Irisin Protects Brain against Ischemia/Reperfusion Injury through Suppressing TLR4/MyD88 Pathway

2020 ◽  
Vol 49 (4) ◽  
pp. 346-354
Author(s):  
Qian Yu ◽  
Guangyao Li ◽  
Qian Ding ◽  
Lei Tao ◽  
Jiangjing Li ◽  
...  

Background: Inflammatory response exerts an important role in ischemia/reperfusion (I/R) injury. TLR4 and myeloid differentiation factor 88 (MyD88) are key components in inflammation and are involved in the cerebral I/R injury. Irisin is a skeletal muscle-derived myokine produced after exercise, which was found to suppress inflammation. In this study, we investigated whether irisin could protect the brain from I/R injury through the TLR4/MyD88 pathway. Methods: Male Sprague Dawley rats (20 months, 190 ∼ 240 g) were pretreated with irisin at 10, 50, or 100 mg/kg for consecutive 3 days and then subjected to surgery of middle cerebral artery occlusion or sham operation. Infarct size and neuron loss were measured to evaluate brain damage. The mRNA and protein levels of TLR4 and MyD88 were measured by in situ hybridization and immunohistochemistry, respectively. NF-κB activation was assessed by electrophoretic mobility shift assay. Neurological function was evaluated by neurobehavior score test and passive avoidance test. Results: Irisin could reduce neuronal damage and neurofunctional impairment after I/R injury. This effect was mediated by downregulating the TLR4/MyD88 and inhibiting NF-κB activation. Conclusion: Irisin plays a beneficial effect in I/R injury through regulating the TLR4/MyD88 pathway.

2006 ◽  
Vol 291 (3) ◽  
pp. F619-F628 ◽  
Author(s):  
Zhengrong Guan ◽  
Glenda Gobé ◽  
Desley Willgoss ◽  
Zoltán H. Endre

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase (eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide (NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral (U) or bilateral (B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor (EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance (RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 μM furosemide. Autoregulation was enhanced by Nω-nitro-l-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.


2002 ◽  
Vol 283 (3) ◽  
pp. H1005-H1011 ◽  
Author(s):  
Katsuyoshi Shimizu ◽  
Zsombor Lacza ◽  
Nishadi Rajapakse ◽  
Takashi Horiguchi ◽  
James Snipes ◽  
...  

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% ( n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% ( n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels ( n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.


2021 ◽  
Vol 12 ◽  
Author(s):  
Li Yu ◽  
Yangyang Zhang ◽  
Xixi Zhao ◽  
Haitong Wan ◽  
Yu He ◽  
...  

Guhong injection (GHI) is a drug for ischemic stroke created by combining safflower, a traditional Chinese medicine, and aceglutamide, a Western medicine. In this study, we investigated the curative effect of GHI on cerebral ischemia–reperfusion (I/R) injury via the PKC/HIF-1α pathway in rats. Adult male Sprague Dawley rats were randomly divided into seven groups: sham-operated, middle cerebral artery occlusion (MCAO), GHI, nimodipine injection (NMDP), MCAO + LY317615 (PKC inhibitor), GHI + LY317615, and NMDP + LY317615. After establishing an MCAO rat model, we performed neurological deficit testing, 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assay, Western blotting, and q-PCR to detect the brain damage in rats. Compared with the MCAO group, the GHI and GHI + LY317615 group showed neurological damage amelioration as well as decreases in serum hypoxia-inducible factor-1α (HIF-1α), protein kinase C (PKC), and erythropoietin levels; brain HIF-1α and inducible nitric oxide synthase protein expression; and brain HIF-1α and NOX-4 mRNA expression. These effects were similar to those in the positive control groups NMDP and NMDP + LY317615. Thus, our results confirmed GHI can ameliorate cerebral I/R injury in MCAO rats possibly via the PKC/HIF-1α pathway.


2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Shi Shu ◽  
Chun-Ming Li ◽  
Yan-Li You ◽  
Xiao-Lu Qian ◽  
Shuang Zhou ◽  
...  

Background. The therapeutic mechanisms of cerebral ischemia treatment by acupuncture are yet not well addressed.Objective. We investigated the effects of electroacupuncture (EA) at GV26 observing the expression of autophagy-related proteins Beclin-1 and LC3B and proportion of apoptotic cells and Bcl-2 positive cells in MCAO/R model rats.Methods. Sprague-Dawley (SD) male rats were randomly assigned to 7 groups: model groups (M6h, M24h, and M72h), EA treatment groups (T6h, T24h, and T72h), and sham operation group (S). Neurological deficit and cerebral infarction volume were measured to assess the improvement effect, while the expression of Beclin-1 and LC3B and proportion of Tunel-positive and Bcl-2 positive cells were examined to explore EA effect on autophagy and apoptosis.Results. EA significantly decreased neurological deficit scores and the volume of cerebral infarction. Beclin-1 was significantly decreased in T24h, while LC3B-II/LC3B-I ratio markedly reduced in 6th hour. EA groups markedly reduced the number of Tunel positive cells, especially in T24h. Meanwhile, the number of Bcl-2 positive cells obviously increased after EA treatment, especially in T6h and T24h.Conclusions. The alleviation of inadequate autophagy and apoptosis may be a key mechanism involved in the reflex regulation of EA at GV26 to treat cerebral ischemia.


2021 ◽  
Vol 20 (11) ◽  
pp. 2273-2278
Author(s):  
Ting Wen ◽  
Ia Liu ◽  
Shibiao Chen ◽  
Benchao Hou ◽  
Gan Li ◽  
...  

Purpose: To study the effect of dexmedetomidine (Dex) on myocardial ischemia-reperfusion injury (MIRI), and the associated mechanism of action.Methods: Sixty Sprague-Dawley (SD) rats were assigned to sham, ischemia-reperfusion (I/R), Dex, and MD groups (methyllycaconitine prior to injection with Dex), with 15 rats in each group. Pathological changes in myocardial tissues were determined in all groups. Protein expression levels of HMGB1, TLR4, NF-κB and myeloid differentiation protein 88 (MyD88) in serum and myocardial tissues were assayed and compared.Results: Protein levels of HMGB1, TLR4, MyD88 and NF-κB were significantly higher in heart muscle I/R rats than those in sham group, but lower in heart muscle of rats in Dex group than in heart muscle of I/R rats (p < 0.05). However, they were significantly up-regulated in MD group, relative to Dex group (p< 0.05).Conclusion: Dex exerts a protective effect against ischemia/reperfusion-induced myocardial damage via HMGB1-TLR4-NF-κB signal axis via CAP, and thus, is a potential agent for the management of myocardial disease.


2021 ◽  
Author(s):  
Lin Zhu ◽  
Xiao Yang ◽  
Zhiwen Yao ◽  
Ziyi Wang ◽  
Yupei Lai ◽  
...  

Abstract BackgroundRecently, an increasing number of studies have reported the roles of competitive endogenous RNA (ceRNA) networks in ischemia/reperfusion (I/R) injury, which include the liver, kidney, heart, brain, and intestine. However, the functions and mechanisms of long non-coding RNAs (lncRNAs), which serve as ceRNA networks in intestinal I/R injury, are still unclear. MethodsIn this study, bioinformatics methods were used to filter and construct the lncRNA-miRNA-mRNA networks in intestinal I/R injury. RNA expression data were retrieved from NCBI GEO datasets, the expression profiles between mouse small intestine with superior mesenteric artery occlusion and Sham operation was analyzed, and 189 microRNA differential expressed genes(miDEGs) were discovered successfully from miRNA GEO dataset (GSE83701). Next, targeted lncRNAs and mRNA in the database were matched based on miDEGs. Then, lncRNA-miRNA-mRNA networks were constructed with Cytoscape. The hub lncRNA-miRNA-mRNA networks were selected via Cytoscape plug-in CytoHubba and intersected mRNAs of datasets GSE96733 and GSE83701. Finally, the vital nodes of the ceRNA networks were validated by qPCR. ResultsThe 1700020114Rik/mmu-miR-7a-5p/Klf4 axis was postulated to play a potential role in intestinal I/R injury.ConclusionThe results shed novel insight into the molecular mechanism of ceRNA networks in intestinal I/R injury and highlighted the potential of 170002700020114Rik/mmu-miR-7a-5p/Klf4 ceRNA network in the prevention and treatment of intestinal I/R injury.


2013 ◽  
Vol 4 (3) ◽  
pp. 174
Author(s):  
Hulya Ozturk ◽  
Hayrettin Ozturk ◽  
Kaan Gideroglu ◽  
Hakan Terzi ◽  
Guler Bugdayci

Introduction: In this study, we investigate the effect of montelukaston histologic damage induced by testicular torsion-detorsion in rats.Methods: Twenty-one male Sprague-Dawley rats were separatedinto 3 groups, each containing 7 rats. A sham operation was performedin group 1 (control). In group 2 (ischemia-reperfusion [IR]/untreated), 1-hour detorsion of the testis was performed after6 hours of unilateral testicular torsion. In group 3 (I-R/dextroamphetamine),after performing the same surgical procedures as ingroup 2, montelukast was given intraperitoneally. In all experimentalrats, ipsilateral orchiectomies were performed for histologicalexamination and tissue malondialdehyde (MDA), glutathioneand myeloperoxidase assays.Results: Montelukast treatment significantly decreased the I-Rinducedelevation in testes tissue MDA and glutathione levelswere found to be preserved. The level of myeloperoxidase (MPO)activity was significantly increased in the testes tissue of the IR/untreated group. However, in I-R/montelukast treatment groupsignificantly decreased testes tissue MPO level. Histopathologically,the in the group 2 rats, edema, congestion, hemorrhage betweenseminiferous tubules and necrosis of the germinal cells were predominantfeatures in sections. However, most of the specimensin the montelukast treated group 3 showed grades-I and II injury.Additionally, the testicular injury score was lower in group 3 ratscompared with group 2.Conclusion: The current findings demonstrate that the montelukastdecreased the severity of testicular injury by reversing the oxidativeeffects of testes I-R.Introduction : Dans cette étude, nous examinons l’effet du montélukastsur les lésions tissulaires provoquées par torsion-détorsiontesticulaire chez le rat.Méthodologie : Vingt-et-un rats Sprague-Dawley mâles ont étérépartis en trois groupes de 7 rats. Une opération fictive a étéréalisée dans le groupe 1 (groupe témoin). Dans le groupe 2(ischémie-reperfusion / non traité), une détorsion testiculaire d’uneheure a été réalisée après 6 heures de torsion testiculaire unilatérale.Dans le groupe 3 (ischémie-reperfusion / dextroamphétamine),on a administré du montélukast par voie intrapéritonéaleaprès les mêmes interventions chirurgicales que pour le groupe 2.Chez tous les rats, une orchidectomie homolatérale a été effectuéeen vue d’un examen histologique et de mesures du malonaldéhyde,du glutathion et de la myéloperoxidase dans les tissus.Résultats : Le traitement par montélukast a significativement réduitl’élévation dans les tissus testiculaires provoquée par l’ischémiereperfusion,mais les taux de malonaldéhyde et de glutathion sontdemeurés les mêmes. Le niveau d’activité de la myéloperoxidase(MPO) a significativement augmenté dans les tissus testiculairesdu groupe ayant subi l’ischémie-reperfusion sans traitement subséquent.Cependant, dans le groupe ayant subi l’ischémiereperfusionavec traitement par montélukast, le taux de MPO dansles tissus testiculaires avait significativement diminué. Selon les examensd’histopathologie, dans le groupe 2, de l’oedème, de la congestion,des hémorragies entre les tubules séminifères et une nécrosedes cellules germinales étaient les caractéristiques prédominantesobservées dans les coupes. Par comparaison, la plupart des échantillonsdu groupe 3 (traité par montélukast) présentaient des lésionsde stade I et II. En outre, le score de lésions testiculaires était plusfaible dans le groupe 3 que dans le groupe 2.Conclusion : Les observations actuelles montrent que l’administrationde montélukast diminue la gravité des lésions testiculaires enannulant les effets oxydatifs de l’ischémie-reperfusion des testicules.


2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Feng Yu ◽  
Wei Xue ◽  
Liuyi Dong ◽  
Xiangyang Hu ◽  
Dake Huang ◽  
...  

Tetrahydroxystilbene glucoside (TSG) is the active ingredient extracted from the traditional Chinese medicine Fallopia multiflora, which has extensive pharmacological activities. The current study aimed to observe the neuroprotective mechanism of TSG in the ischemia/reperfusion (I/R) brain injury-induced apoptosis and autophagy from the point of view of oxidative stress (OS). The middle cerebral artery occlusion (MCAO) model was prepared through the suture-occluded method, and TSG was administered through tail vein injection at the time of reperfusion at the doses of 3.0, 6.0, and 12.0 mg/kg. Compared with sham group, the neurological score in I/R mice was increased (P<0.05), along with remarkably elevated cerebral infarct volume (P<0.05); while TSG administration could reduce the neurological score and cerebral infarct volume (P<0.05) and improve the neuronal damage in ischemic cortex and hippocampus (P<0.05). The expression of NOX4, activated caspase-3(9), and Beclin 1 (P<0.05), as well as the LC3BII/I ratio, had been markedly elevated (P<0.05), while TSG administration could effectively suppress the expression of the above-mentioned proteins (P<0.05). In conclusion, TSG shows obvious protection against brain injury in I/R mice, and its mechanism may be related to suppressing the NADPH-induced OS and reducing neuronal apoptosis as well as autophagy.


2020 ◽  
Vol 98 (5) ◽  
pp. 259-266 ◽  
Author(s):  
Shi-Jing Wang ◽  
Heng Chen ◽  
Li-Jing Tang ◽  
Hua Tu ◽  
Bin Liu ◽  
...  

Mitochondrial dysfunctions are responsible for myocardial injury upon ischemia/reperfusion (I/R), and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays an important role in maintaining mitochondrial functions. This study aims to explore the function of Mul1 in myocardial I/R injury and the underlying mechanisms. The Sprague–Dawley rat hearts were subjected to 1 h of ischemia plus 3 h of reperfusion, which showed the I/R injury (increase in infarct size and creatine kinase release) and the elevated total and mitochondrial protein levels of Mul1 and p53 accompanied by the enhanced interactions between Mul1 and p53 as well as p53 and small a ubiquitin-like modifier (SUMO1). Consistently, hypoxia/reoxygenation (H/R) treated cardiac (H9c2) cells displayed cellular injury (apoptosis and necrosis), upregulation of total and mitochondrial protein levels of Mul1 and p53, and enhanced interactions between p53 and SUMO1 concomitant with mitochondrial dysfunctions (an increase in mitochondrial membrane potential and reactive oxygen species production with a decrease in ATP production); these phenomena were attenuated by knockdown of Mul1 expression. Based on these observations, we conclude that a novel role of Mul1 has been identified in the myocardial mitochondria, where Mul1 stabilizes and activates p53 through its function of SUMOylation following I/R, leading to p53-mediated mitochondrial dysfunction and cell death.


2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaoliang Gan ◽  
Guangjie Su ◽  
Weicheng Zhao ◽  
Pinjie Huang ◽  
Gangjian Luo ◽  
...  

The study aimed to investigate whether sevoflurane preconditioning can protect against small intestinal ischemia reperfusion (IIR) injury and to explore whether mast cell (MC) is involved in the protections provided by sevoflurane preconditioning. Sprague-Dawley rats exposed to sevoflurane or treated with MC stabilizer cromolyn sodium (CS) were subjected to 75-minute superior mesenteric artery occlusion followed by 2-hour reperfusion in the presence or absence of MC degranulator compound 48/80 (CP). Small intestinal ischemia reperfusion resulted in severe intestinal injury as demonstrated by significant elevations in intestinal injury scores and p47phoxand gp91phox, ICAM-1 protein expressions and malondialdehyde and IL-6 contents, and MPO activities as well as significant reductions in SOD activities, accompanied with concomitant increases in mast cell degranulation evidenced by significant increases in MC counts, tryptase expression, andβ-hexosaminidase concentrations, and those alterations were further upregulated in the presence of CP. Sevoflurane preconditioning dramatically attenuated the previous IIR-induced alterations except MC counts, tryptase, andβ-hexosaminidase which were significantly reduced by CS treatment. Furthermore, CP exacerbated IIR injury was abrogated by CS but not by sevoflurane preconditioning. The data collectively indicate that sevoflurane preconditioning confers protections against IIR injury, and MC is not involved in the protective process.


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