Modulation of oxidative–nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia–reperfusion: the role of mammalian target of rapamycin

Kocak, Zumrut; Temiz-Resitoglu, Meryem; Guden, Demet Sinem; Vezir, Özden; Sucu, Nehir; Balcı, Şenay; Tamer-Gumus, Lulufer; Tunçtan, Bahar; Malik, Kafait U.; Şahan-Fırat, Seyhan

doi:10.1139/cjpp-2019-0394

Cited by 6 publications

(11 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, the evidence that mTOR inhibitor rapamycin prevents the harmful effects of HL I/R in rats in both target and remote organs supports mTOR's critical role. This observation is consistent with the results of our previous studies and other researchers' findings that report the increment in the activity of mTOR signaling in in vitro and in vivo HL I/R injuries 19,23,32 . However, the role of mTOR activation in HL I/R remains controversial.…”

Section: Discussionsupporting

confidence: 94%

“…Previously, we examined whether mTOR has a protective or deleterious role during HL I/R injury and provided the first evidence that mTOR contributes to inflammatory response and oxidative/nitrosative stress in both target and remote organs injuries in the murine model 23 . In the current study, we examined further looked out the molecular mechanism involved in the contribution of mTOR in HL I/R-induced organ injuries related to MEK1/ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we showed for the first time that mTOR activates inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65, triggering oxidative/nitrosative stress and inflammation resulting in muscle and kidney injury in a murine model of HL I/R 23 . In parallel with this, demonstration of mitogen-activated protein kinase kinase (MEK)1/extracellular signal-regulated kinase (ERK) 1/2 activation also participates in oxidative/nitrosative stress and inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

UYSAL

REŞİTOĞLU

Guden

et al. 2022

Cukurova Medical Journal

Self Cite

View full text Add to dashboard Cite

We have previously demonstrated that activation of the mammalian target of rapamycin (mTOR)/inhibitory-κB-α/nuclear factor-κB p65 signaling pathway mediates organ injuries through increased oxidative/nitrosative stress and inflammatory response in rat models of hind limb ischemia/reperfusion (HL I/R). Following up our previous findings regarding I/R injury through mammalian target of rapamycin (mTOR), we aimed to focus on the possible interaction between mammalian target of rapamycin (mTOR and mitogenactivated protein kinase kinase (MEK)1/extracellular signal-regulated kinase (ERK) 1/2 pathway in hind limb ischemia/reperfusion (HL I/R) resulting in target and remote organ injuries in the present study. Materials and Methods: Male Wistar rats were divided into four groups. HL I/R was induced by occluding with tourniquets of both hind limbs. Following 4 h, the tourniquets were removed following reperfusion for 4 h. After 4 h of reperfusion blood, kidney, and gastrocnemius muscle were collected. Results: HL I/R caused an increase in phosphorylation and/or expression of rpS6, MEK1, ERK1/2, tumor necrosis factor-α, inducible nitric oxide synthase, gp91 phox , p22 phox , and nitrotyrosine as well as nitrite levels in Amaç: Arka bacak iskemisi/reperfüzyonun (İ/R) sıçan modellerinde, rapamisinin memelilerdeki hedefi (mTOR)/inhibitör-κB-α/nükleer faktör-κB p65 sinyal ileti yolu etkinliğinin, artan oksidatif/nitrozatif stres ve inflamatuvar yanıt yoluyla organ zedelenmelerine aracılık ettiğini daha önce göstermiştik. mTOR'un İ/R zedelenmesine katkıda bulunduğuna ilişkin önceki bulgularımızı referans alarak, bu çalışmada arka bacak İ/R'ye bağlı hedef ve uzak organ zedelenmelerinde mTOR ile MEK1/ERK1/2 yolu arasındaki olası etkileşime odaklanmayı amaçladık. Gereç ve Yöntem: Erkek Wistar sıçanlar dört gruba ayrıldı. Arka bacak İ/R, her iki arka ekstremitelerine turnikeler uygulanarak iskemi oluşturuldu. İskemiden 4 saat sonra turnikeler açılarak 4 saat reperfüzyon uygulandı. 4 saatlik reperfüzyondan sonra kan, böbrek ve gastroknemius kası izole edildi. Bulgular: Arka bacak İ/R uygulaması gastroknemius kasında, böbrekte ve/veya serumda rpS6, MEK1, ERK1/2, tümör nekroz faktörü-α, indüklenebilir nitrik oksit sentaz, gp91phox, p22phox ve nitrotirozinin fosforilasyonu ve/veya ekspresyonu ile birlikte nitrit düzeylerinde artışa neden oldu. Ayrıca, İ/R uygulanan sıçanların dokularında nikotinamit adenin dinükleotit Akıncı-Uysal et al.Cukurova Medical Journal 220 gastrocnemius muscle, kidney, and/or serum. Additionally, nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase levels were increased in the tissues of rats subjected to HL I/R. Rapamycin, the selective inhibitor of mTOR, abolished all the effects mentioned above caused by HL I/R in the rat's muscle and kidney. Conclusion: These data suggest that activation of the MEK1/ERK1/2 pathway contributes to mTORmediated HL I/R-induced target and remote organ injury. fosfat oksidaz ve miyeloperoksidaz seviyeleri arttı. mTOR'un seçici inhibitörü olan rapamisin, sıçanl...

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

UYSAL

REŞİTOĞLU

Guden

et al. 2022

Cukurova Medical Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was shown that mTOR inhibition is associated with the up-regulation of autophagy and protective effects in experimental ischemia and reperfusion [7]. Rapamycin, an immunosuppressive agent and mTOR inhibitor, exerts cytoprotective effects in both cell and animal models of ischemia [18,19]. The available data suggest that rapamycin activates protective autophagy and inhibits ER stress in ischemic neurons, hepatocytes and nephrons [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Endothelial protective effect of rapamycin against simulated ischemia injury through up-regulation of autophagy and inhibition of endoplasmic reticulum stress

Gabryel¹

2020

Arch Med Sci Civil Dis

View full text Add to dashboard Cite

Introduction: Rapamycin has been shown to have cytoprotective properties in some experimental models of ischemia. However, the precise molecular mechanisms underlying the positive effect of rapamycin on endothelial cells in ischemic injury remain unknown. It is very important because endothelial cells are firstly exposed to ischemia and play an important role in ischemic organ damage. Autophagy and endoplasmic reticulum stress are suggested to be implicated in hypoxic/ischemic injury of endothelial cells. This study aims to explore whether the endothelial protective effect of rapamycin is associated with exacerbation of autophagy and attenuation of endoplasmic reticulum stress. Material and methods: The protective effects of rapamycin against oxygen and glucose deprivation (OGD)-induced cell injury were explored in human vascular endothelial cells (HUVECs). Cell viability was measured by MTT assay. The protein levels of Beclin 1, p62, p-mTOR, p-S6K, p-4EBP, GRP78, p-PERK and p-IRE1 were analyzed using immunoblotting. Results: Rapamycin in the simulated ischemia model increased the cell viability, indicating its cytoprotective effect (p < 0.05). Experiments with 3-methyladenine as an inhibitor of autophagy and thapsigargin as an inducer of endoplasmic reticulum stress support that rapamycin exerts endothelial protective effects against OGD-induced damage via autophagy-endoplasmic reticulum stress pathway. Conclusions: This study demonstrated that rapamycin protects ischemic HUVECs via down-regulation of the mTOR pathway, enhancement of autophagy and inhibition of endoplasmic reticulum stress.

show abstract

“…In addition, mTOR activation can significantly upregulate the expression of the proapoptotic proteins Bax and Bad, which can trigger apoptosis. Furthermore, rapamycin, an inhibitor of mTOR, can protect cells against oxidative stress-induced damage by inhibiting apoptosis [ 57 , 58 ]. Park et al proved that an abnormal increase in mTOR could evoke severe oxidative stress, neuroinflammation, and neuronal death in the hippocampus in an animal model of transient ischemia (TI) established in gerbils with high-fat diet- (HFD-) induced obesity [ 59 ].…”

Section: Signaling Pathways Of Oxidative Stressmentioning

confidence: 99%

Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms

Chen

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Ginsenosides are a class of active components extracted from ginseng plants (such as Panax ginseng, Panax quinquefolium, and Panax notoginseng). Ginsenosides have significant protective effects on the nervous system, cardiovascular system, and immune system, so they have been widely used in the treatment of related diseases. Entry of a variety of endogenous or exogenous harmful substances into the body can lead to an imbalance between the antioxidant defense system and reactive oxygen species, thus producing toxic effects on a variety of tissues and cells. In addition, oxidative stress can alter multiple signaling pathways, including the Keap1/Nrf2/ARE, PI3K/AKT, Wnt/β-catenin, and NF-κB pathways. With the deepening of research in this field, various ginsenoside monomers have been reported to exert antioxidant effects through multiple signaling pathways and thus have good application prospects. This article summarized the research advancements regarding the antioxidative effects and related mechanisms of ginsenosides, providing a theoretical basis for experimental research on and clinical treatment with ginsenosides.

show abstract

Modulation of oxidative–nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia–reperfusion: the role of mammalian target of rapamycin

Cited by 6 publications

References 48 publications

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

Endothelial protective effect of rapamycin against simulated ischemia injury through up-regulation of autophagy and inhibition of endoplasmic reticulum stress

Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms

Contact Info

Product

Resources

About