Metabolite Of Artemisinin Research Articles

Nonclassical mechanisms to irreversibly suppress β-hematin crystal growth

Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials.

Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

Dihydroartemisinin and its Analogs: A New Class of Antitubercular Agents.

Tuberculosis is one of the leading causes of mortality worldwide. Resistance against the frontline anti-tubercular drugs has worsened the already alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-tubercular agents possessing novel modes of action. Chemical transformation of dihydroartemisinin for anti-tubercular lead optimization. Dihydroartemisinin, a metabolite of artemisinin was chemically converted into eight acyl derivatives and were evaluated for anti-tubercular potential against H37Rv virulent strain of Mycobacterium tuberculosis by agar-based proportion assay. Further, synergistic activity of 12-O-m-anisoyl dihydroartemisinin was also studied with the front-line anti-TB drugs, isoniazid and rifampicin. The results showed that all the derivatives were active but out of eight, 12-O-m-anisoyl dihydroartemisinin and 12-O-p-anisoyl dihydroartemisinin were significantly active (MIC 25.0 µg/mL). In synergistic activity evaluation, the 12-O-m-anisoyl dihydroartemisinin derivative showed reduction in MIC (by 1/8th, i.e. 3.12 µg/mL and that of rifampicin by ¼th, i.e. 0.05 µg/mL) with the front-line anti-TB drug, rifampicin. The sumfractional inhibitory concentration (Σ FIC) was 0.375. These results suggested a synergistic effect of the 12-O-m-anisoyl dihydroartemisinin with rifampicin and established its base for the development of anti-tubercular agents from an in-expensive and non-toxic natural product. To the best of our knowledge this is the first ever report on the anti-tubercular potential of dihydroartemisinin and its derivatives.

Mechanism of anti-tumor effect of dihydroartemisinin

Dihydroartemisinin (DHA), the major active metabolite of artemisinin, participates in tumor progression through the following ways: forming free radicals to induce cancer cells death dependent on iron, inducing apoptosis, inhibiting angiogenesis, tumor cells invasion and metastasis, modulating multidrug resistance, controlling intracellular Ca2+ concentration, regulating cell cycles, cell autophagy and the immune system and so on. Generally, it is considered to be a potential anti-tumor drug. Key words: Artemisinins; Neoplasms; Apoptosis; Cell proliferation; Dihydroartemisinin

Dihydroartemisinin inhibits activation of the Toll-like receptor 4 signaling pathway and production of type I interferon in spleen cells from lupus-prone MRL/lpr mice.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by various immunological abnormalities. Dihydroartemisinin (DHA), a metabolite of artemisinin, has been recently reported to exhibit immunosuppressive properties. The present study aims to determine the effects of DHA on spleen cell activation triggered by lipopolysaccharide (LPS) and investigate the effects of DHA on LPS-induced activation of the Toll-like receptor 4 (TLR4)/interferon regulatory factor (IRF) signaling pathway. Spleen cells from lupus-prone MRL/lpr mice were isolated, prepared and cultured. Cells were treated with LPS alone or LPS with DHA, and spleen cell proliferation was analyzed using MTS assay. Protein expressions of TLR4, IRF3, and IRF7 were analyzed by Western blot. IRF3 phosphorylation was also determined. Gene expression levels of IFN-α and IFN-β were measured using real-time PCR, and protein levels in cells' supernatants were determined by ELISA. DHA was found to inhibit LPS-induced spleen cell proliferation, decrease LPS-induced protein expression of TLR4, and inhibit IRF3 phosphorylation. Furthermore, LPS significantly induced IRF3 expression and slightly increased IRF7 expression in the nucleus of spleen cells, which was accompanied by enhanced IFN-α and IFN-β production. DHA inhibited the effects of LPS in spleen cells of MRL/lpr mice. Taken together, the data obtained reveal that DHA inhibits LPS-induced cell activation possibly by suppressing the TLR4/IRF/IFN pathway in spleen cells of MRL/lpr mice. These data suggest that DHA has the potential therapeutic utility for the treatment of SLE.