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

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qin Zhang ◽  
Xiao-Ming Liu ◽  
Qian Hu ◽  
Zheng-Ren Liu ◽  
Zhi-Yi Liu ◽  
...  
Keyword(s):  
Glial Cells ◽  
Intestinal Ischemia ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
High Morbidity ◽  
P53 Pathway ◽  
P53 Expression ◽  
Enteric Glial Cells ◽  
Intestinal Ischemia Reperfusion

Abstract Background Intestinal ischemia/reperfusion (I/R) injury commonly occurs during perioperative periods, resulting in high morbidity and mortality on a global scale. Dexmedetomidine (Dex) is a selective α2-agonist that is frequently applied during perioperative periods for its analgesia effect; however, its ability to provide protection against intestinal I/R injury and underlying molecular mechanisms remain unclear. Methods To fill this gap, the protection of Dex against I/R injury was examined in a rat model of intestinal I/R injury and in an inflammation cell model, which was induced by tumor necrosis factor-alpha (TNF-α) plus interferon-gamma (IFN-γ) stimulation. Results Our data demonstrated that Dex had protective effects against intestinal I/R injury in rats. Dex was also found to promote mitophagy and inhibit apoptosis of enteric glial cells (EGCs) in the inflammation cell model. PINK1 downregulated p53 expression by promoting the phosphorylation of HDAC3. Further studies revealed that Dex provided protection against experimentally induced intestinal I/R injury in rats, while enhancing mitophagy, and suppressing apoptosis of EGCs through SIRT3-mediated PINK1/HDAC3/p53 pathway in the inflammation cell model. Conclusion Hence, these findings provide evidence supporting the protective effect of Dex against intestinal I/R injury and its underlying mechanism involving the SIRT3/PINK1/HDAC3/p53 axis.

scholarly journals Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Fan ◽  
Juan Du ◽  
Mao-Hua Wang ◽  
Jia-Man Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Inflammasome Activation ◽  
High Morbidity ◽  
Antibody Treatment ◽  
Sod Activity ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R), which is associated with high morbidity and mortality, is also accompanied with abnormal energy metabolism and liver injury. Irisin, a novel exercise-induced hormone, can regulate adipose browning and thermogenesis. The following study investigated the potential role of dexmedetomidine in liver injury during intestinal I/R in rats. Adult male Sprague–Dawley rats underwent occlusion of the superior mesenteric artery for 90 min followed by 2 h of reperfusion. Dexmedetomidine or irisin-neutralizing antibody was intravenously administered for 1 h before surgery. The results demonstrated that severe intestine and liver injuries occurred during intestinal I/R as evidenced by pathological scores and an apparent increase in serum diamine oxidase (DAO), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. In addition, the hepatic irisin, cleaved caspase-3, Bax, and NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1), protein expressions, apoptotic index, reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 levels increased; however, the serum irisin level and hepatic Bcl-2 protein expression and superoxide dismutase (SOD) activity decreased after intestinal I/R. Interestingly, dexmedetomidine could reduce the above listed changes and increase the irisin levels in plasma and the liver in I/R rats. Dexmedetomidine-mediated protective effects on liver injury and NLRP3 inflammasome activation during intestinal I/R were partially abrogated via irisin-neutralizing antibody treatment. The results suggest that irisin might contribute to the hepatoprotection of dexmedetomidine during intestinal ischemia/reperfusion.

scholarly journals Antioxidant-Based Therapy Reduces Early-Stage Intestinal Ischemia-Reperfusion Injury in Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 853
Author(s):  
Gaizka Gutiérrez-Sánchez ◽  
Ignacio García-Alonso ◽  
Jorge Gutiérrez Sáenz de Santa María ◽  
Ana Alonso-Varona ◽  
Borja Herrero de la Parte
Keyword(s):  
Reperfusion Injury ◽  
Intestinal Ischemia ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Early Stage ◽  
Ischemia Reperfusion ◽  
Mucosal Damage ◽  
Intestinal Damage ◽  
Oxygen Species ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia-reperfusion injury (i-IRI) is a rare disorder with a high mortality rate, resulting from the loss of blood flow to an intestinal segment. Most of the damage is triggered by the restoration of flow and the arrival of cytokines and reactive oxygen species (ROS), among others. Inactivation of these molecules before tissue reperfusion could reduce intestinal damage. The aim of this work was to analyze the preventive effect of allopurinol and nitroindazole on intestinal mucosal damage after i-IRI. Wag/RijHsd rats were subjected to i-IRI by clamping the superior mesenteric artery (for 1 or 2 h) followed by a 30 min period of reperfusion. Histopathological intestinal damage (HID) was assessed by microscopic examination of histological sections obtained from injured intestine. HID was increased by almost 20% by doubling the ischemia time (from 1 to 2 h). Nitroindazole reduced HID in both the 1 and 2 h period of ischemia by approximately 30% and 60%, respectively (p < 0.001). Our preliminary results demonstrate that nitroindazole has a preventive/protective effect against tissue damage in the early stages of i-IRI. However, to better understand the molecular mechanisms underlying this phenomenon, further studies are needed.

scholarly journals Cellular Signal Transduction Pathways Involved in Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Guangyao Li ◽  
Yingyi Zhang ◽  
Zhe Fan
Keyword(s):  
Signal Transduction ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Intestinal Ischemia ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Organ Injury ◽  
Intestinal Barrier Function ◽  
Signal Transduction Pathways ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia-reperfusion (II/R) injury is a common type of tissue and organ injury, secondary to intestinal and mesenteric vascular diseases. II/R is characterized by a high incidence rate and mortality. In the II/R process, intestinal barrier function is impaired and bacterial translocation leads to excessive reactive oxygen species, inflammatory cytokine release, and even apoptosis. A large number of inflammatory mediators and oxidative factors are released into the circulation, leading to severe systemic inflammation and multiple organ failure of the lung, liver, and kidney. Acute lung injury (ALI) is the most common complication, which gradually develops into acute respiratory distress syndrome and is the main cause of its high mortality. This review summarizes the signal transduction pathways and key molecules in the pathophysiological process of ALI induced by II/R injury and provides a new therapeutic basis for further exploration of the molecular mechanisms of ALI induced by II/R injury. In particular, this article will focus on the biomarkers involved in II/R-induced ALI.

scholarly journals Local and Remote Postconditioning Decrease Intestinal Injury in a Rabbit Ischemia/Reperfusion Model

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Mu Yang ◽  
Jian-Xin Dong ◽  
Lu-Bin Li ◽  
Hai-Jie Che ◽  
Jun Yong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Morbidity And Mortality ◽  
Significant Problem ◽  
High Morbidity ◽  
Local Ischemia ◽  
Injury Model ◽  
Remote Postconditioning ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R) injury is a significant problem that is associated with high morbidity and mortality in critical settings. This injury may be ameliorated using postconditioning protocol. In our study, we created a rabbit intestinal I/R injury model to analyze the effects of local ischemia postconditioning (LIPo) and remote ischemia postconditioning (RIPo) on intestinal I/R injury. We concluded that LIPo affords protection in intestinal I/R injury in a comparable fashion with RIPo by decreasing oxidative stress, neutrophil activation, and apoptosis.

scholarly journals Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Meng Chen ◽  
Xue-Tao Yan ◽  
Li Ye ◽  
Jun-Jiao Tang ◽  
Zong-Ze Zhang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protective Effect ◽  
Receptor Antagonist ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Akt Pathway ◽  
High Morbidity ◽  
Protective Effects ◽  
Sod Activity ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R) is a clinical emergency, which often causes lung injury with high morbidity and mortality. Although dexmedetomidine has been identified to have a protective effect on lung injury caused by intestinal I/R, its specific mechanism is still elucidated. In recent years, the cannabinoid (CB2) receptor pathway has been found to be involved in I/R injury of some organs. In the current study, we investigated whether the CB2 receptor pathway contributes to the protective effect of dexmedetomidine on the intestinal I/R-induced lung injury in rats. Dexmedetomidine treatment upregulated the expression of CB2 receptor and suppressed the I/R-induced increases in lung injury scores, inflammatory cell infiltration, lung wet/dry ratio, MPO activity, MDA level, inflammatory cytokines, and caspase-3 expression while augmenting SOD activity and Bcl-2 expression, indicating attenuation of lung injury. Dexmedetomidine treatment also increased the expression of Akt. The protective effects of dexmedetomidine treatment were reversed by the CB2 receptor antagonist AM630 or the PI3K inhibitor wortmannin. And the CB2 receptor antagonist AM630 also downregulated the expression of Akt. Thus, our findings suggest that treatment with dexmedetomidine provides a protective role against lung injury caused by intestinal I/R in rats, possibly due to the upregulation of the CB2 receptor, followed by the activation of the PI3K/Akt pathway.

scholarly journals Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL−33/ST2 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Fan Deng ◽  
Jing-Juan Hu ◽  
Xiao Yang ◽  
Qi-Shun Sun ◽  
Ze-Bin Lin ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Intestinal Flora ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
High Morbidity ◽  
Type Ii ◽  
Microbial Metabolite ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.

scholarly journals Phosphoproteomic Analysis of Rat Neutrophils Shows the Effect of Intestinal Ischemia/Reperfusion and Preconditioning on Kinases and Phosphatases

2020 ◽  
Vol 21 (16) ◽  
pp. 5799
Author(s):  
Muhammad Tahir ◽  
Samina Arshid ◽  
Belchor Fontes ◽  
Mariana S. Castro ◽  
Simone Sidoli ◽  
...  
Keyword(s):  
Protective Effect ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Morbidity ◽  
Ischemia And Reperfusion ◽  
Cellular Functions ◽  
Regulation Mechanisms ◽  
And Migration ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia reperfusion injury (iIRI) is a severe clinical condition presenting high morbidity and mortality worldwide. Some of the systemic consequences of IRI can be prevented by applying ischemic preconditioning (IPC), a series of short ischemia/reperfusion events preceding the major ischemia. Although neutrophils are key players in the pathophysiology of ischemic injuries, neither the dysregulation presented by these cells in iIRI nor the protective effect of iIPC have their regulation mechanisms fully understood. Protein phosphorylation, as well as the regulation of the respective phosphatases and kinases are responsible for regulating a large number of cellular functions in the inflammatory response. Moreover, in previous work we found hydrolases and transferases to be modulated in iIR and iIPC, suggesting the possible involvement of phosphatases and kinases in the process. Therefore, in the present study, we analyzed the phosphoproteome of neutrophils from rats submitted to mesenteric ischemia and reperfusion, either submitted or not to IPC, compared to quiescent controls and sham laparotomy. Proteomic analysis was performed by multi-step enrichment of phosphopeptides, isobaric labeling, and LC-MS/MS analysis. Bioinformatics was used to determine phosphosite and phosphopeptide abundance and clustering, as well as kinases and phosphatases sites and domains. We found that most of the phosphorylation-regulated proteins are involved in apoptosis and migration, and most of the regulatory kinases belong to CAMK and CMGC families. An interesting finding revealed groups of proteins that are modulated by iIR, but such modulation can be prevented by iIPC. Among the regulated proteins related to the iIPC protective effect, Vamp8 and Inpp5d/Ship are discussed as possible candidates for control of the iIR damage.

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