Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling

Thummuri, Dinesh; Jeengar, Manish Kumar; Shrivastava, Shweta; Nemani, Harishankar; Ramavat, Ravindar Naik; Chaudhari, Pradip; Naidu, V.G.M.

doi:10.1016/j.phrs.2015.05.006

Cited by 106 publications

(68 citation statements)

References 44 publications

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“…In addition, attenuation of H 2 O 2 stimulation increases osteoblasts viabilities and differentiation (Yan et al, 2017) through improving the mitochondrial redox homeostasis and functions (Dai et al, 2017). Elimination of ROS generation inhibits bone resorption through receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) mediated NF-κB activation (Thummuri et al, 2015). Further, emerging evidence suggests that Chinese herbal medicines may exhibit anti-osteoporotic effects through an improvement of antioxidant activity (Rufus et al, 2013; Huang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Wang

Guo

et al. 2017

Front. Pharmacol.

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Purpose: This study is designed to explore whether Fructus ligustri lucidi (FLL) exhibits antioxidant effect in ovariectomized (OVX) rats, and to identify the signaling pathway involved in this process.Methods: OVX rats were treated with FLL aqueous extract (3.5 g/kg) for 12 weeks. Serum, uteri, and tibias were harvested from the rats and the levels of total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), 8-hydroxy-desoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were determined. Changes in the levels of NF-κB-p65, phosphorylation of NF-κB-p65 (NF-κB-pp65), NF-κB inhibitor alpha (IκBα), phosphorylation of IκBα (p-IκBα), and NADPH oxidase 4 (Nox4) in uteri and tibias were determined by western blot, immunofluorescent and immunohistochemical analysis, respectively. In addition, the expression of cytochrome C (Cyto-C) and B-cell lymphoma-2 (Bcl-2) were determined in the tibias of rats. Histopathological changes in the bones were evaluated by hematoxylin-eosin staining. Bone mineral density (BMD) was determined in rat femurs by dual X-ray absorptiometry.Results: Treatment of OVX rats with FLL aqueous extract improved redox homeostasis by increasing the levels of TAC and NO as well as decreasing the levels of MDA and 8-OHdG in serum, tibias, and uteri. Further, FLL extract also downregulated the expression of Nox4, NF-κB-p65, NF-κB-pp65, and p-IκBα in the uteri and tibias. Furthermore, administration of FLL–OVX rats increased Bcl-2 expression and prevented cytoplasmic release of mitochondrial Cyto-C in the tibias. In addition, FLL treatment also improved bone microstructure and increased cortical bone thickness as well as increased BMD values in the femurs of OVX rats.Conclusions: FLL treatment may suppress oxidative stress response in OVX rats via regulating the Nox4/ROS/NF-κB signaling pathway. These results suggest the potential of using FLL as a natural antioxidant agent in preventing the development of osteoporosis.

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Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Wang

Guo

et al. 2017

Front. Pharmacol.

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“…The synthesis of COX-2 as well as production of proinflammatory cytokines including TNF and IL-6 is directly modulated by the pleiotropic transcription factor NF-κB 32, 33 . Phosphorylation of IKKα/β (ser 176/180) is a critical step in NF-κB activation and the expression of P-IKKα/β (ser 176/180) was found to be markedly increased in DSS control group 31 .…”

Section: Discussionmentioning

confidence: 99%

Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice

Jeengar

Thummuri

Magnusson

et al. 2017

Sci Rep

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Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1β and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF- α, COX-2, P-NFkB and P-Ikk-βα in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-κB signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.

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“…As the downstream target of NF‐κB and MAPK pathways, NFATc1 was the most important transcription factor for osteoclastogenesis . The activation of NFATc1 triggers the expression of osteoclastogenesis‐related marker genes, such as TRAP, Cathepsin K, CTR and MMP‐9.…”

Section: Discussionmentioning

confidence: 99%

l‐tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways

Zhi

Wang

Chen

et al. 2019

J Cellular Molecular Medi

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Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)‐activated NF‐κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l‐tetrahydropalmatine (l‐THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l‐THP inhibited osteoclastic differentiation at the early stage, down‐regulated transcription level of osteoclastogenesis‐related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l‐THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF‐κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co‐immunoprecipitation indicated that l‐THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l‐THP significantly inhibited ovariectomy‐induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l‐THP suppressed osteoclastogenesis by blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways. l‐THP is a promising agent for treating osteoclastogenesis‐related diseases such as post‐menopausal osteoporosis.

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Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling

Cited by 106 publications

References 44 publications

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice

l‐tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways

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