Explore the vast range of titles available.

Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants’ phenotypes in the nervous system and hindgut during embryogenesis, and found that 10 of the 19 Notch mutants had defects in both lateral inhibition and inductive Notch signaling, showing context dependency. Of these 10 mutants, six accumulated Notch in the endoplasmic reticulum (ER), and these six were located in EGF-like repeats 8–10 or 25. Mutations with cysteine substitutions were not always coupled with ER accumulation. This suggests that certain EGF-like repeats may be particularly susceptible to structural perturbation, resulting in a misfolded and inactive Notch product that accumulates in the ER. Thus, we propose that these EGF-like repeats may be integral to Notch folding.

Pomegranate peel is a kind of traditional Chinese medicine for treating acne. Its main active ingredient is pomegranate peel polyphenols(PPPs), but its mechanism is not clear. Inflammatory response is still the focus of current treatment. Interestingly, Notch signaling is considered to be a key regulator of macrophage activation, which can promote the occurrence and development of Acne vulgaris (AV) by activating nuclear factor kappa-B (NF-κB) to produce a large number of inflammatory factors. This study aims to explore the potential mechanism of PPPs for treating AV. An in-vivo model of acne was established by injecting SD rats with Cutibacterium acnes( . acnes),and the RAW264.7 Cells were induced by lipopolysaccharide(LPS) in vitro. After treatment, the levels of inflammatory factors and Notch/NF-κB signaling pathway were observed. PPPs improved the levels of IL-1α, TNF-α, IL-6, IL-8 and IL-12 in serum and pathological skin lesions of SD rats induced by , and decreased the expression of macrophages in skin lesions. Notch, NF-κB, IL-1α, IL-6, TNF-α protein and mRNA expression and NF-κB phosphorylation were inhibited. PPPs can inhibit Notch/NF-κB signaling pathway, reduce inflammatory response, and exert anti-acne effects.

The Notch signaling pathway plays a key role in angiogenesis and endothelial cell formation, but it remains unclear whether it is involved in vascular repair by endothelial progenitor cells after traumatic brain injury. Therefore, in the present study, we controlled the Notch signaling pathway using overexpression and knockdown constructs. Activation of the Notch signaling pathway by Notch1 or Jagged1 overexpression enhanced the migration, invasiveness and angiogenic ability of endothelial progenitor cells. Suppression of the Notch signaling pathway with Notch1 or Jagged1 si RNAs reduced the migratory capacity, invasiveness and angiogenic ability of endothelial progenitor cells. Activation of the Notch signaling pathway in vivo in a rat model of mild traumatic brain injury promoted neurovascular repair. These findings suggest that the activation of the Notch signaling pathway promotes blood vessel formation and tissue repair after brain trauma.

The Notch signaling pathway, known to be a highly conserved signaling pathway in embryonic development and adult tissue homeostasis, participates in cell fate decisions that include cellular differentiation, cell survival and cell death. However, other studies have shown that aberrant in Notch signaling is pro-tumorigenic, particularly in hepatocellular carcinoma (HCC). HCC is one of the most common malignant tumors in the world and has a high mortality rate. Growing evidence supports that Notch signaling plays a critical role in the development of HCC by regulating the tumor microenvironment, tumorigenesis, progression, angiogenesis, invasion and metastasis. Accordingly, overexpression of Notch is closely associated with poor prognosis in HCC. In this review, we focus on the pro-tumorigenic role of Notch signaling in HCC, summarize the current knowledge of Notch signaling and its role in HCC development, and outline the therapeutic potential of targeting Notch signaling in HCC.

Ca2＋ channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I （HWTX-I）, a spider peptide toxin that blocks Ca2＋ channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I ＋ aerobic exercise group. The combined effects of HWTX I and exercise were superior to HWTX-I or aerobic exercise alone. HWTX-I effectively activated the Notch signal transduction pathway in brain tissue. Aerobic exercise up-regulated synaptophysin mRNA expression. These results demonstrated that aerobic exercise, in combination with HWTX-I, effectively relieved neuronal injury induced by chronic cerebral ischemia via the Notch signaling pathway and promoting synaptic regeneration.

Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.

[This corrects the article DOI: 10.3389/fphar.2021.671152.].

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma characterized by dual hepatocytic and cholangiocytic differentiation. Accurate diagnosis remains challenging, and the underlying molecular mechanisms that could inform treatment and prognostic predictions are not fully understood. The Notch signaling pathway has been implicated in the carcinogenesis and tumor biology of cHCC-CCA, yet its role has not been comprehensively investigated. In this study, we analyzed 35 cHCC-CCA, 38 hepatocellular carcinoma (HCC), and 32 intrahepatic cholangiocarcinoma (CCA) samples using immunohistochemistry and RNA sequencing. Compared to HCC and CCA, cHCC-CCA exhibited elevated expression of NOTCH1 and its downstream targets (HES5, ASCL1, and HES1). Based on NOTCH1 and HES5 expression levels, cHCC-CCA tumors were stratified into three subgroups: Group 1 (Notch inactivated; low NOTCH1, variable HES5), Group 2 (Notch-responsive; high NOTCH1 and HES5), and Group 3 (Notch-unresponsive; high NOTCH1, low HES5). Notch-responsive tumors (Group 2) displayed the most aggressive biological characteristics, including higher rates of vascular invasion and significantly poorer progression-free survival. Transcriptomic analyses revealed that the molecular profiles of Group 2 cHCC-CCA resembled those of CCA, further confirming Notch signaling activation and identifying enriched pathways associated with increased tumor invasiveness and poor prognosis. These findings highlight the significant heterogeneity within cHCC-CCA and emphasize the potential of NOTCH1 and HES5 as biomarkers for subgroup classification. Moreover, these subgroups offer actionable insights into targeted therapies, including Notch pathway inhibitors, particularly for Notch-responsive tumors.

NG2 cells are highly proliferative glial cells that can self-renew or differentiate into oligodendrocytes, promoting remyelination. Following demyelination, the proliferative and differentiation potentials of NG2 cells increase rapidly, enhancing their differentiation into functional myelinating cells. Levels of the transcription factors Olig1 and Olig2 increase during the differentiation of NG2 cells and play important roles in the development and repair of oligodendrocytes. However, the ability to generate new oligodendrocytes is hampered by injury-related factors (e.g., myelin fragments, Wnt and Notch signaling components), leading to failed differentiation and maturation of NG2 cells into oligodendrocytes. Here, we review Notch signaling as a negative regulator of oligodendrocyte differentiation and discuss the extracellular ligands, intracellular pathways, and key transcription factors involved.

Myocardial infarction (MI) is a pathological process, evidencing as massive death of cardiomyocytes associated with hypoxic and oxidative stress. The formation of areas of fibrosis ultimately leads to heart failure. There are some mechanisms that contribute to the functional repair of the heart. In most mammals, including humans, the Notch signaling pathway has cardioprotective effects. It is involved in the formation of the heart in embryogenesis and in the restoration of cardiac function after MI due to: (1) reducing oxidative stress; (2) prevention of apoptosis; (3) regulation of inflammation; (4) containment of fibrosis and hypertrophy of cardiomyocytes; (5) tissue revascularization; and (6) regulation of proliferation and differentiation of cardiomyocytes. In addition, the Notch signaling pathway interacts with other signaling cascades involved in the pathogenesis of MI and subsequent cardiac repair. In this review, we consider the Notch signaling pathway as a potential target for therapeutic approaches aimed at improving cardiac recovery after MI.