Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades

Liu, Xiaoming; Chen, Qiuhong; Hu, Qian; Liu, Zhen; Wu, Qiong; Liang, Si-Si; Zhang, Huai‐Gen; Zhang, Qin; Zhang, Xuekang

doi:10.1016/j.yexmp.2020.104444

Cited by 23 publications

(21 citation statements)

References 33 publications

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“…Recently, DEX was reported to alleviate IRI of the intestine or sepsis in the lungs by targeting the p38MAPK signalling pathway. 25,26 In our present study, we applied a classic H/R model and TG-induced specific ERS model to examine the effects of DEX on H/R and stress injury based on ERS and further determined if the targeting molecule in this process is p38MAPK. This study confirmed that DEX attenuated the myocardial damage induced by either H/R or TG by attenuating ERS, which subsequently led to the downregulation of the expression of several key molecules related to ERS and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence has shown that DEX has the capacity to alleviate inflammation and IRI by regulating p38 MAPK signalling. [25][26][27] Wang et al found that DEX could attenuate mouse Neuro 2A neuroblastoma cell apoptosis under H/R conditions by targeting p38 MAPK signalling, 28 which confirmed that DEX might positively affect cells under H/R conditions.…”

Section: Introductionmentioning

confidence: 89%

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<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Zhu

Ling

Zhou

et al. 2020

DDDT

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Background: Myocardial ischaemia-reperfusion injury (IRI) has been confirmed to induce endoplasmic reticulum stress (ERS) when myocardial cell function continues to deteriorate to a certain degree. The clinical applications of effective tested strategies are sometimes inconsistent with the applications evaluated in experiments, although reasonable mechanisms and diverse signalling pathways have been broadly explored. Dexmedetomidine (DEX) has been shown to attenuate IRI of the heart in animal studies. This study aimed to determine whether DEX can protect injured cardiomyocytes under hypoxia/reoxygenation (H/R) at the cellular level and whether the mechanism is related to ERS and the p38 MAPK pathway. Methods: H9c2 cells were subjected to H/R or thapsigargin (TG) to build a model. DEX or 4-PBA was added to the medium either 1 h or 24 h before modelling, respectively. Model parameters were determined by assessing cell viability and injury, which were measured by assessing cell counting kit-8 (CCK8), lactate dehydrogenase (LDH) release and flow cytometry results, and the expression of GRP78, CHOP and caspase-12. In addition, the protein expression of p38MAPK and p-p38MAPK was examined, and SB202190, a negative regulator, was also preincubated in medium. Results: Compared to that of cells in the control group, the activity of cells in the H/R and TG groups was decreased dramatically, and the LDH concentration and proportion of apoptotic cells were increased. DEX could correspondingly reverse the changes induced by H/R or TG. Additionally, DEX effectively attenuated ERS defined as increased expression of GRP78, CHOP and caspase-12. Additionally, DEX could obviously depress the P38 MAPK phosphorylation and high p-p38 MAPK expression in the TG group, indicating DEX has a function similar to that of SB202190. Conclusion: H/R injury in H9c2 cells can lead to abnormal ERS and apoptosis, as well as activation of the p38MAPK signalling pathway. DEX can protect cardiomyocytes by intervening in ERS, regulating p38MAPK and the downstream apoptotic signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Zhu

Ling

Zhou

et al. 2020

DDDT

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“…Therefore, targeting this new axis may emerge as a novel therapeutic intervention in the treatment of inflammation in NPP. Nevertheless, Dex has been proposed to protect intestine against ischemia–reperfusion injury by impairing the p38 mitogen activated protein kinase (MAPK)‐modulated mitochondrial apoptosis and inflammatory response (Liu et al., 2020). We cannot exclude the involvement of p38 MAPK signalling in the neuroprotection of Dex due to the complex microenvironments, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

Zhang

Cui

et al. 2020

Experimental Physiology

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New Findings What is the central question of this study?Dexmedetomidine has a capacity for sedation, anti‐anxiety and analgesia with minimal suppression of respiratory function; what is its role in neuropathic pain and what is the involvement of miRNAs? What is the main finding and its importance?Dexmedetomidine attenuates inflammation and apoptosis and the stimulation of TLR4–NF‐κB signalling in rat spinal cord via miR‐101 overexpression and E2F2 downregulation. Abstract The significant analgesic effect of dexmedetomidine (Dex) has been underscored in neuropathic pain (NPP), but the underlying mechanism remains unclear. This study explored the functional effect of Dex on microRNA (miR)‐101‐regulated E2 promoter binding factor 2 (E2F2) with the engagement of Toll‐like receptor 4 (TLR4)–nuclear factor‐κB (NF‐κB) signalling. Chronic constriction injury (CCI) was performed to generate an NPP rat model. The expression of miR‐101, E2F2 and TLR4–NF‐κB signalling‐relevant proteins was assessed by RT–quantitative PCR, immunoblotting and immunohistochemistry. Inflammatory factors were detected by enzyme‐linked immunosorbent assay. The results showed that Dex increased mechanical withdrawal threshold and thermal latency to withdraw. The expression of interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐α was increased in CCI rats, but these trends were reversed by Dex. In addition, Dex repressed caspase‐9 expression and apoptotic cell numbers in spinal cord tissues in CCI rats. Moreover, the expression of E2F2 was significantly increased, while miR‐101 was diminished in CCI rats, which was reversed by Dex. Furthermore, miR‐101 inhibitor, E2F2 restoration or administration of a TLR4‐specific agonist weakened the effect of Dex. Together, these results suggest that Dex has the capacity to ameliorate NPP by regulating the miR‐101–E2F2–TLR4–NF‐κB axis in rats subjected to CCI.

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“…Recently, a growing number of studies have reported the protective properties of Dex on I/R injury of different organs, such as renal, 19 hepatic, 9 intestinal, 20 Apoptosis is a major cause of tissue damage, second only to reperfusion injury following cardiac ischemia. 24 Consistent with the previous study, 25 CMECs under OGD/R condition resulted in elevated ROS production and increased apoptotic rates.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a growing number of studies have reported the protective properties of Dex on I/R injury of different organs, such as renal, 19 hepatic, 9 intestinal, 20 and myocardial 21 I/R injury. Peng et al 22 identified that Dex exerted its cardioprotective role through inhibiting cardiomyocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects cardiac microvascular endothelial cells from the damage of ogd/r through regulation of the pparδ‐mediated autophagy

Shao

Xia

et al. 2021

Microcirculation

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Background: Dexmedetomidine (Dex) exerts an effective therapeutic role in numerous diseases associated with ischemia/reperfusion (I/R) injury via its anti-apoptosis properties. Therefore, this study explores the cardioprotective effects of Dex in cardiac microvascular endothelial cells (CMECs) in response to oxygen-glucose deprivation and re-oxygenation (OGD/R) injury and its potential mechanism. Material and methods: CMECs were pretreatment with different concentration of Dex, then exposed to OGD/R. Cell viability was measured with CCK-8 assay. Apoptosis was evaluated by flow cytometry, and apoptosis-related protein was determined by Western blot. Autophagy was assessed by transmission electron microscopy and autophagy-related proteins. Besides, the role peroxisome proliferator-activated receptors (PPARδ) in Dex-mediated anti-apoptosis property was validated with agonist and antagonist. Results: OGD/R significantly decreased cell viability, increased reactive oxygen species, caused disorder of autophagy, and increased apoptosis in CMECs. Dex enhanced the viability of the OGD/R-treated CMECs and effectively decreased reactive oxygen species production. Autophagy in CMECs was activated by Dex, as evidenced by the increase in the ratio of LC3B-II/I, expression level of Beclin1 and number of autophagosomes in the OGD/R-induced CMECs. The mechanistic investigation indicated that PPARδ antagonist GW501516 aggravated cell damage following OGD/R, while PPARδ agonist GW6471 partly abolished the Dex-mediated protective effects.Conclusions: Dex activated the PPARδ-AMPK-PGC-1α pathway-mediated autophagy in CMECs, therefore to inhibit excessive apoptosis induced by OGD/R. Dex may potentially be a therapeutic intervention for myocardial I/R injury.

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Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades

Cited by 23 publications

References 33 publications

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

Dexmedetomidine protects cardiac microvascular endothelial cells from the damage of ogd/r through regulation of the pparδ‐mediated autophagy

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