A Novel Inhibitor of I-KappaB Kinase Beta Ameliorates Experimental Arthritis through Downregulation of Proinflammatory Cytokines in Arthritic Joints

Tanaka, Shinji; Toki, Tadashi; Yokoyama, Mika; Shimizu, H.; Yamasaki, Tomonori; Yoneda, Yasuko; Muro, Fumihito; Yasukochi, Takanori; Iimura, Soshi; Morishita, Kaoru

doi:10.1248/bpb.b13-00628

Cited by 3 publications

(3 citation statements)

References 49 publications

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“…McIntyre and co-workers investigated the protective effect of BMS-345541, an IKKβ inhibitor, and found that it could suppress the IL-1β level to attenuate inflammation and joint destruction, contributing to alleviate collagen-induced arthritis in the mouse model 117 . The similar result was observed in the rheumatoid arthritis through inhibiting the IKKβ activity by 4-[6-(cyclobutylamino)imidazo[1,2- b ]pyridazin-3-yl]-2-fluoro- N -([(2 S ,4 R )-4-fluoropyrrolidin-2-yl])methylbenzamide 118 . Furthermore, the selective IKKβ inhibitor SC-514 inhibited the IκBα degradation to inactivate the NF-κB signal, further triggering to impair RANKL (receptor activator of nuclear factor-κB ligand)-induced osteoclastogenesis 119 , which was further supported by Thummuri's study showing that inhibition of IKKβ by abietic acid attenuated RANKL-induced osteoporosis 120 .…”

Section: Biological Potentials For Ikkβ Inhibitionsupporting

confidence: 81%

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

Zhang¹,

Zhang²,

Li³

et al. 2023

Int. J. Biol. Sci.

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The effective approach to discover innovative drugs will ask natural products for answers because of their complex and changeable structures and multiple biological activities. Inhibitory kappa B kinase beta (IKKβ), known as IKK2, is a key regulatory kinase responsible for the activation of NF-κB through its phosphorylation at Ser177 and Ser181 to promote the phosphorylation of inhibitors of kappa B (IκBs), triggering their ubiquitination and degradation to active the nuclear factor kappa-B (NF-κB) cascade. Chemical inhibition of IKKβ or its genetic knockout has become an effective method to block NF-κB-mediated proliferation and migration of tumor cells and inflammatory response. In this review, we summarized the structural feature and transduction mechanism of IKKβ and the discovery of inhibitors from natural resources (e.g. sesquiterpenoids, diterpenoids, triterpenoids, flavonoids, and alkaloids) and chemical synthesis (e.g. pyrimidines, pyridines, pyrazines, quinoxalines, thiophenes, and thiazolidines). In addition, the biosynthetic pathway of novel natural IKKβ inhibitors and their biological potentials were discussed. This review will provide inspiration for the structural modification of IKKβ inhibitors based on the skeleton of natural products or chemical synthesis and further phytochemistry investigations.

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Section: Biological Potentials For Ikkβ Inhibitionsupporting

confidence: 81%

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

Zhang¹,

Zhang²,

Li³

et al. 2023

Int. J. Biol. Sci.

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“…Activation of NFB family of transcription factors results in the expression of numerous genes involved in the regulation of the innate and adaptive immune responses, and has been implicated as a key mechanism in RA [32]. Previous data have demonstrated that selectively blocking NFB promoter activity and NFB-driven production TNF␣and interleukin-6 inhibited arthritis progression even when treatment occurred after disease development [33].…”

Section: Discussionmentioning

confidence: 99%

Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis

2015

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“…The p50/p65 form is the most common combination form (5). Various studies have shown that NF-κB participates in the transcription of genes regulating apoptosis and hyperplasia (6).…”

Section: Introductionmentioning

confidence: 99%

Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway

Zhang

Zhao

et al. 2017

Oncology Letters

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Abstract. Modern pharmacological research has revealed that andrographolide has various functions, including anti-bacterial, anti-inflammatory and anti-viral effects, immunoregulation, treating cardiovascular and cerebrovascular diseases, and prevention and treatment of alcoholic liver injury. The present study investigated whether andrographolide suppresses the proliferation of human colon cancer cell through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB/matrix metalloproteinase-9 (MMP-9) signaling pathway. The MTT assay and lactate dehydrogenase assay were used to evaluate the anticancer effects of andrographolide on cell proliferation and cytotoxicity in human colon cancer SW620 cells.Flow cytometry was used to analyze the anticancer effects of andrographolide on apoptosis by Annexin V-fluorescein isothiocyanate/propidium iodide kit. The effects of andrographolide on the activity of caspase-3/9 were measured using ELISA. Western blot analysis was also used to analyze the protein expression of TLR4, myeloid differentiation primary response gene 88 (MyD88), NF-κB-p65 and MMP-9. In the present study, it was found that andrographolide suppressed the cell proliferation, augmented cytotoxicity, evoked cell apoptosis and activated caspase-3/9 activities in human colon cancer SW620 cells. The results revealed that the anti-proliferation effects of andrographolide on the SW620 cells was associated with the inhibition of TLR4, MyD88, NF-κB-p65 and MMP-9 signaling activation. The results suggest that andrographolide is a promising drug for treatment of human colon cancer via suppression of the TLR4/NF-κB/MMP-9 signaling pathway.

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A Novel Inhibitor of I-KappaB Kinase Beta Ameliorates Experimental Arthritis through Downregulation of Proinflammatory Cytokines in Arthritic Joints

Cited by 3 publications

References 49 publications

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis

Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway

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