miRNA-223 Suppresses Mouse Gallstone Formation by Targeting Key Transporters in Hepatobiliary Cholesterol Secretion Pathway

Zhao, Feng; Ma, Shiyu; Zhou, Yiming; Wei, Bailing; Hao, Zhen; Cui, Xiaolin; Xing, Lina; Liu, Gang; Jin, Lingling; Ma, Tonghui; Shi, Lei

doi:10.7150/ijbs.65485

Cited by 8 publications

(5 citation statements)

References 25 publications

(36 reference statements)

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“…Western Blot. Western blot was conducted as previously described [37]. Briefly, HUVECs were subjected to SDS-PAGE and transferred to nitrocellulose membranes.…”

Section: Apoptosis Assay Apoptosis Was Measured By Annexinmentioning

confidence: 99%

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

Wei

Hao

Zheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.

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“…Western Blot. Western blot was conducted as previously described [37]. Briefly, HUVECs were subjected to SDS-PAGE and transferred to nitrocellulose membranes.…”

Section: Apoptosis Assay Apoptosis Was Measured By Annexinmentioning

confidence: 99%

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

Wei

Hao

Zheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The above studies provide strong evidence to support our conclusion that the negative causality of GSD on AMI risk is mediated by ABCG5/8 gain of function, which makes the results more reliable and valuable. miRNA-223, on the other hand, has been found by researchers to directly target the inhibition of ABCG5/8 to reduce the occurrence of GSD, but whether it will inversely lead to an increased risk of AMI is not conclusive 51 . In addition, animal studies have shown that deletion of the ABCG5/8 gene does not eliminate hepatic cholesterol secretion to the gallbladder and that other ABCG5/8 nondependent pathways involved in hepatic cholesterol secretion exist 52 , 53 .…”

Section: Discussionmentioning

confidence: 99%

Causal effect of gallstone disease on the risk of coronary heart disease or acute myocardial infarction: a Mendelian randomization study

Fu,

Shen,

et al. 2023

Sci Rep

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Gallstone disease (GSD) is thought to be associated with the risk of coronary heart disease (CHD) or acute myocardial infarction (AMI), which may be due to abnormal cholesterol metabolism. We used multiple Mendelian randomization (MR) methods based on publicly available genome-wide association study data to assess whether this association is genetically causal and to search for loci driving causality. Pooled data for GSD were obtained from FinnGen Biobank and Biobank Japan, while CHD and AMI were obtained as pooled data from the CARDIoGRAMplusC4D consortium. In this MR study, we found a significant negative causal effect of genetic susceptibility to GSD on AMI in the Finnish population, but no causal effect was found on CHD. This causal effect was not confounded by reverse causality and the same findings were obtained in the Japanese population. Furthermore, the negative causal effect of GSD on AMI risk may be driven by the rs4245791-regulated ABCG5/8 protein. In conclusion, the results of this MR study support a negative causal effect of GSD on AMI and suggest that rs4245791 is the causal driver locus of this effect, which provides new ideas and evidence for the prevention and etiologic study of AMI in patients with GSD.

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“…For instance, miR-33a downregulates the expression of both ABCG5 and ABCG8 [82]. Similarly, miR-223 has been shown to downregulate the expression of ABCG5/ABCG8 [83].…”

Section: Transcriptional and Post-transcriptional Regulation Of Abcg5...mentioning

confidence: 99%

Regulation of Cholesterol Transporters by Nuclear Receptors

Matsuo

2023

Receptors

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Atherosclerosis is a pathological condition characterized by the accumulation of plaques in the arteries, leading to cardiovascular diseases. The deposition of cholesterol in peripheral cells increases the risk of atherosclerosis. Reverse cholesterol transport (RCT) is essential to reduce the risk of atherosclerosis because it removes excessive cholesterol from the peripheral tissues. ATP-binding cassette transporters such as ABCA1, ABCG1, ABCG5, and ABCG8 are involved in the efflux of cholesterol. The upregulation of these ABC transporters enhances RCT, thereby promoting the removal of excess cholesterol from the body. The expression and activity of ABC transporters are regulated by transcriptional and post-transcriptional mechanisms, as well as by post-translational modifications. In this review, the regulation of ABC transporters by nuclear receptors such as farnesoid X receptor, liver X receptor, retinoid X receptor, retinoic acid receptor, and peroxisome proliferator-activated receptors is discussed. Pharmacological and natural compounds serving as agonists for the nuclear receptors have been identified to elevate the mRNA levels of the transporters. Consequently, it is anticipated that these compounds will attenuate the development of atherosclerosis through stimulation of the ABC transporters, thereby enhancing RCT and fecal cholesterol excretion. Understanding these regulatory processes can aid in the development of therapeutic approaches to prevent atherosclerosis.

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miRNA-223 Suppresses Mouse Gallstone Formation by Targeting Key Transporters in Hepatobiliary Cholesterol Secretion Pathway

Cited by 8 publications

References 25 publications

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

Causal effect of gallstone disease on the risk of coronary heart disease or acute myocardial infarction: a Mendelian randomization study

Regulation of Cholesterol Transporters by Nuclear Receptors

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