Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway

Li, Juan; Ruan, Shirong; Jia, Jinhui; Li, Qian; Jia, Rumeng; Wan, Li; Yang, Xing; Teng, Peng; Peng, Qilin; Shi, Ya-dan; Pan, Yinbing; Duan, Manlin; Li, Wentao; Zhang, Li; Hu, Liang

doi:10.1186/s12974-022-02670-0

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…ASK1 is known to modulate apoptosis and inflammation by activating downstream JNKs and p38 signaling pathways [ 24 – 30 ]. In order to examine the impact of ASK1-K716R on the activation of JNKs/p38, western blotting was performed on day 3 post-TBI.…”

Section: Resultsmentioning

confidence: 99%

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood–brain barrier integrity after traumatic brain injury

Meng,

Cao,

Huang

et al. 2023

J Neuroinflammation

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Background Traumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI. Methods We employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood–brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests. Results The activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI. Conclusion ASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

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Section: Resultsmentioning

confidence: 99%

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood–brain barrier integrity after traumatic brain injury

Meng,

Cao,

Huang

et al. 2023

J Neuroinflammation

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“…[5,13]. This account becomes essential to shed light once again on the ETSN and also to discuss new approaches to the technique, such as the need to address innovations like the technique of promoting the proximal and distal ends of defective peripheral nerves into normal peripheral nerves using the End-to-Side anastomosis [17] and supercharged ETS transfer [2]. In this procedure, the damaged proximal nerve is primarily repaired and then overloaded with an End-to-Side coaptation of a donor nerve closer to the target muscle.…”

Section: Studies Bymentioning

confidence: 99%

End-to-Side Neurorrhaphy Technique: Exploring Neuronal Regeneration to Restore Nerve Function

Oliveira,

Maia,

Galvão

et al. 2024

JAMMR

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Aims: To report the case of a pediatric patient with total left brachial plexopathy (TLBP), exhibiting partially restored motor function and impaired sensitivity, who was treated with the End-to-Side neurorrhaphy (ETSN) technique. Presentation of Case: A 13-year-old female was involved in a car accident. After clinical and imaging evaluation, the diagnostic hypothesis was TLBP with partially restored function and loss of protective sensitivity in the pincer region. A surgical intervention was recommended. Due to case characteristics, ETSN appeared to be the most appropriate technique. Discussion: ETSN is a technique utilized for repairing nerve injuries. It involves suturing the distal end of a transected nerve to the lateral side of a healthy donor nerve, aiming to restore neurons through peripheral plasticity. The regeneration mechanism promoted by this technique shares some similarities with that promoted by standard techniques, with important roles being assigned to Schwann cells (SC), for example. However, this procedure has its own particularities, which still require further investigation. Generally, ETSN cannot replicate the efficacy of model techniques, but remains valid in select cases, such as instances involving nerve injuries exceeding 3-4 cm or in the absence of donor nerves. Therefore, ETSN stands as a choice and deserves consideration. Conclusion: The patient progressed with a good prognosis and recovered protective sensitivity in the pincer region. ETSN is efficient for peripheral nerve injuries with inaccessible proximal trunks or long nerve defects. The discussion surrounding ETSN remains controversial, making this study essential for expanding scientific knowledge.

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“…ASK1 is known to modulate apoptosis and in ammation by activating downstream JNKs and p38 signaling pathways [23][24][25][26][27][28][29]. In order to examine the impact of ASK1-K716R on the activation of JNKs/p38, western blotting was performed on day 3 post-TBI.…”

Section: Construction Of Ask1-k716rmentioning

confidence: 99%

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood-brain barrier integrity after traumatic brain injury

Meng

Cao

Huang

et al. 2023

Preprint

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Background Traumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI. Methods We employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood-brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, Sensorimotor function and cognitive function were assessed by a series of behavioral tests. Results The activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI. Conclusion ASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

show abstract

Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway

Cited by 5 publications

References 37 publications

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood–brain barrier integrity after traumatic brain injury

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood–brain barrier integrity after traumatic brain injury

End-to-Side Neurorrhaphy Technique: Exploring Neuronal Regeneration to Restore Nerve Function

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood-brain barrier integrity after traumatic brain injury

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