Artemisinin Research Articles

Abstract Bioelectric fields play a critical role in skin wound repair by guiding cell proliferation, migration, and differentiation, and thereby accelerating wound healing. However, the biochemical microenvironment in diabetic wounds can diminish the endogenous electric fields (EEFs) and severely delay the healing process. Therefore, constructing bionic skin capable of restoring the EEF is an effective strategy for diabetic wound repair. In this study, a thermoelectric hydrogel‐based bionic skin is developed using an artemisinin (ART)‐loaded silver selenide methacrylate hydrogel (Ag 2 Se@GelMA/ART). Using the thermoelectric effect, the bionic skin can generate a bioelectric field driven by a skin‐to‐air temperature gradient, thereby offering a novel approach for restoring EEFs. In vitro studies show that Ag 2 Se@GelMA/ART bionic skin significantly promoted the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells. In vivo, the bionic skin accelerated diabetic wound healing and enhanced neovascularization and collagen deposition. Subsequent observation suggested that the bionic thermoelectric skin generating the external electric field inhibits the expression of prolyl hydroxylase domain‐containing protein 2 (PHD2), and upregulates the hypoxia inducible factor (HIF)‐1α and vascular endothelial growth factor (VEGF)‐A, which can benefit the process of angiogenesis. Thermoelectric bionic skin represents a novel therapeutic strategy for diabetic wound care, offering new avenues for tissue engineering.

ABSTRACTClostridium perfringens is a multi‐host opportunistic pathogen whose plasmid‐encoded toxins cause gas gangrene, necrotic enteritis and enterotoxemia, resulting in substantial economic losses in animal husbandry. In light of antibiotic bans and the need for alternatives, we employed reverse network pharmacology to screen and in vitro validate artemisinin (ART), then assessed its efficacy in murine and rabbit infection models challenged with C. perfringens type F. ART treatment did not significantly affect body weight change or intestinal histopathological damage. However, it significantly modulated inflammatory cytokines and antioxidant parameters in a tissue‐ and species‐dependent manner. Specifically, ART increased serum TNF‐α in mice, decreased IL‐1β in rabbits and elevated IL‐10 in multiple tissues. In addition, ART enhanced hepatic SOD and T‐AOC in mice and reduced hepatic MDA in rabbits. Microbiota analysis revealed limited and subtle shifts in community structure following ART intervention. Transcriptomic analysis further indicated that ART treatment induced marked changes in hepatic gene expression, particularly involving detoxification, lipid metabolism and stress response pathways, with notable species‐specific differences in enrichment profiles. While correlation analysis suggested associations of Anaerotruncus with hepatic detoxification genes and Bacteroides with inflammation‐regulatory genes, these genus‐level findings are based on correlation only and should be interpreted with caution given the lack of significant changes in overall microbial community structure. Collectively, these results indicate that ART can modulate host inflammatory and antioxidant responses, but its impact on gut microbiota composition in C. perfringens infection models appears limited, and the biological significance of observed genus‐level associations remains to be elucidated.

Elucidating artemisinin (ART)-heme as a biomarker for ART resistance and ATP-dependent transport of ART in Plasmodium falciparum.

AimsDepression is a leading cause of disability worldwide, with current treatments often limited by efficacy and side effects. Artemisinin (ART), a natural compound with known anti-inflammatory and neuroprotective properties, has not been extensively studied for its potential antidepressant effects. This study aimed to elucidate the neuroprotective mechanisms of artemisinin against corticosterone (CORT)-induced toxicity in PC12 cells model, and to assess its antidepressant-like behavioral effects in a chronic unpredictable mild stress (CUMS) mouse model.MethodsIn vitro, PC12 cells and primary hippocampal neurons were treated with CORT and artemisinin to assess cell viability, oxidative stress, mitochondrial function, and apoptosis. Pharmacological inhibition and CRISPR/Cas9 gene editing were used to explore the roles of AKT and ERK signaling pathways. In vivo, CUMS-induced depression-like behaviors in mice were evaluated using sucrose preference, tail suspension, and forced swim tests. Western blotting and immunohistochemistry studies were performed to analyze molecular mechanisms.ResultsArtemisinin attenuated CORT-induced cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in PC12 cells and hippocampal neurons. These effects were mediated through the activation of AKT and ERK pathways. In CUMS mice, artemisinin improved depression-like behaviors, upregulated the AKT/GSK/NRF2/HO1 and BDNF/TrkB/ERK/CREB pathways, modulated astrocyte activity, and promoted neurogenesis in the hippocampus.ConclusionArtemisinin exerts significant neuroprotective and antidepressant-like effects through multiple molecular and cellular mechanisms, highlighting its potential as a novel therapeutic agent for depression.

Cryptococcus neoformans (C. neoformans) has emerged as a global pathogen of concern. While much is known about its pathobiology, its management is complicated by strains displaying non-fluconazole susceptibility. This contribution assessed the repurposing of artemisinin (ART) as an anti-Cryptococcus antifungal. An in vitro susceptibility assay was performed to assess the drug response of cells. To establish the ART mode of action, assays examining mitochondrial health were set up. The phagocytosis efficiency of a murine macrophage cell line towards ART-treated and non-treated cells was determined. To complement this, the immunomodulatory effects of ART were further characterised in Galleria mellonella (G. mellonella) by assessing haemocytes’ phagocytosis and expression of immune genes, i.e., insect metalloproteinase inhibitor (IMPI) and hemolin, essential for the insect antimicrobial response. In the end, the survival rate of infected larvae was calculated. We established that ART was antifungal, with cell death triggered by the uncoupling of the cytochrome c (cyt c) from the mitochondria, leading to activation of caspase-3-dependent-like apoptosis. Moreover, treatment induced ultrastructural changes with treated cells appearing more deformed than non-treated cells (p < 0.05). Treatment also increased the susceptibility of cells towards both macrophage and haemocyte phagocytosis compared to non-treated cells (p < 0.05). Importantly, treatment seemed to weaken the cells, decreasing their virulence potential based on analysis of the expression of the immune gene markers, which translated into treatment rescuing 75% of the larvae infected with 0.1 ART-treated cells. These preliminary findings support the repurposing of ART as an anti-Cryptococcus antifungal.

BackgroundChrysosplenetin (CHR), a polymethoxy flavonol co-occurring with artemisinin (ART) in Artemisia annua L., reverses ART resistance in Plasmodium berghei K173 potentially by downregulating intestinal P-glycoprotein (P-gp, encoded by Mdr1a) expression. In the present study, we further elaborated on the mechanism by comparing differences in antimalarial activity and resistance-associated molecular expression profiles between ART alone and combination therapy in blood and tissues of Mdr1a wild-type (WT) and knockout (KO) mice infected with either sensitive or resistant malarial parasites.MethodsWe evaluated the effects of monotherapy and combination therapy in WT and KO mice infected with sensitive and resistant P. berghei K173 strains. The mRNA expressions of multi-resistance proteins (Mrp1, 2, 4, 5) and breast cancer resistance proteins (Bcrp) were detected. Hemoglobin levels, mRNA expressions of cytokines including tumor necrosis factor-α (IFN-α), interferon-α (IFN-α), and interleukin (IL-1β) in blood and tissues, and redox balance (ROS/GSH levels), as well as gene or protein expression of signaling pathway (PI3K/AKT-mTOR and MAPK) were investigated.ResultsIn drug-resistant mice, combination therapy maintained the highest survival (100%) and inhibition (30%) rates and the lowest parasitaemia percentage (approximately 20.0%), irrespective of Mdr1a gene status. Furthermore, combination reshaped the spatial and ART resistance-phenotypic disparities in Mrps and Bcrp mRNA expressions (with a fold change ranging from 1.35 to 38.03), ROS/GSH balance (ranging from 1.02-fold to 10.18-fold), hemoglobin levels (ranging from 1.04-fold to 1.20-fold), and cytokine profiles (ranging from 1.14-fold to 37.79-fold) induced by ART alone, which were partially dysregulated by Mdr1a deficiency. Monotherapy and combination exert oppositely regulatory effects on the PI3K/AKT-mTOR pathway in a tissue-, Mdr1a genotype-, and parasite sensitivity/resistance-dependent manner (ranging from 1.52-fold to 84.00-fold). Specifically, CHR reversed ART-induced changes via PI3K/AKT protein inhibition (ranging from 1.20-fold to 63.00-fold), which was contingent on P-gp functionality. Finally, mitogen-activated protein kinase (MAPK) pathway was involved in the antagonistic regulation between ART alone and combination therapy in a P-gp-independent manner (ranging from 1.39-fold to 16.69-fold).ConclusionsThe efflux pump function of P-gp is probably not a critical factor in the mechanism by which CHR reverses ART resistance. Instead, CHR acts as a homeostasis stabilizer with dual functions: it disrupts Plasmodium berghei K173 resistance to ART driven by both ABC transporters and the heme-ROS/GSH axis, in which the non-transport function of P-gp on ART is involved.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s13071-025-07018-0.

Neuroinflammation caused by neuroimmune dysfunction is important for the pathogenesis of major depressive disorders; new antidepressant treatments are urgently needed. Artemisinin (ART) has anti-inflammatory and neuroprotective effects; it can alleviate the inflammatory response in the central nervous system. This study investigated the antidepressant effects and potential mechanisms of action of ART in mice with depression. Mice with chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-induced depression were used to investigate the antidepressant effects and mechanisms of ART. Mice were treated with ART for 60 min or 5 days. Behavioral tests, RNA sequence analysis, molecular docking, immunofluorescence, and Western blotting were used to evaluate the antidepressant effects of ART as well as its potential therapeutic targets and signaling pathways. Additionally, LPS- and ATP-treated BV2 microglia were analyzed in vitro to confirm the effect of ART on the NLRP3 signaling pathway. After 60 min or 5 days of treatment, ART alleviated depression-like behavior in CSDS-induced mice. RNA sequence analysis and molecular docking revealed that ART inhibited the TLR4/NLRP3 signaling pathway. After 5 days of treatment, ART suppressed CSDS-induced microglia, astrocytes, and NLRP3 inflammasome activation as well as the expression of IL-17A in the hippocampus. Mechanistically, ART markedly inhibited TLR4, MyD88, p-NF-κB, and NLRP3 inflammasome-associated proteins in the hippocampus of CSDS-induced mice. Furthermore, ART improved LPS-induced depression-like behavior by inhibiting the TLR4/NLRP3 signaling pathway. ART, a novel antidepressant with clinical potential, inhibits neuroinflammation by downregulating the TLR4/MyD88/NF-κB/NLRP3 signaling pathway in the mouse hippocampus.

In vitro and in vivo activity of a lipid-based artemisinin formulation against Leishmania (Leishmania) amazonensis.

Malaria is an infectious disease caused in the human species by Plasmodium parasites. There are five parasite species that cause malaria in humans, and two of these species, Plasmodium falciparum and Plasmodium vivax, cause the majority of malaria cases and deaths. The WHO World Malaria Report 2021 reported nearly 241 million malaria cases in 2020 from 85 malaria-endemic countries. The discovery of artemisinin (ART) by Professor Tu Youyou and her team as a traditional medicine to conquer life-threatening diseases worldwide has saved millions of lives over the years. Professor Tu Youyou was rewarded with the Nobel Prize in Physiology or Medicine 2015 “for her discoveries concerning a novel therapy against Malaria”. These traditional medicines for malaria have continuously gained a reputation as an alternate drug, for their high efficacy against malaria parasites and safety profile. There has been an increased prevalence of antimalarial resistance to standard drugs such as chloroquine, quinine, proguanil, pyrimethamine, etc. Thus, artemisinin-based combination therapy (ACT) is currently recommended by the World Health Organisation (WHO) and used as a first-line malaria therapy in endemic countries to treat uncomplicated falciparum malaria. Artemisinins are highly effective with rapid clearance of the parasites and minimal side effects. Presently, six ACTs are recommended by the WHO for treating malaria cases globally. Artemisinin-derived drugs have revolutionized malaria treatment and infused a newer emphasis on folklore and traditional remedies that can be used to derive novel phytochemicals or design chemical compounds with clinical significance. This article focuses on the pleiotropic activities shown by the traditional medicine artemisinin against various pathogens or disease conditions.

Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of aggregated of hyperphosphorylated tau protein, which normally helps stabilize microtubules in neurons. Nowadays, artemisinin (ART) as well as its semisynthetic derivatives (ARTs) are seen as potential neuroprotectors. The goal of the present study is the assessment of neuroprotective, antibacterial activity of ART, as well as in silico studies of ART affinity to Aβ-peptides and the search of potential targets for ART. The study is referring to explores the impact of ART on an animal model of AD that is induced by the aggregated amyloidogenic peptide Aβ1-42 by electrophysiology and morphology analysis. Specifically, the focus is on the activation of the entorhinal cortex (ENT) as synaptic potentiation. Electrophysiological and histochemical have demonstrated that therapeutic injection of ART or its derivatives acts as a neuroprotective This treatment appears to prevent or slow down damage to brain tissue, and it promotes the restoration of neurons and their surrounding environment. The protective effects of ART may involve various mechanisms, including antioxidant activity, anti-inflammatory effects, and the inhibition of apoptosis. in silico studies revealed a direct, strong interaction of ART with the amyloidogenic peptides 5Aβ17-42, 12Aβ9-40, and 18Aβ9-40. in silico screening revealed several protein targets for ART, including cytochrome P-450 2B6 (CYP2B6). The highest binding affinity was found on the active site of CYP2B6. ART has great potential for discovering new drugs using combined therapies.

Metabolite quantification without a radiolabeled analogue or the reference standard is challenging. This study presented a novel high resolution mass spectrometry (HRMS)-based analytical strategy for simultaneous metabolite profiling and standard-free metabolite quantification of drug candidates with limited restriction on structure. The model drug was artemisinin (ART), which is widely used in clinic to treat malaria. A major hydroxylated metabolite (M1) with minor isomer M2 was first found for ART in human liver microsomes using LC-HRMS. Second, the MS response ratio (MRR) of the hydroxylation pathway in specific biological matrix was investigated using several probe substituents (midazolam, etc.). In contrast to varying (0.5-1.9-fold difference) MS response of probe drugs and their metabolites at equimolar concentration, the MRR ratio of the hydroxylation pathway was relatively constant (∼0.6-fold). Third, simulated calculation curves for M1 were obtained based on the calibration curves of ART and the MRR ratios of the hydroxylation pathway. Fourth, the present analytical strategy provided reliable (< 31.7% deviation from that obtained using a validated LC-MS technique) quantitative data on enzyme kinetics and pharmacokinetics. As a result, M1 was found to be the predominant metabolite for ART (3.6-fold of ART exposure) in human, and another unidentified hydroxylated metabolite M2 accounted for ∼40.0% of ART exposure. The results demonstrated that the new HRMS-based analytical strategy along with the MRR ratio of a metabolic pathway evaluated by appropriate probe substituents can be a valuable tool for the simultaneous metabolite profiling and standard-free metabolite quantification in early drug development.

Oral leukoplakia (OL) is the most common potentially malignant oral disorder, with variable risk of progression to oral squamous cell carcinoma (OSCC). This study evaluated the chemopreventive and immunomodulatory potential of Artemisinin (ART) and Rubus occidentalis (RO), alone or combined (ARO), in a 4NQO-induced murine model. Mice received 4NQO (100 µg/mL) in drinking water, and treatments began at week 8. Animals were euthanized at weeks 12 and 16 for histological, apoptotic (caspases-3, -8, -9; calreticulin), inflammatory (IL-1β, IL-10, HMGB1), and immune (CD8, CD68, CD56, IFN-γ, GM-CSF) marker analyses. RO-treated animals showed delayed malignant transformation, with no carcinomas at week 16 and increased expression of caspase-9, calreticulin, HMGB1, IFN-γ, and GM-CSF, indicating transient activation of antitumor immune responses. ART-treated mice showed increased CD68 and reduced CD56 expression, suggesting an immunosuppressive profile and higher carcinoma incidence. The ARO combination did not improve outcomes beyond ART alone. These findings support the immunomodulatory and pro-apoptotic effects of RO in delaying OL progression, highlighting its chemopreventive potential. ART showed limited benefit under current conditions, warranting further investigation into dose optimization and synergistic strategies.

Artemisinin synergizes with CCCP in autophagic cell death induction via ER stress in uveal melanoma.

Pharmacokinetics and metabolism of artemisinin (ART) in Plasmodium yoelii: ART-heme adduct as a potential biomarker for its resistance.

Multiple sclerosis (MS) is a demyelinating autoimmune disease (AD) accompanied by immune disorders and complement over activation. Although re-instatement of immune balance does alleviate MS symptoms, exploration of concomitant complement inhibition for neuron protection has not been evaluated. Herein, we developed myelin oligodendrocyte glycoprotein 35-55 (MOG) peptide and artemisinin (ART) co-loaded liposomes (MOG-ART-Lip) to simultaneously restore immune balance and inhibit complement activation. This nanoplatform enhanced solubility of both components while enabling CNS delivery. Liposomes loaded with MOG would induce tolerogenic DCs (tol-DCs) that express low-levels of costimulatory molecules, capable of antigenic peptide presentation and induction of regulatory T cells, while ART shifted microglia from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes. Importantly, ART suppressed complement-mediated demyelination via the C3/C3a receptor (C3aR) pathway. In vivo studies showed MOG-ART-Lip significantly reduced neuroinflammation, attenuated demyelination, and promoted neural repair, leading to functional recovery. Overall, results of this study suggest that a combination of an auto-antigenic peptide and an immune-modulator provides a promising modality for the treatment of MS by re-establishing antigen-specific immune tolerance. As such, the results of the study provide valuable insight into a new approach for development of combinatorial complement therapies for the treatment of MS patients.

Brain metastasis (BM), most vital and common metastasis phenotype occurs during tumorigenesis, the incidence of which varied remarkedly in various cancers. Overwhelming evidence suggested blood-brain barrier (BBB) can attenuate the anti-BM efficacy of chemotherapies via hindering their penetration. This study aimed to investigate the preferential cancer type that is more prone to BM, and bioactive compound that suppress BM through penetrating BBB. By intracardiac injection of lung cancer cells, breast cancer cells and melanoma cells, BM models were established. By two cycles of primary-isolation and incubation of H446-luc cells to improve the incidence of BM. Artemisinin (ART) and its derivatives were evaluated to suppress BM in vitro and in vivo. Compared to lung cancer-driven BM (66.67%), the incidence of BM in breast cancer (16.67%-33.33%) and melanoma (33.33%) were extremely low. The incidence of BM in lung cancer increased from 66.67 (1st generation) to 80% (2nd generation). Compared to other ingredients, artesunate (ARTS) exerted a more significant inhibitory effect on cell proliferation, especially in lung cancer cells. Simultaneously, ARTS suppressed lung cancer migration via decreasing N-cadherin and Snail, and enhancing E-cadherin. Most importantly, we found that ARTS could strikingly suppress tumor growth in brain with high concentration, implying that ARTS might penetrate BBB and accumulate in brain tissue to hinder lung cancer-driven BM. Our findings not only suggest lung cancer exhibited tumor specificity in cancer-driven BM model, but also provide ARTS as a promising candidate for clinical treatment of lung cancer-relayed BM.

Colorectal cancer is one of the major types of cancer that humans are suffering from; however, drugs that can be used for treatment with no side effects have still not been discovered. By research, Chinese traditional medicine called artemisinin (ART) was known for undergoing ferroptosis in cells. Therefore, some experimental tests need to verify the effect of whether artemisinin allows ferroptosis to apply to colorectal cancer cells. The result of this experiment can allow a better understanding of the direction of colorectal cancer treatment and how Chinese traditional medicine can perform as treatments for CRC. Therefore, during this experiment, ART was used to test ferroptosis in the SNU-C2A colorectal cell line to see whether it’s a suitable drug to use for CRC patients.

The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. Berghei-infected mice.

The hematin-dihydroartemisinin adduct mobilizes a potent mechanism to suppress β-hematin crystallization

This study investigates the therapeutic mechanisms of artemisinin (ARS) and its derivatives in atopic dermatitis (AD) using network pharmacology and molecular docking. Molecules and disease targets were screened using public databases, including SwissTargetPrediction, PharmMapper, and Genecards. Core targets were identified, and a protein-protein interaction (PPI) network was constructed using STRING and Cytoscape for topological analysis. Relevant data were obtained from the DAVID database for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking of ARS and its derivatives with target genes was performed using AutoDock, with results visualized in Pymol. A functional PPI network was established, and molecular docking demonstrated strong binding activity between ARS derivatives and target protein. Mitogen-Activated Protein Kinase14 (MAPK14) and Mitogen-Activated Protein Kinase10 (MAPK10) was found to be a common target for their treatment of AD. ARS and its derivatives may treat AD by modulating pathways such as Prolactin signaling, cancer pathways, neuroactive ligand-receptor interaction, and IL-17 signaling. ARS and its derivatives have the potential to treat AD. Artemisinin, artesunate, dihydroartemisinin, artemether, artemisinin and artemisinone could potentially treat AD by targeting MAPK14 and MAPK10.