Identification of critical endoplasmic reticulum stress-related genes in advanced atherosclerotic plaque

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 15, 2025

Atherosclerosis (AS) is the principal pathological cause of atherosclerotic cardiovascular diseases. Chronic endoplasmic reticulum stress (ERS) has been implicated in AS aetiopathogenesis, but underlying molecular interactions remain unclear. This study aims to identify mechanisms ERS pathogenesis inform innovative diagnostic approaches and therapeutic targets for managing AS. GSE28829 GSE43292—human early advanced carotid tissue samples—were obtained from Gene Expression Omnibus database. Endoplasmic stress-related genes (ERSRGs) were GeneCards. Differential gene expression weighted co-expression network analyses conducted associated with atherosclerosis, intersection ER-related revealed three ERSRGs (i.e. CTSB, LYN, CYBB) plaque. These exhibited associations various immune cells. Additionally, upregulated human tissues, mouse models progressive lesions, vitro macrophage models. In conclusion, this identified CYBB as potentially critical plaque, demonstrating their good utility offering novel insights into potential pathobiology progression, paving way exploring targets.

Language: Английский

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IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(13), P. 4181 - 4203

Published: Jan. 1, 2023

The effective approach to discover innovative drugs will ask natural products for answers because of their complex and changeable structures multiple biological activities.Inhibitory kappa B kinase beta (IKKβ), known as IKK2, is a key regulatory responsible the activation NF-κB through its phosphorylation at Ser177 Ser181 promote inhibitors (IκBs), triggering ubiquitination degradation active nuclear factor kappa-B (NF-κB) cascade.Chemical inhibition IKKβ or genetic knockout has become an method block NF-κB-mediated proliferation migration tumor cells inflammatory response.In this review, we summarized structural feature transduction mechanism discovery from resources (e.g.sesquiterpenoids, diterpenoids, triterpenoids, flavonoids, alkaloids) chemical synthesis (e.g.pyrimidines, pyridines, pyrazines, quinoxalines, thiophenes, thiazolidines).In addition, biosynthetic pathway novel potentials were discussed.This review provide inspiration modification based on skeleton further phytochemistry investigations.

Language: Английский

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Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(5)

Published: March 10, 2023

Abstract Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), microtubule‐associated protein kinase, involved in neurogenesis human cancers. However, the role of DCLK1 atherosclerosis remains undefined. In this study, we identified upregulated macrophages atherosclerotic lesions ApoE −/− mice fed an HFD determined that macrophage‐specific deletion attenuates by reducing inflammation mice. Mechanistically, RNA sequencing analysis indicated mediates oxLDL‐induced via NF‐κB signaling pathway primary macrophages. Coimmunoprecipitation followed LC–MS/MS IKKβ as binding DCLK1. We confirmed directly interacts phosphorylates at S177/181, thereby facilitating subsequent activation gene expression Finally, pharmacological inhibitor prevents progression both vitro vivo. Our findings demonstrated macrophage promotes to activating IKKβ/NF‐κB. This study reports new regulator potential therapeutic target for atherosclerosis.

Language: Английский

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Shared signaling pathways and comprehensive therapeutic approaches among diabetes complications

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 8, 2025

The growing global prevalence of diabetes mellitus (DM), along with its associated complications, continues to rise. When clinically detected most DM complications are irreversible. It is therefore crucial detect and address these early systematically in order improve patient care outcomes. current clinical practice often prioritizes by addressing one complication while overlooking others that could occur. proposed the commonly targeted cell types including vascular cells, immune glial fibroblasts mediate might share responses diabetes. In addition, impact be influenced other complications. Recognizing focusing on shared among impacted cellular constituents, will allow simultaneously all DM-related limit adverse treatment impacts. This review explores understanding pathological signaling mechanisms recognizes new concepts benefit from further investigation both basic settings. ultimate goal develop more comprehensive strategies, which effectively multiple organs

Language: Английский

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Roles of pyroptosis in atherosclerosis pathogenesis

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 166, P. 115369 - 115369

Published: Aug. 27, 2023

Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin protein-mediated membrane pore formation, swelling, and rapid lysis. Recent studies have suggested that pyroptosis closely related to atherosclerosis (AS). Previous reported involving endothelial cells (ECs), macrophages, smooth muscle (SMCs) plays an important role in the formation development AS. not only causes local inflammation but also amplifies inflammatory response it aggravates plaque instability, leading rupture thrombosis, eventually resulting acute cardiovascular events. In this review, we clarified some novel pathways mechanics presented potential drugs.

Language: Английский

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Natural product/diet-based regulation of macrophage polarization: Implications in treatment of inflammatory-related diseases and cancer

The Journal of Nutritional Biochemistry, Journal Year: 2024, Volume and Issue: 130, P. 109647 - 109647

Published: April 10, 2024

Language: Английский

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DCLK1 in gastrointestinal cancer: A driver of tumor progression and a promising therapeutic target

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 8, 2025

Cancers of the gastrointestinal (GI) tract, including colorectal, pancreatic, and hepatocellular carcinomas, represent a significant global health burden due to their high incidence mortality rates. Doublecortin-like kinase 1 (DCLK1), initially identified for its role in neurogenesis, has emerged as crucial player GI cancer progression. This review comprehensively examines multifaceted roles DCLK1 cancers, focusing on structural isoforms, functions normal inflammatory states, contributions progression metastasis. is overexpressed various cancers associated with poor prognosis, enhanced tumorigenic potential, increased metastatic capacity. The discusses molecular mechanisms through which influences stem cell maintenance, epithelial-mesenchymal transition (EMT), survival pathways, well interactions key signaling pathways such Notch, WNT/β-catenin, NF-κB. potential therapeutic target also explored, highlighting preclinical early clinical efforts inhibit function using small molecule inhibitors or monoclonal antibodies. Despite advancements, further research needed fully elucidate DCLK1's develop effective strategies targeting this protein.

Language: Английский

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Epigenetic upregulation of CLEC5A contributes to monocyte/macrophage dysfunction in coronary artery disease

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142471 - 142471

Published: March 1, 2025

Language: Английский

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A New Insight on Atherosclerosis Mechanism and Lipid-Lowering Drugs

Reviews in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: 26(3)

Published: March 5, 2025

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries, involving complex pathological mechanisms such as inflammatory responses, lipid metabolism disorders plaque formation. In recent years, several emerging research hotspots have appeared in the field of atherosclerosis, including gut microbiota, pyroptosis, ferroptosis, autophagy, cuproptosis, exosomes non-coding RNA. Traditional lipid-lowering drugs play crucial role treatment AS but are not able to significantly reverse changes. This article aims summarize latest progress pathogenesis diagnosis by comprehensively analyzing relevant literature mainly from past five years. Additionally, action advances statins, cholesterol absorption inhibitors, fibrates novel reviewed provide new insights into AS.

Language: Английский

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Macrophage WEE1 Directly Binds to and Phosphorylates NF‐κB p65 Subunit to Induce Inflammatory Response and Drive Atherosclerosis

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Abstract Atherosclerosis has an urgent need for new therapeutic targets. Protein kinases orchestrate multiple cellular events in atherosclerosis and may provide targets atherosclerosis. Here, a protein kinase, WEE1 G2 checkpoint kinase (WEE1), promoting inflammation is identified. Kinase enrichment analysis experimental evidences reveal macrophage phosphorylation at S642 human mouse atherosclerotic tissues. RNA‐seq analysis, combined with experiment studies using mutant plasmids, shows that phosphorylation, rather than expression, mediated oxLDL‐induced macrophages. Macrophage‐specific deletion of or pharmacological inhibition activity attenuates by reducing mice. Mechanistically, co‐immunoprecipitation followed proteomics are used to explore the mechanism substrate WEE1. p‐WEE1 promoted inflammatory response through activating NF‐κB shown further revealed can directly bind p65 subunit. It confirmed interacts RHD domain phosphorylates S536, thereby facilitating subsequent activation The findings demonstrate drives phosphorylating S536. This study identifies as upstream potential target

Language: Английский

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