α-Lipoic Acid Reduces Infarct Size and Preserves Cardiac Function in Rat Myocardial Ischemia/Reperfusion Injury through Activation of PI3K/Akt/Nrf2 Pathway

Deng, Chao; Sun, Zhongchan; Tong, Guang; Yi, Wei; Ma, Li; Zhao, Bowen; Lü, Cheng; Zhang, Jinzhou; Cao, Feng; Yi, Dan

doi:10.1371/journal.pone.0058371

Cited by 133 publications

(109 citation statements)

References 42 publications

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“…45,46) Activation of MAPKs or Akt is known to be involved in the upstream signaling pathway for the expression of HO-1 in neuronal and other cell types. 47,48) It has been reported that berberine, an alkaloid derived from Coptis chinensis, induces the stimulation of Akt and p38 MAPK, which is linked to HO-1 expression and neuroprotection in SH-SY5Y cells.…”

Section: Discussionmentioning

confidence: 99%

Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1

Kim

Chin

Cho

2017

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 99%

Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1

Kim

Chin

Cho

2017

Biological & Pharmaceutical Bulletin

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“…Under homeostatic conditions, NRF2 levels are also maintained at low levels due to E3 ubiquitin ligase-mediated ubiquitylation and proteasome-dependent degradation of NRF2 (14). Under ischemia-stress conditions, NRF2 degradation was markedly inhibited by high levels of oxidative stress in the liver, heart, kidney and brain (15)(16)(17)(18). Activation of NRF2 induces the expression of heme oxygenase-1 (HO-1), suggesting that NRF2 is essential for the regulation of HO-1.…”

Section: Introductionmentioning

confidence: 99%

ATF3-Mediated NRF2/HO-1 Signaling Regulates TLR4 Innate Immune Responses in Mouse Liver Ischemia/Reperfusion Injury

Rao

Qian

et al. 2015

American Journal of Transplantation

117

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Activating transcription factor 3 (ATF3) is a stressinduced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. However, little is known about the roles and mechanisms of ATF3 in liver ischemia/ reperfusion injury (IRI). In warm and cold liver IRI models, we showed that ATF3 deficiency significantly increased ischemia/reperfusion (IR)-stressed liver injury, as evidenced by increased serum alanine aminotransferase levels, histological liver damage, and hepatocellular apoptosis. These may correlate with inhibition of the intrahepatic nuclear factor erythroid-derived 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway leading to enhancing Toll-like receptor 4/nuclear factor kappa beta (TLR4/NF-kB) activation, pro-inflammatory programs and macrophage/neutrophil trafficking, while simultaneously repressing antiapoptotic molecules in ischemic liver. Interestingly, activation of NRF2/HO-1 signaling using an NRF2 activator, oltipraz (M2), during hepatic IRI-rescued ATF3 anti-inflammatory functions in ATF3-deficient mice. For in vitro studies, ATF3 ablation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMMs) depressed levels of NRF2/HO-1 and PI3K/AKT, resulting in enhanced TLR4/NF-kB activation. Pretreatment of LPS-stimulated BMMs with M2 increased NRF2/HO-1 expression, promoted PI3K/AKT, which in turn suppressed TLR4/NF-kB-mediated proinflammatory mediators. Thus, our results first demonstrate ATF3-mediated NRF2/HO-1 signaling in the regulation of TLR4-driven inflammatory responses in IR-stressed livers. Our findings provide a rationale for a novel therapeutic strategy for managing IR-induced liver injury.Abbreviations: ATF3, activating transcription factor 3; BMMs, bone marrow-derived macrophages; bZIP, basic leucine zipper; HMGB1, high mobility group box 1; HO-1, heme oxygenase-1; HPF, high power field; IR, ischemia/reperfusion; IRI, ischemia/reperfusion injury; LPS, lipopolysaccharide; MPO, myeloperoxidase; NF-kB, nuclear factor kappa beta; NRF2, nuclear factor erythroid-derived 2-related factor 2; OLT, orthotopic liver transplantation; sALT, serum alanine aminotransferase; TLR4, Toll-like receptor 4; TNF-a, tumor necrosis factor-alpha; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling

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“…In previous decades, using several different experimental models of I/R, studies have demonstrated the protective effects of LA against I/R-induced injury, including myocardial injury (7), peripheral nerve injury (8), testicular injury (9) and retinal injury (10). In addition, it has been reported that LA can activate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways to induce protection against I/R injury in other organs (11)(12)(13) to the best of our knowledge, few studies were reported to address whether LA has neuroprotective effects against cerebral I/R-induced injury and its potential mechanisms. In the present study, the neuroprotective effects of LA in rats were investigated with 90 min middle cerebral artery occlusion (MCAO)/24 h reperfusion-induced injury.…”

Section: Introductionmentioning

confidence: 99%

α-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats

Deng

Zuo

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. It is well established that the brain is sensitive to ischemia/reperfusion (I/R)-induced injury. α-lipoic acid (LA), a free radical scavenger and antioxidant, has a neuroprotective effect against cerebral I/R-induced injury, however, the underlying mechanisms remain to be elucidated. Therefore, the present study was undertaken to evaluate whether LA was able to protect against cerebral I/R-induced injury and to examine the potential mechanisms. The neuroprotective effects of LA were investigated in a rat model of transient focal ischemia induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. Adult male Sprague-Dawley rats were randomly assigned into the sham, cerebral I/R injury model and model plus LA groups. Cerebral I/R injury was induced by 90 min MCAO followed by reperfusion for 24 h. Cerebral infarct size was detected by 2,3,5-triphenyltetrazolium chloride staining. Neurological deficit score (NDS), brain water content and oxidative parameters, including malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were measured. The expression of cleaved caspase-3, brain-derived neurotrophic factor (BDNF), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), p-Akt and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) were also analyzed using western blotting. The present study demonstrated that pretreatment with LA significantly decreased the infarction size, brain water content and improved NDS. LA reversed the levels of oxidative parameters, including MDA, NO, T-AOC and SOD to their normal state in rat brains following cerebral I/R. Furthermore, the expression of cleaved caspase-3 markedly decreased and the expression of BDNF, PI3K, p-Akt and p-ERK1/2 significantly increased following administration of LA. On the basis of these findings, it was concluded that LA protected the brain from cerebral I/R damage by attenuation of oxidative stress and caspase-dependent apoptosis. Furthermore, LA exerts its neuroprotective effects potentially through activation of the BDNF-PI3K/Akt-ERK1/2 pathway. IntroductionCerebral ischemic injury is one of the leading causes of human mortality and disability worldwide (1). Restoration of blood flow to the ischemic brain is often used to treat patients in clinical experiments. However, reperfusion itself also has the potential to produce additional injuries in the ischemic brain due to overproduction of reactive oxygen species (ROS). The potential pathological mechanisms of ischemia/reperfusion (I/R) injury include glutamate excitotoxicity, calcium overload, nitric oxide (NO) production, oxidative stress, inflammation and apoptosis, which eventually lead to cell death (2). Oxidative stress and apoptosis following cerebral I/R are the two major processes that induce neuronal injury (3,4). For this reason, multifunctional molecules with anti-oxidative and anti-apoptotic properties are ideal neuroprotective agents.α-lipoic acid (LA), an endogenous short-chain fatty acid, is a cofact...

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α-Lipoic Acid Reduces Infarct Size and Preserves Cardiac Function in Rat Myocardial Ischemia/Reperfusion Injury through Activation of PI3K/Akt/Nrf2 Pathway

Cited by 133 publications

References 42 publications

Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1

Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1

ATF3-Mediated NRF2/HO-1 Signaling Regulates TLR4 Innate Immune Responses in Mouse Liver Ischemia/Reperfusion Injury

α-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats

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