Dataset Information

Osthole protects against Ang II-induced endotheliocyte death by targeting NF-?B pathway and Keap-1/Nrf2 pathway.

ABSTRACT: Osthole, the main active constituents in traditional Chinese medicine fructus cnidii, has anti-inflammatory and anti-oxidant activities. Apoptosis of vascular endothelial cells is an important cause of cardiovascular disease. Inflammation and oxidative stress are two key factors in injury of endotheliocyte. In this study, we investigated the effect of osthole on Ang II-induced apoptosis of rat aortic endothelial cells (RAECs) and explored the underlying mechanisms. In the present study, the protective effects of osthole on RAECs induced by Ang II in vitro were tested. Additionally, molecular docking and molecular dynamics (MD) simulations were utilized to investigate the potential binding mode of osthole to NF-?B and Keap1. Our results showed osthole remarkably attenuates Ang II-induced apoptosis of RAECs via alleviating inflammation and oxidative stress. Molecular docking and MD simulations revealed the potential interaction of osthole bind to the P65 subunit of NF-?B and the Keap1 protein, an adaptor for the degradation of Nrf2. We further found that osthole decreased Ang II-induced inflammation and oxidative stress through respectively modulating NF-?B and Nrf2 pathways in RAECs. These studies provide evidence that osthole may represent a potential therapeutic agent for the treatment of vascular injury.

SUBMITTER: Tao L

PROVIDER: S-EPMC6357313 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Osthole protects against Ang II-induced endotheliocyte death by targeting NF-κB pathway and Keap-1/Nrf2 pathway.

Tao Luyuan L Gu Xingjian X Xu Enguo E Ren Shijia S Zhang Li L Liu Wenhua W Lin Xiaofeng X Yang Jianguang J Chen Changgong C

American journal of translational research 20190115 1

Osthole, the main active constituents in traditional Chinese medicine fructus cnidii, has anti-inflammatory and anti-oxidant activities. Apoptosis of vascular endothelial cells is an important cause of cardiovascular disease. Inflammation and oxidative stress are two key factors in injury of endotheliocyte. In this study, we investigated the effect of osthole on Ang II-induced apoptosis of rat aortic endothelial cells (RAECs) and explored the underlying mechanisms. In the present study, the prot ...[more]

PMID: 30787975

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Project description:Brain damage following cerebral ischemia-reperfusion (I/R) is a complicated pathophysiological course, in which inflammation and oxidative stress have been suggested to serve an important role. Toll-like receptor 4 (TLR4) has been suggested to be involved in secondary inflammatory process in cerebral ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidant host defense, maintains the cellular redox homeostasis. Tissue kallikrein (TK) has been proven to elicit a variety of biological effects in ischemic stroke through its anti-inflammatory and anti-oxidant properties. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study examined the hypothesis that TK attenuates ischemic cerebral injury via the TLR4/nuclear factor-κB (NF-κB) and Nrf2 signaling pathways. Using a transient rat middle cerebral artery occlusion (MCAO) model, the effects of immediate and delayed TK treatment subsequent to reperfusion were investigated. The neurological deficits, infarct size, and the expression of TLR4/NF-κB and Nrf2 pathway in ischemic brain tissues were measured at 24 following MCAO. The results indicated that TK immediate treatment significantly improved neurological deficits and reduced the infarct size, accompanied by the inhibition of TLR4 and NF-κB levels, and the activation of Nrf2 pathway. Furthermore, TK delayed treatment also exerted neuroprotection against I/R injury. However, the neuroprotective effect of TK immediate treatment was better compared with that of TK delayed treatment. In conclusion, the results indicated that TK protected the brain against ischemic injury in rats after MCAO through its anti-oxidative and anti-inflammatory effects. Suppression of TLR4/NF-κB and activation of the Nrf2 pathway contributed to the neuroprotective effects induced by TK in cerebral ischemia. Therefore, TK may provide an effective intervention with a wider therapeutic window for ischemic stroke.

Project description:Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. We found that the structural perturbations had minimal dominant effects on nuclear stiffness, suggesting that the muscle pathology was not accompanied by major structural disruption of the peripheral nuclear lamina. However, subtle alterations in the lamina network and subnuclear reorganization of lamins remain possible. Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. Nrf2 is normally sequestered in the cytoplasm by Keap-1. Under oxidative stress Nrf2 dissociates from Keap-1, translocates into the nucleus, and activates gene expression. Unexpectedly, biochemical analyses revealed high levels of reducing agents, indicative of reductive stress. The accumulation of cytoplasmic lamin aggregates correlated with elevated levels of the autophagy adaptor p62/SQSTM1, which also binds Keap-1, abrogating Nrf2 cytoplasmic sequestration, allowing Nrf2 nuclear translocation and target gene activation. Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis.

Dataset Information

Osthole protects against Ang II-induced endotheliocyte death by targeting NF-?B pathway and Keap-1/Nrf2 pathway.

Publications

Osthole protects against Ang II-induced endotheliocyte death by targeting NF-κB pathway and Keap-1/Nrf2 pathway.

Similar Datasets

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