Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.
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Therapeutic Suppression of Atherosclerotic Burden and Vulnerability via Inhibition in Plaque Macrophages Using Dual-Targeted Liposomes.
ACS Appl Bio Mater
November 2024
Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
Atherosclerosis, characterized by chronic inflammation within the arterial wall, remains a pivotal concern in cardiovascular health. We developed a dual-targeted liposomal system encapsulating Dll4-targeting siRNA, designed to selectively bind to pro-inflammatory M1 macrophages through surface conjugation with anti-F4/80 and anti-CD68 antibodies. The Dll4-targeting siRNA is then delivered to the macrophages, where it silences Dll4 expression, inhibiting Notch signaling and reducing plaque vulnerability.
View Article and Find Full Text PDFAstrocytic DLL4-NOTCH1 signaling pathway promotes neuroinflammation via the IL-6-STAT3 axis.
J Neuroinflammation
October 2024
Univ. Bordeaux, INSERM, Biology of Cardiovascular Diseases, U1034, 01 avenue de Magellan, Pessac, 33601, France.
Article Synopsis
- Under neuroinflammatory conditions, astrocytes adopt a reactive phenotype that exacerbates inflammation and contributes to neurodegeneration, with the study focusing on the role of astrocytic DLL4 and its interaction with NOTCH1 in regulating this reactivity.
- The research found that during neuroinflammation, DLL4 is upregulated in both mice and humans, leading to increased astrocyte reactivity, blood-brain barrier permeability, and inflammatory responses through the DLL4-NOTCH1 signaling pathway.
- Blocking DLL4 with antibodies showed promise in alleviating symptoms of experimental autoimmune encephalomyelitis in mice, suggesting a new potential therapeutic approach for treating CNS autoimmune diseases.
Neutrophil extracellular traps activate Notch-γ-secretase signaling in hidradenitis suppurativa.
J Allergy Clin Immunol
January 2025
Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md. Electronic address:
Background: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring, and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized.
Objective: We aimed to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase signaling.
Environmentally relevant concentrations of benzophenones exposure disrupt intestinal homeostasis, impair the intestinal barrier, and induce inflammation in mice.
Environ Pollut
June 2024
School of Public Health, Ningxia Medical University, Yinchuan, 750004, Ningxia, China; The Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, 750004, Ningxia, China. Electronic address:
The aim of this study is to investigate the adverse effects of benzophenones (BPs) on the intestinal tract of mice and the potential mechanism. F1-generation ICR mice were exposed to BPs (benzophenone-1, benzophenone-2, and benzophenone-3) by breastfeeding from birth until weaning, and by drinking water after weaning until maturity. The offspring mice were executed on postnatal day 56, then their distal colons were sampled.
View Article and Find Full Text PDFUpregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients.
Int J Mol Sci
March 2024
Department of Clinical and Biological Sciences, Severe Asthma and Rare Lung Disease Unit, San Luigi Gonzaga University Hospital, University of Turin, 10043 Orbassano, Italy.
Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses.
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