Lung branching morphogenesis is accompanied by temporal metabolic changes towards a glycolytic preference

Fernandes-Silva, Hugo; Alves, Marco G.; Araújo-Silva, Henrique; Silva, Ana Maria; Correia‐Pinto, Jorge; Oliveira, Pedro F.; Moura, Rute S.

doi:10.1186/s13578-021-00654-w

Cited by 15 publications

(62 citation statements)

References 68 publications

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“…LDHA is an important oxidoreductase in the glycolysis pathway in vivo. LDHA mediated glycolysis which was involved in pulmonary branch morphogenesis [25]. The expression of LDHA was up-regulated during the abnormal transformation of human bronchial epithelial cells induced by hexavalent chromium [26].…”

Section: Discussionmentioning

confidence: 99%

Aspirin inhibited the Warburg effect induced by Ni-refining fumes via the Wnt/β-catenin pathway in Beas-2B cells

Gao

Zhang

et al. 2022

Preprint

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The natural metal nickel (Ni) can be found in the air, water, sediment, and soil. Although epidemiological research and experimental data have shown that nickel is linked to lung cancer, the precise mechanism of nickel carcinogenesis is unclear. We investigated whether Ni-refining fumes stimulated the Wnt/β-catenin pathway and caused the Warburg effect in Beas-2B cells, then if aspirin could protect the cells. The findings demonstrated that Beas-2B cells were significantly toxicated by Ni-refining fumes. With the increase of Ni-refining fumes concentration, the proteins and mRNAs level of the Wnt/β-catenin pathway were significantly increased and Warburg effect-related proteins: pyruvate dehydrogenase kinase 1 (PDK1), monocarborxylat transporter 1 (MCT1) and lactate dehydrogenase A (LDHA) also increased significantly. Pyruvate dehydrogenase (PDH) activity was reduced and reactive oxygen species (ROS) production was increased. When given the Wnt/β-catenin pathway inhibitor XAV-939, Warburg effect-related proteins expression can be inhibited. Aspirin at various concentrations could improve the relative viability of cells exposed to nickel refining fumes, with 2.5 mmol/L aspirin providing the most significant protection (P<0.05). Compared with the nickel staining group, aspirin treatment significantly decreased the expression of the Wnt/β-catenin pathway and Warburg effect-related proteins whereas it inhibited the production of ROS, too.

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Section: Discussionmentioning

confidence: 99%

Aspirin inhibited the Warburg effect induced by Ni-refining fumes via the Wnt/β-catenin pathway in Beas-2B cells

Gao

Zhang

et al. 2022

Preprint

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“…In this sense, we explored potential metabolic alterations induced by RA signaling stimulation versus inhibition. Since both the embryonic and the adult lungs preferentially use glucose as the primary energy source [20][21][22][23], we started by focusing on glucose metabolism (Fig. 2A).…”

Section: Retinoic Acid Signaling Stimulation Requires Less Glucose Co...mentioning

confidence: 99%

Retinoic acid signaling regulates the energy metabolism of embryonic lung branching

Fernandes-Silva¹,

Alves²,

Garcez³

et al. 2023

Preprint

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Background: Lung branching morphogenesis is characterized by epithelial-mesenchymal interactions and mediated by complex signaling that ultimately defines the airway conducting system. Retinoic Acid (RA) signaling is crucial for lung organogenesis and modulates proximal-distal patterning and branching morphogenesis. However, how signaling networks and energy metabolism work together to shape embryonic lung development remains unexplored. Here, we investigate how RA signaling influences the metabolic profile of lung branching. Methods: We performed ex vivo lung explant culture using embryonic chicken lungs (Gallus gallus) treated with DMSO, 1 uM RA (stimulation), or 10 uM of BMS493 (inhibition). Explant culture media was collected, and the consumption/production of extracellular metabolites was evaluated by 1H-NMR spectroscopy. Lung explants were analyzed to determine mitochondrial respiration and biogenesis. Proliferation was assessed using an EdU‐based assay. Western blot, qPCR, and in situ hybridization were performed to assess the expression of metabolic/signaling components. Results: Upon stimulation, RA signaling increases lung branching, maintaining proper morphology. Besides, there is an increase in the amount of glucose directed into pyruvate and succinate rather than into alanine or lactate production. On the other hand, RA signaling inhibition decreases lung branching, induces a cystic-like phenotype, and promotes mitochondrial function. Proliferation status and lactate dehydrogenase expression are both regulated by RA signaling. Furthermore, RA signaling controls fatty acid metabolism through an AMPK-dependent mechanism. Conclusions: This report shows that RA signaling modulates the energy metabolism of lung branching morphogenesis and highlights the importance of metabolic regulation in this phase, contributing to understanding the etiology of congenital lung disorders.

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“…HIPPO/YAP signaling regulates myosin light chain kinase activity, creating mechanical forces that influence cell shape required for branching [ 71 ]. In addition, recent data highlighted the importance of metabolic regulation during the early stages of lung branching morphogenesis [ 72 ]. The key signaling pathways underlying branching morphogenesis are shown in Figure 2 .…”

Section: Lung Developmentmentioning

confidence: 99%

Developmental Pathways Underlying Lung Development and Congenital Lung Disorders

Caldeira

Fernandes-Silva

Machado-Costa

et al. 2021

Cells

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Lung organogenesis is a highly coordinated process governed by a network of conserved signaling pathways that ultimately control patterning, growth, and differentiation. This rigorously regulated developmental process culminates with the formation of a fully functional organ. Conversely, failure to correctly regulate this intricate series of events results in severe abnormalities that may compromise postnatal survival or affect/disrupt lung function through early life and adulthood. Conditions like congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchogenic cysts, and congenital diaphragmatic hernia display unique forms of lung abnormalities. The etiology of these disorders is not yet completely understood; however, specific developmental pathways have already been reported as deregulated. In this sense, this review focuses on the molecular mechanisms that contribute to normal/abnormal lung growth and development and their impact on postnatal survival.

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Lung branching morphogenesis is accompanied by temporal metabolic changes towards a glycolytic preference

Cited by 15 publications

References 68 publications

Aspirin inhibited the Warburg effect induced by Ni-refining fumes via the Wnt/β-catenin pathway in Beas-2B cells

Aspirin inhibited the Warburg effect induced by Ni-refining fumes via the Wnt/β-catenin pathway in Beas-2B cells

Retinoic acid signaling regulates the energy metabolism of embryonic lung branching

Developmental Pathways Underlying Lung Development and Congenital Lung Disorders

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