bims-noxint 2021-07-18 papers

Issue of 2021–07–18
three papers selected by
Laia Caja Puigsubira, Uppsala University

Int Immunopharmacol. 2021 Mar 18. pii: S1567-5769(20)33677-8. [Epub ahead of print] 107210

Poncirin ameliorates oxygen glucose deprivation/reperfusion injury in cortical neurons via inhibiting NOX4-mediated NLRP3 inflammasome activation.

Ruili Wang, Lei Li, Baogong Wang.

Poncirin, a natural flavonoid present abundantly in citrus fruits, possesses anti-oxidant and anti-inflammatory activities that contribute to neuroprotection, but its roles and mechanisms in neuronal injury is still poorly understood. In this study, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in primary cortical neurons to induce neuronal injury in vitro. Poncirin effectively attenuated OGD/R-induced neuronal damage by enhancing cell viability, restraining lactate dehydrogenase release, and reducing apoptosis of neurons. Poncirin restrained mitochondrial dysfunction and oxidative stress by increasing mitochondrial membrane potential, declining reactive oxygen species production, lessening malondialdehyde generation, and increasing the activities of antioxidant enzymes in OGD/R-treated neurons. Poncirin also repressed inflammatory responses by reducing the secretion of pro-inflammatory factors, and inhibiting NLRP3 inflammasome activation. Importantly, poncirin administration notably abolished OGD/R-induced upregulation of NADPH oxidase 4 (NOX4), and overexpression of NOX4 neutralized poncirin-mediated neuroprotection. In conclusion, poncirin protects cortical neurons from OGD/R injury via inhibiting NOX4/ROS/NLRP3 axis.

Keywords: NLRP3; NOX4; Oxygen-glucose deprivation/reperfusion; Poncirin

DOI: https://doi.org/10.1016/j.intimp.2020.107210

Clin Sci (Lond). 2021 Jul 16. pii: CS20210468. [Epub ahead of print]

Lysophosphatidylcholine induces oxidative stress in human endothelial cells via NOX5 activation - implications in atherosclerosis.

Josiane Fernandes da Silva, Juliano V Alves, Julio A Silva-Neto, Rafael Menezes Costa, Karla Bianca Neves, Rheure Alves-Lopes, Livia De Lucca Camargo, Francisco Rios, Augusto C Montezano, Rhian M Touyz, Rita C Tostes.

OBJECTIVE: The mechanisms involved in NOX5 activation in atherosclerotic processes are not completely understood. This study tested the hypothesis that lysophosphatidylcholine (LPC), a proatherogenic component of oxLDL, induces endothelial calcium influx, which drives NOX5-dependent reactive oxygen species (ROS) production, oxidative stress, and endothelial cell dysfunction. Approach: Human aortic endothelial cells (HAEC) were stimulated with LPC (10-5 M, for different time points). Pharmacological inhibition of NOX5 (Melittin, 10-7 M) and NOX5 gene silencing (siRNA) were used to determine the role of NOX5-dependent ROS production in endothelial oxidative stress induced by LPC. ROS production was determined by lucigenin assay and electron paramagnetic spectroscopy (EPR), calcium transients by Fluo4 fluorimetry, and NOX5 activity and protein expression by pharmacological assays and immunoblotting, respectively.
RESULTS: LPC increased ROS generation in endothelial cells at short (15 min) and long (4 h) stimulation times. LPC-induced ROS was abolished by a selective NOX5 inhibitor and by NOX5 siRNA. NOX1/4 dual inhibition and selective NOX1 inhibition only decreased ROS generation at 4 h. LPC increased HAEC intracellular calcium, important for NOX5 activation, and this was blocked by nifedipine and thapsigargin. Bapta-AM, selective Ca2+ chelator, prevented LPC-induced ROS production. NOX5 knockdown decreased LPC-induced ICAM-1 mRNA expression and monocyte adhesion to endothelial cells.
CONCLUSION: These results suggest that NOX5, by mechanisms linked to increased intracellular calcium, is key to early LPC-induced endothelial oxidative stress and pro-inflammatory processes. Since these are essential events in the formation and progression of atherosclerotic lesions, this study highlights an important role for NOX5 in atherosclerosis.

Keywords: Endothelial cells; Lysophosphatidylcholine; NADPH oxidase; NOX5; Oxidative stress

DOI: https://doi.org/10.1042/CS20210468

Oxid Med Cell Longev. 2021 ;2021 5549047

NOX4-Derived ROS Mediates TGF-β1-Induced Metabolic Reprogramming during Epithelial-Mesenchymal Transition through the PI3K/AKT/HIF-1α Pathway in Glioblastoma.

Xiangsheng Su, Yihang Yang, Changfa Guo, Rui Zhang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Yibing Fu, Qi Pang.

Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-β1 (TGF-β1) released from TME plays a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-β1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-β1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-β1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-β1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1α (HIF-1α) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-β1-induced metabolic changes and tumorigenesis. Moreover, TGF-β1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1α signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-β1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.

DOI: https://doi.org/10.1155/2021/5549047