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Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.

ABSTRACT: The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.

SUBMITTER: Wang B

PROVIDER: S-EPMC7910446 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.

Wang Bei B Wu Lujin L Chen Jing J Dong Lingli L Chen Chen C Wen Zheng Z Hu Jiong J Fleming Ingrid I Wang Dao Wen DW

Signal transduction and targeted therapy 20210226 1

The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic a ...[more]

PMID: 33637672

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Project description:BackgroundIntervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the sole recourse in severe cases. The metabolic pathway of arachidonic acid (AA), a pivotal regulator of inflammatory responses, influences the development and progression of IVDD.MethodsInitially, a comparative analysis was conducted to investigate the relationship between AA expression patterns and different stages of IVDD using single-cell sequencing (scRNA-seq) data. Additionally, three machine learning methods (LASSO, random forest, and support vector machine recursive feature elimination) were employed to identify hub genes associated with IVDD. Subsequently, a novel artificial intelligence prediction model was developed for IVDD based on an artificial neural network algorithm and validated using an independent dataset. The identified hub genes were further subjected to functional enrichment, immune infiltration, and Connectivity Map analysis. Moreover, external validation was performed using flow cytometry and real-time reverse transcription polymerase chain reaction analysis.ResultsBoth scRNA-seq and bulk RNA-seq data revealed a positive correlation between the severity of IVDD and the AA metabolic pathway. They also revealed increased AA metabolic activity in macrophages and neutrophils, as well as enhanced intercellular communication with nucleus pulposus cells. Utilizing advanced machine learning algorithms, five hub genes (AKR1C3, ALOX5, CYP2B6, EPHX2, and PLB1) were identified, and an incipient diagnostic model was developed with an AUC of 0.961 in the training cohort and 0.72 in the validation cohort. An in-depth exploration of the functionality of these hub genes revealed their notable association with inflammatory responses and immune cell infiltration. Lastly, AH6809 was found to delay IVDD by inhibiting AKR1C3.ConclusionsThis study offers comprehensive insights into potential biomarkers and small molecules associated with the early pathogenesis of IVDD. The identified biomarkers and the developed integrated diagnostic model hold great promise in predicting the onset of early IVDD. AH6809 was established as a therapeutic target for AKR1C3 in the treatment of IVDD, as evidenced by computer simulations and biological experiments.

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Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.

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Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.

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