| Description: |
Fraxinellone is a selective blocker of voltage-dependent Ca2+ channel, which possesses antimicrobial, anti-inflammatory, neuroprotective and vasorelaxing activities, Fraxinellone exhibits a variety of insecticidal activities including feeding-deterrent activity, inhibition of growth, and larvicidal activity. It inhibited the production of iNOS, COX-2, NF-kappa B, and PGE(2). |
| In vitro: |
| Biochem Pharmacol. 2009 Jun 1;77(11):1717-24. | | Selective triggering of apoptosis of concanavalin A-activated T cells by fraxinellone for the treatment of T-cell-dependent hepatitis in mice.[Pubmed: 19428326 ] | Selectively inducing apoptosis of activated T cells is essential for the clearance of pathogenic injurious cells and subsequent efficient resolution of inflammation. However, few chemicals have been reported to trigger apoptosis of activated T cells in the treatment of hepatitis without affecting quiescent T cells.
CONCLUSIONS:
In the present study, we found that fraxinellone, a small natural compound isolated from the root bark of Dictamnus dasycarpus, selectively facilitated apoptosis of concanavalin A (Con A)-activated CD4(+) T cells rather than those non-activated, by disrupting the mitochondrial transmembrane potential, decreasing the ratio of Bcl-2/Bax, and increasing cytochrome c release from the mitochondria to the cytosol. The enhancement in Fas expression and caspase-8 activity, truncation of Bid, and down-regulation of anti-apoptotic cellular FLICE-inhibitory protein expression by fraxinellone also suggested the participation of an extrinsic apoptosis pathway. Furthermore, fraxinellone significantly alleviated Con A-induced T-cell-dependent hepatitis in mice, which was closely associated with reduced serum transaminases, pro-inflammatory cytokines, and pathologic parameters. Consistent with the in vitro results, fraxinellone dramatically induced apoptosis of activated peripheral CD4(+) T cells in vivo, consequently resulting in less CD4(+) T-cell activation and infiltration to the liver.
CONCLUSIONS:
These results strongly suggest fraxinellone might be a potential leading compound useful in treating T-cell-mediated liver disorders in humans. | | Molecules. 2013 Mar 1;18(3):2754-62. | | Insecticidal and feeding deterrent effects of fraxinellone from Dictamnus dasycarpus against four major pests.[Pubmed: 23455666] | Fraxinellone, a well-known and significant naturally occurring compound isolated from Meliaceae and Rutaceae spp. has been widely used as a drug for the treatment of tumors. On the other hand, fraxinellone exhibited a variety of insecticidal activities including feeding-deterrent activity, inhibition of growth, and larvicidal activity.
METHODS AND RESULTS:
The present study focused on the antifeedant and larvicidal activities of fraxinellone against the larvae of Lepidoptera, including Mythimna separata, Agrotis ypsilon, Plutella xylostella, and one kind of sanitary pest, Culux pipiens pallens. Meanwhile, the ovicidal activities and the effects of fraxinellone on the larval development of M. separata were also observed. The LC50 values of fraxinellone against 3rd instar larvae of M. separata, 2nd instar larvae of P. xylostella and 4th instar larvae of C. pipiens pallens were 15.95/6.43/3.60 × 10-2 mg mL-1, and its AFC50 values against 5th instar larvae of M. separata, 2nd instar larvae of P. xylostella and 2nd instar larvae of A. ypsilon were 10.73/7.93/12.58 mg mL-1, respectively.
CONCLUSIONS:
Compared with the control group, fraxinellone obviously inhibited the pupation rate and the growth of M. separata. Once M. separata was treated with fraxinellone at concentrations of 5.0, 10.0, and 20.0 mg mL-1, respectively, the stages from the larvae to adulthood and the egg hatching duration were prolonged to 1/2/3, and 4/3/4 days, respectively. Additionally, fraxinellone strongly inhibited the development rate and the egg hatch proportion of M. separata. | | 2018 Sep;135:166-180. | | Fraxinellone has anticancer activity in vivo by inhibiting programmed cell death-ligand 1 expression by reducing hypoxia-inducible factor-1α and STAT3[Pubmed: 30103001] | | Abstract
Dictamnus dasycarpus is a traditional Chinese medicine thathas been commonly used in the treatment of cancer. Fraxinellone is a natural product isolated from the D. dasycarpus plant, which has been shown to exhibit neuroprotective and anti-inflammatory activities. However, whether fraxinellone exerts anticancer effects and the mechanisms by which it may inhibit tumor growth remain unknown. Here, we found that fraxinellone, in a dose-dependented manner, inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis. It was subsequently shown that fraxinellone reduced HIF-1α protein synthesis via the mTOR/p70S6K/eIF4E and MAPK pathways. It also inhibited activation of STAT3 via the JAK1, JAK2, and Src pathways. Immunoprecipitation and western blotting assays showed that fraxinellone inhibited PD-L1 expression by reducing STAT3 and HIF-1α cooperatively. Flow cytometry, colony formation, and EdU incorporation assays demonstrated that fraxinellone inhibited cell proliferation through suppression of PD-L1. Tube formation, migration, and invasion assays showed that fraxinellone inhibits angiogenesis by suppressing PD-L1. In vivo studies further supported anticancer role for fraxinellone, demonstrating that fraxinellone treatment inhibited the growth of tumor xenografts. We concluded that fraxinellone inhibits PD-L1 expression by downregulating the STAT3 and HIF-1α signaling pathways, subsequently inhibiting proliferation and angiogenesis in cancer cells. These studies reveal previously unknown characteristics of fraxinellone and provide new perspectives into the mechanism of cancer inhibition of the compound.
Keywords: Angiogenesis; Fraxinellone; HIF-1α; PD-L1; Proliferation; STAT3. |
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| In vivo: |
| Toxicol Appl Pharmacol. 2014 Oct 13;281(1):146-156. | | Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone.[Pubmed: 25448682] | Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD.
METHODS AND RESULTS:
Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation.
CONCLUSIONS:
Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. |
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