Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway

Zhang, Bofang; Jiang, Hong; Chen, Jing; Guo, Xin; Li, Yue; Hu, Qi; Yang, Shuo

doi:10.1016/j.intimp.2019.04.060

Cited by 53 publications

(65 citation statements)

References 47 publications

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“…CHOP, a member of the C/EBP family, is a specific transcription factor involved in erS-induced apoptosis. The levels of cHoP are relatively low under normal conditions, but can be markedly increased following prolonged erS (26). The results of the present study are consistent with a previous study (14) and indicate that i/r contributes to sustained erS and severe renal injury, as evidenced the increased levels of caspase-12,cHoP and GrP78, as well as apoptotic rates.…”

Section: Discussionsupporting

confidence: 92%

“…it is well-known that the most effective therapy for acute kidney injury is to successfully restore reperfusion in the ischemic region in an early stage (26,36,37). nevertheless, the accompanied i/r injury largely decreases the benefits of this approach.…”

Section: Discussionmentioning

confidence: 99%

“…These results indicated that noB could reduce cr and Bun levels, as well as renal damage following i/r injury. (25), and noB is reported to be involved in the regulation of erS (26). GrP78 is an er chaperone that plays an essential role in apoptosis during renal i/r injury (27).…”

Section: Nob Pre-treatment Reduces Renal Damage Caused By I/r Injurymentioning

confidence: 99%

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Nobiletin alleviates ischemia/reperfusion injury in the kidney by activating PI3K/AKT pathway

et al. 2020

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recent studies have demonstrated that nobiletin (NOB) displays anti-oxidative and anti-apoptotic efficacies against multiple pathological insults. However, the potential effects of noB on the injury caused by ischemia and reperfusion (i/r) in the kidney remain undetermined. in the present study, i/r injury was elicited by right kidney removal and left renal pedicel clamping for 45 min, followed by reperfusion for 24 h. noB was added at the start of reperfusion. Histological examination, detection of biomarkers in plasma, and measurement of apoptosis induced by endoplasmic reticulum stress (erS) were used to evaluate renal injury. additionally, the Pi3K/aKT inhibitor lY294002 was also used in mechanistic experiments. NOB pre-treatment significantly reduced renal damage caused by i/r injury, as indicated by decreased serum levels of creatine, blood urea nitrogen and tubular injury scores. Furthermore, noB inhibited elevated erS-associated apoptosis, as evidenced by reduced apoptotic rates and erS-related signaling molecules (such as, c/eBP homologous protein, caspase-12 and glucose-regulated protein of 78 kda). noB increased phosphorylation of proteins in the Pi3K/aKT pathway. The inhibition of Pi3K/aKT signaling with pharmacological inhibitors could reverse the beneficial effects of NOB during renal i/r insult. in conclusion, noB pre-treatment may alleviate i/r injury in the kidney by inhibiting reactive oxygen species production and erS-induced apoptosis, partly through the Pi3K/aKT signaling pathway.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Nobiletin alleviates ischemia/reperfusion injury in the kidney by activating PI3K/AKT pathway

et al. 2020

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“…Apoptosis is the main cause of cell death caused by ischemia-reperfusion injury, which induces the activation of the apoptotic pathway (40,41). The PI3K/AKT signaling pathway is a classical cell survival pathway that has been suggested to be involved in the regulation of apoptosis induced by MIRI, mainly via the promotion of cell survival (9,42). The PI3K/AKT signaling pathway is regulated by a variety of factors.…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA GAS5 regulates myocardial ischemia‑reperfusion injury through the PI3K/AKT apoptosis pathway by sponging miR‑532‑5p

Han

Xia

et al. 2020

Int J Mol Med

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Long non-coding RNAs (lncRNAs) have been revealed to have a marked effect in cardiovascular diseases, including during cardiac development, cardiac hypertrophy, myocardial fibrosis and myocardial ischemic injury. The mechanism of myocardial ischemia-reperfusion injury (MIRI) is very complicated. Although studies have confirmed that lncRNAs are involved, the specific mechanism remains largely unknown. The lncRNA growth arrest specific 5 (GAS5) is known as a regulator of a number of diseases, including certain cancer types. The present study aimed to investigate the function of lncRNA GAS5 in MIRI. The present study reported that the expression of lncRNA GAS5 in H9c2 cells treated with anoxia and reoxygenation was significantly upregulated compared with the control group (P<0.05). Similarly, the expression of lncRNA GAS5 in myocardial tissue obtained from rats treated with MIRI was significantly upregulated compared with the untreated controls (P<0.05). Silencing of lncRNA GAS5 was able to attenuate myocardial damage, as cell viability increased and the apoptosis rate decreased. classical apoptotic proteins involved in MIRI, including B-cell lymphoma 2, Bcl-2-associated X protein and cleaved caspase-3, also exhibited the same trend. At the same time, when lncRNA GAS5 was silenced, microRNA (miR)-532-5p, which was originally expressed at the stage of injury, was upregulated. The luciferase reporter assay results indicated that the lncRNA GAS5 functioned as a molecular sponge of miR-532-5p. The gain-and loss-of-function analysis of miR-532-5p indicated that it was involved in the regulation of MIRI; the trend of results following its overexpression was also consistent with the trend observed following the silencing of lncRNA GAS5. Notably, the protective effect of lncRNA GAS5 silencing on cells was attenuated by miR-532-5p inhibition. Phosphatase and tensin homolog was revealed to be a key target gene for the function of lncRNA GAS5, and its regulation was achieved via binding to miR-532-5p. In other words, silencing lncRNA GAS5 ultimately promoted the activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B pathway (AKT) to reduce myocardial damage. Therefore, lncRNA GAS5 was able to regulate MIRI through the PI3K/AKT apoptosis pathway by sponging miR-532-5p.

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“…When the upstream signal stimulation persists, CHOP expression is elevated, followed by an increase of Caspase-12, ultimately leading to the initiation of apoptotic activities. Several studies demonstrate that suppression of CHOP/Caspase-12 signal flow is beneficial for alleviating ER stress-induced cell apoptosis and then improving H/R injury [34][35][36]. Due to the vital roles of CHOP/Caspase-12 cascade in H/R injury and inhibitory effects of the PERK/Nrf2/HO-1 axis on ER stress development, we postulated that the overexpression of the PERK and downstream Nrf2/HO-1 pathway possibly improved H/ R damage through reducing ER stress-related proapoptotic signal factors.…”

Section: Discussionmentioning

confidence: 99%

PERK Overexpression-Mediated Nrf2/HO-1 Pathway Alleviates Hypoxia/Reoxygenation-Induced Injury in Neonatal Murine Cardiomyocytes via Improving Endoplasmic Reticulum Stress

Wang

Lü

Chen

et al. 2020

BioMed Research International

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Reperfusion processes following acute myocardial infarction (AMI) have been reported to induce additional cardiomyocyte death, known as ischemia-reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress is reported to be involved in the development of I/R injury. There is evidence that PERK exerts beneficial roles in alleviating ER stress. Here, we investigated whether upregulation of PERK improved cardiomyocytes injury induced by I/R. Specific siRNAs or adenovirus vectors were incubated with isolated neonatal cardiomyocytes (NCMs) to regulate expression levels of target genes including PERK, Nrf2, and HO-1. Afterwards, hypoxia and subsequent reoxygenation (H/R) administration was performed as the in vitro model of I/R injury. MTT assay showed that H/R intervention decreased the viability of cells, yet PERK overexpression increased the cellular proliferative rate. Moreover, the upregulation of Nrf2 or HO-1 elevated the growth rate of cells, while gene silencing of Nrf2 or HO-1 reduced the viability of NCMs treated with PERK-rAAV9. In addition, we observed that the apoptotic index of cells with H/R stimulation was reduced when NCMs were pretreated with PERK-rAAV9, Nrf2-rAAV9, or HO-1-rAAV9. After cells were incubated with Nrf2-siRNA or HO-1-siRNA, the upregulation of PERK had no roles in affecting the apoptosis rate of NCMs damaged by H/R. Then, our findings indicated that there was a level decrease of GRP78, CRT, CHOP, and Caspase-12 in NCMs of the PERK-rAAV9 group compared to that of the H/R group. Both Nrf2 overexpression and HO-1 upregulation reduced the expression of ER stress-related proapoptotic factors, yet the expression suppression of Nrf2 and HO-1 increased levels of GRP78, CRT, CHOP, and Caspase-12 in NCMs treated with PERK-rAAV9. Taken together, our results suggested that the effects of PERK against H/R injury might be attributed to the upregulation of Nrf2/HO-1 cascade, followed by the inhibition of ER stress-related apoptotic pathway.

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Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway

Cited by 53 publications

References 47 publications

Nobiletin alleviates ischemia/reperfusion injury in the kidney by activating PI3K/AKT pathway

Nobiletin alleviates ischemia/reperfusion injury in the kidney by activating PI3K/AKT pathway

Long non‑coding RNA GAS5 regulates myocardial ischemia‑reperfusion injury through the PI3K/AKT apoptosis pathway by sponging miR‑532‑5p

PERK Overexpression-Mediated Nrf2/HO-1 Pathway Alleviates Hypoxia/Reoxygenation-Induced Injury in Neonatal Murine Cardiomyocytes via Improving Endoplasmic Reticulum Stress

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