Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway

Zhang, Qin; Liu, Xiaoming; Hu, Qian; Liu, Zheng‐Ren; Liu, Zhiyi; Zhang, Huai‐Gen; Huang, Yuanlu; Chen, Qiuhong; Wang, Wenxiang; Zhang, Xuekang

doi:10.1186/s12967-021-03027-6

Cited by 31 publications

(23 citation statements)

References 76 publications

(72 reference statements)

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“…The antioxidant capacity of dexmedetomidine have been reported in some studies (33). A recent study reported that dexmedetomidine protects against oxidative injury through the regulation of oxidative stress via SIRT3 after intestinal ischemia reperfusion (34). In addition, several researches have reported that SIRT3 could regulate ROS generation mainly by changing the acetylation of SOD2, thereby controlling redox equilibrium (35,36).…”

Section: Discussionmentioning

confidence: 97%

The activation of SIRT3 by dexmedetomidine mitigates limb ischemia-reperfusion–induced lung injury

et al. 2022

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Background:The lung is one of the most sensitive organs, and is vulnerable to injury caused by limb ischemia-reperfusion (LIR). Dexmedetomidine, an anesthetic adjunct, has been shown to have therapeutic effects on lung injury secondary to LIR. This study aimed to investigate the role of dexmedetomidine in ameliorating LIR-induced lung injury in a mouse model of bilateral hind LIR.Methods: In this study, 75 mice were randomly divided into 5 groups to prepare the LIR model. After the model was established, arterial blood was extracted for blood gas analysis. The pathological changes of lung tissue, lung wet/dry weight ratio, arterial blood gas analysis, detection of myeloperoxidase (MPO) activity, the content of reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in oxidative stress indexes, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) content and cytochrome c content were measured, and the relative protein expression levels of sirtuin-3 (SIRT3) and apoptosis factor Bcl-2 related X protein (Bax), B-cell Lymphoma 2 (Bcl-2), cleaved caspase 3, and nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1 (HO-1).Results: Pretreatment with dexmedetomidine dramatically ameliorated LIR-induced lung injury, the wet/dry weight ratio, the arterial blood gas parameters, and enhanced SIRT3 expression. Moreover, dexmedetomidine significantly inhibits ROS and MDA level and restores antioxidant enzyme activities (SOD, GSH-Px). Of note, dexmedetomidine suppressed LIR-induced lung tissue apoptosis by modulating apoptosis-associated protein such as Bax, Bcl-2, and cleaved caspase 3. Moreover, dexmedetomidine inhibited the LIR-induced decreases in MMP, ATP levels, and the release of cytochrome c of LIR to maintain mitochondrial function. Latest study has shown that activating Nrf2 could promote SIRT3 expression to alleviate IR injury. Intriguingly, dexmedetomidine could facilitate nuclear Nrf2 and cytoplasmic HO-1 expression.Conclusions: Our findings suggest that dexmedetomidine protects against LIR-induced lung injury by inhibiting the oxidative response, mitochondrial dysfunction and apoptosis. The mechanism appears to be at least partly mediated through the upregulation of SIRT3 expression.

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Section: Discussionmentioning

confidence: 97%

The activation of SIRT3 by dexmedetomidine mitigates limb ischemia-reperfusion–induced lung injury

et al. 2022

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“…Consistently, Zhang et al ( 9 , 16 ) proved that DEX could protect against intestinal I/R-induced intestinal injury by suppressing apoptosis and inflammatory response of intestinal mucosal epithelial, preserving gut-vascular barrier impairment and subsequent liver damage. The other study indicated that pretreatment with DEX markedly attenuate the intestinal I/R injury, probably by enhancing mitophagy and reducing apoptosis of enteric glial cells ( 7 ). Moreover, DEX could inhibit hypoxia/reoxygenation-induced IEC ER stress, apoptosis, and pyroptosis via activating SIRT1 expression ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…DEX has been reported to be a potential drug for the prevention and treatment of intestinal I/R injury ( 7 , 9 , 16 , 18 , 19 ). Our results elaborated that the protection from DEX in mice with intestinal I/R injury evidenced with an inhibition of inflammation, ER stress-dependent apoptosis, and oxidative stress in the intestinal mucosa.…”

Section: Discussionmentioning

confidence: 99%

“…Dexmedetomidine (DEX), an α2-adrenergic receptor (α2-AR) agonist, has sedative, anxiolytic, sympatholytic, and opioid-sparing effects and is applied commonly in a clinical setting (4). It is known to influence inflammation, oxidative damage, endoplasmic reticulum (ER) stress, apoptosis, autophagy, and so on, in several diseases (5)(6)(7)(8). The role of DEX in the treatment of intestinal I/R injury has been highlighted in recent studies (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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DEXMEDETOMIDINE PREVENTS PDIA3 DECREASE BY ACTIVATING Α2-Adrenergic RECEPTOR TO ALLEVIATE INTESTINAL I/R IN MICE

Zhan

Chen

Qiu

et al. 2022

Shock

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Background: Dexmedetomidine (DEX) attenuates intestinal I/R injury, but its mechanism of action remains to be further elucidated. Protein disulfide isomerase A3 (PDIA3) has been reported as a therapeutic protein for the prevention and treatment of intestinal I/R injury. This study was to investigate whether PDIA3 is involved in intestinal protection of DEX and explore the underlying mechanisms. Methods: The potential involvement of PDIA3 in DEX attenuation of intestinal I/R injury was tested in PDIA3 Flox/Flox mice and PDIA3 conditional knockout (cKO) in intestinal epithelium mice subjected to 45 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Furthermore, the α2-adrenergic receptor (α2-AR) antagonist, yohimbine, was administered in wild-type C57BL/6N mice intestinal I/R model to investigate the role of α2-AR in the intestinal protection conferred by DEX. Results: In the present study, we identified intestinal I/R-induced obvious inflammation, endoplasmic reticulum (ER) stress-dependent apoptosis, and oxidative stress, and all the aforementioned changes were improved by the administration of DEX. PDIA3 cKO in the intestinal epithelium have reversed the protective effects of DEX. Moreover, yohimbine also reversed the intestinal protection of DEX and downregulated the messenger RNA and protein levels of PDIA3. Conclusion: DEX prevents PDIA3 decrease by activating α2-AR to inhibit intestinal I/R-induced inflammation, ER stress-dependent apoptosis, and oxidative stress in mice.

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“…The action mechanism of dexmedetomidine on mitochondria is strongly related to the SIRT family, which inhibits endoplasmic reticulum stress-induced pyroptosis in intestinal epithelial cells via SIRT1 expression ( 82 ). Moreover, the SIRT3-dependent regulation of the PINK1/HDAC3/p53 pathway can inhibit mitochondrial damage and apoptosis in enteric glial cells ( 83 ).…”

Section: Discussionmentioning

confidence: 99%

Bibliometric and visual analysis of intestinal ischemia reperfusion from 2004 to 2022

et al. 2022

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BackgroundIntestinal ischemia/reperfusion (I/R) injury is a common tissue-organ damage occurring in surgical practice. This study aims to comprehensively review the collaboration and impact of countries, institutions, authors, subject areas, journals, keywords, and critical literature on intestinal I/R injury from a bibliometric perspective, and to assess the evolution of clustering of knowledge structures and identify hot trends and emerging topics.MethodsArticles and reviews related to intestinal I/R were retrieved through subject search from Web of Science Core Collection. Bibliometric analyses were conducted on Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio).ResultsA total of 1069 articles and reviews were included from 2004 to 2022. The number of articles on intestinal I/R injury gradually plateaued, but the number of citations increased. These publications were mainly from 985 institutions in 46 countries, led by China and the United States. Liu Kx published the most papers, while Chiu Cj had the largest number of co-citations. Analysis of the journals with the most outputs showed that most journals focused on surgical sciences, cell biology, and immunology. Macroscopic sketch and microscopic characterization of the entire knowledge domain were achieved through co-citation analysis. The roles of cell death, exosomes, intestinal flora, and anesthetics in intestinal I/R injury are the current and developing research focuses. The keywords “dexmedetomidine”, “proliferation”, and “ferroptosis” may also become new trends and focus of future research.ConclusionThis study comprehensively reviews the research on intestinal I/R injury using bibliometric and visualization methods, and will help scholars better understand the dynamic evolution of intestinal I/R injury and provide directions for future research.

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Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway

Cited by 31 publications

References 76 publications

The activation of SIRT3 by dexmedetomidine mitigates limb ischemia-reperfusion–induced lung injury

The activation of SIRT3 by dexmedetomidine mitigates limb ischemia-reperfusion–induced lung injury

DEXMEDETOMIDINE PREVENTS PDIA3 DECREASE BY ACTIVATING Α2-Adrenergic RECEPTOR TO ALLEVIATE INTESTINAL I/R IN MICE

Bibliometric and visual analysis of intestinal ischemia reperfusion from 2004 to 2022

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