Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury.
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ABSTRACT:
SUBMITTER: Liu D
PROVIDER: S-EPMC6345330 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury.
Liu Dong D Xu Liqun L Zhang Xiaoyan X Shi Changhong C Qiao Shubin S Ma Zhiqiang Z Yuan Jiansong J
Aging and disease 20190201 1
Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association be ...[more]
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| S-EPMC9949953 | biostudies-literature
Project description:Liver ischemia-reperfusion injury (IRI) is a pathophysiological insult that often occurs during liver surgery. Blackberry leaves are known for their anti-inflammatory and antioxidant activities.AimsTo achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms.MethodsIRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed.Key findingsPre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors.SignificanceBBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.
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| S-EPMC6381635 | biostudies-literature
Project description:BackgroundLiver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development.MethodData from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes.ResultsA total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network.ConclusionsIn summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.
| S-EPMC9578272 | biostudies-literature
Project description:Eugenol, as an active compound isolated from Acorus gramineus, has been shown to protect against cerebral ischemia-reperfusion (I/R) injury. Nonetheless, the detailed neuroprotective mechanisms of eugenol in cerebral I/R injury have not been elaborated. In the present study, cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO) in rats. HT22 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic cerebral I/R injury in vitro. The results showed that eugenol pre-treatment relieved cerebral I/R injury as evidenced by improving neurological deficits and reducing infarct volume. Autophagy was induced by MCAO, which was further promoted by eugenol administration. Moreover, rapamycin, an activator of autophagy, promoted eugenol-induced decreases in neurological score, infarct volume, brain water content, and apoptosis. However, pretreatment with 3-MA, an inhibitor of autophagy, led to the opposite results. Similarly, eugenol pretreatment increased the viability and restrained apoptosis of OGD/R-challenged HT22 cells. OGD/R-induced autophagy was strengthened by eugenol. Mechanically, eugenol promoted autophagy through regulating AMPK/mTOR/P70S6K signaling pathway in vivo and in vitro. In conclusion, pretreatment with eugenol attenuated cerebral I/R injury by inducing autophagy via AMPK/mTOR/P70S6K signaling pathway.
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Project description:BackgroundOxidative stress is the primary cause of ischemia-reperfusion injury (IRI) in kidney transplantation, leading to delayed graft function (DGF) and implications on patient health. Necroptosis is believed to play a role in renal IRI. This research presents a comprehensive analysis of necroptosis-related genes and their functional implications in the context of IRI in renal transplantation.MethodsThe necroptosis-related differentially expressed genes (NR-DEGs) were identified using gene expression data from pre- and post-reperfusion renal biopsies, and consensus clustering analysis was performed to distinguish necroptosis-related clusters. A predictive model for DGF was developed based on the NR-DEGs and patients were divided into high- and low-risk groups. We investigated the differences in functional enrichment and immune infiltration between different clusters and risk groups and further validated them in single-cell RNA-sequencing (scRNA-seq) data. Finally, we verified the expression changes of NR-DEGs in an IRI mouse model.ResultsFive NR-DEGs were identified and were involved in various biological processes. The renal samples were further stratified into two necroptosis-related clusters (C1 and C2) showing different occurrences of DGF. The predictive model had a reliable performance in identifying patients at higher risk of DGF with the area under the curve as 0.798. Additionally, immune infiltration analysis indicated more abundant proinflammatory cells in the high-risk group, which was also found in C2 cluster with more DGF patients. Validation of NR-DEG in scRNA-seq data further supported their involvement in immune cells. Lastly, the mouse model validated the up-regulation of NR-DEGs after IR and indicated the correlations with kidney function markers.ConclusionsOur research provides valuable insights into the identification and functional characterization of NR-DEGs in the context of renal transplantation and sheds light on their involvement in immune responses and the progression of IRI and DGF.
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Project description:Hepatic ischemia-reperfusion (I/R) injury is a serious complication in patients who have undergone hepatic surgery such as orthotopic liver transplantation and partial hepatectomy. Recently, a new cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), was reported to protect against hepatic I/R injury. However, the protective mechanism of UDCA-LPE is not fully understood. Therefore, we conducted this study to explore its underlying mechanism. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the liver lipid metabolism changes in mice during I/R. KEGG enrichment indicated that UDCA-LPE is likely to exert its protective role by regulating fatty acid (FA) metabolism. Further analysis found that UDCA-LPE significantly increased the ratio of oleic acid (OA) to palmitic acid (PA). We found that mice pretreated with OA improved tolerance to hepatic I/R injury. In addition, the phosphorylation level of AKT was markedly upregulated during oxidative stress to promote p65 nuclear translocation, triggering an inflammatory response that exacerbated cell damage and OA treatment significantly inhibited this process. Notably, OA was found to inhibit H2O2-induced oxidative stress, inflammation, and cell death in HepG2 cells. Furthermore, we found that OA supplementation to the medium did not result in a significant increase in intracellular OA, but marked increase in the ratio of OA to PA, which may be an important mechanism for the inflammatory response induced by oxidative stress during I/R. Finally, we demonstrated that OA increased the level of autophagy in HepG2 cells, which may be one of the protective mechanisms against oxidative stress. Collectively, this study revealed that FA metabolism functionally determines the oxidative stress-related inflammation caused by hepatic I/R. We hypothesize that OA treatment may be a promising strategy for preventing and treating I/R-induced liver damage.
| S-EPMC6930725 | biostudies-literature