A novel peptide inhibitor of Dll4‐Notch1 signalling and its pro‐angiogenic functions

Zhu, Guofu; Lin, Ying; Ge, Tandi; Singh, Shekhar; Liu, Hao; Fan, Linlin; Wang, Shumin; Rhen, Jordan; Jiang, Da-Quan; Lyu, Yuanyuan; Yin, Yuzhen; Li, Xiankai; Benoit, Danielle S. W.; Li, Weiming; Xu, Yawei; Pang, Jinjiang

doi:10.1111/bph.15743

Cited by 7 publications

(8 citation statements)

References 59 publications

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“…The results showed that Dll4, Bmpr2, and Nrf2 were highly expressed in endothelial cells. Inhibition of the Dll4-Notch1 pathway promotes excessive sprouts and endothelial proliferation in the retina (Zhu et al, 2022), and the high expression of Bmpr2 is also conducive to regulating excessive angiogenesis. In an experimental model of Bmpr2 knockout, vascular endothelial cell proliferation was observed (Theilmann et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

Wang

Yang

et al. 2022

Front. Mol. Neurosci.

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As the basic pathological changes of diabetic retinopathy (DR), the destruction of the blood-retina barrier (BRB) and vascular leakage have attracted extensive attention. Without timely intervention, BRB damage will eventually lead to serious visual impairment. However, due to the delicate structure and complex function of the BRB, the mechanism underlying damage to the BRB in DR has not been fully clarified. Here, we used single-cell RNA sequencing (RNA-seq) technology to analyze 35,910 cells from the retina of healthy and streptozotocin (STZ)-induced diabetic rats, focusing on the degeneration of the main cells constituting the rat BRB in DR and the new definition of two subpopulations of Müller cells at the cell level, Ctxn3+Müller and Ctxn3−Müller cells. We analyzed the characteristics and significant differences between the two groups of Müller cells and emphasized the importance of the Ctxn3+Müller subgroup in diseases. In endothelial cells, we found possible mechanisms of self-protection and adhesion and recruitment to pericytes. In addition, we constructed a communication network between endothelial cells, pericytes, and Müller subsets and clarified the complex regulatory relationship between cells. In summary, we constructed an atlas of the iBRB in the early stage of DR and elucidate the degeneration of its constituent cells and Müller cells and the regulatory relationship between them, providing a series of potential targets for the early treatment of DR.

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

Wang

Yang

et al. 2022

Front. Mol. Neurosci.

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“…Dll4 is the only Notch ligand mainly expressed in endothelial cells, especially in arterial endothelial cells [5]. Different from other ligands, Dll4 is cell contact-dependent and can propagate through positive feedback mechanism through activation of Notch signal [6]. Dll4 gene is located on chromosome 15q14, which is a type I single transmembrane protein composed of 685 amino acids.…”

Section: Dll4 Ligand Structurementioning

confidence: 99%

“…In Dll4 heterozygous mice, the haploid mortality was insufficient due to defects in sprouting angiogenesis and arteriovenous formation. So far, Dll4 is the second gene causing hypo haploid death, and the first gene is vascular endothelial growth factor (VEGF), indicating that Dll4 and VEGF play an indispensable role in angiogenesis 6 . The blocking of DLL4 inhibits tumor growth by regulating tumor angiogenesis, which is characterized by promoting pathological activation of endothelial cells and excessive tumor vascular growth without function [8].…”

Section: Dll4 Ligand Structurementioning

confidence: 99%

“…Notch signaling pathway is initiated when the extracellular domain of Notch ligand expressed on the surface of signaling cells binds to the extracellular domain of Notch receptor expressed on adjacent cells (recipient cells) [14]. After binding to ligands, the receptor undergo conformational changes, which trigger proteolytic activation of the receptor, release the intracellular domain (NICD), translocation into the nucleus [6], and interact with transcription factor RBPJK/CSL and coactivator manipulation protein (MAML) to regulate the expression of target genes [4]. This leads to induction or down-regulation of a variety of downstream targets for Notch signaling, the best downstream targets include the basic helix-loop-helix family of transcriptional inhibitors, cleavage of hairy and enhancers (HECS-1, HECS-5 and HECS-7) and hes1-related (Hey-1, -hey 2 and Hey-L) protein families [3].…”

Section: Notch Signaling Pathwaymentioning

confidence: 99%

“…Dll4-notch signaling pathway plays an important role in angiogenesis, vascular remodeling, and arterial or venous regulation [6]. DLL4-mediated activation of Notch signaling in blood vessels leads to a process known as lateral inhibition, which is critical for regulating branch formation during angiogenesis [20].…”

Section: Interaction and Mechanism Of Dll4-notch-vegfr2 Signaling Pat...mentioning

confidence: 99%

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The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis

Zhou¹,

Duan²,

Xiong³

et al. 2022

CRJ

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Tumor angiogenesis is the center of tumor growth and metastasis, and it increases the supply of nutrients and oxygen to tumors, thereby supporting tumor growth and progression. Vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis and also plays a key role in the process of angiogenesis. Overexpression of VEGF is associated with tumor angiogenesis, promotion of tumor growth and reduced survival rate of patients. Notch signaling is a key pathway that regulates the response to angiogenesis stimulation during embryonic vascular development and postnatal angiogenesis, and is involved in multiple steps of angiogenesis. Dll4 is the only Notch ligand mainly expressed in endothelial cells, which can propagate by activating Notch signal and regulate tumor angiogenesis. Notch signaling pathway and VEGF pathway have both independent and synergistic effects, and Notch is necessary for VEGF-mediated vascular remodeling. The pathways cross each other and jointly regulate tumor angiogenesis. This review reviews the relationship between dLL4-notch-VEGFR2 signaling pathway composition, transduction and regulation and tumor angiogenesis. Combined blocking of DLL4-notch-VEGFR2 signaling pathway can significantly reduce vascular perfusion, resulting in vascular degeneration and reduced tumor survival. It can destroy the vascular system and survival ability of the primary tumor more than blocking alone, thus providing a new idea for the treatment of tumor, which is of great significance for the future anti-angiogenesis therapy.

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Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP‐J/NRF2/FDX1 pathway

Zhang,

Shi,

et al. 2024

Molecular Carcinogenesis

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Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1‐propyl‐3,5‐bis(2‐bromobenzylidene)‐4‐piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit‐8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP‐J) and nuclear factor erythroid 2‐related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP‐J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP‐J resulted in the enrichment of RBP‐J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

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A novel peptide inhibitor of Dll4‐Notch1 signalling and its pro‐angiogenic functions

Cited by 7 publications

References 59 publications

Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis

Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP‐J/NRF2/FDX1 pathway

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