Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway

Jin, Jiajia; Xu, Weizong; Wan, Bing; Wang, Xiaoxia; Zhou, Zejun; Miao, Yingying; Lv, Tangfeng; Song, Yong

doi:10.1016/j.jss.2018.08.057

Cited by 19 publications

(13 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LPS has been well accepted as the ideal model to explore the pathogenesis of ALI [30]. Lung edema derived from the disruption of the capillary-alveolar barrier is an important characteristic of ALI [31]. The lung wet/dry ratio is an indicator of pulmonary edema [29], and the total protein concentrations in the BLAF serve as a measurement of pulmonary vascular permeability [32].…”

Section: Discussionmentioning

confidence: 99%

Oxyberberine Prevented Lipopolysaccharide‐Induced Acute Lung Injury through Inhibition of Mitophagy

Zhao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Acute lung injury (ALI) is a serious respiratory syndrome characterized with uncontrolled inflammatory response. Oxyberberine has strong potential for clinical usage since it showed strong anti-inflammatory, antifungal, and antiarrhythmic effects in various diseases. In the present study, we evaluated whether oxyberberine can inhibit lipopolysaccharide- (LPS-) induced ALI in vivo and further evaluated the possible involvement of mitophagy in vitro by using A549 cells, a human lung epithelial cell line. Our in vivo study shows that oxyberberine significantly inhibited LPS-induced lung pathological injury and lung edema, as indicated by the changes in lung wet/dry ratio and total protein levels in the BALF in mice. Moreover, oxyberberine inhibited inflammation, as indicated by the changes of neutrophil accumulation and production of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 in both the lung and bronchoalveolar lavage fluid (BALF) in ALI mice. Our in vitro study shows that LPS significantly decreased the protein level of mitochondrial proteins, including cytochrome c oxidase subunit IV (COX IV), p62, and mitofusin-2 (Mfn2) in A549 cells. In addition, LPS induced significant Parkin1 translocation from cytoplasm to mitochondria. These changes were significantly inhibited by oxyberberine. Notably, the inhibitory effect of oxyberberine was almost totally lost in the presence of lysosome fusion inhibitor bafilomycin A1 (Baf), a mitophagy inhibitor. In conclusion, the present study demonstrated that oxyberberine alleviated LPS-induced inflammation in ALI via inhibition of Parkin-mediated mitophagy.

show abstract

Section: Discussionmentioning

confidence: 99%

Oxyberberine Prevented Lipopolysaccharide‐Induced Acute Lung Injury through Inhibition of Mitophagy

Zhao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…To further clarify the role of HIF-1α in LPS-stimulated H9c2 cells, HIF-1α was overexpressed by transfection with pcDNA-HIF-1α, and topotecan, an inhibitor of HIF-1α, was executed for treat cells under LPS exposure condition. Topotecan is reported to attenuate LPS-mediated acute lung injury via the NF-κB pathway [ 22 ]. Additionally, Oleg et al [ 23 ] demonstrated that targeted inhibition of HIF-1 might represent a novel neuroprotective strategy by preventing neuronal apoptosis in rat hippocampus caused by severe hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the expression of HIF-1α in cardiac leukocytes correlates with the severity of myocarditis in end-stage Chagas disease patients [ 8 ]. Topotecan, an inhibitors of HIF-1α, has been demonstrated to mitigate LPS-induced acute lung injury by the NF-kappa B signaling [ 9 ]. By reducing inflammation, topotecan can alleviate the development of radiation necrosis in the mouse brain by inhibiting HIF-1α expression [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible transcription factor-1α inhibition by topotecan protects against lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes

Zhang

Zhou

et al. 2021

BioMed Eng OnLine

View full text Add to dashboard Cite

Background Myocarditis, an inflammatory disease of the myocardium, is a serious hazard to human life due to the expansion of inflammatory lesions in the myocardium. The aim of this study was to investigate the role of hypoxia-inducible transcription factor (HIF)-1α and its inhibitor topotecan in the pathogenesis of myocarditis. Methods H9c2 cardiomyoblasts was stimulated with lipopolysaccharide (LPS) to simulate myocarditis model in vitro. The levels of myocardial damage markers were determined using commercially available kits. Western blotting was used to evaluate HIF-1α expression after LPS challenge. Then, after HIF-1α silencing, the contents of inflammatory factors were determined with enzyme-linked immunosorbent assay (ELISA). Cell viability was tested by means of a cell counting kit-8 (CCK-8) assay. Cell apoptosis was assessed by flow cytometry, and the expression of apoptotic proteins was examined using western blot analysis. Subsequently, HIF-1α was overexpressed and topotecan was employed to treat H9c2 cells under LPS exposure condition. The biological functions were detected again. Results LPS significantly elevated the levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin-I (cTn-I) in supernatant of H9c2 cell lysates. Additionally, LPS led to the notably upregulated expression of HIF-1α. HIF-1α-knockdown markedly decreased the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 compared with the LPS-induced group. Moreover, the cell viability was conspicuously enhanced and cell apoptotic ratio was remarkably reduced, accompanied by downregulated expression of Bax, Bim, caspase 3 and caspase 9 after HIF-1α silencing. Consistently, HIF-1α gain-of-function significantly promoted the production of inflammatory cytokines and cell apoptosis, which was partially counteracted by topotecan administration. Conclusion To conclude, these findings demonstrated that HIF-1α inhibition by topotecan ameliorates LPS-induced myocarditis in vitro, providing a new approach in the treatment of myocarditis.

show abstract

“…Vice versa, the reported inhibitory activity of TOP1 inhibitors on the LPS- and virus-induced host response together with its protective effect in a model of LPS-induced cell death repurposed TOP1 inhibitors as agents for the treatment of septic shock [47]. Recent evidence also showed an alleviation of LPS-mediated acute lung injury by TPT [48]. Conditions associated with systemic release of large amounts of cytokines or even a cytokine storm such systemic inflammatory response syndrome (SIRS), sepsis or graft-versus-host disease are difficult to treat and can lead to the cytokine-induced lethal multiple organ dysfunction syndrome [49].…”

Section: Discussionmentioning

confidence: 99%

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Riedlinger

Bartkuhn

Zimmermann

et al. 2019

Cancers

View full text Add to dashboard Cite

Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNFα-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNFα stimulation led to inducible recruitment of TOP1 to the gene body of IL8, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases.

show abstract

Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway

Cited by 19 publications

References 41 publications

Oxyberberine Prevented Lipopolysaccharide‐Induced Acute Lung Injury through Inhibition of Mitophagy

Oxyberberine Prevented Lipopolysaccharide‐Induced Acute Lung Injury through Inhibition of Mitophagy

Hypoxia-inducible transcription factor-1α inhibition by topotecan protects against lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Contact Info

Product

Resources

About