Trigonelline, an alkaloid isolated from Trigonella foenum-graecum L or Leonurus artemisia, is a potent and specific inhibitor of Nrf2[1]. Nrf2 (nuclear factor erythroid 2–related factor 2) is the master transcriptional regulator of cellular antioxidant defense, eliminating reactive oxygen species and maintaining redox homeostasis by up-regulating genes such as HO-1 and NQO1[2]. Trigonelline is widely used in research related to anti-diabetes, anti-oxidation, anti-inflammation and neuroprotection by blocking NrF2-dependent proteasome activity[3][4].
In vitro, pretreatment of H9c2 cells with Trigonelline (25-125µM; 24h) before H₂O₂ stimulation significantly rescued cell morphology, attenuated H₂O₂-induced cell deaths, enhanced antioxidant activity, down-regulated the expression of apoptotic genes (caspase-3, caspase-9), and up-regulated the expression of anti-apoptotic genes (Bcl-2, Bcl-XL)[5]. Trigonelline (0.1-1mM; 16h) significantly inhibited Nrf2 activity in pancreatic cancer cell lines (Panc1, Colo357, MiaPaca2) and H6c7 pancreatic duct cells, reduced nuclear Nrf2 levels and proteasome activity, and enhanced cell sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and etoposide-induced apoptosis, increasing caspase-3/7 activity by 2.3-4.3 fold[6].
In vivo, Trigonelline (10mg/kg/day; i.p.; 14 days) reversed silica-induced pulmonary fibrosis, reduced the expression of fibrotic markers (such as Collagen 1 and Fibronectin) in lung tissues, inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling, and improved fibrotic pathological features in a silica-induced pulmonary fibrosis mouse model[7].
References:
[1] Nguyen V, Taine EG, Meng D, Cui T, Tan W. Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline. Int J Mol Sci. 2024;25(6):3385.
[2] Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865(5):721-733.
[3] Ozçelik B, Kartal M, Orhan I. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol. 2011;49(4):396-402.
[4] Su Y, Zhao B, Zhou L, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 2020;483:127-136.
[5] Ilavenil S, Kim DH, Jeong YI, et al. Trigonelline protects the cardiocyte from hydrogen peroxide induced apoptosis in H9c2 cells. Asian Pac J Trop Med. 2015;8(4):263-268.
[6] Arlt A, Sebens S, Krebs S, et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. 2013;32(40):4825-4835.
[7] Zhang F, Yue H, Dong R, et al. Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation. Respir Res. 2024;25(1):242.
Trigonelline是一种从Trigonella foenum-graecum L或Leonurus artemisia中分离出来的生物碱，是一种强效且特异性的Nrf2抑制剂[1]。Nrf2（核因子E2相关因子2）是细胞抗氧化防御的主要转录调控因子，通过上调HO-1和NQO1等基因的表达清除活性氧并维持氧化还原稳态[2]。Trigonelline通过阻断Nrf2依赖的蛋白酶体活性，广泛应用于抗糖尿病、抗氧化、抗炎和神经保护等相关研究[3][4]。
在体外实验中，在H₂O₂ 刺激前用Trigonelline（25-125µM；24小时）预处理H9c2细胞可显著改善细胞形态，减轻H₂O₂ 诱导的细胞死亡，增强抗氧化活性，下调凋亡基因（caspase-3、caspase-9）的表达，并上调抗凋亡基因（Bcl-2、Bcl-XL）的表达[5]。Trigonelline（0.1-1mM；16小时）显著抑制胰腺癌细胞系（Panc1、Colo357、MiaPaca2）和H6c7胰腺导管细胞中的Nrf2活性，降低核内Nrf2水平和蛋白酶体活性，并增强细胞对肿瘤坏死因子相关的凋亡诱导配体（TRAIL）和依托泊苷诱导凋亡的敏感性，使caspase-3/7活性增加了 2.3-4.3 倍[6]。
在体内实验中，在二氧化硅诱导的肺纤维化小鼠模型中，Trigonelline（10mg/kg/天；腹腔注射；14天）逆转了二氧化硅诱导的肺纤维化，降低了肺组织中纤维化标志物（如胶原蛋白1和纤维连接蛋白）的表达，通过抑制TGF-β/Smad信号通路抑制了成纤维细胞向肌成纤维细胞的分化，并改善了纤维化病理特征[7]。