Niloticin inhibits osteoclastogenesis by blocking RANKL–RANK interaction and suppressing the AKT, MAPK, and NF-κB signaling pathways

Xu, Huanhuan; Jia, Yuankan; Li, Jin; Huang, Xueqin; Jiang, Li; Xiang, Ting; Xie, Yuanhao; Yang, Xiaomei; Liu, Titi; Xiang, Zemin; Sheng, Jun

doi:10.1016/j.biopha.2022.112902

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…In comparison with 19 (inhibition = 51.9%), the inhibitory activities were almost unchanged by introducing methoxy (22), ethoxy (23), and amino (25) groups to the pyrimidine at a low concentration of 0.1 μM. To our delight, the inhibitory effects were enhanced significantly as methyl (20) and ethyl (21) 3. As the double bond of the C-17 side chain of compound 20 was a reduction to a single bond (26), the inhibitory effect was maintained at 0.1 μM (inhibition = 96%), however, decreased significantly at 0.01 μM (inhibition = 9.2%).…”

Section: Synthesis Of Inhibitorsmentioning

confidence: 68%

“…In comparison with 19 (inhibition = 51.9%), the inhibitory activities were almost unchanged by introducing methoxy (22), ethoxy (23), and amino (25) groups to the pyrimidine at a low concentration of 0.1 μM. To our delight, the inhibitory effects were enhanced significantly as methyl (20) and ethyl (21) PPD (IC 50 = 10.3 μM, Figure S1B). The cell viability test (Table 3) showed no cell destructions by these derivatives at the concentration of 10 μM; therefore, these compounds on osteoclast differentiation were not from their cytotoxicity.…”

Section: Synthesis Of Inhibitorsmentioning

confidence: 86%

“…Natural products and their structural analogues have made a major contribution to pharmacotherapy and drug discovery . In searching for new types of antiosteoporosis chemical entities, some natural compounds, especially tetracyclic triterpenoids, have been found to inhibit osteoclast formation and activation, such as niloticin from Dysoxylum variabile, 25-acetylcimigenol xylopyranoside (ACCX) from black cohosh, ganoderic acid DM, and F from Ganoderma lucidum (Figure ). , Ginseng (Panax ginseng Meyer) has been regarded as a traditional herbal medicine in East Asia over 2000 years.…”

Section: Introductionmentioning

confidence: 99%

“…It is associated with intrinsic attributes, such as antioxidant, anticancer, antidiabetic, antiadipogenic, and antiosteoporosis activities. 24−26 20(S)-protopanaxadiol (PPD, Figure 1), an active metabolite of ginseng, is also a natural tetracyclic triterpenoid, which has been reported to exhibit a variety of biological activities, such as anti-inflammatory, 27 antifatigue, 28 antiestrogenic, 29 antitumor, 30 and antidepressantlike activities. 31 Recently, Pan et al 32 also reported that PPD inhibits titanium particle-induced inflammatory osteolysis and RANKL-mediated osteoclastogenesis via MAPK and NF-κB signaling pathways.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20(S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

Wang,

Zhang,

Zhang

et al. 2023

J. Med. Chem.

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A series of heterocyclic ring-fused derivatives of 20(S)-protopanaxadiol (PPD) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these compounds, 33 (SH491, IC 50 = 11.8 nM) showed the highest potency with 100% inhibition at 0.1 μM and 44.4% inhibition at an even lower concentration of 0.01 μM, which was much more potent than the lead compound PPD (IC 50 = 10.3 μM). Cytotoxicity tests indicated that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation was not due to their cytotoxicity. Interestingly, SH491 also exhibited a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. Mechanistic studies revealed that SH491 inhibits the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, CTSK, MMP-9, and ATPase v0d2. In vivo, SH491 could dramatically decrease the ovariectomy-induced osteoclast activity and relieve osteoporosis obviously. Thus, these PPD derivatives could be served as promising leads for the development of novel antiosteoporosis agents.

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Section: Synthesis Of Inhibitorsmentioning

confidence: 68%

“…In comparison with 19 (inhibition = 51.9%), the inhibitory activities were almost unchanged by introducing methoxy (22), ethoxy (23), and amino (25) groups to the pyrimidine at a low concentration of 0.1 μM. To our delight, the inhibitory effects were enhanced significantly as methyl (20) and ethyl (21) PPD (IC 50 = 10.3 μM, Figure S1B). The cell viability test (Table 3) showed no cell destructions by these derivatives at the concentration of 10 μM; therefore, these compounds on osteoclast differentiation were not from their cytotoxicity.…”

Section: Synthesis Of Inhibitorsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20(S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

Wang,

Zhang,

Zhang

et al. 2023

J. Med. Chem.

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“…BMMs were seeded into 96-well plates and cultured overnight in α-MEM containing M-CSF (25 ng/mL) to adhere, after which RANKL (50 ng/mL, LifeTein, LLC, Beijing, China) was added to the medium to induce the formation of OCs [29], which were then treated with different concentrations (0-512 nM) of FTY720. The culture medium was replaced every 48 h for 7 days.…”

Section: Osteoclastogenesis and Trap Staining Assaysmentioning

confidence: 99%

FTY720 Attenuates LPS-Induced Inflammatory Bone Loss by Inhibiting Osteoclastogenesis via the NF-κB and HDAC4/ATF Pathways

Chen

Zong

Wang

et al. 2023

Journal of Immunology Research

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Osteoclast (OC) abnormalities lead to many osteolytic diseases, such as osteoporosis, inflammatory bone erosion, and tumor-induced osteolysis. Exploring effective strategies to remediate OCs dysregulation is essential. FTY720, also known as fingolimod, has been approved for the treatment of multiple sclerosis and has anti-inflammatory and immunosuppressive effects. Here, we found that FTY720 inhibited osteoclastogenesis and OC function by inhibiting nuclear factor kappa-B (NF-κB) signaling. Interestingly, we also found that FTY720 inhibited osteoclastogenesis by upregulating histone deacetylase 4 (HDAC4) expression levels and downregulating activating transcription factor 4 (ATF4) expression levels. In vivo, FTY720 treatment prevented lipopolysaccharide- (LPS-) induced calvarial osteolysis and significantly reduced the number of tartrate-resistant acid phosphatase- (TRAP-) positive OCs. Taken together, these results demonstrate that FTY720 can inhibit osteoclastogenesis and ameliorate inflammation-induced bone loss. Which may provide evidence of a new therapeutic target for skeletal diseases caused by OC abnormalities.

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Trifolirhizin reduces osteoclast formation and prevents inflammatory osteolysis by inhibiting RANKL‐induced activation of NF‐κB and MAPK signaling pathways and ROS

Huang,

Song,

et al. 2024

Phytotherapy Research

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Inflammatory osteolysis is often caused by the excessive activation of osteoclasts stimulated by bacterial products such as lipopolysaccharide. The natural flavonoid trifolirhizin (TRI) has anti‐inflammatory properties; however, its function in inflammatory bone lysis remains unclear. This study aimed to elucidate the potential regulatory mechanisms of TRI in osteoclasts.Tartrate‐resistant acid phosphatase (TRAP) staining, acid secretion assays, podosomal actin belt fluorescence staining, and bone resorption assays were used to investigate the effects of TRI on osteoclast differentiation and bone resorption. A reactive oxygen species (ROS) measurement kit was used to detect the effect of TRI on ROS levels in osteoclasts. The effects of TRI on genes and signaling pathways related to osteoclast differentiation were determined by quantitative polymerase chain reaction (qPCR) and western blotting. A mouse model of lipopolysaccharide‐mediated inflammatory osteolysis was established, and the effects of TRI treatment on bone mass were observed using micro‐CT and histological examination. Mechanistically, TRI reduced ROS production by inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced activation of the nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling pathways, and by upregulating the expression levels of the anti‐ROS enzymes heme oxygenase‐1 (HO‐1) and catalase (CAT), which contributed to the degradation of ROS, ultimately leading to a decrease in osteoclastogenesis. TRI inhibited osteoclast formation and ameliorated lipopolysaccharide (LPS)‐mediated inflammatory osteolysis. Thus, TRI may be a candidate agent for anti‐inflammatory osteolysis.

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Niloticin inhibits osteoclastogenesis by blocking RANKL–RANK interaction and suppressing the AKT, MAPK, and NF-κB signaling pathways

Cited by 11 publications

References 40 publications

Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20(S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20(S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

FTY720 Attenuates LPS-Induced Inflammatory Bone Loss by Inhibiting Osteoclastogenesis via the NF-κB and HDAC4/ATF Pathways

Trifolirhizin reduces osteoclast formation and prevents inflammatory osteolysis by inhibiting RANKL‐induced activation of NF‐κB and MAPK signaling pathways and ROS

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