Targeting autophagy drug discovery: Targets, indications and development trends

Jiang, Mengjia; Wu, Wayne; Xiong, Zijie; Yu, Xiaoping; Ye, Zihong; Wu, Zhiping

doi:10.1016/j.ejmech.2023.116117

European Journal of Medicinal Chemistry

2024

DOI: 10.1016/j.ejmech.2023.116117

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Targeting autophagy drug discovery: Targets, indications and development trends

Mengjia Jiang,

Wayne Wu,

Zijie Xiong

et al.

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Cited by 4 publications

References 582 publications

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BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC

Chavda,

Siwach,

Sabharwal

et al. 2024

ACS Med. Chem. Lett.

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Lysosomal enzymes and high accumulation of lipid droplets are associated with breast cancer. The lysosomes and lipid droplets were monitored by BODIPYs, acting as autophagy activators in cancer cells. BD-1 and BD-2 were synthesized and characterized by Mass, UV−visible, fluorescence, and NMR spectroscopies. In BODIPYs, the effect of carbazole groups was reflected by the large Stokes shifts (2143−1651 cm −1 ) and red fluorescence. BODIPYs generated ROS and induced autophagy in triple negative breast cancer cells (MDA-MB-231) under white light. Confocal experiments revealed that BD-1 and BD-2 preferentially colocalized in lysosomes and lipid droplets. Autophagic lysosomes and lipid droplets released Ca 2+ ions in the cytoplasm, which was evident with blue fluorescence of Fura-2M dye. In combination with an autophagy inhibitor, BD-1 displayed excellent photocytotoxicity (5.57 μM) on triple negative breast cancer cells under white light. This work demonstrates the potential of BODIPYs as theranostic agents for the photodynamic therapy against TNBC.

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BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC

Chavda,

Siwach,

Sabharwal

et al. 2024

ACS Med. Chem. Lett.

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Lipids associated with autophagy: mechanisms and therapeutic targets

Jarocki,

Turek,

Saczko

et al. 2024

Cell Death Discov.

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Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.

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Cinnamaldehyde, A Bioactive Compound from the Leaves of Cinnamomum osmophloeum Kaneh, Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Inhibiting the NLRP3 Inflammasome

Liu,

Wong,

Weng

et al. 2024

Journal of Physiological Investigation

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Inflammatory bowel disease (IBD) comprises a group of idiopathic intestinal disorders, including ulcerative colitis and Crohn’s disease, significantly impacting the quality of life for affected individuals. The effective management of these conditions remains a persistent challenge. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a complex molecular structure, regulates the production of pro-inflammatory cytokines such as interleukin-1β. Abnormal activation of the NLRP3 inflammasome plays a pivotal role in the development of IBD, making it a compelling target for therapeutic intervention. Our research revealed that cinnamaldehyde (CA), a major bioactive compound found in the leaves of Cinnamomum osmophloeum kaneh, demonstrated a remarkable ability to alleviate colitis induced by dextran sulfate sodium (DSS) in a mouse model. This effect was attributed to CA’s ability to downregulate the activation of the NLRP3 inflammasome and reduce the expression of pro-inflammatory mediators in the colon. In the mechanism study, we observed that CA inhibited the NLRP3 inflammasome in macrophages, at least partially, by enhancing the autophagic response, without reducing mitochondrial damage. These findings collectively suggest that CA holds significant potential as a therapeutic agent for enhancing the management of IBD, offering a promising avenue for further research and development.

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Targeting autophagy drug discovery: Targets, indications and development trends

Cited by 4 publications

References 582 publications

BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC

BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC

Lipids associated with autophagy: mechanisms and therapeutic targets

Cinnamaldehyde, A Bioactive Compound from the Leaves of Cinnamomum osmophloeum Kaneh, Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Inhibiting the NLRP3 Inflammasome

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