Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS: Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS: Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION: Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.

Retraction notice to "The cytoprotective effects of Δ-17 fatty acid desaturase on injured HUVECs and its underlying mechanism" [Saudi Pharm. J. 25(4) (2017) 587-594].

[This retracts the article DOI: 10.1016/j.jsps.2017.04.028.].

Identification of the metabolites of n-butylidenephthalide in rat and human liver microsomes by liquid chromatography-high-resolution mass spectrometry.

n-Butylidenephthalide (NBDP) is one of the bioactive constituents originally isolated from Ligusticum chuanxiong Hort. The aim of this study was to study the metabolic profiles of NBDP in rat and human liver microsomes. NBDP was individually incubated with liver microsomes of rat and human at 37°C for 1 h and the samples incubated were analyzed by ultra-high-performance liquid chromatography combined with high-resolution mass spectrometry. The identities of the metabolites were identified by accurate masses, product ions and retention times. Under the current conditions, a total of 14 metabolites were detected and identified. M12, M13 and M14 were biosynthesized and unambiguously characterized by nuclear magnetic resonance spectroscopy. All the metabolites can be detected in rat liver microsomes, whereas in human liver microsomes, M1, M3, M4, M5, M6 and M7 were not detected. Our results demonstrated that the metabolic pathways of NBDP included hydroxylation, hydration, hydrolysis and glutathione conjugation. This study provides an overview of the metabolic profiles of NBDP in vitro, which is helpful to understand the action of this compound.

The cytoprotective effects of Δ-17 fatty acid desaturase on injured HUVECs and its underlying mechanism.

Endothelium toxicity has been involved in early endothelial dysfunction to show the pathogenesis of multiple cardiovascular disease that shows atherosclerosis and its complications. Saturated free fatty acids are the main inducing factors of endothelial cell apoptosis and inflammatory cytokines. In humans, stearoyl-CoA desaturase 1 (SCD-1) is a restriction step to saturation to unsaturated fatty acid desaturation, which plays a beneficial role protecting endothelial cells against lipotoxicity. Δ-17 fatty acid desaturase (FAD) is a newly identified FAD which shares 55% identity at the amino acid level with SCD-1. Whether Δ-17 FAD has similar beneficial effect remains poorly understood. Oxidized low density lipoprotein (ox-LDL) was used to induce lipotoxicity in human umbilical vein endothelial cells (HUVECs) to establish a model of oxidative injury. Then HUVECs were transfected with FAD lentivirus to introduce cytoprotective effects. The alterations in cell proliferation and apoptosis, nitric oxide content, malonyldialdehyde (MDA) content, SOD enzyme content, LDH content, GSH-PX level, vascular growth factor (VEGF) expression were evaluated. Studies showed that ox-LDL-induced excess HUVEC apoptosis can be abrogated by upregulation of Δ-17 FAD. The nitric oxide content, GSH-PX content, and SOD enzyme content were increased and the activity of MDA was suppressed by upregulation of Δ-17 FAD. In addition, upregulation of Δ-17 FAD significantly increased VEGF expression. In vitro tube formation assay showed that Δ-17 FAD promoted angiogenesis to a significant degree. These results suggest that Δ-17 fatty acid desaturase may have beneficial action in the prevention of ox-LDL-induced cellular damage.

Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling.

BACKGROUND: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. METHODS: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1-4) was detected by western blot. RESULTS: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. CONCLUSION: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis.