A novel NADPH oxidase inhibitor targeting Nox4 in TGFβ-induced lens epithelial to mesenchymal transition

Das, Shannon; Wikström, Pernilla; Walum, Erik; Lovicu, Frank J.

doi:10.1016/j.exer.2019.107692

Cited by 12 publications

(11 citation statements)

References 25 publications

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“…Together, these results confirmed that TGF β induces EMT in HLE cells as previously reported. [ 27–52 ] Moreover, our results demonstrated that TGF β also suppressed a panel of epithelial cell markers (Figure S3B, Supporting Information), and upregulates numerous other EMT markers including EMT transcription factors such as SNAI1 and SNAI2 and different members of the collagen and extracellular matrix (ECM) family proteins (Figure S3C–E, Supporting Information).…”

Section: Resultsmentioning

confidence: 81%

“…EMT plays an important role during embryonic development, and moreover, it is one of the most prominent biological activities during the progression of various diseases, including fibrosis and tumor metastasis. [ 25–52,58–68 ] Mechanistically, EMT is characteristic of reprogramming the gene expression profile, which involves prominent chromatin modifications. [ 1 ] It has been well established that different signaling pathways mediate EMT in the ocular lens.…”

Section: Discussionmentioning

confidence: 99%

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MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

Zhang

Hou

et al. 2022

Advanced Science

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The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2-S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT-EZH2 axis is important in TGF𝜷-induced epithelial-mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2-S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2-S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2-S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation.

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

Zhang

Hou

et al. 2022

Advanced Science

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“…In vitro studies report that GLX7013114 may protect against cell death, enhanced by either a combination of high glucose and palmitate concentrations or the presence of cytokines . Furthermore, it was shown to negatively interfere with transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition in mice . This compound appears to be an excellent tool for NOX4-specific studies due to its high specificity and reported absence of off-target activity.…”

Section: Small-molecule Inhibitors Of Ros Productionmentioning

confidence: 99%

“…141 Furthermore it was shown to negatively interfere with transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition in mice. 142 This compound appears to be an excellent tool for NOX4-specific studies due to its high specificity and reported absence of off-target activity. NOX1 134 Active in NOX2, NOX3, NOX4 and NOX5 (marginal activity) 134 Cancer (NOX1 overexpression) 134 GSK2795039 (25)…”

Section: Site-specific Ros Inhibitorsmentioning

confidence: 99%

Small-Molecule Inhibitors of Reactive Oxygen Species Production

2021

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Reactive oxygen species (ROS) are involved in physiological cellular processes including differentiation, proliferation, and apoptosis by acting as signaling molecules or regulators of transcription factors. The maintenance of appropriate cellular ROS levels is termed redox homeostasis, a balance between their production and neutralization. High concentrations of ROS may contribute to severe pathological events including cancer, neurodegenerative, and cardiovascular diseases. In recent years, approaches to target the sources of ROS production directly in order to develop tool compounds or potential therapeutics have been explored. Herein, we briefly outline the major sources of cellular ROS production and comprehensively review the targeting of these by small-molecule inhibitors. We critically assess the value of ROS inhibitors with different mechanisms-of-action, including their potency, mode-of-action, known off-target effects, and clinical or preclinical status, while suggesting future avenues of research in the field.

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“…[4] The diamino-1,3,5-triazine scaffold has also been used for the development of diverse bioactive compounds. [5] Inhibitors of the NADPH oxidase 4, [6,7] RAD6 ubiquitin-conjugating enzyme, [8] Burton's tyrosine kinase, [9] and lysophosphatidic acid transferase β [10] were identified among diamino-substituted 1,3,5triazines. Compounds with this skeleton have also been found to possess anticancer activity [11][12][13][14][15] and 5-HT 6 -receptor antagonism with procognitive properties.…”

Section: Introductionmentioning

confidence: 99%

One‐Pot Multicomponent Synthesis of Bis(diamino‐1,3,5‐triazines) under Microwave Irradiation

2022

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A new method for the synthesis of bis(1,3,5‐triazine‐2,4‐diamines) was developed using a one‐pot multicomponent approach. The synthesis was performed using the acid‐catalyzed reaction of cyanoguanidine with amines and aldehydes, followed by dehydrogenative aromatization of the dihydrotriazine intermediates upon heating with alkali. Two types of bis(1,3,5‐triazine‐2,4‐diamines) were prepared using either piperazine as the bifunctional amine or terephthaldehyde as the bifunctional aldehyde thus affording products with a piperazine or p‐phenylene link between two 1,3,5‐triazine rings. The microwave‐assisted method allows fast and convenient synthesis of diverse bis(1,3,5‐triazine‐2,4‐diamines).

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A novel NADPH oxidase inhibitor targeting Nox4 in TGFβ-induced lens epithelial to mesenchymal transition

Cited by 12 publications

References 25 publications

MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

Small-Molecule Inhibitors of Reactive Oxygen Species Production

One‐Pot Multicomponent Synthesis of Bis(diamino‐1,3,5‐triazines) under Microwave Irradiation

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