Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Lee, Hyein; Lee, Gong Rak; Lee, Jiae; Kim, Na-Rae; Kwon, Minjeong; Kim, Hyun Jin; Kim, Nam Young; Park, Jin Ha; Jeong, Woojin

doi:10.5483/bmbrep.2020.53.4.220

Cited by 19 publications

(17 citation statements)

References 29 publications

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“…AMPK and Nrf2 were also reported to be involved in Gram-positive bacteria-mediated inflammation [ 41 ], and activation of the AMPK/Nrf2 signaling pathway could reduce inflammation by enhancing M2 polarization [ 13 ]. A previous study found that DHL exhibits the ability to activate Nrf2 [ 42 ]; our results make this finding more credible, as DHL promotes the phosphorylation of AMPK, an upstream gene of Nrf2, as well as accelerates the expression and nuclear translocation of Nrf2. HO-1, a downstream gene of Nrf2, has also been demonstrated to alleviate inflammation by altering the balance of M1/M2 macrophages [ 14 , 43 ].…”

Section: Discussionsupporting

confidence: 69%

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization

Jiang

Liu

et al. 2021

IJMS

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Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.

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Section: Discussionsupporting

confidence: 69%

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization

Jiang

Liu

et al. 2021

IJMS

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“…Bone marrow‐derived macrophages (BMMs) were prepared as osteoclast precursor cells as previously described (Lee et al, 2020). Bone marrow cells were flushed from femurs and tibiae of 8‐week‐old C57BL/6 male mice using α‐minimum essential medium (α‐MEM) containing 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml streptomycin followed by incubation at 37°C for 1 day.…”

Section: Methodsmentioning

confidence: 99%

“…Bone marrow-derived macrophages (BMMs) were prepared as osteoclast precursor cells as previously described (Lee et al, 2020).…”

Section: Preparation Of Bone Marrow-derived Macrophagesmentioning

confidence: 99%

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis

Lee

Kim

et al. 2020

Journal Cellular Physiology

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Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor βactivated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1β (PGC1β), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1β resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide-and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

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“…These data suggested that NRF2 is crucial to OC activity, but the underlying mechanism of NRF2 in regulating OC activity remains unclear [123]. Increased p38 MAP kinase activity but not the NF-kB pathway was associated to ROS elevation in NFR2 knockout mice [124][125][126][127]. Moreover, NRF2 also represses OC activity via regulating the activity of NFATc1, which is the master transcription factor for osteoclastogenesis [124,128].…”

Section: The Effects Of Nrf2 On Ocmentioning

confidence: 99%

Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2

Yen

Hsu

Hsiao

et al. 2020

IJMS

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Osteolytic bone lesions are one of the central features of multiple myeloma (MM) and lead to bone pain, fractures, decreased quality of life, and decreased survival. Dysfunction of the osteoclast (OC)/osteoblast (OB) axis plays a key role in the development of myeloma-associated osteolytic lesions. Many signaling pathways and factors are associated with myeloma bone diseases (MBDs), including the RANKL/OPG and NF-κB pathways. NRF2, a master regulator of inflammatory signaling, might play a role in the regulation of bone metabolism via anti-inflammatory signaling and decreased reactive oxygen species (ROS) levels. The loss of NRF2 expression in OCs reduced bone mass via the RANK/RANKL pathway and other downstream signaling pathways that affect osteoclastogenesis. The NRF2 level in OBs could interfere with interleukin (IL)-6 expression, which is associated with bone metabolism and myeloma cells. In addition to direct impact on OCs and OBs, the activity of NRF2 on myeloma cells and mesenchymal stromal cells influences the inflammatory stress/ROS level in these cells, which has an impact on OCs, OBs, and osteocytes. The interaction between these cells and OCs affects the osteoclastogenesis of myeloma bone lesions associated with NRF2. Therefore, we have reviewed the effects of NRF2 on OCs and OBs in MBDs.

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Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Cited by 19 publications

References 29 publications

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis

Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2

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