炎症是身体对病原体引起的组织损伤或感染信号的自然反应。然而,当它变得不平衡时,它会导致各种疾病,如癌症,肥胖,心血管问题,神经系统疾病,和糖尿病。内源性大麻素系统,它存在于全身,在不同的器官中发挥调节作用,并影响食物摄入等功能,疼痛感知,应激反应,葡萄糖耐量,炎症,细胞生长和专业化,和新陈代谢。源自大麻的植物大麻素可以与该系统相互作用并影响其功能。在这项研究中,我们研究了三种次要植物大麻素的抗炎作用的机制,包括四氢大麻素(THCV),大麻酚(CBC),和大麻酚(CBN)使用体外系统。我们用不同剂量的植物大麻素或载体预处理THP-1巨噬细胞一小时,然后用500ng/mL的LPS处理细胞或使它们不处理3小时。诱导NLRP3炎症小体激活的第二阶段,用5mMATP进一步处理LPS处理的细胞30分钟。我们的发现表明,PANX1/P2X7轴的缓解在THCV和CBC对NLRP3炎性体激活的抗炎作用中起着重要作用。此外,我们观察到CBC和THCV也可以下调IL-6/TYK-2/STAT-3通路。此外,我们发现CBN可能通过减少PANX1裂解对NLRP3炎性体的组装产生抑制作用。有趣的是,我们还发现,在LPS-巨噬细胞中,升高的ADAR1转录物对THCV和CBC呈阴性反应,表明ADAR1可能参与这两种植物大麻素的抗炎作用。THCV和CBN抑制P-NF-κB,下调促炎基因转录。总之,THCV,CBC,和CBN通过影响基因表达的不同阶段发挥抗炎作用:转录,转录后调控,翻译,和翻译后调节。
Inflammation is a natural response of the body to signals of tissue damage or infection caused by pathogens. However, when it becomes imbalanced, it can lead to various disorders such as cancer, obesity, cardiovascular problems, neurological conditions, and diabetes. The endocannabinoid system, which is present throughout the body, plays a regulatory role in different organs and influences functions such as food intake, pain perception, stress response, glucose tolerance, inflammation, cell growth and specialization, and metabolism. Phytocannabinoids derived from Cannabis sativa can interact with this system and affect its functioning. In this study, we investigate the mechanisms underlying the anti-inflammatory effects of three minor phytocannabinoids including tetrahydrocannabivarin (THCV), cannabichromene (CBC), and cannabinol (CBN) using an in vitro system. We pre-treated THP-1 macrophages with different doses of phytocannabinoids or vehicle for one hour, followed by treating the cells with 500 ng/mL of LPS or leaving them untreated for three hours. To induce the second phase of NLRP3 inflammasome activation, LPS-treated cells were further treated with 5 mM ATP for 30 min. Our findings suggest that the mitigation of the PANX1/P2X7 axis plays a significant role in the anti-inflammatory effects of
THCV and CBC on NLRP3 inflammasome activation. Additionally, we observed that CBC and
THCV could also downregulate the IL-6/TYK-2/STAT-3 pathway. Furthermore, we discovered that CBN may exert its inhibitory impact on the assembly of the NLRP3 inflammasome by reducing PANX1 cleavage. Interestingly, we also found that the elevated ADAR1 transcript responded negatively to
THCV and CBC in LPS-macrophages, indicating a potential involvement of ADAR1 in the anti-inflammatory effects of these two phytocannabinoids.
THCV and CBN inhibit P-NF-κB, downregulating proinflammatory gene transcription. In summary,
THCV, CBC, and CBN exert anti-inflammatory effects by influencing different stages of gene expression: transcription, post-transcriptional regulation, translation, and post-translational regulation.