scholarly journals Kaempferol Alleviates Oxidative Stress and Apoptosis Through Mitochondria-dependent Pathway During Lung Ischemia-Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunli Yang ◽  
Wenkai Yang ◽  
Zhaohui He ◽  
Jinghua Guo ◽  
Xiaogang Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Alveolar Epithelial Cells ◽  
Mitochondrial Cytochrome ◽  
L2 Cells ◽  
Mitochondrial Cytochrome C

In previous study, we reported that kaempferol ameliorates significantly lung ischemia-reperfusion injury (LIRI), and may be achieved by targeting the SIRT 1 pathway. This study further explored the anti-LIRI mechanism of kaempferol. In vitro, the rat alveolar epithelial cells L2 was cultured and subjected to anoxia/reoxygenation (A/R) insult. In vivo, SD rats were operated to establish LIRI model. The related indicators of oxidative stress and apoptosis in L2 cells and rats lung tissues were detected. Results showed that kaempferol pre-treatment significantly increased the cell viability, improved mitochondrial membrane potential, inhibited the opening of mitochondrial permeability transition pores, reduced the levels of oxidative stress and apoptosis, increased the expressions of Bcl-2 and mitochondrial cytochrome c, and decreased the expressions of Bax and cytoplasmic cytochrome c in L2 cells after A/R insult. In vivo, kaempferol improved the pathological injury, inhibited the levels of oxidative stress and apoptosis, increased the expressions of Bcl-2 and mitochondrial cytochrome c, and decreased the expressions of Bax and cytoplasmic cytochrome c in rats lung tissues after I/R. However, the aforementioned effects of kaempferol were significantly attenuated by the SIRT 1 inhibitor EX527 or the PGC-1α inhibitor SR-18292. What’s more, SR-18292 has not reversed the effect of kaempferol on increasing the protein activity of SIRT 1. Above results suggest that kaempferol ameliorates LIRI by improving mitochondrial function, reducing oxidative stress and inhibiting cell apoptosis. Its molecular mechanism of action includes the SIRT 1/PGC-1α/mitochondria signaling pathway.

scholarly journals MicroRNA-141-3p Attenuates Oxidative Stress-induced Hepatic Ischemia Reperfusion Injury via Keap1/Nrf2 Pathway

2021 ◽  
Author(s):  
Tingting Li ◽  
Qingsong Chen ◽  
Jiangwen Dai ◽  
Zuotian Huang ◽  
Yunhai Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Abstract Hepatic ischemia reperfusion injury (IRI) is a major factor affecting the prognosis of liver transplantation through a series of severe cell death and inflammatory responses. MicroRNA-141-3p (miR-141-3p) has been reported to be associated with hepatic steatosis and other liver diseases. However, the potential role of miR-141-3p in hepatic IRI is currently unknown. In the present study, we found that miR-141-3p levels were negatively correlated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) in liver transplantation patients. The results demonstrated that miR-141-3p was decreased in mouse liver tissue after hepatic IRI in mice and in hepatocytes after hypoxia/reoxygenation (H/R). Overexpression of miR-141-3p directly decreased Kelch-like ECH-associated protein 1 (Keap1) levels and attenuated cell apoptosis in vivo and in vitro, while inhibition of miR-141-3p facilitated apoptosis. Further experiments revealed that overexpression of miR-141-3p also attenuated oxidative stress-induced damage in hepatocytes under H/R conditions. Taken together, our results indicate that miR-141-3p plays a major role in hepatic IRI through the Keap1 signaling pathway, and the present study suggests that miR-141-3p might have a protective effect on hepatic IRI to some extent.

scholarly journals CYP2J2 and EETs Protect Against Pulmonary Hypertension with Lung Ischemia-Reperfusion Injury In Vivo and In Vitro

2021 ◽  
Author(s):  
Yun Ding ◽  
Pengjie Tu ◽  
Yiyong Chen ◽  
Yangyun Huang ◽  
Xiaojie Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Lung Tissue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia-reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo.Methods CYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by tail vein injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with hypoxic reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs.Results CYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by PPARγ pathway; the anti-apoptotic effects might be mediated by the PI3K/Ak pathway.Conclusions CYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.

In vivo protective effects of urocortin on ischemia-reperfusion injury in rat heart via free radical mechanisms

2005 ◽  
Vol 83 (6) ◽  
pp. 459-465 ◽  
Author(s):  
Chun-Na Liu ◽  
Cui Yang ◽  
Xin-Yu Liu ◽  
Shengnan Li
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Reperfusion Injury ◽  
Body Mass ◽  
Normal Saline ◽  
Saline Solution ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Infarction Size

The aim of this study was to investigate the effects of urocortin (UCN) on oxidative stress and the mechanisms of urocortin on ischemia–reperfusion injury in vivo in the rat model. Thirty-six Sprague–Dawley rats were divided into 6 groups, including sham, control (normal saline solution), UCN1, UCN2, UCN3, and verapamil groups. The left anterior descending coronary artery of all rats except those in the sham group was treated with a 30-min occlusion followed by a 60-min reperfusion. Just before the occlusion, normal saline solution, UCN (5, 10, and 20 µg/kg body mass), or verapamil (1 mg/kg body mass) was administered. Heart rates, beating rhythm, and S-T segments were constantly monitored using an ECG. At the completion of the drug adminstration, blood samples were taken to measure the activity of superoxide dismutase (SOD), malonaldehyde (MDA), glutathione peroxidase (GSH-PX), and nitric oxide (NO) to evaluate the effects of UCN on oxidative stress. Finally, the size of infarction was measured. Arrhythmia rates were significantly lower, and the infarction size was significantly smaller (p < 0.01), in the UCN groups vs. the control group. Verapamil also significantly reduced arrhythmia rates and infarction size. The MDA activities were remarkably diminished, whereas the SOD, GSH-PX, and NO activities were significantly higher in the UCN and VER groups (p < 0.01). MDA, SOD, and NO activities were strongly correlated with UCN doses. These results suggest that UCN may play a protective role in ischemia–reperfusion injury in rat hearts against the oxidative stress by inhibiting free radicals' activities. Key words: urocortin, ischemia–reperfusion injury, arrhythmias, free radical anti-oxidative enzymes, oxidative stress.

scholarly journals Upregulation of Bcl-2 Through Caspase-3 Inhibition Ameliorates Ischemia/Reperfusion Injury in Rat Cardiac Allografts

Circulation ◽  
2001 ◽  
Vol 104 (suppl_1) ◽  
Author(s):  
Jürg Grünenfelder ◽  
Douglas N. Miniati ◽  
Seiichiro Murata ◽  
Volkmar Falk ◽  
E. Grant Hoyt ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Reperfusion Injury ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Myeloperoxidase Activity ◽  
Mitochondrial Cytochrome ◽  
Cytochrome C Release ◽  
Tnf Α ◽  
Cardiac Allografts ◽  
Mitochondrial Cytochrome C

Background Oxidative stress after ischemia/reperfusion of cardiac allografts leads to cytokine production. Bcl-2, an inhibitor of apoptosis, also has strong antioxidant properties. Caspase-3 is known to cleave bcl-2. This study tests the hypothesis that bcl-2 is downregulated while tumor necrosis factor-α (TNF-α) levels increase after cardiac transplantation. Furthermore, the use of caspase-3 inhibition was investigated as a strategy for preserving myocardial bcl-2 and mitochondrial cytochrome c after transplantation. Methods and Results PVG-to-ACI rat heterotopic cardiac transplantations were performed in 4 groups designed with 30 minutes’ ischemia and 4 or 8 hours of reperfusion (n=4 per group). Treatment consisted of DEVD-CHO 500 μg IP per animal to donor and recipient 2 hours before transplantation and 250 μg IC into allograft. Controls were treated with saline. Grafts were analyzed by reverse transcription–polymerase chain reaction for bcl-2 mRNA, by ELISA for TNF-α, for myeloperoxidase activity, and by Western blot for cytochrome c. In untreated groups, bcl-2 mRNA decreased significantly over time, whereas TNF-α increased significantly at 4 hours ( P =0.003) and returned to baseline after 8 hours’ reperfusion ( P =NS compared with normal hearts). Treatment with caspase-3 inhibitor showed significant upregulation of bcl-2 mRNA expression after 4 and 8 hours of reperfusion ( P <0.001 versus control), with a concomitant decrease in TNF-α to baseline levels. Myeloperoxidase activity in all groups was no different from that of normal hearts. Mitochondrial cytochrome c release increased in both control and treatment groups. Conclusions Bcl-2 is actively downregulated and TNF-α is upregulated in this model of cardiac allograft ischemia/reperfusion. Furthermore, the caspase-3 pathway is linked to this process, and blockade of caspase-3 can ameliorate reperfusion injury by upregulating bcl-2 and inhibiting TNF-α without affecting cytochrome c release.

scholarly journals Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat.

2020 ◽  
Author(s):  
yang zhou ◽  
Li Peng ◽  
Ning Jiang ◽  
Jingxian Wu ◽  
Yixin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Abstract Background Astrocytes mediate brain defense against oxidative stress-induced injury. Silent information regulator 1 (SIRT1) has anti-oxidative stress effects in many diseases and is highly expressed in astrocytes. However, the neuroprotective effects of SIRT1 on astrocytes after cerebral ischemia/reperfusion injury are unclear. Methods Here, we evaluated the effects of SIRT1 in astrocytes after cerebral ischemia/reperfusion injury using oxygen-glucose deprivation/recovery in astrocytes in vitro and middle cerebral artery occlusion in rats in vivo. Results SIRT1 knockdown reduced cell viability, increased oxidative stress, and decreased peroxisome proliferator activated receptor (PPAR)-γ coactivator (PGC)-1α, PPARγ, nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase (HO)-1, and NAD(P)H:quinone oxidoreductase-1 (NQO1) expression. Moreover, SIRT1 knockdown also suppressed PGC-1α activity, the PGC-1α/PPARγ interaction, and the PPARγ/peroxisome proliferator-response element (PPRE) interaction. Similarly, in our in vivo experiments, SIRT1 overexpression and PGC-1α or PPARγ knockdown reduced PGC-1α, PPARγ, NRF2, HO-1, and NQO1 protein expression and blocked the PGC-1α/PPARγ interaction. SIRT1 overexpression plus PPARγ knockdown inhibited the interaction of PPARγ with PPRE. NRF2 knockdown blocked NRF2 expression and downstream proteins induced by SIRT1 overexpression. Conclusion Overall, our data indicated that SIRT1 directly mediated the PGC-1α/PPARγ pathway in response to focal cerebral ischemia/reperfusion-induced neurological deficit, providing insights into the treatment of focal cerebral ischemia/reperfusion injury.

scholarly journals Ultrasound-Induced Destruction of Nitric Oxide–Loaded Microbubbles in the Treatment of Thrombus and Ischemia–Reperfusion Injury

2022 ◽  
Vol 12 ◽  
Author(s):  
Zenghui Liang ◽  
Huafang Chen ◽  
Xuehao Gong ◽  
Binbin Shi ◽  
Lili Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acoustic Cavitation ◽  
Liver And Kidney ◽  
Underlying Mechanisms

Objectives: Early recanalization of large vessels in thromboembolism, such as myocardial infarction and ischemic stroke, is associated with improved clinical outcomes. Nitric oxide (NO), a biological gas signaling molecule, has been proven to protect against ischemia–reperfusion injury (IRI). However, the underlying mechanisms remain to be explored. This study investigated whether NO could mitigate IRI and the role of NO during acoustic cavitation.Methods:In vivo, thrombi in the iliac artery of rats were induced by 5% FeCl3. NO-loaded microbubbles (NO-MBs) and ultrasound (US) were used to treat thrombi. B-mode and Doppler US and histological analyses were utilized to evaluate the thrombolysis effect in rats with thrombi. Immunohistochemistry, immunofluorescence, and western blotting were conducted to investigate the underlying mechanisms of NO during acoustic cavitation. In vitro, hypoxia was used to stimulate cells, and NO-MBs were employed to alleviate oxidative stress and apoptosis.Results: We developed NO-MBs that significantly improve the circulation time of NO in vivo, are visible, and effectively release therapeutic gas under US. US-targeted microbubble destruction (UTMD) and NO-loaded UTMD (NO + UTMD) caused a significant decrease in the thrombus area and an increase in the recanalization rates and blood flow velocities compared to the control and US groups. We discovered that UTMD induced NO generation through activation of endothelial NO synthase (eNOS) in vivo. More importantly, we also observed significantly increased NO content and eNOS expression in the NO + UTMD group compared to the UTMD group. NO + UTMD can mitigate oxidative stress and apoptosis in the hind limb muscle without influencing blood pressure or liver and kidney functions. In vitro, NO-MBs alleviated oxidative stress and apoptosis in cells pretreated with hypoxia.Conclusion: Based on these data, UTMD affects the vascular endothelium by activating eNOS, and NO exerts a protective effect against IRI.

Diosmetin alleviated cerebral ischemia/reperfusion injury in vivo and in vitro by inhibiting oxidative stress via SIRT1/Nrf2 signaling pathway

2021 ◽  
Author(s):  
Zhigang Mei ◽  
Lipeng Du ◽  
Xiaolu Liu ◽  
Xiangyu Chen ◽  
Huan Tian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Nrf2 Signaling Pathway ◽  
Cerebral Ischemia Reperfusion Injury

Oxidative stress is known to play a pivotal role in the pathogenesis of cerebral ischemia reperfusion (I/R) injury. Accumulating studies have revealed that diosmetin (Dios) could protect against oxidative stress...

scholarly journals Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats

2014 ◽  
Vol 17 (1) ◽  
pp. 121 ◽  
Author(s):  
Camilla A Thorling ◽  
Michael S Roberts ◽  
Xin Liu ◽  
Linda M Fletcher ◽  
Darrell Crawford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Multiphoton Microscopy ◽  
Rhodamine 123 ◽  
P Glycoprotein

PURPOSE: Ischemia-reperfusion injury is a common complication in liver surgery with oxidative stress related graft failure as a potential complication. The oxidative stress could affect hepatic drug transporters such as P-glycoprotein, which is crucial in the hepatic clearance of certain immunosuppressant drugs. Thus,, it is important to study its function after ischemia-reperfusion injury in vivo. Rhodamine 123 is a fluorescent substrate of P-glycoprotein and its hepatic disposition can be visualized using multiphoton microscopy in vivo using anaesthetized animals. The aim of this study was to investigate the effect of long-term ischemia-reperfusion injury on P-glycoprotein function in hepatocytes using in vivo multiphoton microscopy. METHODS: Localized ischemia was induced for 1 hour in rats. The liver was reperfused for 4, 24, 48 hours or 1 week, where-after rhodamine 123 was injected intravenously. Multiphoton microscopy imaged the liver and bile was collected continuously up to 6 hours following drug administration. The liver was harvested for histology andprotein expression of P-glycoprotein. RESULTS: Ischemia-reperfusion injury resulted in extensive liver damage, inflammatory cell infiltration and apoptosis in the midzonal and centrilobular regions of the liver acinus. P-glycoprotein protein expression decreased. Cellular concentration of rhodamine 123 increased as visualized by multiphoton microscopy, which was confirmed with decreased excretion of rhodamine 123 in collected bile. CONCLUSIONS: This study showed reduced function of P-glycoprotein in ischemia-reperfusion injury as reflected by decreased biliary excretion of Rhodamine 123, as well as reduced protein expression of the transporter. Multiphoton microscopy could be used to visualize and quantitate the intracellular levels of rhodamine 123. These findings stipulate the importance of using multiphoton microscopy to understand transmembrane drug flux and reflect on careful drug dosing after hepatic surgery. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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