Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro

Chen, Yan; Cao, Xiankun; Pan, Bin; Du, Han; Li, Baixing; Yang, Xiaobin; Chen, Xuzhuo; Wang, Xin; Zhou, Ting; Qin, An; Zhao, Chang-Qing; Zhao, Jie

doi:10.1016/j.intimp.2023.110789

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…The latest findings from our work and others have revealed a strong association between NRF2/KEAP1 pathway dysfunction and the development of various spinal-related diseases including IVDD and osteoporosis, and thyroid toxicity. 17 , 18 , 26 , 27 Consistent with these findings, our results demonstrated that LWDHD containing varying CO significantly upregulated the decreased NRF2 (S40) but lowered the increased KEAP1 expression in NP tissues, except for a higher upregulation in KEAP1 in 10 × CO-treated mice. These results suggest that moderately increasing the CO dose in LWDHD can achieve better anti-oxidant and anti-pyroptosis effects on NP cells.…”

Section: Discussionsupporting

confidence: 88%

Augmented Cornus officinalis Levels in Liuwei Dihuang Decoction Inhibits Nucleus Pulposus Cell Pyroptosis to Enhance Therapeutic Efficacy Against Intervertebral Disc Degeneration

Ge,

Xie,

Chai

et al. 2024

JIR

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Background Intervertebral disc (IVD) degeneration (IVDD) is highly prevalent among the elderly population and stands as a leading cause of low back pain. Our prior studies have highlighted the therapeutic potential of Liuwei Dihuang decoction (LWDHD) and its component Cornus officinalis (CO)-derived compounds in alleviating IVDD and osteoarthritis, suggesting beneficial effects of CO in treating degenerative osteoarthropathies. However, uncertainty remains regarding the optimal CO dosage within LWDHD and its potential mechanism for effectively treating IVDD. Objective To ascertain the optimal dosage of CO within LWDHD for enhancing its therapeutic efficacy in treating IVDD, through a comparison of its effects across varied dosages using a mouse IVDD model. Methods Eight-week-old male C57BL/6J mice were subjected to a lumbar spine instability surgery to induce an IVDD model and received a modified LWDHD formulation containing varied dosages of CO (original dose of CO, or 5- or 10-time dose of CO (referred to as 1 × CO, 5 × CO, and 10 × CO)) for 8 weeks. The therapeutic efficacy on IVDD was evaluated through changes in lumbar spine function, histopathological morphology, extracellular matrix metabolism, nucleus pulposus cell viability, sensory nerve ingrowth, and nucleus pulposus (NP) cell pyroptosis. Results Augmenting CO levels in LWDHD led to a dose-dependent increase in the levels of CO-sourced active compounds in the plasma of mice. The modified LWDHD formulations, particularly the 5 × CO, exhibited a favorable pharmacological effect on lumbar function, structural integrity, ECM composition, NP cell viability, and sensory nerve ingrowth. Importantly, all 3 formulations notably mitigated NP cell pyroptosis by activating NRF2/KEAP1 pathway, with the 5 × CO formulation exhibiting superior efficacy. Additionally, a comprehensive score analysis indicated that 5 × CO formulation achieved the highest score. Conclusion These data underscore that elevating the dosage of CO to a specific threshold can enhance the effectiveness of LWDHD in treating IVDD.

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Section: Discussionsupporting

confidence: 88%

Augmented Cornus officinalis Levels in Liuwei Dihuang Decoction Inhibits Nucleus Pulposus Cell Pyroptosis to Enhance Therapeutic Efficacy Against Intervertebral Disc Degeneration

Ge,

Xie,

Chai

et al. 2024

JIR

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“…Verapamil, a pharmaceutical agent frequently employed in the management of cardiovascular ailments, has recently garnered attention. Plenty of contemporary studies have highlighted its distinct role in attenuating inflammation and providing antioxidant benefits in a variety of pathologies, including intervertebral disc degeneration, hepatic inflammation, acute liver failure, and hyperglycemic stroke, among others [24,[38][39][40], but little is known about its efficacy in tendinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports suggested that oxidative stress is closely related to extracellular matrix degradation, inflammation, and apoptosis [24,30,31]. Consequently, ROS levels were assessed by employing the DCFH-DA fluorescent probe.…”

Section: Verapamil Rescues Mitochondrial Dysfunction and Reactive Oxy...mentioning

confidence: 99%

“…Recent scientific investigations have brought to light the distinctive therapeutic properties of verapamil, notably, its remarkable anti-inflammatory and antioxidant effects [22,23]. The scholarly work by Chen, Cao, and Pan et al elucidated the fact that verapamil possesses the capacity to modulate anti-inflammatory and anti-oxidative pathways by regulating the translocation of Nrf2 to the nucleus [24]. Henceforth, verapamil emerges as a promising therapeutic agent for the management of tendinopathy.…”

Section: Introductionmentioning

confidence: 99%

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Verapamil Attenuates the Severity of Tendinopathy by Mitigating Mitochondrial Dysfunction through the Activation of the Nrf2/HO-1 Pathway

Wang,

Dong,

et al. 2024

Biomedicines

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Tendinopathy is a prevalent condition in orthopedics patients, exerting a profound impact on tendon functionality. However, its underlying mechanism remains elusive and the efficacy of pharmacological interventions continues to be suboptimal. Verapamil is a clinically used medicine with anti-inflammation and antioxidant functions. This investigation aimed to elucidate the impact of verapamil in tendinopathy and the underlying mechanisms through which verapamil ameliorates the severity of tendinopathy. In in vitro experiments, primary tenocytes were exposed to interleukin-1 beta (IL−1β) along with verapamil at a concentration of 5 μM. In addition, an in vivo rat tendinopathy model was induced through the localized injection of collagenase into the Achilles tendons of rats, and verapamil was injected into these tendons at a concentration of 5 μM. The in vitro findings highlighted the remarkable ability of verapamil to attenuate extracellular matrix degradation and apoptosis triggered by inflammation in tenocytes stimulated by IL−1β. Furthermore, verapamil was observed to significantly suppress the inflammation-related MAPK/NFκB pathway. Subsequent investigations revealed that verapamil exerts a remediating effect on mitochondrial dysfunction, which was achieved through activation of the Nrf2/HO-1 pathway. Nevertheless, the protective effect of verapamil was nullified with the utilization of the Nrf2 inhibitor ML385. In summary, the in vivo and in vitro results indicate that the administration of verapamil profoundly mitigates the severity of tendinopathy through suppression of inflammation and activation of the Nrf2/HO-1 pathway. These findings suggest that verapamil is a promising therapeutic agent for the treatment of tendinopathy, deserving further and expanded research.

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Homoplantaginin alleviates intervertebral disc degeneration by blocking the NF-κB/MAPK pathways via binding to TAK1

Li,

Hu,

Chen

et al. 2024

Biochemical Pharmacology

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Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro

Cited by 6 publications

References 59 publications

Augmented Cornus officinalis Levels in Liuwei Dihuang Decoction Inhibits Nucleus Pulposus Cell Pyroptosis to Enhance Therapeutic Efficacy Against Intervertebral Disc Degeneration

Augmented Cornus officinalis Levels in Liuwei Dihuang Decoction Inhibits Nucleus Pulposus Cell Pyroptosis to Enhance Therapeutic Efficacy Against Intervertebral Disc Degeneration

Verapamil Attenuates the Severity of Tendinopathy by Mitigating Mitochondrial Dysfunction through the Activation of the Nrf2/HO-1 Pathway

Homoplantaginin alleviates intervertebral disc degeneration by blocking the NF-κB/MAPK pathways via binding to TAK1

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