In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.
Conformational transitions of biopolymers are well-known to be affected by noncovalent interactions with small molecules. We found that synthetic polymers, poly- and oligo(meta-ethynylpyridine)s, are guided to helical structures by uncharged hydrogen-bonding interactions with saccharides enclosed in the inner sphere of the polymers. Circular dichroism (CD) studies revealed that chirality of saccharide was transferred to the helical sense of the polymers. Among the n-octyl pyranosides of naturally important hexoses, beta-glucoside induced CDs most effectively. Size-regulated 18-mer and longer oligomers also showed the induced CDs similar to those for the polymers. Furthermore, native monosaccharides were extracted into less polar organic solvent with the help of the polymers, inducing similar CD signals.
Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.
The circulatory system distributes blood flow to each tissue and transports oxygen and nutrients. Peripheral circulation is required to maintain the physiological function in each tissue. Disturbance of circulation, therefore, decreases oxygen delivery, leading to tissue hypoxia which takes place in several cardiovascular disorders including atherosclerosis, pulmonary arterial hypertension and heart failure. While tissue hypoxia can be induced because of cardiovascular disorders, hypoxia signaling itself has a potential to modulate tissue remodeling processes or the severity of the cardiovascular disorders. Hypoxia inducible factor-1α (HIF-1α) and HIF-2α belongs to a group of transcription factors which mediate most of the cellular responses to hypoxia at a transcriptional level. We, and others, have reported that HIF-α signaling plays a critical role in the initiation or the regulation of inflammation. HIF-α signaling contributes to the tissue remodeling processes; thus it has a potential to become a therapeutic target. Elucidation of the molecular link, therefore, between hypoxia signaling and tissue remodeling will greatly help us to understand the pathophysiology of the cardiovascular disorders. The purpose of this review is to give a brief overview of the current understanding about the function HIF-α in inflammation processes especially by focusing on its roles in macrophages. In addition, the pathophysiological roles of hypoxia signaling for the development of cardiovascular disease will be discussed.
[figure: see text] Under hydrogen pressure, a catalytic amount of palladium(II) trifluoroacetate and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) promoted asymmetric hydrogenation of alpha-fluorinated iminoesters to afford highly enantioenriched beta-fluorinated alpha-amino esters. The yield and ee were much improved by employing fluorinated alcohols such as 2,2,2-trifluoroethanol (up to 91% ee).
The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C
hi
monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.
In a binary mixture of oligomers of styrene and f-caprolactone, we have studied a transition from metastability to instability by changing a quench depth systematically under an off-critical quench condition. The concentration distribution function turns out to be a good fingerprint for determining whether phase separation is nucleation-growth type or spinodal-decomposition type. We also demonstrate clear morphological and kinetic evidence of a diffuse metastable-unstable transition or crossover phenomena theoretically predicted for the system with a finite-range interaction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.