beta-aminoarteether-maleate and Disease-Models--Animal

Artemisinin and its derivatives are the well-known anti-malarial drugs derived from a traditional Chinese medicine. In addition to antimalarial, artemisinin and its derivatives possess distinguished anti-cancer, anti-oxidant, anti-inflammatory and anti-viral activities, but the poor solubility and low bioavailability hinder their clinical application. In the last decades a series of new water-soluble and oil-soluble derivatives were synthesized. Among them, we have found a water-soluble derivative β-aminoarteether maleate (SM934) that exhibits outstanding suppression on lymphocytes proliferation in immunosuppressive capacity and cytotoxicity screening assays with 35-fold higher potency than dihydroartemisinin. SM934 displays significant therapeutic effects on various autoimmune and inflammatory diseases, including systemic lupus erythematosus, antiphospholipid syndrome nephropathy, membranous nephropathy, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and dry eye disease. Here, we summarize the immunomodulatory effects, anti-inflammatory, anti-oxidative and anti-fibrosis activities of SM934 in disease-relevant animal models and present the probable pharmacological mechanisms involved in its therapeutic efficacy. This review also delineates a typical example of natural product-based drug discovery, which might further vitalize natural product exploration and development in pharmacotherapy.

Topics: Animals; Artemisinins; Autoimmune Diseases; Biological Products; Disease Models, Animal; Water

Systemic lupus erythematosus (SLE) is a complex, potentially fatal autoimmune disease with no complete cure. Current treatments for SLE are limited by suboptimal efficacy and increased risk of infections and malignancies, and cannot meet the clinical demands of patients with SLE. Artemisinin and its derivatives (artemisinins), a new class of anti-malarial drugs, have recently been reported to have an immunosuppressive effect on lupus patients. In this review, we evaluate the therapeutic properties and potential mechanisms of artemisinins for the treatment of SLE.. Both clinical and animal studies suggest that artemisinins have potential beneficial effects for SLE. The beneficial effects associated with artemisinin treatment include improving symptoms, reducing level of antibodies and proteinuria, ameliorating renal damage, and diminishing the dosage of prednisone use. Animal studies suggest that mechanisms of action of artemisinins may include regulating T cell subsets, inhibiting activation of B cells and production of inflammatory cytokines, as well as blocking the NF-κB signal transduction pathway, thus playing a role in anti-inflammation and immunomodulation. Artemisinin family drugs are a promising potential new medication that may challenge the current treatment paradigms available for SLE.

Topics: Animals; Artemisinins; Artesunate; Disease Models, Animal; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mice

Kidney is a major target organ in both antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The etiology of antiphospholipid syndrome nephropathy associated lupus nephritis (APSN-LN) is intricate and remains largely unrevealed. We proposed in present work, that generation of antiphospholipid antibodies (aPLs), especially those directed towards the oxidized neoepitopes, are largely linked with the redox status along with disease progression. Moreover, we observed that compromised antioxidative capacity coincided with turbulence of inflammatory cytokine profile in the kidney of male NZW×BXSB F1 mice suffered from APSN-LN. SM934 is an artemisinin derivative that has been proved to have potent immunosuppressive properties. In current study, we elaborated the therapeutic benefits of SM934 in male NZW×BXSB F1 mice, a murine model develops syndrome resembled human APS associated with SLE, for the first time. SM934 treatment comprehensively impeded autoantibodies production, inflammatory cytokine accumulation and excessive oxidative stress in kidney. Among others, we interpreted in present work that both anti-inflammatory and antioxidative effects of SM934 is closely correlated with the enhancement of Nrf2 signaling and expression of its targets. Collectively, our finding confirmed that therapeutic strategy simultaneously exerting antioxidant and anti-inflammatory efficacy provide a novel feasible remedy for treating APSN-LN.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Artemisinins; Cytokines; Disease Models, Animal; Inflammation; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mice; NF-E2-Related Factor 2; Reactive Oxygen Species; Signal Transduction

SM934 is an artemisinin analogue with immunosuppressive properties and potent therapeutic activity against lupus-like diseases in autoimmune mice. In this report, the therapeutic efficacy and underlying mechanisms of SM934 on rheumatoid arthritis (RA) was investigated using collagen-induced arthritis (CIA) in DBA/1J mice. We demonstrated that SM934 treatment alleviate the severity of arthritis in CIA mice with established manifestations. The therapeutic benefits were associated with ameliorated joint swelling and reduced extent of bone erosion and destruction. Further, administration of SM934 diminished the development of T follicular helper (Tfh) cells and Th17 cells and suppressed the production of pathogenic antibodies, without altering the proportion of germinal center B cells. Ex vivo, SM934 treatment inhibited the bovine type II collagen (CII) induced proliferation and inflammatory cytokines secretion of CII -reactive T cells. In vitro, SM934 impeded the polarization of naïve CD4

Topics: Animals; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Cattle; CD4-Positive T-Lymphocytes; Collagen Type II; Disease Models, Animal; Female; Interferon-gamma; Interleukins; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Proto-Oncogene Proteins c-bcl-6; STAT3 Transcription Factor; Th17 Cells

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.. 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.. In vitro, SM934 inhibited interferon-γ (IFNγ) and interleukin-17 (IL-17) production from polyclonal CD4+ T cells activated by T cell receptor engagement and the differentiation of naive CD4+ T cells into Th1 and Th17 cells, but not Treg cells. In vivo, 12-week-old MRL/lpr mice treated with SM934 for 4 weeks showed significantly ameliorated proteinuria and renal lesion severity; decreased levels of blood urea nitrogen, serum IFNγ, and serum anti-double-stranded DNA antibodies; decreased spleen size; and a lower percentage of CD3+B220+CD4-CD8- T cells; 16-week-old MRL/lpr mice treated with SM934 for 8 weeks avoided severe proteinuria and survived longer. Ex vivo, SM934 treatment elevated the percentage of Treg cells, inhibited the development of Th1 and Th17 cells, and impeded the comprehensive activation of STAT-1, STAT-3, and STAT-5 proteins in splenocytes.. Taken together, the results of this study demonstrated that the artemisinin analog SM934 had therapeutic effects in lupus-prone female MRL/lpr mice by inhibiting both Th1 cell and Th17 cell responses. Moreover, this study indicated that both IFNγ and IL-17 are required for the elicitation and development of murine lupus.

Topics: Animals; Artemisinins; Disease Models, Animal; Female; Interferon-gamma; Lupus Erythematosus, Systemic; Mice; Th1 Cells; Th17 Cells; Treatment Outcome