Cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.
Although cancer cells are frequently faced with nutrient-and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anti-cancer strategy. The gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) was downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low glucose condition. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo UTP synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-Lnorleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation. Recent findings emphasize the role of the hexosamine-biosynthesis pathway (HBP), a sub-branch of glucose metabolism, in carcinogenesis (9, 10). The HBP and glycolysis share the first two steps and diverge at fructose-6-phosphate (F6P). Glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the HBP, converts F6P and glutamine to glucosamine-6-phosphate and glutamate. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end products of HBP, is a donor substrate for O-linked β-N-acetylglucosamine (O-GlcNAc) modification (also known as O-GlcNAcylation) (11). O-GlcNAc transferase (OGT)-mediated protein O-GlcNAcylation is highly dependent on the intracellular concentration of the donor substrate UDP-GlcNAc, which is proposed to be a nutrient sensor that couples metabolic and signaling pathways (12, 13). Increased glucose flux through the HBP and elevated UDP-GlcNAc contribute to hyper-O-GlcNAcylation in cancer cells (14). Previous data suggested that elevated O-GlcNAcylation may serve as a hallmark of cancer (15). Similar to phosphorylation, O-GlcNAcylation is a dynamic post-translational modification that regulates protein subcellular localization, stability, protein-protein interactions, or enzymatic activity according to the nutrient demands of cells (16). OGT and O-GlcNAcase (OGA) are the only enzymes known to be responsible for adding and removing N-acetylglucosamine (GlcNAc) on ...
Metabolomics is a powerful and essential technology for profiling metabolic phenotypes and exploring metabolic reprogramming, which enables the identification of biomarkers and provides mechanistic insights into physiology and disease. However, its applications are still limited by the technical challenges particularly in its detection sensitivity for the analysis of biological samples with limited amount, necessitating the development of highly sensitive approaches. Here, we developed a h ighly s ensitive liquid chromatography tandem mass spectrometry method based on a 3-nitrophenylhydrazine (3-NPH) d erivatization strategy that simultaneously targets c arbonyl, c arboxyl, and p hosphoryl groups for t argeted m etabolomic analysis (HSDccp-TM) in biological samples. By testing 130 endogenous metabolites including organic acids, amino acids, carbohydrates, nucleotides, carnitines, and vitamins, we showed that the derivatization strategy resulted in significantly improved detection sensitivity and chromatographic separation capability. Metabolic profiling of merely 60 oocytes and 5000 hematopoietic stem cells primarily isolated from mice demonstrated that this method enabled routine metabolomic analysis in trace amounts of biospecimens. Moreover, the derivatization strategy bypassed the tediousness of inferring the MS fragmentation patterns and simplified the complexity of monitoring ion pairs of metabolites, which greatly facilitated the metabolic flux analysis (MFA) for glycolysis, the tricarboxylic acid (TCA) cycle, and pentose phosphate pathway (PPP) in cell cultures. In summary, the novel 3-NPH derivatization-based method with high sensitivity, good chromatographic separation, and broad coverage showed great potential in promoting metabolomics and MFA, especially in trace amounts of biospecimens.
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