Abstract Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2 , PKM2 , and HIF‐1α . Intriguingly, inhibition of glycolysis by 2‐deoxyglucose (2‐DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2‐DG treatment also strongly suppressed the activation of the NOD‐like receptor (NLR) family and pyrin domain‐containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2‐DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor‐α messenger RNA (mRNA), pro‐interleukin (IL)‐1β mRNA, pro‐IL‐18 mRNA, NLRP3 mRNA, caspase‐1 mRNA, and IL‐1β protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti‐inflammatory strategy in treating ALI.
Abstract Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citrate mt ) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor–mediated inhibition of Idh3α and Slc25a1 induced citrate mt accumulation and necroptosis in vitro. Mice with AEC-specific Idh3α and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3α and Slc25a1 decreased citrate mt levels and rescued AECs from necroptosis. Mechanistically, citrate mt accumulation induced mitochondrial fission and excessive mitophagy in AECs. Furthermore, citrate mt directly interacted with FUN14 domain-containing protein 1 (FUNDC1) and promoted the interaction of FUNDC1 with dynamin-related protein 1 (DRP1), leading to excessive mitophagy-mediated necroptosis and thereby initiating and promoting ALI. Importantly, necroptosis induced by citrate mt accumulation was inhibited in FUNDC1-knockout AECs. We show that citrate mt accumulation is a novel target for protection against ALI involving necroptosis.
Arachidonic acid can be metabolized to prostaglandins and epoxyeicosatrienoic acids (EETs) by cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP), respectively. While protective EETs are degraded by soluble epoxide hydrolase (sEH) very fast. We have reported that dual inhibition of COX-2 and sEH with specific inhibitor PTUPB shows anti-pulmonary fibrosis and renal protection. However, the effect of PTUPB on cecal ligation and puncture (CLP)-induced sepsis remains unclear. The current study aimed to investigate the protective effects of PTUPB against CLP-induced sepsis in mice and the underlying mechanisms. We found that COX-2 expressions were increased, while CYPs expressions were decreased in the liver, lung, and kidney of mice undergone CLP. PTUPB treatment significantly improved the survival rate, reduced the clinical scores and systemic inflammatory response, alleviated liver and kidney dysfunction, and ameliorated the multiple-organ injury of the mice with sepsis. Besides, PTUPB treatment reduced the expression of hypoxia-inducible factor-1α in the liver, lung, and kidney of septic mice. Importantly, we found that PTUPB treatment suppressed the activation of NLRP3 inflammasome in the liver and lung of septic mice. Meanwhile, we found that PTUPB attenuated the oxidative stress, which contributed to the activation of NLRP3 inflammasome. Altogether, our data, for the first time, demonstrate that dual inhibition of COX-2 and sEH with PTUPB ameliorates the multiple organ dysfunction in septic mice.
Abstract Keyword extraction is one of the work of computer text topic mining, and it is also the basis of text analysis and public opinion analysis. The keywords extracted by the traditional TF-IDF algorithm are mainly calculated based on the word frequency. The importance of other feature words with fewer occurrences and the comments of readers below the article are not considered. Aiming at the above problems, this paper improves the traditional TF-IDF algorithm, adds the part of speech and the reader’s comment as the impact factor, and recalculates the weight of TF-IDF, so that the accuracy of the algorithm is improved. This paper uses the Python language programming to crawl from the media article and implement the improvement of the algorithm. Experiments show that the improved TF-IDF algorithm has significantly improved compared with the traditional TF-IDF, in terms of accuracy, recall rate, F1, MacAvg_P, MacAvg_R and MacAvg_F1.
Abstract Background: Arachidonic acid (ARA) metabolites are involved in the pathogenesis of epithelial-mesenchymal transformation (EMT). However, the role of ARA metabolism in the progression of EMT in pulmonary fibrosis (PF) has not been fully elucidated. The purpose of this study was to investigate the role of cytochrome P450 oxidase (CYP)/ soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) metabolic disorders of ARA in EMT during PF. Methods: A signal intratracheal injection of bleomycin (BLM) was given to induce PF in C57BL/6J mice. A COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation to EMT in PF mice. In vitro experiments, murine alveolar epithelial cells (MLE12) and human alveolar epithelial cells (A549) were used to explore the roles and mechanisms of PTUPB on transforming growth factor (TGF)-β1-induced EMT. Results: PTUPB treatment reversed the increase of mesenchymal marker molecule α-smooth muscle actin (α-SMA) and the loss of epithelial marker molecule E-Cadherin in lung tissue of PF mice. In vitro , COX-2 and sEH protein levels were increased in TGF-β1-treated alveolar epithelial cells (AECs). PTUPB decreased the expression of α-SMA and restored the expression of E-cadherin in TGF-β1-treated AECs, accompanied by reduced migration and collagen synthesis. Moreover, PTUPB alleviated the activation of the TGF-β1-Smad2/3 pathway induced by TGF-β1 in AECs. Conclusion: PTUPB inhibits TGF-β1-induced EMT via inhibition of the TGF-β1-Smad2/3 pathway, which holds great promise for the clinical treatment of PF.
Epoxyeicosatrienoic acids (EETs) derived from arachidonic acid exert anti-inflammation effects. We have reported that blocking the degradation of EETs with a soluble epoxide hydrolase (sEH) inhibitor protects mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI). The underlying mechanisms remain essential questions. In this study, we investigated the effects of EETs on the activation of nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in murine macrophages. In an LPS-induced ALI murine model, we found that sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl), TPPU, profoundly attenuated the pathological injury and inhibited the activation of the NLRP3 inflammasome, characterized by the reduction of the protein expression of NLRP3, ASC, pro-caspase-1, interleukin precursor (pro-IL-1β), and IL-1β p17 in the lungs of LPS-treated mice. In vitro, primary peritoneal macrophages from C57BL/6 were primed with LPS and activated with exogenous adenosine triphosphate (ATP). TPPU treatment remarkably reduced the expression of NLRP3 inflammasome-related molecules and blocked the activation of NLRP3 inflammasome. Importantly, four EETs (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) inhibited the activation of NLRP3 inflammasome induced by LPS + ATP or LPS + nigericin in macrophages in various degree. While the inhibitory effect of 5,6-EET was the weakest. Mechanismly, EETs profoundly decreased the content of reactive oxygen species (ROS) and restored the calcium overload in macrophages receiving LPS + ATP stimulation. In conclusion, this study suggests that EETs inhibit the activation of the NLRP3 inflammasome by suppressing calcium overload and ROS production in macrophages, contributing to the therapeutic potency to ALI.
Balancing different forest management goals related to economic, ecological, and social sustainability, a rapid simulation system uses CPU+GPU heterogeneous patterns to accelerate the computation of dynamic processes, supporting quick and intelligent decision making.
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