Monoacylglycerol lipase (MAGL) as a promising therapeutic target

Gil-Ordóñez, Ana; Martín‐Fontecha, Mar; Ortega-Gutiérrez, Sílvia; López-Rodrı́guez, Marı́a L.

doi:10.1016/j.bcp.2018.07.036

Cited by 92 publications

(95 citation statements)

References 150 publications

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“…Although CB1 and CB2 are the most extensively studied proteins of ECS, there are also important factors regarding other molecular targets. In the case of eCB degrading enzymes, MAGL and FAAH, it is important to distinguish between reversible and irreversible inhibition [66,67]. For MAGL, it was shown that its irreversible inhibitors, through prolonged inactivation of this enzyme, may cause physical dependence, CB1 desensitization, and impaired eCB-dependent synaptic plasticity [68].…”

Section: Molecular Mechanisms Of the Main Proteins Of Ecs-implicationmentioning

confidence: 99%

“…For MAGL, it was shown that its irreversible inhibitors, through prolonged inactivation of this enzyme, may cause physical dependence, CB1 desensitization, and impaired eCB-dependent synaptic plasticity [68]. Moreover, MAGL and FAAH form homodimers [66,69]. Recently, FAAH dimers have been proven to be dependent on the signaling between their subunits and its allosteric regulation.…”

Section: Molecular Mechanisms Of the Main Proteins Of Ecs-implicationmentioning

confidence: 99%

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A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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Section: Molecular Mechanisms Of the Main Proteins Of Ecs-implicationmentioning

confidence: 99%

Section: Molecular Mechanisms Of the Main Proteins Of Ecs-implicationmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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“…MAGL, a member of the serine hydrolase superfamily, is a key enzyme in the production of free fatty acids (FFA) in lipid metabolism via its hydrolysis of triglycerides. Previous research has shown that MAGL plays an essential role in many pathological and physiological processes, such as inflammation, pain, neuroprotection, neurodegenerative disorders, metabolic disorders and cancer . In addition, recently, an increasing number of scholars have paid attention to the role of MAGL in lipid metabolism and tumor development.…”

Section: Introductionmentioning

confidence: 99%

“…Previous research has shown that MAGL plays an essential role in many pathological and physiological processes, such as inflammation, pain, neuroprotection, neurodegenerative disorders, metabolic disorders and cancer. 8,9 In addition, recently, an increasing number of scholars have paid attention to the role of MAGL in lipid metabolism and tumor development. In cancer cells, MAGL hydrolyzes triglycerides into FFA and induces an increase in a series of lipid signaling molecules, such as lysophosphatidic acid (LPA), prostaglandin E2 (PGE2), lysophospholipid , lysophosphatidyl ethanolamine and phosphatidic acid ; some of these molecules (LPA and PGE2) induce carcinogenesis and tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Effect of monoacylglycerol lipase on the tumor growth in endometrial cancer

Gao

et al. 2019

J of Obstet and Gynaecol

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Aim Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth. Methods Immunohistochemistry and quantitative real‐time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real‐time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro. Results We found that MAGL was overexpressed in EC and was significantly correlated with surgical‐pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA‐mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl‐2. Conclusion In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.

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“…Remarkably, FAAH and MAGL inhibition also reduces arachidonic acid, a key precursor of pro-inflammatory prostaglandins and thromboxanes. FAAH and MAGL inhibitors may have a large number of therapeutic applications, including pain, nausea, neurodegenerative pathologies, inflammation, metabolic disorders, and cancer [31,32].…”

Section: The Human Ecsmentioning

confidence: 99%

The Role of Cannabinoids in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2020

Angelina

Pérez‐Diego

López‐Abente

et al. 2020

Int Arch Allergy Immunol

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The human endocannabinoid system (ECS) is a complex signalling network involved in many key physiological processes. The ECS includes the cannabinoid receptors, the endocannabinoid ligands, and the enzymes related to their synthesis and degradation. Other cannabinoids encompass the phytocannabinoids from Cannabis sativa L. (marijuana) and the synthetic cannabinoids. Alterations in the ECS are associated with different diseases, including inflammatory and immune-mediated disorders such as allergy. Allergy is a global health problem of increasing prevalence with high socioeconomic impact. Different studies have convincingly demonstrated that cannabinoids play a role in allergy, but their actual contribution is still controversial. It has been shown that cannabinoids exert anti-inflammatory properties in the airways and the skin of allergic patients. Other studies reported that cannabinoids might exacerbate asthma and atopic dermatitis mainly depending on CB2-mediated signalling pathways. A better understanding of the molecular mechanisms involved in the mode of action of specific cannabinoids and cannabinoid receptors on relevant immune cells under different biological contexts might well contribute to the design of novel strategies for the prevention and treatment of allergic diseases. Future research in this promising emerging field in the context of allergy is warranted for the upcoming years.

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Monoacylglycerol lipase (MAGL) as a promising therapeutic target

Cited by 92 publications

References 150 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

Effect of monoacylglycerol lipase on the tumor growth in endometrial cancer

The Role of Cannabinoids in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2020

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