scholarly journals Enhanced Effect of IL-1β-Activated Adipose-Derived MSCs (ADMSCs) on Repair of Intestinal Ischemia-Reperfusion Injury via COX-2-PGE2 Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Liu Liu ◽  
Yi Ren He ◽  
Shao Jun Liu ◽  
Lei Hu ◽  
Li Chuang Liang ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Suppressive Effect ◽  
Signaling Axis ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Intestinal Ischemia Reperfusion

Adipose-derived mesenchymal stem cells (ADMSCs) have been used for treating tissue injury, and preactivation enhances their therapeutic effect. This study is aimed at investigating the therapeutic effect of activated ADMSCs by IL-1β on the intestinal ischaemia-reperfusion (IR) injury and exploring potential mechanisms. ADMSCs were pretreated with IL-1β in vitro, and activation of ADMSCs was assessed by α-SMA and COX-2 expressions and secretary function. Activated ADMSCs was transplanted into IR-injured intestine in a mouse model, and therapeutic effect was evaluated. In addition, to explore underlying mechanisms, COX-2 expression was silenced to investigate its role in activated ADMSCs for treatment of intestinal IR injury. When ADMSCs were pretreated with 50 ng/ml IL-1β for 24 hr, expressions of α-SMA and COX-2 were significantly upregulated, and secretions of PGE2, SDF-1, and VEGF were increased. When COX-2 was silenced, the effect of IL-1β treatment was abolished. Activated ADMSCs with IL-1β significantly suppressed inflammation and apoptosis and enhanced healing of intestinal IR injury in mice, and these effects were impaired by COX-2 silencing. The results of RNA sequencing suggested that compared with the IR injury group activated ADMSCs induced alterations in mRNA expression and suppressed the activation of the NF-κB-P65, MAPK-ERK1/2, and PI3K-AKT pathways induced by intestinal IR injury, whereas silencing COX-2 impaired the suppressive effect of activated ADMSCs on these pathway activations induced by IR injury. These data suggested that IL-1β pretreatment enhanced the therapeutic effect of ADMSCs on intestinal IR injury repairing via activating ADMSC COX-2-PGE2 signaling axis and via suppressing the NF-κB-P65, MAPK-ERK1/2, and PI3K-AKT pathways in the intestinal IR-injured tissue.

scholarly journals Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Guo Zu ◽  
Jing Guo ◽  
Ningwei Che ◽  
Tingting Zhou ◽  
Xiangwen Zhang
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Ginsenoside Rg1 ◽  
Intestinal Ischemia Reperfusion

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.

scholarly journals Prophylactic Ozone Administration Reduces Intestinal Mucosa Injury Induced by Intestinal Ischemia-Reperfusion in the Rat

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Ozkan Onal ◽  
Fahri Yetisir ◽  
A. Ebru Salman Sarer ◽  
N. Dilara Zeybek ◽  
C. Oztug Onal ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Intestinal Injury ◽  
Control Group ◽  
Injury Score ◽  
Tissue Samples ◽  
Intestinal Ischemia Reperfusion

Objectives. Intestinal ischemia-reperfusion injury is associated with mucosal damage and has a high rate of mortality. Various beneficial effects of ozone have been shown. The aim of the present study was to show the effects of ozone in ischemia reperfusion model in intestine.Material and Method. Twenty eight Wistar rats were randomized into four groups with seven rats in each group. Control group was administered serum physiologic (SF) intraperitoneally (ip) for five days. Ozone group was administered 1 mg/kg ozone ip for five days. Ischemia Reperfusion (IR) group underwent superior mesenteric artery occlusion for one hour and then reperfusion for two hours. Ozone + IR group was administered 1 mg/kg ozone ip for five days and at sixth day IR model was applied. Rats were anesthetized with ketamine∖xyzlazine and their intracardiac blood was drawn completely and they were sacrificed. Intestinal tissue samples were examined under light microscope. Levels of superoxide dismutase (SOD), catalase (CAT), glutathioneperoxidase (GSH-Px), malondyaldehide (MDA), and protein carbonyl (PCO) were analyzed in tissue samples. Total oxidant status (TOS), and total antioxidant capacity (TAC) were analyzed in blood samples. Data were evaluated statistically by Kruskal Wallis test.Results. In the ozone administered group, degree of intestinal injury was not different from the control group. IR caused an increase in intestinal injury score. The intestinal epithelium maintained its integrity and decrease in intestinal injury score was detected in Ozone + IR group. SOD, GSH-Px, and CAT values were high in ozone group and low in IR. TOS parameter was highest in the IR group and the TAC parameter was highest in the ozone group and lowest in the IR group.Conclusion. In the present study, IR model caused an increase in intestinal injury.In the present study, ozone administration had an effect improving IR associated tissue injury. In the present study, ozone therapy prevented intestine from ischemia reperfusion injury. It is thought that the therapeutic effect of ozone is associated with increase in antioxidant enzymes and protection of cells from oxidation and inflammation.

scholarly journals SIRT3 deficiency exacerbates ischemia-reperfusion injury: implication for aged hearts

2014 ◽  
Vol 306 (12) ◽  
pp. H1602-H1609 ◽  
Author(s):  
George A. Porter ◽  
William R. Urciuoli ◽  
Paul S. Brookes ◽  
Sergiy M. Nadtochiy
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Critical Feature ◽  
Age Related ◽  
Lysine Deacetylase ◽  
Consumption Rates ◽  
Vitro Model ◽  
Underlying Mechanisms

Ischemia-reperfusion (IR) injury is significantly worse in aged hearts, but the underlying mechanisms are poorly understood. Age-related damage to mitochondria may be a critical feature, which manifests in an exacerbation of IR injury. Silent information regulator of transcription 3 (SIRT3), the major mitochondrial NAD+-dependent lysine deacetylase, regulates a variety of functions, and its inhibition may disrupt mitochondrial function to impact recovery from IR injury. In this study, the role of SIRT3 in mediating the response to cardiac IR injury was examined using an in vitro model of SIRT3 knockdown (SIRT3kd) in H9c2 cardiac-derived cells and in Langendorff preparations from adult (7 mo old) wild-type (WT) and SIRT3+/− hearts and aged (18 mo old) WT hearts. SIRT3kd cells were more vulnerable to simulated IR injury and exhibited a 46% decrease in mitochondrial complex I (Cx I) activity with low O2 consumption rates compared with controls. In the Langendorff model, SIRT3+/− adult hearts showed less functional recovery and greater infarct vs. WT, which recapitulates the in vitro results. In WT aged hearts, recovery from IR injury was similar to SIRT3+/− adult hearts. Mitochondrial protein acetylation was increased in both SIRT3+/− adult and WT aged hearts (relative to WT adult), suggesting similar activities of SIRT3. Also, enzymatic activities of two SIRT3 targets, Cx I and MnSOD, were similarly and significantly inhibited in SIRT3+/− adult and WT aged cardiac mitochondria. In conclusion, decreased SIRT3 may increase the susceptibility of cardiac-derived cells and adult hearts to IR injury and may contribute to a greater level of IR injury in the aged heart.

scholarly journals Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mohamed Bejaoui ◽  
Eirini Pantazi ◽  
Maria Calvo ◽  
Emma Folch-Puy ◽  
Anna Serafín ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Rat Liver ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Water Soluble ◽  
Effective Strategy ◽  
Sprague Dawley ◽  
Hepatic Ischemia

Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in variousin vivoandin vitromodels of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI.

Inhibition of p66Shc-mediated mitochondrial apoptosis via targeting prolyl-isomerase Pin1 attenuates intestinal ischemia/reperfusion injury in rats

2017 ◽  
Vol 131 (8) ◽  
pp. 759-773 ◽  
Author(s):  
Dongcheng Feng ◽  
Jihong Yao ◽  
Guangzhi Wang ◽  
Zhenlu Li ◽  
Guo Zu ◽  
...  
Keyword(s):  
Intestinal Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Mitochondrial Apoptosis ◽  
Prolyl Isomerase ◽  
Apoptotic Pathway ◽  
Apoptosis Pathway ◽  
Intestinal Ischemia Reperfusion

Intestinal epithelial oxidative stress and apoptosis constitute key pathogenic mechanisms underlying intestinal ischemia/reperfusion (I/R) injury. We previously reported that the adaptor 66 kDa isoform of the adaptor molecule ShcA (p66Shc)-mediated pro-apoptotic pathway was activated after intestinal I/R. However, the upstream regulators of the p66Shc pathway involved in intestinal I/R remain to be fully identified. Here, we focused on the role of a prolyl-isomerase, peptidyl–prolyl cis–trans isomerase (Pin1), in the regulation of p66Shc activity during intestinal I/R. Intestinal I/R was induced in rats by superior mesenteric artery (SMA) occlusion. Juglone (Pin1 inhibitor) or vehicle was injected intraperitoneally before I/R challenge. Caco-2 cells were exposed to hypoxia/reoxygenation (H/R) in vitro to simulate an in vivo I/R model. We found that p66Shc was significantly up-regulated in the I/R intestine and that this up-regulation resulted in the accumulation of intestinal mitochondrial reactive oxygen species (ROS) and massive epithelial apoptosis. Moreover, intestinal I/R resulted in elevated protein expression and enzyme activity of Pin1 as well as increased interaction between Pin1 and p66Shc. This Pin1 activation was responsible for the translocation of p66Shc to the mitochondria during intestinal I/R, as Pin1 suppression by juglone or siRNA markedly blunted p66Shc mitochondrial translocation and the subsequent ROS generation and cellular apoptosis. Additionally, Pin1 inhibition alleviated gut damage and secondary lung injury, leading to improvement of survival after I/R. Collectively, our findings demonstrate for the first time that Pin1 inhibition protects against intestinal I/R injury, which could be partially attributed to the p66Shc-mediated mitochondrial apoptosis pathway. This may represent a novel prophylactic target for intestinal I/R injury.

scholarly journals MicroRNA files in the prevention of intestinal ischemia/reperfusion injury by hydrogen rich saline

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Weifeng Yao ◽  
Xiaoyu Lin ◽  
Xue Han ◽  
Lanfen Zeng ◽  
Anshun Guo ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Mucosal Injury ◽  
Regulatory Subunit ◽  
Protective Effects ◽  
Intestinal Ischemia Reperfusion

Abstract Background: Hydrogen-rich saline (HRS) has been proven effective against ischemia/reperfusion (I/R) injury. However, knowledge on the underlying signaling events remain poor. Having recent highlight of microRNAs (miRNAs) in mediating intestinal I/R injury, we hypothesized that HRS may protect intestine against I/R injury by regulating miRNAs. Method: Mice were given intraperitoneal injection of saline or HRS once daily for five consecutive days before undergoing intestinal I/R that was induced by 60-min ischemia followed by 180-min reperfusion of superior mesenteric artery. The intestine was collected for histopathological assay, miRNA microarray profiling, Real-Time PCR, and Western blotting. Next, miR-199a-3p mimics or inhibitors were transfected into IEC-6 cells to explore the relationship between HRS treatment and miR-199a-3p. Results: I/R-induced mucosal injury and epithelial cells apoptosis were attenuated by HRS pretreatment. A total of 64 intestinal I/R-responsive miRNAs were altered significantly by HRS pretreatment, in which we validated four novel miRNAs with top significance by Real-Time PCR, namely miR-199a-3p, miR-296-5p, miR-5126, and miR-6538. Particularly, miR-199a-3p was drastically increased by I/R but reduced by HRS. Computational analysis predicts insulin-like growth factor (IGF)-1, mammalian target of rapamycin (mTOR), and phosphoinositide-3-kinase (PI3K) regulatory subunit 1 as targets of miR-199a-3p, suggesting involvement of the pro-survival pathway, IGF- 1/PI3K/Akt/mTOR. In in vitro experiment, HRS treatment reduced miR-199a-3p level, increase IGF-1, PI3K and mTOR mRNA expression, restore IEC-6 cells viability, and this protective effects were reversed under miR-199a-3p mimics treatment. Conclusion: Collectively, miR-199a-3p may serve a key role in the anti-apoptotic mechanism of HRS that contributes to its protection of the intestine against I/R injury.

scholarly journals Combination of Paeoniflorin and Calycosin-7-glucoside Promotes Ischemic Stroke Recovery via the PI3K/AKT Signaling Pathway

2020 ◽  
Author(s):  
shengxin Wang ◽  
Xiangli Yan ◽  
Yingying He ◽  
Haozhen Zheng ◽  
PengCheng Wang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Gsk 3Β

Abstract Background Paeoniflorin (PF) and calycosin-7-glucoside (CG) play a role in protecting against brain damage following cerebral ischemia. However, the mechanism of action of PF in combination with CG (PF + CG) against ischemia/reperfusion injury remains unclear. Methods The aim of this study was to investigate the protective role of PF + CG on ischemia/reperfusion injury in vivo and in vitro, as well as its potential mechanism of action indicating that PF + CG attenuates middle cerebral artery occlusion (MCAO) /oxygen-glucose deprivation reperfusion (OGD/R) injury via the PI3K/AKT pathway. MCAO rat model was prepared by modified suture method, and behavioral scoring, cerebral infarction area, brain tissue water content measurement, using PI3K, p-PI3K, AKT, p-AKT, Bcl-2, Bax, GSK-3β protein expression as indicators, observe the effect of PI3K / AKT signaling pathway inhibitor LY294002 on the anti-ischemia-reperfusion effect of PF + CG. Oxygen deprivation method was used to prepare the OGD/R model, CCK-8 was used to determine the survival rate of HT22 cells, the contents of SOR, ROS, MDA, and LHD were determined, and apoptosis was detected by flow cytometry and mitochondrial membrane potential, using PI3K, p-PI3K, AKT, p-AKT, Bcl-2, Bax, GSK-3β protein expression as indicators, observe the effect of PI3K/AKT signaling pathway inhibitor LY294002 on the anti- oxidative and glucose deprivation effect of PF + CG. Results The animal studies showed that PF + CG significantly decreased neurobehavioral deficits, cerebral infarct volume, and brain edema; ameliorated histopathological damage in model rats; increased levels of PI3K, AKT, p-PI3K, p-AKT, and Bcl-2; and reduced BAX and GSK-3β expression. After treatment with PF + CG, the morphology and number of cells in brain tissue were restored to normal, demonstrating a therapeutic effect in cerebral ischemia-reperfusion injury. Results of further studies revealed that, in vitro, PF + CG has a therapeutic effect to enhance cell vitality; elevate levels of superoxide dismutase (SOD); reduce levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA); decrease apoptosis rate; increase levels of PI3K, AKT, p-PI3K, p-AKT, and Bcl-2; and reduce BAX and GSK-3β expression. Conclusion These results demonstrate that PF + CG has a positive therapeutic effect on ischemia/reperfusion and OGD/R injury, and the mechanism is attributed to activation of the PI3K/AKT signaling pathway.

scholarly journals DHA Attenuates Hypoxia/Reoxygenation Injury by Activating SSeCKS in Human Cerebrovascular Pericytes

2019 ◽  
Vol 45 (2) ◽  
pp. 310-321
Author(s):  
Yanli Yu ◽  
Haibin Fang ◽  
Zhen Qiu ◽  
Zhongyuan Xia ◽  
Bin Zhou
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Junctions ◽  
Cell Permeability ◽  
Vegf Expression ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Ldh Release ◽  
Underlying Mechanisms ◽  
Hypoxia Reoxygenation

AbstractDocosahexaenoic acid (DHA) can alleviate cerebral ischemia/reperfusion injury by reducing blood–brain barrier permeability and maintaining its integrity, accompanied by an increased Ang-1/Ang-2 ratio; however, the underlying mechanisms of these effects remain unclear. Src-suppressed C kinase substrates (SSeCKS), a substrate of protein kinase C, plays an important role in maintaining cell junctions and cell morphology and regulating cell permeability. However, whether DHA can increase SSeCKS expression and then mediate the Ang-1/Ang-2 ratio still needs to be studied. Human cerebrovascular pericytes (HBVPs) cultured in vitro were divided into groups, treated with or without DHA along with SSeCKS siRNA to knockdown SSeCKS expression, and then subjected to 24 h of hypoxia followed by 6 h of reoxygenation. Cell viability; lactate dehydrogenase (LDH) release; and Ang-1, Ang-2 and VEGF activity were detected by using ELISA kits. The apoptosis rate was assessed by TUNEL flow cytometry. Expression of the SSeCKS, Ang-1, Ang-2 and VEGF proteins was evaluated by western blotting. Pretreatment with 10 μM or 40 μM DHA efficiently attenuated hypoxia/reoxygenation (H/R) injury by activating SSeCKS to increase the Ang-1/Ang-2 ratio and downregulate VEGF expression in HBVPs, as evidenced by decreased LDH release and apoptotic rates and increased HBVPs viability. Meanwhile, after we used SSeCKS siRNA to knock down SSeCKS protein expression, the protective effect of DHA on HBVPs following H/R injury was reversed. In conclusion, DHA can activate SSeCKS to increase the Ang-1/Ang-2 ratio and downregulate VEGF expression in HBVPs, thus reducing H/R injury.

scholarly journals NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury

2021 ◽  
Author(s):  
Zhi-yong Xie ◽  
Wei Dong ◽  
Li Zhang ◽  
Meng-jie Wang ◽  
Zhen-meng Xiao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Ckd Progression ◽  
Renal Tubulointerstitial Fibrosis ◽  
Underlying Mechanisms

AbstractAcute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFβ-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

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