ReferenceID 4338
Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER α to inhibit RANKL signaling
Acta Pharm Sin B
Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis a
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Record Fields
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- Reference Id
- 4338
- Evidence Id
- 20928
- Core Evidence Id
- 20928
- Source Reference Id
- 1942
- Herb2 Reference Id
- HBREF002739
- Subject Paper Key
- HBIN001101_33643823
- Pubmed Id
- 33643823
- Doi
- 10.1016/j.apsb.2020.09.012
- Paper Title
- Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER α to inhibit RANKL signaling
- Paper Abstract
- Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents. Here, we defined that norlichexanthone (NOR), a natural product, is a ligand of estrogen receptor-alpha (ERalpha) and revealed its therapeutic potential for postmenopausal osteoporosis. We used mammalian-one hybrid assay to screen for ERalpha modulators from crude extracts of several plant endophytes. As a result, NOR purified from the extract of endophyte ARL-13 was identified as a selective ERalpha modulator. NOR directly bound to ERalpha with an affinity in nanomolar range, revealing that it is a natural ligand of ERalpha. NOR induced osteoblast formation in MC3T3-E1 precursor cells. Conversely, NOR inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes. Mechanistically, NOR inhibited RANKL-induced association of ERalpha and TRAF6 to prevent ERalpha-mediated TRAF6 activation via Lys63-linked ubiquitination. Importantly, NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model. Comparing to estrogen, NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation. Taken together, our study identified NOR as a natural and high affinity ligand of ERalpha with substantial anti-osteoporosis but less estrogenic activity.
- Journal
- Acta Pharm Sin B
- Publish Year
- 2021
- Experiment Subject
- mouse; mc3t3-e1 precursor cells; raw264.7 macrophages
- Experiment Type
- Cell Experiment
- Phenotype Related
- Endometrial Hyperplasia; Cancer; Postmenopausal Osteoporosis
- Paper Title Cn
- Paper Title En
- Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER α to inhibit RANKL signaling
- Bilingual Status
- semi_complete