Mechanism Of Artemisinin Research Articles

Artemisinin promotes apoptosis of spinal tuberculosis macrophages by inhibiting NF-κB

Artemisinin has been proved to have a wide range of pharmacological effects, mainly used in anti-malaria, anti-inflammatory, antiviral, etc., but the effect and mechanism of artemisinin on tuberculosis-infected macrophages have not yet been elucidated. THP-1 cell line was cultured and randomly divided into the following 4 groups; control group, which was infected with Mtb standard human virulence strain H37Rv; low-dose, medium-dose and high-dose artemisinin groups, which were treated with artemisinin at 50 μM, 150 μM and 300 μM, respectively. The effect of artemisinin on cell proliferation was determined by MTT assay. MMP-2 and MMP-9 were detected by PCR. The inflammatory cytokines IL-6 and TNF-α were detected by ELISA. The above tests were used to understand apoptosis, inflammation and proliferation. The expressions of Bcl-2, osteoprotectin (OPG), nuclear factor κB receptor activator (RANK) and NF-κB were detected by Western blot. Acting on macrophages infected with mycobacterium tuberculosis, artemisinin can significantly inhibit cell proliferation, promote cell apoptosis, inhibit the expression of MMP-2 and MMP-9, and reduce the secretion of IL-6 and TNF-α. Artemisinin also decreased the expression of Bcl-2, OPG, RANK and NF-κB (p < 0.05), and the change was more significant with the increase of dose. Artemisinin could down-regulate the expression of OPG, RANK and NF-κB, and inhibiting the expression of inflammatory factors and Matrix metalloproteinases (MMPs), and then promoting apoptosis of spinal tuberculosis macrophages.

To investigate the effects of artemisinin on inflammatory factors and intestinal microbiota in rats with ulcerative colitis based on network pharmacology

ObjectiveTo investigate the therapeutic effect and possible mechanism of artemisinin on ulcerative colitis (UC) induced by sodium glucan sulfate (DSS) in rats based on network pharmacology.MethodsFirst, according to the 3D structure of artemisinin, the effective targets of the active compounds were obtained through the Swissstarge website (www.swisstargetprediction.ch/) and the TargetNet website (http://targetnet.scbdd.com/). With the aid of Genecards (https://www.genecards.org/), OMIM (https://omim.org/), TTD (http://db.idrblab.net/ttd/) to obtain effective targets of disease. The disease gene-drug target network was constructed by extracting the intersection targets of the two, and the visualization operation and analysis were performed by using Cytoscape 3.7.2. Gene function enrichment analysis and pathway analysis were performed on the intersection targets with the help of R language software. Autidock Vina was used for molecular docking of artemisinin to key targets. Then, 40 male Wistar rats were randomly divided into normal group, model group, mesalazine group (0.315 g/kg·d) and artemisinin group (0.1 g/kg·d), with 10 rats in each group. Except for the normal group, the rats in the other groups were given 3.5% DSS solution freely for 10 days to replicate the UC model. After the successful modeling, the rats were given intragastric administration. The normal group and the model group were given the same amount of 0.9% normal saline, once a day, for 14 days. The general condition of the rats was recorded every day and the disease activity index (DAI) score was performed. After the administration, the colonic mucosal damage index (CMDI) was scored, the histopathological changes of the colon were observed by HE staining, and the levels or activities of serum CRP, TNF-α, MDA, SOD, HIF-1α and T-AOC were detected by ELISA, and fecal and intestinal microbiota of rats were detected by 16S rDNA sequencing.ResultsNetwork pharmacology shows that, there were 98 key targets of artemisinin screening, 4853 effective targets of UC, and 43 intersection targets for artemisinin and UC, involving 48 signaling pathways. The molecular docking results showed that the binding energies of the key proteins to artemisinin were less than -5.0 kJ·mol-1, and the binding energy of PTGS2 NOS3 to artemisinin was the best. Animal experiments have shown that, Compared with the model group, the DAI and CMDI scores of the artemisinin group and the mesalazine group decreased, the levels and activities of serum CRP, TNF-α, MDA and HIF-1α decreased, the levels and activities of SOD and T-AOC increased, the abundance and diversity of inteatinal microbiota increased, and the abundance of p-Acidobacteria, p-Chloroflexi, p-Gemmatimonadetes, p-Nitrospirae in artemisinin group increased (P＜0.05), and there was no significant change in others.ConclusionArtemisinin intervenes with UC through key target proteins such as PTGS2 and ESR1, and involves various biological processes such as inflammation and intestinal microbiota, revealing that molecular basis of artemisinin in the treatment of UC. Artemisinin is effective in improving the symptoms of UC rats, and its mechanism may be to relieve oxidative stress response by inhibiting inflammation, thus promoting intestinal mucosal repair. The regulatory effect on intestinal microbiota needs to be further studied.

Protective Effect and Possible Mechanisms of Artemisinin and Its Derivatives for Diabetic Nephropathy: A Systematic Review and Meta-Analysis in Animal Models.

Background Artemisinin and its derivatives have potential antidiabetic effects. There is no evaluation of reported studies in the literature on the treatment of diabetic nephropathy (DN), one of the commonest diabetic microangiopathies, with artemisinins. Here, we aimed to evaluate preclinical evidence for the efficacy and possible mechanisms of artemisinins in reducing diabetic renal injury. Methods We conducted an electronic literature search in fourteen databases from their inception to November 2021. All animal studies assessing the efficacy and safety of artemisinins in DN were included, regardless of publication or language. Overall, 178 articles were screened according to predefined inclusion and exclusion criteria. Finally, 18 eligible articles were included in this systematic review. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool was used to assess the risk of bias in the included studies. The primary outcomes were kidney function, proteinuria, and renal pathology. Secondary endpoints included changes in fasting plasma glucose (FPG) levels, body weight, and relevant mechanisms. Results Of the 18 included articles involving 418 animal models of DN, 1, 2, 6, and 9 used dihydroartemisinin, artemether, artesunate, and artemisinin, respectively. Overall, artemisinins reduced indicators of renal function, including blood urea nitrogen (P < 0.00001), serum creatinine (P < 0.00001), and kidney index (P = 0.0001) compared with control group treatment. Measurements of proteinuria (P < 0.00001), microalbuminuria (P < 0.05), and protein excretion (P = 0.0002) suggested that treatment with artemisinins reduced protein loss in animals with DN. Artemisinins may lower blood glucose levels (P = 0.01), but there is a risk of weight gain (P < 0.00001). Possible mechanisms of action of artemisinins include delaying renal fibrosis, reducing oxidative stress, and exerting antiapoptotic and anti-inflammatory effects. Conclusion Available evidence suggests that artemisinins may be protective against renal injury secondary to diabetes in preclinical studies; however, high-quality and long-term trials are needed to reliably determine the balance of benefits and harms.

Artemisinin Alleviates Intestinal Inflammation and Metabolic Disturbance in Ulcerative Colitis Rats Induced by DSS.

Objective This study is aimed to reveal the possible mechanisms of artemisinin in the treatment of ulcerative colitis (UC) through bioinformatics analysis and experimental verification in UC model rats. Methods Firstly, we searched two microarray data of the Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) between UC samples and normal samples. Then, we selected DEGs for gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The acute UC model of rats was established by using 3.5% dextran sulfate sodium (DSS) for 10 days to verify the core pathway. Finally, we evaluated the therapeutic effect of artemisinin at the molecular level and used metabonomics to study the endogenous metabolites in the rat serum. Results We screened in the GEO database and selected two eligible microarray datasets, GSE36807 and GSE9452. We performed GO function and KEGG pathway enrichment analyses of DEGs and found that these DEGs were mainly enriched in the inflammatory response, immune response, and IL-17 and NF-κB signaling pathways. Finally, we verified the IL-17 signaling pathway and key cytokines, and ELISA and immunohistochemical results showed that artemisinin could downregulate the expression of proinflammatory cytokines such as IL-1β and IL-17 in the IL-17 signaling pathway and upregulate the expression of the anti-inflammatory cytokine PPAR-γ. Metabolomics analysis showed that 33 differential metabolites were identified in the artemisinin group (AG) compared to the model group (MG). Differential metabolites were mainly involved in alanine, aspartate, and glutamate metabolism and synthesis and degradation of ketone bodies. Conclusion In this study, we found that artemisinin can significantly inhibit the inflammatory response in UC rats and regulate metabolites and related metabolic pathways. This study provides a foundation for further research on the mechanism of artemisinin in the treatment of UC.

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy

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The Potential Roles of Artemisinin and Its Derivatives in the Treatment of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a global public health problem. Studies on T2DM prevention and treatment mostly focus on discovering therapeutic drugs. Artemisinin and its derivatives were originally used as antimalarial treatments. In recent years, the roles of artemisinins in T2DM have attracted much attention. Artemisinin treatments not only attenuate insulin resistance and restore islet ß-cell function in T2DM but also have potential therapeutic effects on diabetic complications, including diabetic kidney disease, cognitive impairment, diabetic retinopathy, and diabetic cardiovascular disease. Many in vitro and in vivo experiments have confirmed the therapeutic utility of artemisinin and its derivatives on T2DM, but no article has systematically demonstrated the specific role artemisinin plays in the treatment of T2DM. This review summarizes the potential therapeutic effects and mechanism of artemisinin and its derivatives in T2DM and associated complications, providing a reference for subsequent related research.

Therapeutic Potentials and Mechanisms of Artemisinin and its Derivatives for Tumorigenesis and Metastasis.

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. We have searched and reviewed the literatures about ARM and its derivatives (ARMs) for cancer using keywords "artemisinin" until May 2019. 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. 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.

Method for rapid synchronization of different growth cycles of Plasmodium falciparum in vitro and application in differential gene expression profile of 3D7 after dihydroartemisinin treatment

Plasmodium culture in vitro is often used as an antimalarial drug evaluation model, but the lifecycle of P. falciparum culture in vitro tends to be disordered, which affects the research and evaluation of antimalarial drug mechanism in vitro. By combining magnetic bead separation method with sorbitol synchronization method, a synchronization method was constructed to quickly acquire different lifecycles of P. falciparum and obtain large amounts of parasite with a narrow synchronization window in a short period. Furthermore, the dihydroartemisinin(DHA) was used to treat the early trophozoite phase of P. falciparum 3 D7 for 4 h. Then mRNA was extracted and RNA-seq was conducted to analyze the differential expression of mRNA after drug treatment and obtain the differential gene expression profile. Differential expression of up-regulated genes and down-regulated genes was analyzed according to the screening criteria of |log_2FC|&gt;1 and P&lt;0.05. There, 262 genes were up-regulated and 77 genes were down-regulated. GO functional enrichment analysis of all the differentially expressed genes showed that the enrichment items mainly included cell membrane components, transporter activity, serine/threonine kinase activity, Maurer's clefts(MCs), rhoptry, antigen variation and immune evasion. The enrichment of KEGG pathway included malaria, fatty acid metabolism and peroxisome. Protein-protein interaction(PPI) analysis showed that the down-regulated genes in the modules with high degree of association included rhoptry, myosin complex, transporter and other genes related to the important life activities of malaria invasion and immune escape; the up-regulated genes were mainly related to various toxic exportins of malaria, such as PfSBP1 of MCs. qRT-PCR was used to verify the expression level of some genes, and most of the results were the same as the sequencing results. SBP1 was significantly up-regulated, while some antigenic protein expression levels were down-regulated. Above all, key molecules of DHA therapy were mainly involved in the parasites' rhoptry, transporter, antigenic variation, plasmodium exportin. These results offer us many hints to guide the further studies on mechanism of artemisinin and provide a new way for development of new antimalarial drugs.

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy.

Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis. Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway. Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.

Effects and Mechanism of Action of Artemisinin on Mitochondria of Plasmodium berghei.

To study the antimalarial effects and mechanisms of artemisinin (Qinghaosu in Chinese, QHS) on mitochondria in mice infected with Plasmodium berghei. A total of 108 C57 mice infected with Plasmodium berghei were randomly divided into 3 groups by weight: the control group, 200 and 400 mg/kg QHS groups. The two QHS treatment groups were further divided into 4 sub-groups with 12 animals each time according to the treatment time, 0.5, 1, 2, and 4 h. Normal saline was intragastrically (i.g.) administered to the control group. The other two groups received different doses of QHS by i.g. administration. Animals were treated once with QHS for different detection time as follows: 0.5, 1, 2, and 4 h. The mitochondrial energy metabolism, oxidative damage, membrane potential, and membrane permeability and other indexes were detected. After administration of 200 and 400 mg/kg QHS, adenosine triphosphate (ATP) levels in Plasmodium and its mitochondria were reduced (P<0.05), the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were increased (P<0.05), and the activity of superoxide dismutase (SOD) was also increased (P<0.05). At the same time, the membrane potential of the mitochondria was reduced and the degree to which the membrane permeability transition pore was opened was irreversibly increased (P<0.05). Mitochondria in Plasmodium were the targets of QHS, which can adversely affect mitochondrial energy metabolism, oxidative damage, membrane potential, and membrane opening, and ultimately exert an antimalarial effect.

Methemoglobin as a redox-responsive nanocarrier to trigger the in situ anticancer ability of artemisinin

Learning from the antimalarial mechanism of artemisinin (ART) in nature, we explored methemoglobin (MHb) as a smart nanocarrier of ART, in which anticancer abilities can be turned on in situ through the upregulated reducing capacity of tumor tissue. Ultra violet–visible, electron paramagnetic resonance spectrometry and in vitro cell assessment proved that a reducing agent such as glutathione can work as an excellent biogenic trigger to reduce ferric iron in MHb to the ferrous state, activating the ability of ART to generate free radicals and resulting in cytotoxicity and apoptosis. In vivo investigations showed that the MHb–ART complex had encouraging anticancer outcomes. The bioinspired nanocarrier may pave a new way to achieve targeted toxicity to cancer cells with extremely low side effects.

The recent advances of chemical biology in artemisinin target and mechanism

Artemisinin is a natural compound that is extracted from the plant Artemisia annua. While it was used to treat fever and pain in the past, it is currently approved by World Health Organization (WHO) to be used in combating malaria. It is an effective anti-malarial drug because of its high efficacy even towards multi-drug resistant Plasmodium strains and exhibits no significant side effects in humans. However, artemisinin has poor solubility in water or oil, poor bioavailability and a short half-life in vivo . Therefore, derivatives of artemisinin consisting of semi-synthetic and fully synthetic compounds with improved properties have been synthesized. Semi-synthetic derivatives include artesunate, artemether and dihydroartemisinin. Artemisinin and its derivatives are sesquiterpene lactones that contain a unique endoperoxide bond in its trioxane ring, which is essential for their anti-malarial activity. The importance of this bond is shown by the findings of studies that the abrogation of the endoperoxide bond led to a significant reduction in toxicity of the drugs. For example, the removal of one O-atom in the endoperoxide moiety was associated with a complete loss of anti-malarial activity. The activation mechanism of artemisinin is hypothesized to involve the reduction of the endoperoxide bond by Fe2+, which is a catalyst that can generate free radicals from peroxidic structures. The selective toxicity of the drug towards parasite-infected cells as compared to non-infected cells is attributed to the higher heme level in parasite-infected cells. In malarial parasite-infected red blood cells, the parasites break down hemoglobin in the food vacuole to gain amino acids for synthesis of their parasite-specific proteins. As a result, heme is released, which can be further degraded into iron in the vacuole. Therefore, hemoglobin degradation gives rise in an increase in both heme and free iron level in infected erythrocytes. As a result, whether heme or iron is the crucial activator of the drug is yet to be elucidated. One of the pleiotropic effects of the drug is that the reduced endoperoxide bond forms cytotoxic carbon-centered radicals that can alkylate target proteins and affect their functions. Other effects include the alkylation of heme, generation of reactive oxygen species (ROS) and inhibition of PfATP6, which is the P. falciparum ortholog of the endoplasmic reticulum Ca2+ pump. Some studies have also found that artemisinin builds up within neutral lipids and damage the parasite membrane. The combination of these toxic effects of artemisinin and its derivatives result in parasitic death. Artemisinin is used to relieve pain and fever in the older days. Today, artemisinin is widely used as an anti-malarial drug as our first line of defense to combat the emergence of drug resistance malaria parasite. Besides its anti-malarial properties, artemisinin is being investigated in other diseases. It is found to possess a wide spectrum of pharmacological activities, including anticancer, anti-asthma etc. However, its mechanism of action (MOA) is still not fully understood. Recently, “omics” approach has been used in identify the targets and unravel the mechanism of action of artemisinin. This review will summarize the recent progress in artemisinin target and mechanism study.

The pharmacological activities and mechanisms of artemisinin and its derivatives: a systematic review

Artemisinin and its derivatives have now become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although artemisinin was first used for the treatment of malarial ailments, lots of subsequent studies have demonstrated it possesses other multiple pharmacological functions such as antitumor, antiarrhythmic, anti-fibrosis, as well as the activity against schistosomiasis. A wide array of the molecular mechanisms based on above-mentioned functions of artemisinin and its derivatives have also been explored. Experimental evidences suggest that artemisinin compounds may exert its functions via mechanisms like regulating key factors such as apoptosis-related BAX, FASL and caspase-3, multi-drug resistence genes, cytokines such as CD4+ and CD8+, inflammation-related NF-κB and COX2, telomerase, oxidative stress molecules, and so on. In this article, the proposed mechanisms of action of artemisinins are reviewed with the hope of gaining more insight into the multiple actions of these potent drugs and how they work.

Anti-tumor effect and its molecular mechanism of artemisinin and its derivatives

Artemisinin and its derivatives are the first choices for the treatment of malaria medicine. In recent years, a large number of studies in vivo and in vitro show that artemisinin and its derivatives have good anti-tumor activities. Its antitumor mechanism mainly includes the oxidation damage reaction, inhibiting tumor cell proliferation and resistance to new angiogenesis. Artemisinin and its derivatives have little side effect, low cost, effective aginst multidrug-resistant cell and a synergistic effect on radiotherapy and chemotherapy, which may become promising clinical anticancer compounds. Key words: Artemisinin; Antineoplastic agents; Molecular mechanisms of pharmacological action

Correction: New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replication

[This corrects the article on p. e72519 in vol. 8.].