Carnosol as a Nrf2 Activator Improves Endothelial Barrier Function Through Antioxidative Mechanisms

Xi, Li; Zhang, Qiao; Hou, Ning; Li, Jing; Liu, Min; Peng, Sha; Zhang, Yuxin; Luo, Yin-Zhen; Zhao, Bowen; Wang, Shifeng; Zhang, Yanling; Qiao, Yanjiang

doi:10.3390/ijms20040880

Cited by 31 publications

(17 citation statements)

References 42 publications

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“…Moreover, apoptosis of endothelial cells is an important factor of vascular injury, which is directly related to the degree of endothelial damage [59]. In the present study, we observed that oxLDL/β2GPI/anti-β2GPI complex increased the number of apoptotic cells and enhanced the expressions of proapoptotic proteins.…”

Section: Discussionsupporting

confidence: 61%

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Endothelial cell dysfunction plays a fundamental role in the pathogenesis of atherosclerosis (AS), and endothelial autophagy has protective effects on the development of AS. Our previous study had shown that oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex could promote the expressions of inflammatory cytokines and enhance the adhesion of leukocytes to endothelial cells. In the present study, we aimed to assess the effects of oxLDL/β2GPI/anti-β2GPI complex on endothelial autophagy and explore the associated potential mechanisms. Human umbilical vein endothelial cells (HUVECs) and mouse brain endothelial cell line (bEnd.3) were used as models of the vascular endothelial cells. Autophagy was evaluated by examining the expressions of autophagic proteins using western blotting analysis, autophagosome accumulation using transmission electron microscopy, and RFP-GFP-LC3 adenoviral transfection and autophagic flux using lysosome inhibitor chloroquine. The expressions of phospho-PI3K, phospho-AKT, phospho-mTOR, and phospho-eNOS were determined by western blotting analysis. 3-Methyladenine (3-MA) and rapamycin were used to determine the role of autophagy in oxLDL/β2GPI/anti-β2GPI complex-induced endothelial cell dysfunction. We showed that oxLDL/β2GPI/anti-β2GPI complex suppressed the autophagy, evidenced by an increase in p62 protein, a decrease in LC3-II and Beclin1, and a reduction of autophagosome generation in endothelial cells. Moreover, inhibition of autophagy was associated with PI3K/AKT/mTOR and eNOS signaling pathways. Rapamycin attenuated oxLDL/β2GPI/anti-β2GPI complex-induced endothelial inflammation, oxidative stress, and apoptosis, whereas 3-MA alone induced the endothelial injury. Our results suggested that oxLDL/β2GPI/anti-β2GPI complex inhibited endothelial autophagy via PI3K/AKT/mTOR and eNOS signaling pathways and further contributed to endothelial cell dysfunction. Collectively, our findings provided a novel mechanism for vascular endothelial injury in AS patients with an antiphospholipid syndrome (APS) background.

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Section: Discussionsupporting

confidence: 61%

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…CS is a polyphenolic compound with strong oxidative activity. 10,11 It had been reported that CS could promote the expression of Nrf2, 46,47 which would inhibit the activation of Smad pathway 48,49 and promote the mitochondrial respiration of cells. 50,51 Therefore, by acting as an antioxidant agent, CS might inhibit Smad3 pathway and promote mitochondrial respiration and thus ameliorate the increase in protein degradation as well as the decrease in protein synthesis in C2C12 myotubes treated with miR-183-5p.…”

Section: Discussionmentioning

confidence: 99%

Carnosol attenuated atrophy of C2C12 myotubes induced by tumour‐derived exosomal miR‐183‐5p through inhibiting Smad3 pathway activation and keeping mitochondrial respiration

Kuang

Shen

Zhang

et al. 2022

Basic Clin Pharma Tox

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Cancer-derived exosomes are involved in the development of cancer cachexia.Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 μM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.

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“…HEK293-antioxidant response element (ARE) cell line previously established by our research group [ 29 ] was incubated with 275 traditional Chinese medicine (TCM) ingredients (10 μ M). Flex station 3 (Molecular Devices, San Francisco, CA, USA) was applied to detect the luciferase activity and discover the potential active ingredients.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Therapeutic Candidates for Diabetic Retinopathy Based on Molecular Switch Analysis: Application of a Systematic Process

Ren

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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The pathogenesis of diabetic retinopathy (DR) is complicated, and there is no effective drug. Oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury is one of the pathogenic factors for DR. Molecular switches are considered high-risk targets in disease progression. Identification of molecular switch is crucial to interpret the pathogenesis of disease and screen effective ingredients. In this study, a systematic process was executed to discover therapeutic candidates for DR based on HRMECs injury. First of all, the molecular mechanism of HRMECs oxidative stress injury was revealed by transcriptomics and network pharmacology. We found that oxidative stress was one of the pivotal pathogenic factors, which interfered with vascular system development, inflammation, cell adhesion, and cytoskeleton damaged HRMECs through crosstalk. Then, network topology analysis was used to recognize molecular switches. The results indicated that the Keap1-Nrf2-ARE signaling pathway was the molecular switch in HRMECs oxidative stress injury. On this basis, the HEK293-ARE overexpression cell line was applied to obtain 18 active traditional Chinese medicine (TCM) ingredients. Furthermore, andrographolide, one of the 18 candidates, was applied in the HRMECs oxidative stress model to evaluate the accuracy of the systematic process. The efficacy evaluation results showed that andrographolide could regulate oxidative stress, vascular system development, inflammation, adhesion, and skeleton tissue to inhibit HRMECs injury cooperatively. And its mechanism was related to the Nrf2 signaling pathway. Overall, our data suggest that the Nrf2 signaling pathway is the molecular switch in the HRMECs oxidative stress injury. 18 potential Nrf2 agonists are likely to be promising DR candidates.

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Carnosol as a Nrf2 Activator Improves Endothelial Barrier Function Through Antioxidative Mechanisms

Cited by 31 publications

References 42 publications

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Carnosol attenuated atrophy of C2C12 myotubes induced by tumour‐derived exosomal miR‐183‐5p through inhibiting Smad3 pathway activation and keeping mitochondrial respiration

Discovery of Therapeutic Candidates for Diabetic Retinopathy Based on Molecular Switch Analysis: Application of a Systematic Process

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