Efficacy of Terpenoid in Attenuating Aortic Atherosclerosis in Apolipoprotein-E Deficient Mice: A Meta-Analysis of Animal Studies

Liu, Han; Zhang, Yang; Sun, Siqiao; Wang, Shuai

doi:10.1155/2019/2931831

Cited by 5 publications

(4 citation statements)

References 63 publications

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“…Table 2b listed the top ten KEGG pathways significantly enriched for miRNA molecules, where each miRNA molecule was enriched for genes within 300 KB of our gene-by-smoking interaction SNP hits. The top three pathways among these corresponded to growing evidence that terpenoids influence atherosclerosis [41], G protein-coupled odorant receptors regulate myocardial contractility [42], and smokinginduced impairment of ether lipid metabolism via LDL receptors in hepatocytes impacts cardiovascular phenotypes [43,44,45]. Table 2c listed the top GO pathways significantly enriched for transcription factor genes, each transcription factor being enriched for genes within 300 KB of our gene-by-sex interaction SNP hits.…”

Section: Ontological Enrichment Analysismentioning

confidence: 89%

Improving Genetic Association Studies with a Novel Methodology that Unveils the Hidden Complexity of All-Cause Heart Failure

Gregg¹,

Himes²,

Asselbergs³

et al. 2023

Preprint

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Motivation: . Genome-Wide Association Studies (GWAS) commonly assume phenotypic and genetic homogeneity that is not present in complex conditions. We designed Transformative Regression Analysis of Combined Effects (TRACE), a GWAS methodology that better accounts for clinical phenotype heterogeneity and identifies gene-by-environment (GxE) interactions. We demonstrated with UK Biobank (UKB) data that TRACE increased the variance explained in All-Cause Heart Failure (AHF) via the discovery of novel single nucleotide polymorphism (SNP) and SNP-by-environment (i.e. GxE) interaction associations. First, we transformed 312 AHF-related ICD10 codes (including AHF) into continuous low-dimensional features (i.e., latent phenotypes) for a more nuanced disease representation. Then, we ran a standard GWAS on our latent phenotypes to discover main effects and identified GxE interactions with target encoding. Genes near associated SNPs subsequently underwent enrichment analysis to explore potential functional mechanisms underlying associations. Latent phenotypes were regressed against their SNP hits and the estimated latent phenotype values were used to measure the amount of AHF variance explained. Results: . Our method identified over 100 main GWAS effects that were consistent with prior studies and hundreds of novel gene-by-smoking interactions, which collectively accounted for approximately 10% of AHF variance. This represents an improvement over traditional GWAS whose results account for a negligible proportion of AHF variance. Enrichment analyses suggested that hundreds of miRNAs mediated the SNP effect on various AHF-related biological pathways. The TRACE framework can be applied to decode the genetics of other complex diseases. Availability: . All code is available at https://github.com/EpistasisLab/latent_phenotype_project Key words: bioinformatics; computational biology; feature engineering; machine learning; GWAS

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Section: Ontological Enrichment Analysismentioning

confidence: 89%

Improving Genetic Association Studies with a Novel Methodology that Unveils the Hidden Complexity of All-Cause Heart Failure

Gregg¹,

Himes²,

Asselbergs³

et al. 2023

Preprint

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“…We discovered that a lack of total ApoE did not prevent the phosphorylation of Tau or the development of cognitive impairment caused by sevoflurane anesthesia (Figure 2 ). According to previous studies, ApoE can be a carrier of cholesterol essential for neuronal function and injury repair in the brain, and ApoE deficiency can induce blood‐brain barrier (BBB) impairment, cause oxidative damage to neurons, and impede synapse growth, resulting in neurodegeneration (Fuentes et al., 2018 ; Getz & Reardon, 2016 ; Liu et al., 2019 ). As a result, animals lacking the ApoE gene displayed cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia

Yang

Zhuang

et al. 2022

Brain and Behavior

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Background Anesthesia induces Tau phosphorylation and cognitive impairment in young, but not adult, mice. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its toxic fragments are reported to induce neurodegeneration and neurocognitive impairment in patients with Alzheimer's disease (AD). Therefore, we set out to test the hypothesis that the difference in ApoE fragments, but not the full‐length ApoE, contributes to the difference in Tau phosphorylation and neurocognitive functions following sevoflurane anesthesia in young mice. Methods Sevoflurane was administered to wild‐type (WT), ApoE‐knockout (ApoE‐KO), ApoE3‐targeted replacement (ApoE3 expresses both full‐length and fragmented ApoE), and ApoE2‐targeted replacement (ApoE2 only expresses full‐length ApoE) mice. The mRNA and protein levels of ApoE, phosphorylated Tau (pTau), and cognitive function were tested in the mice. Results Sevoflurane anesthesia enhanced ApoE mRNA, total ApoE, full‐length ApoE, ApoE fragments, Tau phosphorylation (AT8 and PHF1), and cognitive impairment in young mice, but not in adult mice. ApoE2, but not ApoE3 or ApoE‐KO, mice showed reduced sevoflurane‐induced pTau elevation and cognitive impairment. Conclusion These data suggest that elevated ApoE fragments rather than full‐length ApoE might be one of the underlying mechanisms of age‐dependent Tau phosphorylation and cognitive impairment in young mice following sevoflurane anesthesia.

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“…Apolipoprotein E is a major carrier of cholesterol that is required for neuronal activity and injury repair in the brain; loss of ApoE might cause blood-brain barrier impairment and neuronal oxidative damage and limit synapse development, resulting in neurodegeneration. 15,26,27 Thus, the generation of ApoE in neurons may be a neuroprotective function in the CNS. To further examine whether total ApoE plays a key role in the presence and severity of tau phosphorylation and neuroinflammation with sevoflurane anesthesia, WT and ApoE-KO neurons were used in the present study.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic 18-kDa apolipoprotein E fragment production contributes to anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation in vitro

Yang

Zhuang

et al. 2022

Hum Exp Toxicol

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Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer’s disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE ε3-and ε2-targeted replacement (ApoE ε3, ApoE ε2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O2, 5% CO2, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O2 and 5% CO2 only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and IL-1β levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-α, IL-6, and IL-1β increases in WT or ApoE ε3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE ε2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.

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Efficacy of Terpenoid in Attenuating Aortic Atherosclerosis in Apolipoprotein-E Deficient Mice: A Meta-Analysis of Animal Studies

Cited by 5 publications

References 63 publications

Improving Genetic Association Studies with a Novel Methodology that Unveils the Hidden Complexity of All-Cause Heart Failure

Improving Genetic Association Studies with a Novel Methodology that Unveils the Hidden Complexity of All-Cause Heart Failure

Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia

Neurotoxic 18-kDa apolipoprotein E fragment production contributes to anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation in vitro

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