Notch signaling pathway: architecture, disease, and therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Март 24, 2022

Abstract The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that signaling is an evolutionarily conserved pathway. receptors undergo three cleavages and translocate into the nucleus to regulate transcription of target genes. deeply participates in development homeostasis multiple tissues organs, aberration which results cancerous noncancerous diseases. However, recent indicate outcomes are changeable highly dependent on context. In terms cancers, can both promote inhibit tumor various types cancer. overall performance NOTCH-targeted therapies clinical trials has failed meet expectations. Additionally, mutation been proposed as a predictive biomarker for immune checkpoint blockade therapy many cancers. Collectively, pathway needs be integrally assessed with new perspectives inspire discoveries applications. this review, we focus classical latest findings related illustrate history, architecture, regulatory mechanisms, contributions physiological development, diseases, therapeutic applications microenvironment cancer immunotherapy also highlighted. We hope review will help not only beginners but experts systematically thoroughly understand

Язык: Английский

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Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

Frontiers in Aging Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Фев. 16, 2022

Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and multiple (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there's continuum different intermediate phenotypes between M1 M2, microglia transit from one phenotype to another. release inflammatory mediators induce inflammation neurotoxicity, while M2 anti-inflammatory neuroprotectivity. considered double-edged sword, performing both harmful helpful effects in diseases. Previous studies showed that balancing M1/M2 polarization had promising therapeutic prospect We suggest shifting may significant we focus on the modulation especially by important signal pathways,

Язык: Английский

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NF-κB in biology and targeted therapy: new insights and translational implications

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 4, 2024

Abstract NF-κB signaling has been discovered for nearly 40 years. Initially, was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have that its role can be expanded to variety of mechanisms, biological processes, human diseases, treatment options. In this review, we first scrutinize the research process signaling, summarize composition, activation, regulatory mechanism signaling. We investigate interaction other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, TLR The physiological pathological states well intricate involvement inflammation, immune regulation, tumor microenvironment, are also explicated. Additionally, illustrate how is involved cancers, autoimmune cardiovascular metabolic neurological COVID-19. Further, discuss therapeutic approaches targeting IKK inhibitors, monoclonal antibodies, proteasome nuclear translocation DNA binding TKIs, non-coding RNAs, immunotherapy, CAR-T. Finally, provide an outlook field hope present stereoscopic, comprehensive will inform future clinical practice.

Язык: Английский

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CRISPR/Cas9 therapeutics: progress and prospects

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 16, 2023

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology is the ideal tool of future for treating diseases by permanently correcting deleterious base mutations or disrupting disease-causing genes with great precision and efficiency. A variety efficient Cas9 variants derivatives have been developed to cope complex genomic changes that occur during diseases. However, strategies effectively deliver CRISPR system diseased cells in vivo are currently lacking, nonviral vectors target recognition functions may be focus research. Pathological physiological resulting from disease onset expected serve as identifying factors targeted delivery targets gene editing. Diseases both varied complex, choice appropriate methods different important. Meanwhile, there still many potential challenges identified when targeting CRISPR/Cas9 treatment. This paper reviews current developments three aspects, namely, type, vector, characteristics. Additionally, this summarizes successful examples clinical trials finally describes possible problems associated applications.

Язык: Английский

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Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11

Cancer Research, Год журнала: 2021, Номер 81(20), С. 5217 - 5229

Опубликована: Авг. 12, 2021

Abstract Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 upregulated in lung stem-like cells (CSLC) can be activated stem transcriptional factor SOX2. Mutation of SOX2 binding site promoter reduced expression increased sensitivity ferroptosis cells. Oxidation at Cys265 inhibited its activity decreased the self-renewal capacity CSLCs. Moreover, tumors with high were more resistant ferroptosis, was positively correlated both mouse human tissue. Together, our study provides mechanism which evade suggests oxidation potential target Significance: This uncovers SOX2–SLC7A11 regulatory axis confers

Язык: Английский

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Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Cancer Communications, Год журнала: 2022, Номер 43(1), С. 3 - 41

Опубликована: Ноя. 24, 2022

As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including transforming growth factor-β (TGF-β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer activator transcription (STAT), mitogen-activated protein (MAPK), phosphoinositide 3-kinase (PI3K)/AKT as well factors, hypoxia-inducible (HIF), heat shock 1 (HSF1), P53, Snail, Twist, constitute complex regulatory networks TME to modulate formation, activation, heterogeneity, metabolic characteristics malignant phenotype CAFs. Activated CAFs remodel influence biological processes cells by altering transcriptional secretory characteristics, this modulation partially depends on regulation cascades. The results preclinical clinical trials indicated that therapies targeting pathways demonstrated promising efficacy but were also accompanied some failures (e.g., NCT01130142 NCT01064622). Hence, comprehensive understanding cascades might help us better understand progression may facilitate development more efficient safer stroma-targeted therapies. Here, we review recent advances studies briefly discuss future perspectives CAF research.

Язык: Английский

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Microglia Mediated Neuroinflammation in Parkinson’s Disease

Cells, Год журнала: 2023, Номер 12(7), С. 1012 - 1012

Опубликована: Март 25, 2023

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder seen, especially in elderly. Tremor, shaking, movement problems, and difficulty with balance coordination are among hallmarks, dopaminergic neuronal loss substantia nigra pars compacta of brain aggregation intracellular protein α-synuclein pathological characterizations. Neuroinflammation has emerged as an involving mechanism at initiation development PD. It a complex network interactions comprising immune non-immune cells addition to mediators response. Microglia, resident macrophages CNS, take on leading role regulating neuroinflammation maintaining homeostasis. Under normal physiological conditions, they exist “homeostatic” but upon stimuli, switch “reactive state”. Pro-inflammatory (M1) anti-inflammatory (M2) phenotypes used classify microglial activity each phenotype having its own markers released mediators. When M1 microglia persistent, will contribute various inflammatory diseases, including such In this review, we focus mediated PD also signaling pathways, receptors, involved process, presenting studies that associate microglia-mediated inflammation A better understanding important seeking new therapies for possibly other diseases.

Язык: Английский

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Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Июнь 15, 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation in the brain. Recent studies have revealed critical role of microglia AD pathogenesis. This review provides comprehensive summary current understanding microglial involvement AD, focusing on genetic determinants, phenotypic state, phagocytic capacity, neuroinflammatory response, and impact synaptic plasticity neuronal regulation. Furthermore, recent developments drug discovery targeting are reviewed, highlighting potential avenues for therapeutic intervention. emphasizes essential insights into treatments.

Язык: Английский

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Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 27, 2024

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The receptor ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical signaling transduction. Accumulating evidence indicates that the pathway serves as both an oncogenic factor a tumor suppressor various cancer types. Dysregulation of this promotes epithelial-mesenchymal transition angiogenesis malignancies, closely linked proliferation, invasion, metastasis. Furthermore, contributes maintaining stem-like properties cells, thereby enhancing invasiveness. regulatory metabolic reprogramming microenvironment suggests pivotal involvement balancing suppressive effects. Moreover, implicated conferring chemoresistance cells. Therefore, comprehensive understanding these biological processes crucial developing innovative therapeutic strategies targeting signaling. This review focuses on research progress cancers, providing in-depth insights into potential mechanisms regulation occurrence progression cancer. Additionally, summarizes pharmaceutical clinical trials therapy, aiming offer new human malignancies.

Язык: Английский

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The Notch signaling pathway: a potential target for cancer immunotherapy

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Май 2, 2023

Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated often affects networks controlling oncogenesis tumor progression. Meanwhile, modulate immune cells involved in anti- or pro-tumor responses immunogenicity. A comprehensive understanding these processes help with designing new drugs that target signaling, thereby enhancing effects cancer immunotherapy. Here, we provide an up-to-date overview how intrinsically regulates alterations stromal extrinsically regulate microenvironment (TME). We also discuss potential role immunity mediated gut microbiota. Finally, propose strategies for targeting These include oncolytic virotherapy combined inhibition nanoparticles (NPs) loaded regulators to specifically tumor-associated macrophages (TAMs) repolarize their functions remodel TME, combining specific efficient inhibitors activators checkpoint blockers (ICBs) synergistic anti-tumor therapy, implementing a customized effective synNotch circuit system enhance safety chimeric antigen receptor (CAR) cells. Collectively, this review aims summarize shapes improve

Язык: Английский

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