Therapeutic effect of artemisinin on lupus nephritis mice and its mechanisms

Wu, Xiumei; Zhang, Wanggang; Shi, Xiaojian; An, Peng; Sun, Wenli; Wang, Zhu

doi:10.1093/abbs/gmq101

Cited by 41 publications

(30 citation statements)

References 26 publications

(35 reference statements)

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“…22 Twice-daily administration of SM934 (5 mg/kg) had a better potential to maintain the survival of MRL/lpr mice than in a previous study. 20 With this optimized dose regimen, we also observed more persistent and more prominent therapeutic effects of SM934 on proteinuria, serum biochemical indices and kidney pathology. In addition, using the twice-daily regimen, SM934 showed better dose dependence than the once-daily regimen.…”

Section: Discussionmentioning

confidence: 63%

“…[18][19][20][21] In our previous study, SM934 exhibited protective effects in two mouse models of SLE, MRL/lpr and NZB/W F1 mice, partly by suppressing pathogenic T-cell development. 22,23 Because of its relatively short biological half-life (approximately 0.5 h tested on rats and dogs), we optimized the dose regimen of SM934 to a twice daily administration and reduced the drug doses compared to previous strategies.…”

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confidence: 99%

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Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Bai

et al. 2015

Cell Mol Immunol

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We previously reported that SM934, a water-soluble artemisinin derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-kB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation. Cellular & Molecular Immunology

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 99%

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Bai

et al. 2015

Cell Mol Immunol

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“…In microglia cells, artemisinin treatment attenuated lipopolysaccharide-induced production by promoting the formation of the inactive p65-p50 heterodimeric NF-κB protein complex that requires the presence of IκB-α [54]. The disruption of NF-κB signaling has also been shown to be involved with the artemisinin inhibition of rat cardiac hypertrophy [55] and is associated with therapeutic effects in lupus nephritis mice [56]. In pancreatic cancer cells, the artemisinin derivative dihydroartemisinin induced a G1 cell cycle arrest and inactivated NF-κB function, although the NF-κB target genes critical for this response were not functionally characterized [57].…”

Section: Discussionmentioning

confidence: 99%

Artemisinin triggers a G1 cell cycle arrest of human Ishikawa endometrial cancer cells and inhibits cyclin-dependent kinase-4 promoter activity and expression by disrupting nuclear factor-κB transcriptional signaling

2014

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Relatively little is known about the anti-proliferative effects of Artemisinin, a naturally occurring anti-malarial compound from Artemisia annua, or sweet wormwood, in human endometrial cancer cells. Artemisinin induced a G1 cell cycle arrest in cultured human Ishikawa endometrial cancer cells and down regulated CDK2 and CDK4 transcript and protein levels. Analysis of CDK4 promoter-luciferase reporter constructs showed that the artemisinin ablation of CDK4 gene expression was accounted for by the loss of CDK4 promoter activity. Chromatin immunoprecipitation demonstrated that artemisinin inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit p65 and p50 interactions with the endogenous Ishikawa cell CDK4 promoter. Coimmunoprecipitation revealed that artemisinin disrupts endogenous p65 and p50 nuclear translocation via increased protein-protein interactions with IκB-α, an NF-κB inhibitor, and disrupts its interaction with the CDK4 promoter, leading to a loss of CDK4 gene expression. Artemisinin treatment stimulated the cellular levels of IκB-α protein without altering the level of IκB-α transcripts. Finally, expression of exogenous p65 resulted in the accumulation of this NF-κB subunit in the nucleus of artemisinin treated and untreated cells, reversed the artemisinin down-regulation of CDK4 protein expression and promoter activity and prevented the artemisinin induced G1 cell cycle arrest. Taken together, our results demonstrate that a key event in the artemisinin anti-proliferative effects in endometrial cancer cells is the transcriptional down-regulation of CDK4 expression by disruption of NF-κB interactions with the CDK4 promoter.

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“…Recently, Wu et al (24) reported that artemisinin treatment for 8 weeks at a dosage of 150 mg/kg/day could ameliorate glomerular injury in a murine model of inducible lupus. Those investigators observed that artemisinin treatment decreased the serum levels of IL-6 and tumor necrosis factor ␣ (TNF␣) and downregulated the expression of NK-B and TGF␤1 mRNA in the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, treatment of SLE involves the use of immunosuppressant agents and cytostatic agents, with extensive use of corticosteroids once disease is stabilized; these treatments have numerous side effects (21). Artemisinin derivatives have shown significant therapeutic benefit in SLE, both clinically and experimentally (22)(23)(24). However, most artemisinin derivatives possess poor water solubility or low bioavailability, which limits their further applications to treat autoimmune diseases.…”

mentioning

confidence: 99%

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

Hou¹,

He²,

Li³

et al. 2011

Arthritis & Rheumatism

106

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Objective. SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice.Methods. In vitro, the effects of SM934 on the activation of polyclonal CD4؉ T cells and the differentiation of naive CD4؉ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease.Results In female MRL/lpr mice, an autoimmune syndrome develops spontaneously that closely resembles human systemic lupus erythematosus (SLE) and is characterized by the production of various autoantibodies and the development of fatal glomerulonephritis (1,2).Disease begins as early as 8 weeks of age in these mice, with the presence of detectable serum autoantibodies. Pronounced lymphadenopathy is observed at 12 weeks of age, which is largely attributable to the accumulation of a population of B220ϩ and CD3ϩ cells that are mostly CD4Ϫ and CD8Ϫ (double-negative T cells). By 12-16 weeks of age, MRL/lpr mice begin to produce a variety of autoantibodies, including antidouble-stranded DNA (anti-dsDNA) antibodies. Multiple organs are affected, and a steady deterioration of renal function manifesting as severe proteinuria begins at approximately 16 weeks of age. From 16 weeks of age to 24 weeks of age, proliferative immune complex-

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Therapeutic effect of artemisinin on lupus nephritis mice and its mechanisms

Cited by 41 publications

References 26 publications

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Artemisinin triggers a G1 cell cycle arrest of human Ishikawa endometrial cancer cells and inhibits cyclin-dependent kinase-4 promoter activity and expression by disrupting nuclear factor-κB transcriptional signaling

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

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