Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
Project description:Mitochondria exhibit diverse effects on cellular responses. Mitochondrial transplantation from gastric epithelial cells GES-1 to gastric cancer cells AGS reduces cancer malignancy was previously reported. We employed proteomic and metabolomic analyses to elucidate underlying mechanisms. iTRAQ/TMT-based proteomics identified 257 upregulated and 34 downregulated proteins, with Ingenuity pathway analysis revealing regulation of 14 signaling pathways. The upregulation of p53, Bax, p-AktS473, p-mTORS2448 and the down-regulation of Sirt 3, p-NRF2S40, and HO-1 were further verified by western blotting. Metabolomic profiling detected 3 upregulated and 8 down-regulated metabolites implicated in glycolysis, TCA cycle, pentose phosphate pathway (PPP), and ATP production. Further investigation showed that decreased extracellular lactate correlating with enhanced MCT1 expression (lactate importer), reduced MCT4 expression (lactate exporter), and increased LDHB expression (lactate to-pyruvate conversion). With the finding that transplanted with GES-1 mitochondria and induced accumulation of pyruvate, the AGS was solely treated with pyruvate and the result showed a cell migration of AGS was retarded. Additionally, isocitrate accumulation preceded decreased α-ketoglutarate, malate, ATP, and NADH levels. In conclusion, integrated proteomic and metabolomic analyses revealed that transplanted GES-1 mitochondria attenuate AGS gastric cancer malignancy through stagnation of glycolysis and the TCA cycle progression, highlighting potential targets for mitochondrial-based therapies.
Project description:We present data of global proteomes for non-small cell lung cancer for squamous cell and adenocarcinoma, and for normal adjacent tissue.
Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH.