NF-κB inhibitor, NEMO-binding domain peptide attenuates intervertebral disc degeneration

Glaeser, Juliane D.; Salehi, Khosrowdad; Kanim, Linda E.A.; NaPier, Zachary; Kropf, Michael A.; Cuéllar, Jason M.; Perry, Tiffany Grace; Bae, Hyun; Sheyn, Dmitriy

doi:10.1016/j.spinee.2020.04.025

Cited by 18 publications

(11 citation statements)

References 68 publications

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“…Downstream targets of NF-κB include numerous matrix-degrading enzymes ( MMP-1/-2/-3/-13, ADAMTS-4/-5 ), ECM proteins ( asporin ), inflammatory mediators ( iNOS, COX-2, prostaglandin E ), and chemokines ( MCP-1 ), supporting the crucial role of this pathway in IVD and inflammation and degeneration [ 153 , 250 , 274 , 275 , 276 , 277 , 278 , 279 ]. In addition to specific NF-κB inhibitors such as ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) or the NF-κB essential modulator (NEMO) binding domain peptide (NBD) [ 275 , 280 ], several natural drugs (e.g., curcumin [ 281 ], epigallocatechin gallate [ 255 ], or resveratrol [ 282 ]) have been described to modulate NF-κB activity. Furthermore, NF-κB signaling can be altered by specific miRNAs (e.g., miR-150 [ 283 ]), but NF-κB activation can also affect expression of numerous miRNAs (e.g., miR-640 [ 284 ]).…”

Section: Ivd Regeneration Strategies: Biological Targets and Biomamentioning

confidence: 99%

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Baumgartner

Wuertz‐Kozak

Maitre

et al. 2021

IJMS

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Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

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Section: Ivd Regeneration Strategies: Biological Targets and Biomamentioning

confidence: 99%

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Baumgartner

Wuertz‐Kozak

Maitre

et al. 2021

IJMS

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“…As an avascular tissue, the IVD has a very limited intrinsic healing potential [ 5 ]. Experimental strategies for the attenuation and regeneration of disc degeneration include the injection of anti-inflammatory agents, growth factors to stimulate extracellular matrix production and cell proliferation, and stem cell therapies [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

Glaeser

Tawackoli

et al. 2020

IJMS

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Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.

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“…First, we used the needle puncture model for induction of IVDD, which may not provoke the identical clinical pathology observed in humans. Although this is the most commonly used animal model [46][47][48], a more appropriate animal model of IVDD needs to be developed for future studies. Second, our study is aimed at exploring the role of t-BHQ in disc degeneration, so the potential effects of t-BHQ on other organs were not shown in our research.…”

mentioning

confidence: 99%

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Zhang

Qian

et al. 2021

Oxidative Medicine and Cellular Longevity

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One of the causes of intervertebral disc degeneration (IVDD) is nucleus pulposus cell (NPC) death, possibly apoptosis. In this study, we explored the role of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated the potential working mechanism. Reactive oxygen species (ROS) assay kits and malondialdehyde (MDA) assay kits were used to assess oxidative stress. Western blot and TUNEL staining were used to examine apoptosis. After siRNA against Nrf2 or lentivirus against Sirt3 was transfected into NPCs, the mechanism of the effect of the Nrf2/Sirt3 pathway on NPCs was assessed. The interaction between t-BHQ and its potential interacting protein NRF2 was further investigated through protein docking analysis. ChIP examined the binding affinity between Nrf2 and Sirt3 promoter. In vivo experiments, X-ray, hematoxylin-eosin (HE) staining, Safranin O staining, and immunohistochemistry were used to evaluate IVDD grades. The results demonstrated that activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5. Furthermore, t-BHQ ameliorated IVDD development in a rat model. In conclusion, our findings indicate that the Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD.

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NF-κB inhibitor, NEMO-binding domain peptide attenuates intervertebral disc degeneration

Cited by 18 publications

References 68 publications

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

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