Background: Lung adenocarcinoma (LUAD) represents a prevalent subtype of non-small cell lung cancer with a complex molecular landscape.Dysregulated cellular energetics, notably the interplay between hypoxia and glycolysis, has emerged as a hallmark feature of LUAD tumorigenesis and progression.In this study, we aimed to identify hypoxia and glycolysis related gene signatures and construct a prognostic model to enhance the clinical management of LUAD.Methods: A gene signature associated with hypoxia and glycolysis was established within the The Cancer Genome Atlas (TCGA) cohort and subsequently validated in the GSE31210 cohort.Additionally, a nomogram was formulated to aid in predictive modeling.Subsequently, an evaluation of the tumor microenvironment and immune checkpoints expression levels was conducted to discern disparities between low risk and high risk groups.Lastly, an exploration for drugs with potential effectiveness was carried out.Results: Our analyses revealed a distinct hypoxia and glycolysis related gene signature consisting of 6 genes significantly associated with LUAD patient survival.Integration of these genes into the prognostic model demonstrated superior predictive accuracy for patient outcomes.Furthermore, we developed a user-friendly nomogram that effectively translates the model's prognostic information into a practical tool for clinical decision-making. Conclusion:This study elucidates the critical role of hypoxia and glycolysis related genes in LUAD and offers a novel prognostic model with promising clinical utility.This model has the potential to refine risk stratification and guide personalized therapeutic interventions, ultimately improving the prognosis of LUAD patients.

Myocardial ischemia/reperfusion injury (MIRI) is closely related to oxidative stress. However, the redox environment of the heart has not been evaluated thoroughly after MIRI, which limits precise redox intervention. In this study, we developed the redox environment metabolomic evaluation (REME) method to analyze the redox metabolites of the heart after MIRI. Based on the targeted metabolomics strategy, we established a detection panel for 22 redox-related molecules, including the major redox couples nicotinamide adenine dinucleotide (NADH/NAD+), nicotinamide adenine dinucleotide phosphate (NADPH/NADP+), and glutathione/glutathione disulfide (GSH/GSSG), reactive oxygen and nitrogen species-related molecules, and some lipid peroxidation products. The high sensitivity and specificity of the method make it suitable for evaluating the endogenous redox environment. The REME method showed that the heart tissue in a MIRI mouse model had a different redox profile from that in the control group. Different redox species changed in different ways. The ratios of GSSG/GSH and NADP+/NADPH increased, but the levels of both NAD+ and NADH decreased in the risk area of the infarcted heart after reperfusion. In addition, some reactive nitrogen species-related metabolites (tetrahydrobiopterin, arginine, and S-nitrosoglutathione) decreased and some lipid peroxides (4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal, and benzaldehyde) increased. The redox metabolites GSH, GSSG, NADPH, NAD+, S-nitrosoglutathione, arginine, and tetrahydrobiopterin had a positive correlation with the ejection fraction and a negative correlation with the level of lactate dehydrogenase in plasma. In summary, we achieved a comprehensive, systemic understanding of the changes in the redox environment after MIRI. Our REME method could be used to evaluate the redox environment in other processes.

Glycerophospholipids (GPs) and sphingolipids (SPs) are important lipid components in the body and play biological functions. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are important nutrients, and their supplements are commonly used for preventing some diseases. However, the effect of n-3 PUFAs on the human glycerophospholipidome and sphingolipidome is unclear. We used targeted lipidomics to study the GP and SP profile of healthy individuals after supplementation with n-3 PUFAs for 3, 7, 14 and 21 days. Fuzzy c-means clustering was used to cluster the lipid species into six classes reflecting different changed-content patterns after n-3 PUFA supplementation. Among the species with significantly changed content, lysophospholipids were the most sensitive; their content started to increase on day 3. The content of phosphatidylserines increased at a later stage. The content of most of the phosphatidylcholines and alkylphosphatidylcholines decreased on day 21. A correlation network analysis of lipid species suggested that some enzymes involved in the metabolism of lysophospholipids and phosphatidylserines were regulated by n-3 PUFAs. Levels of creatine kinase-MB (CK-MB), urea, glucose, triglycerides and total bilirubin were altered by n-3 PUFA at 21 days. Correlation analysis revealed that the level of CK-MB was negatively correlated with those of species in lysophosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and phosphatidylserine classes, which were increased by n-3 PUFA supplementation. With the analysis in this work, we demonstrated the regular pattern of n-3 PUFAs on GP and SP metabolism, which provides a pharmacological basis for n-3 PUFAs for clinical application.

Pre-eclampsia (PE) is considered a leading cause of mortality and morbidity in pregnant women worldwide. Eicosanoids derived from polyunsaturated fatty acids (PUFAs) might play an important role in the occurrence and development of PE. Omega-3 PUFAs are nutrients that are popular supplements for pregnant women and can reduce blood pressure. However, the levels of eicosanoids derived from omega-3 PUFAs in women with PE is not clear. The purpose of this study was to investigate the eicosanoid metabolic signature of PE. We performed a case-control study using data for pregnant women (n = 10) with PE and normotensive pregnant women (n = 10). We investigated the difference in eicosanoid profile between the groups by LC-MS/MS-based metabolomics. The plasma levels of arachidonic acid metabolites and some of the lipoxygenase metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed an increasing trend, and those of the cytochrome P450 metabolites of EPA and DHA were decreased in women with PE. Levels of leukotriene B4, 14,15-dihydroxy-eicosatetraenoate, 16-hydroxydocosahexaenoic acid and 8,9-epoxy eicosatetraenoic acid were significantly correlated with PE occurrence. These eicosanoids might take part in the progression of PE in pregnant women.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown. METHODS: mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH. RESULTS: We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter's phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency-mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1-dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13. CONCLUSIONS: Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs.

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg-1·day-1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation is a recommended preventive approach against cardiovascular diseases, but its mechanism of protection against myocardial infarction (MI) injury is not fully understood. Eicosanoid metabolomics demonstrated an abnormal eicosanoid profile was in the plasma of mice receiving MI surgery. 19,20-EDP, 17,18-EEQ, 14,15-EET and 9,10-EpOME were decreased, and PGE2 was increased by the surgery. N-3 PUFA-rich diets feeding or transgene of Fat-1 shifted the eicosanoid profile to an n-3 PUFA dominant style and attenuated the myocardial infarction injury. Multiple logistic regression analysis suggested the degree of MI injury was related with an eicosanoid pattern, composed by eicosanoids derived from both n-3 and n-6 PUFA in the three enzymatic pathways. These results suggested the benefits of n-3 PUFA on MI was achieved synergistically.