Epigenetic modifications of inflammation in intervertebral disc degeneration

Kang, Liang; Zhang, Huaqing; Jia, Chong-Yu; Zhang, Ren‐Jie; Shen, Cailiang

doi:10.1016/j.arr.2023.101902

Cited by 31 publications

(14 citation statements)

References 90 publications

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“…However, this study focuses on the TA scaffold, both because these compounds displayed the greatest activity, and because they afforded an excellent opportunity to explore the structure-activity relationship of a novel family of tau aggregation inhibitors. A 14-compound library (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) was synthesized based on 8-chloroTA (3), the most potent of the first four compounds, exploring the effects of modifications to the quinazoline ring (Fig. 2A).…”

Section: Design Synthesis and Screening Of Ta Analogsmentioning

confidence: 99%

“…Our approach differs from efforts to develop broad-spectrum aggregation inhibitors, whether based on natural products, 17,18 molecular tweezer 19 or designed peptide scaffolds, [20][21][22] that target later oligomeric or fibrillar states. Instead, we target disordered, monomeric states with the goals of (1) achieving specificity for tau vs. other aggregation-prone proteins, and (2) interrupting aggregation before cytotoxic oligomers are populated.…”

Section: Introductionmentioning

confidence: 99%

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Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

James,

Baggett,

Chang

et al. 2024

Preprint

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Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer's disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable "druggable" pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ~100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.

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Section: Design Synthesis and Screening Of Ta Analogsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

James,

Baggett,

Chang

et al. 2024

Preprint

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“…Not infrequently, its fibrocartilaginous structure can undergo degeneration due to various factors including bad lifestyles, aging, trauma, mechanical stress, or genetic factors. 1,2 In many cases this causes severe spinal disorders that can significantly affect the individual's quality of life, leading to different forms of disability and a socioeconomic burden. 3 It goes without saying that the IVD degeneration (IDD) is a very complex phenomenon, and to date, there are many open questions.…”

Section: Introductionmentioning

confidence: 99%

“…The intervertebral disc (IVD) is the principal joint between two vertebrae in the spine. Not infrequently, its fibrocartilaginous structure can undergo degeneration due to various factors including bad lifestyles, aging, trauma, mechanical stress, or genetic factors 1,2 . In many cases this causes severe spinal disorders that can significantly affect the individual's quality of life, leading to different forms of disability and a socioeconomic burden 3 .…”

Section: Introductionmentioning

confidence: 99%

Wharton's jelly‐derived multifunctional hydrogels: New tools to promote intervertebral disc regeneration in vitro and ex vivo

Penolazzi,

Chierici,

Notarangelo

et al. 2024

J Biomedical Materials Res

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The degeneration of intervertebral disc (IVD) is a disease of the entire joint between two vertebrae in the spine caused by loss of extracellular matrix (ECM) integrity, to date with no cure. The various regenerative approaches proposed so far have led to very limited successes. An emerging opportunity arises from the use of decellularized ECM as a scaffolding material that, directly or in combination with other materials, has greatly facilitated the advancement of tissue engineering. Here we focused on the decellularized matrix obtained from human umbilical cord Wharton's jelly (DWJ) which retains several structural and bioactive molecules very similar to those of the IVD ECM. However, being a viscous gel, DWJ has limited ability to retain ordered structural features when considered as architecture scaffold. To overcome this limitation, we produced DWJ‐based multifunctional hydrogels, in the form of 3D millicylinders containing different percentages of alginate, a seaweed‐derived polysaccharide, and gelatin, denatured collagen, which may impart mechanical integrity to the biologically active DWJ. The developed protocol, based on a freezing step, leads to the consolidation of the entire polymeric dispersion mixture, followed by an ionic gelation step and a freeze‐drying process. Finally, a porous, stable, easily storable, and suitable matrix for ex vivo experiments was obtained. The properties of the millicylinders (Wharton's jelly millicylinders [WJMs]) were then tested in culture of degenerated IVD cells isolated from disc tissues of patients undergoing surgical discectomy. We found that WJMs with the highest percentage of DWJ were effective in supporting cell migration, restoration of the IVD phenotype (increased expression of Collagen type 2, aggrecan, Sox9 and FOXO3a), anti‐inflammatory action, and stem cell activity of resident progenitor/notochordal cells (increased number of CD24 positive cells). We are confident that the DWJ‐based formulations proposed here can provide adequate stimuli to the cells present in the degenerated IVD to restart the anabolic machinery.

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“…Molecules associated with inflammation, oxidative stress, senescence, and degradation of the extracellular matrix are at the center of interest of numerous studies aimed at understanding the different phenomena that support the onset of IDD ( Kamali et al, 2021 ; Zhang et al, 2022 ). More recently, interest has also turned to molecular factors that may play critical roles in regulating discogenic differentiation, such as specific transcription factors or effectors of epigenetic modifications whose activity is conditioned by the complex interaction of IVD cells with the microenvironment ( Lin et al, 2019 ; Ghaffarpasand et al, 2023 ; Kang et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

The NFATc1/P2X7 receptor relationship in human intervertebral disc cells

Notarangelo,

Penolazzi,

Lambertini

et al. 2024

Front. Cell Dev. Biol.

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A comprehensive understanding of the molecules that play key roles in the physiological and pathological homeostasis of the human intervertebral disc (IVD) remains challenging, as does the development of new therapeutic treatments. We recently found a positive correlation between IVD degeneration (IDD) and P2X7 receptor (P2X7R) expression increases both in the cytoplasm and in the nucleus. Using immunocytochemistry, reverse transcription PCR (RT-PCR), overexpression, and chromatin immunoprecipitation, we found that NFATc1 and hypoxia-inducible factor-1α (HIF-1α) are critical regulators of P2X7R. Both transcription factors are recruited at the promoter of the P2RX7 gene and involved in its positive and negative regulation, respectively. Furthermore, using the proximity ligation assay, we revealed that P2X7R and NFATc1 form a molecular complex and that P2X7R is closely associated with lamin A/C, a major component of the nuclear lamina. Collectively, our study identifies, for the first time, P2X7R and NFATc1 as markers of IVD degeneration and demonstrates that both NFATc1 and lamin A/C are interaction partners of P2X7R.

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Epigenetic modifications of inflammation in intervertebral disc degeneration

Cited by 31 publications

References 90 publications

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

Wharton's jelly‐derived multifunctional hydrogels: New tools to promote intervertebral disc regeneration in vitro and ex vivo

The NFATc1/P2X7 receptor relationship in human intervertebral disc cells

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