Nitroxide radical attenuates ischaemia/reperfusion injury to the rat small intestine.
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ABSTRACT:
SUBMITTER: Udassin R
PROVIDER: S-EPMC1727101 | biostudies-other | 1998 May
REPOSITORIES: biostudies-other
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Project description:Background and purposeNicorandil, an ATP-sensitive potassium (K(ATP) ) channel opener and nitric oxide donor, is used in the treatment of angina and acute heart failure. Here we investigated the effects of two K(ATP) channel openers, nicorandil and cromakalim on ischaemia reperfusion (I-R) injury in the kidney.Experimental approachRight nephrectomy was performed in 8-week-old male Sprague-Dawley rats and they were then divided into six groups: control group; I-R, including 30 min of left renal ischaemia followed by 24 h of reperfusion; I-R groups plus nicorandil 3 or 10 mg·kg⁻¹ i.p.; and I-R groups plus cromakalim 100 or 300 µg·kg⁻¹ i.p. After reperfusion, renal function was estimated by serum creatinine (SCr), urinary albumin:creatinine ratio (ACR) and urinary β2-microglobulin (β2-MG). Levels of K(ATP) channel subtypes were investigated by Western blot. Kidney sections were stained for 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine.Key resultsRenal I-R induced significant increases in SCr, ACR and β2-MG levels compared with the control animals. Treatment with K(ATP) channel openers reduced urinary β2-MG levels, raised by I-R. Both K(IR) 6.1 and K(IR) 6.2 channels were expressed. Expression of K(IR) 6.2 channels in the I-R group was lower than in the control group, which was restored to normal by treatment with K(ATP) channel openers. Histologically, severe acute tubular damage was observed in the I-R kidney and this damage was ameliorated by K(ATP) channel openers, dose-dependently.Conclusions and implicationsATP-sensitive potassium channel openers protected against proximal tubule damage after I-R injury. Nicorandil could represent a powerful additional component in the treatment of patients undergoing partial nephrectomy or renal transplantation.
| S-EPMC3087131 | biostudies-literature
Project description:Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.
| S-EPMC8099895 | biostudies-literature
Project description:The chemokine (C-X-C motif) receptor 4 (CXCR4) is expressed on native cardiomyocytes and can modulate isolated cardiomyocyte contractility. This study examines the role of CXCR4 in cardiomyocyte response to ischaemia-reperfusion (I/R) injury. Isolated adult rat ventricular cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) to simulate I/R injury. In response to H/R injury, the decrease in CXCR4 expression was associated with dysfunctional energy metabolism indicated by an increased adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratio. CXCR4-overexpressing cardiomyocytes were used to determine whether such overexpression (OE) can prevent bio-energetic disruption-associated cell death. CXCR4 OE was performed with adenoviral infection with CXCR4 encoding-gene or non-translated nucleotide sequence (Control). The increased CXCR4 expression was observed in cardiomyocytes post CXCR4-adenovirus transduction and this OE significantly reduced the cardiomyocyte contractility under basal conditions. Although the same extent of H/R-provoked cytosolic calcium overload was measured, the hydrogen peroxide-induced decay of mitochondrial membrane potential was suppressed in CXCR4 OE group compared with control group, and the mitochondrial swelling was significantly attenuated in CXCR4 group, implicating that CXCR4 OE prevents permeability transition pore opening exposure to overload calcium. Interestingly, this CXCR4-induced mitochondrial protective effect is associated with the enhanced signal transducer and activator of transcription 3 (expression in mitochondria. Consequently, in the presence of H/R, mitochondrial dysfunction was mitigated and cardiomyocyte death was decreased to 65% in the CXCR4 OE group as compared with the control group. I/R injury leads to the reduction in CXCR4 in cardiomyocytes associated with the dysfunctional energy metabolism, and CXCR4 OE can alleviate mitochondrial dysfunction to improve cardiomyocyte survival.
| S-EPMC4549033 | biostudies-literature
Project description:Cerebral ischaemia/reperfusion (CI/R) injury is a major challenge due to the lack of effective neuroprotective drugs. Hederagenin (HE) is the aglycone part of saponins extracted from Hedera helix Linné that has exhibited anti-apoptotic and anti-inflammatory effects; however, the role of HE in CI/R has not been elucidated. In this study, mice were intraperitoneally (i.p.) injected with HE (26.5, 53, or 106 μmol/kg body weight) for 3 days after middle cerebral artery occlusion (MCAO). Neural function and brain infarct volume were evaluated. HE treatment attenuated CI/R-induced apoptosis and inflammatory cytokine expression within the infarcted areas. HE treatment also decreased the activation of the MLK3 signalling pathway, which potentiates CI/R damage via the MAPK and NFκB pathways. Due to HE's safety profile, it has potential to be used for the clinical treatment of ischaemic stroke.
| S-EPMC7406912 | biostudies-literature
Project description:Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.
| S-EPMC7483549 | biostudies-literature
Project description:Acute mesenteric ischemia (AMI) is caused by considerable intestinal injury, which is associated with intestinal ischemia followed by reperfusion. To elucidate the mechanisms of ischemia/reperfusion injuries, a C5a inhibitory peptide termed AcPepA was used to examine the role of C5a anaphylatoxin, induction of inflammatory cells, and cell proliferation of the intestinal epithelial cells in an experimental AMI model. In this rat model, the superior mesenteric artery was occluded and subsequently reperfused (Induce-I/R). Other groups were treated with AcPepA before ischemia or reperfusion. Induce-I/R induced injuries in the intestine and AcPepA significantly decreased the proportion of severely injured villi. Induce-I/R induced secondary receptor for C5a-positive polymorphonuclear leukocytes in the vessels and CD204-positive macrophages near the injured site; this was correlated with hypoxia-induced factor 1-alpha-positive cells. Induction of these inflammatory cells was attenuated by AcPepA. In addition, AcPepA increased proliferation of epithelial cells in the villi, possibly preventing further damage. Therefore, Induce-I/R activates C5a followed by the accumulation of polymorphonuclear leukocyte and hypoxia-induced factor 1-alpha-producing macrophages, leading to villus injury. AcPepA, a C5a inhibitory peptide, blocks the deleterious effects of C5a, indicating it has a therapeutic effect on the inflammatory consequences of experimental AMI.
| S-EPMC4819679 | biostudies-other
Project description:BACKGROUND AND PURPOSE Renal ischaemia/reperfusion (RI/R) injury is a major cause of acute kidney injury (AKI) and an important determinant of long-term kidney dysfunction. AMP-kinase and histone deacetylase sirtuin 1 (SIRT1) regulate cellular metabolism and are activated during hypoxia. We investigated whether AMP-kinase activator AICAR (5-amino-4-imidazolecarboxamide riboside-1-?-D-ribofuranoside) ameliorates RI/R injury and whether SIRT1 is involved in the pathogenesis. EXPERIMENTAL APPROACH Eight-week-old Sprague Dawley rats were divided into five groups: (i) sham-operated group; (ii) I/R group (40 min bilateral ischaemia followed by 24 h of reperfusion; (iii) I/R group + AICAR 50 mg·kg(-1) i.v. given 60 min before operation; (iv). I/R group + AICAR 160 mg·kg(-1) i.v; (v) I/R group + AICAR 500 mg·kg(-1) i.v. Serum creatinine and urea levels were measured. Acute tubular necrosis (ATN), monocyte/macrophage infiltration and nitrotyrosine expression were scored. Kidney AMP-activated protein kinase (AMPK) and SIRT1 expressions were measured. KEY RESULTS Highest dose of AICAR decreased serum creatinine and urea levels, attenuated I/R injury-induced nitrosative stress and monocyte/macrophage infiltration, and ameliorated the development of ATN. Kidney I/R injury was associated with decreased AMPK phosphorylation and a fivefold increase in kidney SIRT1 expression. AICAR increased pAMPK/AMPK ratio and prevented the I/R-induced increase in renal SIRT1 expression. CONCLUSIONS AND IMPLICATIONS AICAR protects against the development of ATN after kidney I/R injury. Activators of kidney AMP kinase may thus represent a novel therapeutic approach to patients susceptible to AKI and to those undergoing kidney transplantation. The present study also suggests a role for SIRT1 in the pathogenesis of RI/R injury.
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Project description:BACKGROUND AND PURPOSE:Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin, a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanisms, especially the role of luteolin on the antioxidant enzymes, such as the peroxiredoxin family, remain unknown. EXPERIMENTAL APPROACH:We measured the effects of luteolin on myocardial ischaemia/reperfusion (MI/R) injury in vivo (Sprague-Dawley rats) and in vitro, together with the underlying mechanisms, with a focus on signalling by peroxiredoxins. H9c2 cells were used to assess the changes in peroxiredoxins and the other antioxidant enzymes. Oxidative stress, cardiac function, LDH release, ROS and infarct size were also assayed. KEY RESULTS:Luteolin exerted significant cardioprotective effects in vivo and in vitro via improving cardiac function, increasing the expression of anti-apoptotic protein Bcl-2 and decreasing the pro-apoptotic protein Bax and active caspases 3 and 9, associated with MI/R. Mechanistically, luteolin markedly enhanced expression of peroxiredoxin II, without significant effects on other forms of peroxiredoxin, catalase or SOD1. Molecular docking showed that luteolin could indeed bind to the enzymic active pocket of peroxiredoxin II. Furthermore, down-regulation of peroxiredoxin II by peroxiredoxin II-antisense, administered by adenovirus infection of H9c2 cardiomyocytes, and inhibition of peroxiredoxin II in vivo significantly reversed the cardioprotective effects of luteolin. CONCLUSIONS AND IMPLICATIONS:Our findings, for the first time, demonstrate that luteolin protects against MI/R injury through promoting signalling through the endogenous antioxidant enzyme, peroxiredoxin II, indicating the important beneficial role of this antioxidant system in the heart.
| S-EPMC6057904 | biostudies-literature
Project description:BackgroundIschaemia-reperfusion injury (IRI) is a major obstacle during liver transplantation and resection surgeries for cancer, with a need for effective and safe drugs to reduce IRI. Zinc preconditioning has been shown to protect against liver IRI in a partial (70%) ischaemia model. However, its efficacy against a clinically relevant Pringle manoeuvre that results in global liver ischaemia (100%) is unknown.AimsThe aim of this study was to test the efficacy of zinc preconditioning in a rat model of global liver ischaemia.MethodsRats were preconditioned via subcutaneous injection of 10 mg/kg of ZnCl2, 24 h and 4 h before ischaemia. Total liver ischaemia (100%) was induced by placing a clamp across the portal triad for 30 min. Liver injury was assessed by serum alanine transaminase (ALT) and aspartate transaminase (AST) levels in blood taken before ischaemia (baseline) and at 1, 2, 4, 24, 48, 72, 96 and 120 hours after ischaemia. Animals were culled after 7 days, and the harvested livers were histologically analysed.ResultsOn a two-way repeated-measures analysis of variance, there was a statistically significant (p = 0.025) difference in the mean ALT levels between saline- and ZnCl2-treated groups. Specifically at 24 h after ischaemia, the ALT (341 ± 99 U/L) and AST (606 ± 78 U/L) in the zinc-treated group were significantly less than the ALT (2863 ± 828 U/L) and AST (3591 ± 948 U/L) values in the saline-treated group. Zinc significantly reduced neutrophil infiltration and necrosis compared with the saline control.ConclusionZinc preconditioning reduces the overall hepatocellular damage from IRI. These results lay the foundation to assess the benefit of zinc preconditioning for clinical applications.
| S-EPMC7212296 | biostudies-literature
Project description:BackgroundIschaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury.Methods and resultsTransient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning.ConclusionsThe present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.
| S-EPMC8249780 | biostudies-literature