scholarly journals Inhibition of Prolyl Oligopeptidase Prevents Consequences of Reperfusion following Intestinal Ischemia

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1354
Author(s):  
Alessia Filippone ◽  
Giovanna Casili ◽  
Alessio Ardizzone ◽  
Marika Lanza ◽  
Deborah Mannino ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Intestinal Ischemia ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Clinical Event ◽  
High Morbidity ◽  
Intestinal Damage ◽  
Barrier Permeability ◽  
Tissue Ischemia

Background: Intestinal ischemia/reperfusion injury (IRI) remains a clinical event that contributes to high morbidity and mortality rates. Intestinal epithelium is exposed to histological and vascular changes following tissue ischemia. Prolyl endopeptidase (PREP), involved in inflammatory responses, could be targeted for recovery from the permanent consequences following intestinal ischemia. Our aim was to investigate the role of PREP inhibitor KYP-2047 in tissue damage, angiogenesis, and endothelial barrier permeability after intestinal IRI in mice. Methods: KYP-2047 treatments were performed 5 min prior to intestinal damage. Intestinal IRI was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by 1 h of reperfusion. Results: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-ĸB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion. Additionally, loss of epithelial cells during intestinal ischemia occurring by apoptosis was limited by KYP-2047 treatment, which showed strong effects counteracting apoptosis and DNA damage. Conclusions: These findings provide the first evidence that PREP inhibition through KYP-2047 inhibitor use could be a validate strategy for resolving alterations of intestinal epithelium the pathophysiology of intestinal disease.

scholarly journals Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Weicheng Zhao ◽  
Xiaolei Huang ◽  
Xue Han ◽  
Dan Hu ◽  
Xiaohuai Hu ◽  
...  
Keyword(s):  
Mast Cells ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Intestinal Injury ◽  
Cromolyn Sodium ◽  
Inflammasome Activation

Background. Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. Methods. Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups (n=8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. Results. Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and β-hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. Conclusions. In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction.

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 Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Rong Chen ◽  
Yun-yan Zhang ◽  
Jia-nan Lan ◽  
Hui-min Liu ◽  
Wei Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intestinal Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Postconditioning ◽  
Intestinal Barrier Function ◽  
Protective Effects ◽  
Nrf2 Pathway ◽  
Intestinal Ischemia Reperfusion

Aims. Ischemic postconditioning (IPO) has a strong protective effect against intestinal ischemia-reperfusion (IIR) injury that is partly related to autophagy. However, the precise mechanisms involved are unknown. Methods. C57BL/6J mice were subjected to unilateral IIR with or without IPO. After 45 min ischemia and 120 min reperfusion, intestinal tissues and blood were collected for examination. HE staining and Chiu’s score were used to evaluate pathologic injury. We test markers of intestinal barrier function and oxidative stress. Finally, we used WB to detect the expression of key proteins of autophagy and the Akt/GSK-3β/Nrf2 pathway. Results. IPO significantly attenuated IIR injury. Expression levels of LC3 II/I, Beclin-1, and p62 were altered during IIR, indicating that IPO enhanced autophagy. IPO also activated Akt, inhibited GSK-3β, induced Nrf2 nuclear translocation, and upregulated HO-1 and NQO1 expression, thus providing protective effects against IIR injury by suppressing oxidative stress. Consistently, the beneficial effects of IPO were abolished by pretreatment with 3-methyladenine, SC66, and brusatol, potent inhibitors of autophagy, Akt, and Nrf2, respectively. Conclusion. Our study indicates that IPO can ameliorate IIR injury by evoking autophagy, activating Akt, inactivating GSK-3β, and activating Nrf2. These findings may provide novel insights for the alleviation of IIR injury.

scholarly journals Translocation of 99mTc labelled bacteria after intestinal ischemia and reperfusion

2004 ◽  
Vol 19 (4) ◽  
pp. 328-333 ◽  
Author(s):  
Samir Assi João ◽  
Suelene Suassuna Silvestre de Alencar ◽  
Aldo da Cunha Medeiros ◽  
Simone Otília Fernandes Diniz ◽  
Valbert Nascimento Cardoso ◽  
...  
Keyword(s):  
Bacterial Translocation ◽  
Intestinal Ischemia ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Ischemia And Reperfusion ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph ◽  
Colony Forming Units ◽  
Male Wistar Rats ◽  
Intestinal Ischemia Reperfusion

PURPOSE: Ischemia and reperfusion of the small intestine disrupts gut barrier, causes bacterial translocation and activates inflammatory responses. An experimental study was planned to evaluate if 99mTc labelled Escherichia coli translocates to mesenteric lymph nodes, liver, spleen, lung and serum of rats submitted to mesenteric ischemia/reperfusion. Additionally, it was observed if the time of reperfusion influences the level of translocation. METHODS: Forty male Wistar rats underwent 45 minutes of gut ischemia by occlusion of the superior mesenteric artery. The translocation of labelled bacteria to different organs and portal serum was determined in rats reperfused for 30 minutes, 24 hours, sham(S) and controls(C), using radioactivity count and colony forming units/g (CFU). RESULTS: All the organs from rats observed for 24 hours after reperfusion had higher levels of radioactivity and positive cultures (CFU) than did the organs of rats reperfused for 30 minutes, C and S, except in the spleen (p<0,01). CONCLUSION: The results of this study indicated that intestinal ischemia/reperfusion led to bacterial translocation, mostly after 24 hours of reperfusion.

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 Nicaraven Attenuates Postoperative Systemic Inflammatory Responses-Induced Tumor Metastasis

2019 ◽  
Vol 27 (4) ◽  
pp. 1068-1074 ◽  
Author(s):  
Xu Zhang ◽  
Takahito Moriwaki ◽  
Tsuyoshi Kawabata ◽  
Shinji Goto ◽  
Ke-Xiang Liu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Metastasis ◽  
Intestinal Ischemia ◽  
Cancer Metastasis ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Major Surgery ◽  
Lewis Lung Cancer ◽  
Intestinal Ischemia Reperfusion

Abstract Background Inflammation has been demonstrated to promote cancer metastasis. Due to the well-known systemic inflammatory responses (SIR) after major surgery, it is critical to investigate and attenuate SIR-induced tumor metastasis of cancer patients suffering surgical procedures. Methods C57BL/6 mice were intravenously injected with Lewis lung cancer cells at 6, 24, and 72 h after the induction of intestinal ischemia/reperfusion (I/R) injury. We found that the number of tumor nodules significantly increased in lungs of mice injected with cancer cells at 6 h but not at 24 and 72 h after I/R injury. The administration of nicaraven 30 min before and 24 h after I/R injury effectively attenuated the enhanced tumor metastasis to lungs. Protein array showed the increase of various cytokines in plasma of mice at 6 h after I/R injury, but many of them were attenuated by the administration of nicaraven. Immunostaining indicated the increase of Ly6g-, CD206-, and CD11c-positive inflammatory cells in the lungs, but it was also attenuated by nicaraven administration. Conclusions Postoperative SIR-induced tumor metastasis have been clearly evidenced in our experimental model, and the administration of nicaraven may ameliorate the SIR-induced tumor metastasis by suppressing inflammatory responses.

TLR3 exaggerated sepsis induced cardiac dysfunction via activation of TLR4-mediated NF-κB and TRIF/IRF signaling pathways

2014 ◽  
Vol 2 (2) ◽  
pp. 125-136 ◽  
Keyword(s):  
Cardiac Dysfunction ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Binding Activity ◽  
High Morbidity ◽  
Death Domain ◽  
Tir Domain ◽  
Disease States ◽  
Tlr4 Activation

Cardiovascular dysfunction is a major consequence of septic shock and contributes to the high morbidity and mortality of sepsis. Groups of proteins that comprise the Toll or Toll-like family of receptors detect the pathogen and mount a rapid defensive response in vertebrate and invertebrate organisms, through induction of innate immune and inflammatory responses. The engagement of TLR4 homodimers by LPS or other protein cognate the ligands initiates a signaling cascade and thus induces genes involved in the immune response against pathogens. TLRs have been implicated in cardiac dysfunction in several important disease states, including ischemia/reperfusion (I/R) injury. MyD88 contains an N-terminal death domain and a C-terminal TIR domain. When stimulated, MyD88 is recruited and, in the early phase, interacts with the cytoplasmic TIR domain of TLR4. Although TLR3 is known to respond to RNA from damage cells, the importance of this response in vivo during acute inflammatory processes has not been fully understood. Our result shows that TLR3−/− rat significantly attenuated myocardial NF-κB binding activity both the levels of phosphorylated IκBα/IκBα after LPS administration, and improved cardiac function and reduce the inflammatory response. Further, LPS increased levels of TLR4, TRIF and IFN-β in the myocardium. Interestingly the TLR4-activation signaling was significantly prevented by TLR3 deficiency. We concluded that the use of antibody directed against TLR3 might serve as a therapeutic clinical option in the treatment of cardiac dysfunction induced by sepsis.

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.

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