artemisinin inhibits lipopolysaccharide-induced nitric oxide production by blocking IFN-β production and STAT-1 signaling in macrophages (142.2)". Journal of Immunology 184, № 1_Supplement (1 квітня 2010): 142.2. http://dx.doi.org/10.4049/jimmunol.184.supp.142.2.

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Abstract Artemisinin is a well-known anti-malarial drug and has been reported to exert anti-inflammatory and anti-tumor effects. In this study, we investigated the effect of artemisinin on lipopolysaccharide (LPS)-induced NO production in macrophages and the molecular mechanisms responsible for its effects. Artemisinin significantly suppressed NO production and inducible nitric oxide synthase (iNOS) mRNA expression in LPS-stimulated macrophages. NF-κB activity, which is known to be important for NO production and iNOS expression, was minimally inhibited only by highest concentration of artemisinin used and MAPKs were not affected by artemisinin treatment. In contrast, LPS-induced activation of STAT-1 was suppressed by artemisinin treatment in a concentration-dependent manner. Further studies demonstrated that the inhibition of STAT-1 activation by artemisinin might be mediated by blocking interferon-β (IFN-β) production. These results suggest that artemisinin suppresses NO production and iNOS expression, at least in part, by blocking IFN-β production and concomitant down-regulation of STAT-1 signaling.

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Quadros, Helenita C., Mariana C. B. Silva, and Diogo R. M. Moreira. "The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs." Pharmaceuticals 15, no. 1 (January 4, 2022): 60. http://dx.doi.org/10.3390/ph15010060.

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Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of a radical species. This can alkylate proteins vital for parasite survival and alkylate heme into hematin–drug adducts. Heme alkylation is abundant and accompanied by interconversion from the ferrous to the ferric state, which may induce an imbalance in the iron redox homeostasis. In addition to this, hematin–artemisinin adducts antagonize the spontaneous biomineralization of hematin into hemozoin crystals, differing strikingly from artemisinins, which do not directly suppress hematin biomineralization. These hematin–drug adducts, despite being devoid of the peroxide bond required for radical-induced alkylation, are powerful antiplasmodial agents. This review addresses our current understanding of Fe-PPIX as a bioreductive activator and molecular target. A compelling pharmacological model is that by alkylating heme, endoperoxide drugs can cause an imbalance in the iron homeostasis and that the hematin–drug adducts formed have strong cytocidal effects by possibly reproducing some of the toxifying effects of free Fe-PPIX. The antiplasmodial phenotype and the mode of action of hematin–drug adducts open new possibilities for reconciliating the mechanism of endoperoxide drugs and for malaria intervention.

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Zhu, Pan, Chaoping Yue, Xin Zeng, and Xiulai Chen. "Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function." Antioxidants 11, no. 10 (September 20, 2022): 1855. http://dx.doi.org/10.3390/antiox11101855.

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A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we identified that artemisinin and its derivatives possessed antifungal activity through a high-throughput screening of the FDA-approved drug library. Subsequently, drug-resistant strains construction, a molecular dynamics simulation and a transcription level analysis were used to investigate artemisinin’s action mechanism in Candida glabrata. Transcription factor pleiotropic drug resistance 1 (PDR1) was an important determinant of artemisinin’s sensitivity by regulating the drug efflux pump and ergosterol biosynthesis pathway, leading to mitochondrial dysfunction. This dysfunction was shown by a depolarization of the mitochondrial membrane potential, an enhancement of the mitochondrial membrane viscosity and an upregulation of the intracellular ROS level in fungi. The discovery shed new light on the development of antifungal agents and understanding artemisinin’s action mechanism.

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40

Benoit-Vical, Françoise, Anne Robert, and Bernard Meunier. "In Vitro and In Vivo Potentiation of Artemisinin and Synthetic Endoperoxide Antimalarial Drugs by Metalloporphyrins." Antimicrobial Agents and Chemotherapy 44, no. 10 (October 1, 2000): 2836–41. http://dx.doi.org/10.1128/aac.44.10.2836-2841.2000.

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ABSTRACT The in vitro potentiation of artemisinin by synthetic manganese porphyrin complexes has been recently reported (F. Benoit-Vical, A. Robert, and B. Meunier, Antimicrob. Agents Chemother. 43:2555–2558, 1999). Since the activity of artemisinin and synthetic antimalarial endoperoxides is related to their interaction with heme (S. R. Meshnick, A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan, Mol. Biochem. Parasitol. 49:181–190, 1991), an improvement of their efficiency may be expected in the presence of a synthetic metalloporphyrin having the same activating role as endogenous heme. With the aim to boost the activity of antimalarial endoperoxide drugs, we were thus led to evaluate the in vitro and in vivo potentiation of natural and synthetic drugs of this family by a nontoxic and cheap metalloporphyrin. The potentiation of artemisinin, β-artemether, and arteflene (Ro 42-1611) by synthetic heme models is reported. In vitro studies on the chloroquine-resistant Plasmodium falciparumFcB1-Columbia strain indicate a synergistic effect of the manganese complex of meso-tetrakis(4-sulfonatophenylporphyrin) (Mn-TPPS) on the activity of artemisinin or β-artemether, whereas this heme model has no influence on the activity of arteflene. A significant synergistic effect on rodent malaria was also observed in vivo between artemisinin and Mn-TPPS using Plasmodium vinckei petteri strain.

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Agrawal, Ankit. "Antimicrobial Activity of Artemisinin - An Antimalarial Drug." International Journal of Pure & Applied Bioscience 4, no. 5 (October 30, 2016): 52–54. http://dx.doi.org/10.18782/2320-7051.2365.

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42

Asimus, Sara, Trinh Ngoc Hai, Nguyen Van Huong, and Michael Ashton. "Artemisinin and CYP2A6 activity in healthy subjects." European Journal of Clinical Pharmacology 64, no. 3 (December 7, 2007): 283–92. http://dx.doi.org/10.1007/s00228-007-0406-1.

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43

Gao, Feng, Zhou Sun, Fangong Kong, and Jiaqi Xiao. "Artemisinin-derived hybrids and their anticancer activity." European Journal of Medicinal Chemistry 188 (February 2020): 112044. http://dx.doi.org/10.1016/j.ejmech.2020.112044.

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Lorini, Luigi, Salvatore Grisanti, Roberta Ambrosini, Deborah Cosentini, Marta Laganà, Luigi Grazioli, Guido A. M. Tiberio, Sandra Sigala, and Alfredo Berruti. "Antineoplastic activity of artemisinin in adrenocortical carcinoma." Endocrine 66, no. 2 (September 6, 2019): 425–27. http://dx.doi.org/10.1007/s12020-019-02077-7.

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45

Sabir, Farzana, Anil Kumar, Pragya Tiwari, Neelam Pathak, Rajender S. Sangwan, Rajendra S. Bhakuni, and Neelam S. Sangwan. "Bioconversion of Artemisinin to its Nonperoxidic Derivative Deoxyartemisinin through Suspension Cultures of Withania somnifera Dunal." Zeitschrift für Naturforschung C 65, no. 9-10 (October 1, 2010): 607–12. http://dx.doi.org/10.1515/znc-2010-9-1013.

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Biotransformation of artemisinin was investigated with two different cell lines of suspension cultures of Withania somnifera. Both cell lines exhibited potential to transform artemisinin into its nonperoxidic analogue, deoxyartemisinin, by eliminating the peroxo bridge of artemisinin. The enzyme involved in the reaction is assumed to be artemisinin peroxidase, and its activity in extracts of W. somnifera leaves was detected. Thus, the non-native cell-free extract of W. somnifera and suspension culture-mediated bioconversion can be a promising tool for further manipulation of pharmaceutical compounds.

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46

Benoit-Vical, Françoise, Anne Robert, and Bernard Meunier. "Potentiation of Artemisinin Activity against Chloroquine-Resistant Plasmodium falciparum Strains by Using Heme Models." Antimicrobial Agents and Chemotherapy 43, no. 10 (October 1, 1999): 2555–58. http://dx.doi.org/10.1128/aac.43.10.2555.

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ABSTRACT 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 ofmeso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against bothPlasmodium strains.

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Pyatakova, N. V., and I. S. Severina. "Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs." Biomeditsinskaya Khimiya 58, no. 1 (January 2012): 32–42. http://dx.doi.org/10.18097/pbmc20125801032.

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The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

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Appalasamy, Suganthi, Kiah Yann Lo, Song Jin Ch'ng, Ku Nornadia, Ahmad Sofiman Othman, and Lai-Keng Chan. "Antimicrobial Activity of Artemisinin and Precursor Derived fromIn VitroPlantlets ofArtemisia annuaL." BioMed Research International 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/215872.

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Artemisia annuaL., a medicinal herb, produces secondary metabolites with antimicrobial property. In Malaysia due to the tropical hot climate,A. annuacould not be planted for production of artemisinin, the main bioactive compound. In this study, the leaves of threein vitro A. annuaL. clones were, extracted and two bioactive compounds, artemisinin and a precursor, were isolated by thin layer chromatography. These compounds were found to be effective in inhibiting the growth of Gram-positive and Gram-negative bacteria but notCandida albicans. Their antimicrobial activity was similar to that of antibactericidal antibiotic streptomycin. They were found to inhibit the growth of the tested microbes at the minimum inhibition concentration of 0.09 mg/mL, and toxicity test using brine shrimp showed that even the low concentration of 0.09 mg/mL was very lethal towards the brine shrimps with 100% mortality rate. This study hence indicated thatin vitrocultured plantlets ofA. annuacan be used as the alternative method for production of artemisinin and its precursor with antimicrobial activities.

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Zhou, Yuqian. "Anticancer Potential of Artemisinin Derivatives Containing Fluorine Atoms." Highlights in Science, Engineering and Technology 19 (November 17, 2022): 193–99. http://dx.doi.org/10.54097/hset.v19i.2850.

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Artemisinin and its derivatives were widely used in treatment of malaria in last decades years. As a natural compound extracted from Chinese herb Artemisia annua, artemisinin and its derivatives presented high cytotoxicity to tumor cell and low toxicity to human body. If this great medicine can be used in the treatment of other disease, a new treatment will be found. Many researches were carried out to confirm these compounds can be used as a new anticancer agent. Artemisinin and its derivatives presented cytotoxicity to tumor cells were confirmed by many experiments. Besides some common derivatives which were widely used in the malaria therapy, some new artemisinin derivatives were synthesized and evaluated whether these compounds can become potential anticancer drug. There is research carried out by Shu Li and others synthesized a new type of artemisinin derivatives, artemisinin derivatives containing fluorine atoms, and evaluated these new compound’s cytotoxicity to tumor cells. In this review paper, the anticancer activity of artemisinin derivatives containing fluorine atoms were introduced and its cytotoxicity against tumor cells were shown. Then, the anticancer ability of artemisinin containing fluorine atoms and other common artemisinin derivatives: dihydroartemisinin and artesunate were compared. Finally, traditional treatment of cancer, such as chemotherapy and radiotherapy were introduced in this paper. By comparing artemisinin derivatives with traditional treatment of cancer, the big cancer-fighting potential for artemisinin and its derivatives should be see and further investigated. A new series of artemisinin derivatives, compounds containing fluorine atoms have anticancer ability too. Results obtained by literature research and read show artemisinin containing fluorine atoms may be a great potential anticancer drug but still need more exploration and practice like other artemisinin derivatives.

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Deplaine, Guillaume, Catherine Lavazec, Emmanuel Bischoff, Onguma Natalang, Sylvie Perrot, Micheline Guillotte-Blisnick, Jean-Yves Coppée, Bruno Pradines, Odile Mercereau-Puijalon, and Peter H. David. "Artesunate Tolerance in Transgenic Plasmodium falciparum Parasites Overexpressing a Tryptophan-Rich Protein." Antimicrobial Agents and Chemotherapy 55, no. 6 (April 4, 2011): 2576–84. http://dx.doi.org/10.1128/aac.01409-10.

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ABSTRACTDue to their rapid, potent action on young and mature intraerythrocytic stages, artemisinin derivatives are central to drug combination therapies forPlasmodium falciparummalaria. However, the evidence for emerging parasite resistance/tolerance to artemisinins in southeast Asia is of great concern. A better understanding of artemisinin-related drug activity and resistance mechanisms is urgently needed. A recent transcriptome study of parasites exposed to artesunate led us to identify a series of genes with modified levels of expression in the presence of the drug. The gene presenting the largest mRNA level increase,Pf10_0026(PArt), encoding a hypothetical protein of unknown function, was chosen for further study. Immunodetection with PArt-specific sera showed that artesunate induced a dose-dependent increase of the protein level. Bioinformatic analysis showed thatPArtbelongs to aPlasmodium-specific gene family characterized by the presence of a tryptophan-rich domain with a novel hidden Markov model (HMM) profile. Gene disruption could not be achieved, suggesting an essential function. Transgenic parasites overexpressing PArt protein were generated and exhibited tolerance to a spike exposure to high doses of artesunate, with increased survival and reduced growth retardation compared to that of wild-type-treated controls. These data indicate the involvement ofPArtin parasite defense mechanisms against artesunate. This is the first report of genetically manipulated parasites displaying a stable and reproducible decreased susceptibility to artesunate, providing new possibilities to investigate the parasite response to artemisinins.

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