Polydatin ameliorates inflammation and oxidative stress associated with MSU-induced gouty arthritis in mice by regulating PPAR-γ and ferritin activation

Du, Kang; Zhou, Qun; Wang, Ziwen; Mo, Chou; Dong, Wanwen; Wei, Ning; Zhong, Wenshen; You, Yanghee; Wang, Yifei; Wang, Zhiping

doi:10.1016/j.lfs.2023.121766

Cited by 7 publications

(5 citation statements)

References 51 publications

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“…Similarly, another study demonstrated that inducers of PPARγ improved GA by regulating inflammatory factors (Wang and Jiang 2014a ). Du et al further corroborated these findings by verifying that PPARγ activation attenuates GA by mitigating NLRP3-associated inflammation (Du et al 2023 ). Beyond these insights, we reported that PPARγ degradation serves as a catalyst for inflammation and pyroptosis in GA.…”

Section: Discussionmentioning

confidence: 73%

“…Studies have confirmed that mouse models of GA induced by MSU crystals had elevated levels of PPARγ (Du et al 2023 ); however, the molecular mechanisms underlying this aberrant upregulation of PPARγ remain unclear. Prior research has reported that PPARγ is subject to intricate post-transcriptional modulatory mechanisms (PTM), including ubiquitination (Li et al 2016 ; Watanabe et al 2015 ).…”

Section: Introductionmentioning

confidence: 95%

“…In fact, Wang et al revealed that PPARγ agonists demonstrated anti-inflammatory effects in GA by inhibiting the expression of TNF-α and IFN-γ (Wang and Jiang 2014b ). In addition, PPARγ activation could inhibit GA progression by repressing the associated inflammation specifically induced by NLRP3 (Du et al 2023 ). However, the mechanism by which PPARγ exerts its anti-inflammatory effects in GA remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

Xu,

Qiu

2024

Mol Med

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Background Gouty arthritis (GA) is characterized by monosodium urate (MSU) crystal accumulation that instigates NLRP3-mediated pyroptosis; however, the underlying regulatory mechanisms have yet to be fully elucidated. The present research endeavors to elucidate the regulatory mechanisms underpinning this MSU-induced pyroptotic cascade in GA. Methods J774 cells were exposed to lipopolysaccharide and MSU crystals to establish in vitro GA models, whereas C57BL/6 J male mice received MSU crystal injections to mimic in vivo GA conditions. Gene and protein expression levels were evaluated using real-time quantitative PCR, Western blotting, and immunohistochemical assays. Inflammatory markers were quantified via enzyme-linked immunosorbent assays. Pyroptosis was evaluated using immunofluorescence staining for caspase-1 and flow cytometry with caspase-1/propidium iodide staining. The interaction between MDM2 and PPARγ was analyzed through co-immunoprecipitation assays, whereas the interaction between BRD4 and the MDM2 promoter was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Mouse joint tissues were histopathologically evaluated using hematoxylin and eosin staining. Results In GA, PPARγ was downregulated, whereas its overexpression mitigated NLRP3 inflammasome activation and pyroptosis. MDM2, which was upregulated in GA, destabilized PPARγ through the ubiquitin–proteasome degradation pathway, whereas its silencing attenuated NLRP3 activation by elevating PPARγ levels. Concurrently, BRD4 was elevated in GA and exacerbated NLRP3 activation and pyroptosis by transcriptionally upregulating MDM2, thereby promoting PPARγ degradation. In vivo experiments showed that BRD4 silencing ameliorated GA through this MDM2–PPARγ–pyroptosis axis. Conclusion BRD4 promotes inflammation and pyroptosis in GA through MDM2-mediated PPARγ degradation, underscoring the therapeutic potential of targeting this pathway in GA management.

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Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

Xu,

Qiu

2024

Mol Med

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“…An intriguing clinical trial revealed that maintaining iron levels in hyperuricemia patients with gouty arthritis near a state of near-iron deficiency (NID) led to significant reductions in the frequency of gout attacks over a 28-month NID maintenance period, often accompanied by reduced attack severity ( Facchini, 2003 ). In a study by Du et al, it was observed that joint tissues of mice with gouty arthritis exhibited marked increases in free iron, NO, and MDA levels, while GSH levels were notably diminished ( Du et al, 2023 ). Research across various regions has identified a consistent positive correlation between elevated serum ferritin, transferrin, and iron levels and the risk of hyperuricemia and gout attacks.…”

Section: The Roles Of Ferroptosis and Ferritinophagy In Arthritismentioning

confidence: 99%

Mechanistic elucidation of ferroptosis and ferritinophagy: implications for advancing our understanding of arthritis

Guo,

Peng,

Cheng

et al. 2024

Front. Physiol.

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In recent years, the emerging phenomenon of ferroptosis has garnered significant attention as a distinctive mode of programmed cell death. Distinguished by its reliance on iron and dependence on reactive oxygen species (ROS), ferroptosis has emerged as a subject of extensive investigation. Mechanistically, this intricate process involves perturbations in iron homeostasis, dampening of system Xc-activity, morphological dynamics within mitochondria, and the onset of lipid peroxidation. Additionally, the concomitant phenomenon of ferritinophagy, the autophagic degradation of ferritin, assumes a pivotal role by facilitating the liberation of iron ions from ferritin, thereby advancing the progression of ferroptosis. This discussion thoroughly examines the detailed cell structures and basic processes behind ferroptosis and ferritinophagy. Moreover, it scrutinizes the intricate web of regulators that orchestrate these processes and examines their intricate interplay within the context of joint disorders. Against the backdrop of an annual increase in cases of osteoarthritis, rheumatoid arthritis, and gout, these narrative sheds light on the intriguing crossroads of pathophysiology by dissecting the intricate interrelationships between joint diseases, ferroptosis, and ferritinophagy. The newfound insights contribute fresh perspectives and promising therapeutic avenues, potentially revolutionizing the landscape of joint disease management.

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“…[ 96 ] In addition, polydatin ameliorates sodium urate-induced inflammation and oxidative stress by modulating PPAR-γ and ferritin activation in GA model mice. [ 97 ]…”

Section: Iron Metabolism and Arthritismentioning

confidence: 99%

Iron metabolism and arthritis: Exploring connections and therapeutic avenues

Zhuo,

Xiao,

Tang

et al. 2024

Chinese Medical Journal

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Iron is indispensable for the viablility of nearly all living organisms, and it is imperative for cells, tissues, and organisms to acquire this essential metal sufficiently and maintain its metabolic stability for survival. Disruption of iron homeostasis can lead to the development of various diseases. There is a robust connection between iron metabolism and infection, immunity, inflammation, and aging, suggesting that disorders in iron metabolism may contribute to the pathogenesis of arthritis. Numerous studies have focused on the significant role of iron metabolism in the development of arthritis and its potential for targeted drug therapy. Targeting iron metabolism offers a promising approach for individualized treatment of arthritis. Therefore, this review aimed to investigate the mechanisms by which the body maintains iron metabolism and the impacts of iron and iron metabolism disorders on arthritis. Furthermore, this review aimed to identify potential therapeutic targets and active substances related to iron metabolism, which could provide promising research directions in this field.

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Polydatin ameliorates inflammation and oxidative stress associated with MSU-induced gouty arthritis in mice by regulating PPAR-γ and ferritin activation

Cited by 7 publications

References 51 publications

BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

Mechanistic elucidation of ferroptosis and ferritinophagy: implications for advancing our understanding of arthritis

Iron metabolism and arthritis: Exploring connections and therapeutic avenues

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