Cannabinol modulates the endocannabinoid system and shows TRPV1‐mediated anti‐inflammatory properties in human keratinocytes

IF 5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

BioFactors Pub Date : 2024-09-14 DOI:10.1002/biof.2122

Camilla Di Meo, Daniel Tortolani, Sara Standoli, Francesca Ciaramellano, Beatrice Clotilde Angelucci, Annamaria Tisi, Salam Kadhim, Eric Hsu, Cinzia Rapino, Mauro Maccarrone

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Abstract

Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide‐inflamed human keratinocytes (HaCaT cells). CBN was found to increase the expression of cannabinoid receptor 1 (CB1) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2‐arachidonoylglicerol (2‐AG), by increasing the activities of N‐acyl phosphatidylethanolamines‐specific phospholipase D (NAPE‐PLD) and fatty acid amide hydrolase (FAAH)—the biosynthetic and degradative enzyme of AEA—and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2‐AG. CBN also affected keratinocyte inflammation by reducing the release of pro‐inflammatory interleukin (IL)‐8, IL‐12, and IL‐31 and increasing the release of anti‐inflammatory IL‐10. Of note, the release of IL‐31 was mediated by TRPV1. Finally, the mitogen‐activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS‐directed drugs. Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti‐inflammatory effects—remarkably via TRPV1—in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes.

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大麻酚调节内源性大麻素系统，在人类角质细胞中显示出 TRPV1 介导的抗炎特性

大麻酚（CBN）是大麻的一种次级代谢产物，其对人类皮肤炎症性疾病的有益活性已引起越来越多的关注。在此，我们试图研究 CBN 对正常和脂多糖炎症人角质细胞（HaCaT 细胞）中内源性大麻素系统（ECS）主要元素的可能调节作用。研究发现，CBN 在基因水平上增加了大麻素受体 1（CB1）的表达，在蛋白水平上增加了香草素受体 1（TRPV1）的表达，并提高了它们的功能活性。此外，CBN 还通过提高 N-酰基磷脂酰乙醇胺特异性磷脂酶 D（NAPE-PLD）和脂肪酸酰胺水解酶（FAAH）--AEA 的生物合成酶和降解酶--以及单酰基甘油脂肪酶（MAGL）--2-AG 的水解酶--的活性，调节了安乃近（AEA）和 2-AG（2-arachidonoylglicerol）的代谢。CBN 还能减少促炎性白细胞介素 (IL)-8、IL-12 和 IL-31 的释放，增加抗炎性 IL-10 的释放，从而影响角质细胞的炎症反应。值得注意的是，IL-31 的释放是由 TRPV1 介导的。最后，对发炎角质细胞中的丝裂原活化蛋白激酶（MAPK）信号通路进行了研究，结果表明，无论是否存在不同的 ECS 定向药物，在使用 CBN 治疗后，糖原合成酶激酶 3β （GSK3β）都会受到特定的调节。总之，这些结果表明，CBN 可调节不同的 ECS 元素，并通过 TRPV1 在人类角朊细胞中发挥显著的抗炎作用，因此具有治疗和美容的潜力。

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来源期刊

BioFactors 生物-内分泌学与代谢

CiteScore

11.50

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.