FICZ (Formyl-indolo [3,2-b] carbazole), as an endogenous ligand for the aryl hydrocarbon receptor (AhR), can exert pleiotropic effects including protection against inflammation, fibrosis, and oxidative stress[1].
In vitro, treatment with 0.01 nM-1 μM FICZ in HepG2 cells, FICZ stimulated cell growth at low concentrations but inhibited cell growth at high concentrations[2]. In vitro experiment it demonstrated that treatment LPS combined with 200 nM FICZ in YAMC cells did not influence LPS-induced IL-6 release[3]. In vitro, 50 μM FICZ obviously induced apoptosis, whereas all tested compounds in higher concentrations (L-KYN 1 mM, KYNA 5 mM, FICZ 50 μM) increased necrosis in melanoma A375 cells. Statistically, FICZ obviously inhibited DNA synthesis in A375 cells at a concentration range of 10-6-50 μM, but there is only observed inhibitory effect on RPMI7951 cells in the highest tested micromolar concentrations[4].
In vivo efficacy test it shown that per mouse was treatment with 1 μg (50 μg/kg) intraperitoneally enhanced the level of IL-22 in colonic samples, and ameliorated colitis induced by TNBS (trinitrobenzene sulfonic acid) or DSS (dextran sulfate sodium)[5]. In vivo, 10 μg/kg FICZ in mice orally resulted in transient AhR activation, with the effect waning in less than 18h[6].
FICZ（甲酰吲哚 [3,2-b] 咔唑）作为芳基烃受体 (AhR) 的内源性配体，可以发挥多效性作用，包括防止炎症、纤维化和氧化应激[1 ]。
在体外，用 0.01 nM-1 μM FICZ 处理 HepG2 细胞，FICZ 在低浓度下刺激细胞生长，但在高浓度下抑制细胞生长[2]。体外实验表明，LPS联合200 nM FICZ处理YAMC细胞不影响LPS诱导的IL-6释放[3]。在体外，FICZ 50 77777#181;M FICZ 明显诱导细胞凋亡，而所有测试化合物（L-KYN 1 mM，KYNA 5 mM，FICZ 50 μM）增加黑色素瘤 A375 细胞的坏死。据统计，FICZ在10-6-50 μM的浓度范围内明显抑制A375细胞的DNA合成，但仅在最高测试微摩尔浓度下观察到对RPMI7951细胞的抑制作用[4]?.
体内药效试验表明，每只小鼠用1 μg (50 μg/kg)腹腔注射可提高结肠样本中IL-22的水平，并改善TNBS诱导的结肠炎（三硝基苯磺酸）或 DSS（葡聚糖硫酸钠）[5]。在体内，小鼠口服 10 μg/kg FICZ 导致短暂的 AhR 激活，效果在不到 18 小时内减弱[6]。
[1]Tamayo M, et al. The Aryl Hydrocarbon Receptor Ligand FICZ Improves Left Ventricular Remodeling and Cardiac Function at the Onset of Pressure Overload-Induced Heart Failure in Mice. Int J Mol Sci. 2022 May 12;23(10):5403.
[2]Mohammadi-Bardbori A, et al. The highly bioactive molecule and signal substance 6-formylindolo[3,2-b]carbazole (FICZ) plays bi-functional roles in cell growth and apoptosis in vitro. Arch Toxicol. 2017 Oct;91(10):3365-3372.
[3]Li X, et al. 6-Formylindolo (3, 2-b) Carbazole (FICZ)-mediated protection of gut barrier is dependent on T cells in a mouse model of alcohol combined with burn injury. Biochim Biophys Acta Mol Basis Dis. 2020 Nov 1;1866(11):165901.
[4]Walczak K, et al. Effect of Tryptophan-Derived AhR Ligands, Kynurenine, Kynurenic Acid and FICZ, on Proliferation, Cell Cycle Regulation and Cell Death of Melanoma Cells-In Vitro Studies. Int J Mol Sci. 2020 Oct 26;21(21):7946.
[5]Rannug A. How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology. Int J Mol Sci. 2020 Aug 8;21(16):5681.
[6]Wheeler JL, et al. Differential consequences of two distinct AhR ligands on innate and adaptive immune responses to influenza A virus. Toxicol Sci. 2014 Feb;137(2):324-34.
| Cell experiment [1]: | |
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Cell lines |
BMSCs |
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Preparation Method |
To detect the inflammatory responses of BMSCs, the cells were rendered quiescent by serum starvation and then stimulated with 1 μg ml-1 lipopolysaccharide (LPS) supplemented with 500 nM FICZ, 1 μM SR1 (AhR antagonist StemRegenin 1) or dimethyl sulphoxide (DMSO) for 6 h. |
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Reaction Conditions |
500 nM; 6h |
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Applications |
The results demonstrated that LPS significantly up-regulated the expressions of IL-1β, 6 and TNF-α and FICZ or SR1 prevented or exacerbated the inflammatory responses. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6J mice (24-29 g, 10 weeks of age) |
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Preparation Method |
Animals were randomized into the following four groups: Sham-treated with vehicle or with FICZ and TAC-treated with vehicle or with FICZ. Treatment with FICZ (i.p., 5 mg kg-1) or with vehicle (dimethylsulfoxide) was initiated 5 min after Sham or TAC surgery and was repeated 2 days after surgery. CMRI was performed on 8 animals in each group before and 3 days after surgery. Subsequently, animals were anesthetized with isoflurane, and hearts were excised, weighed, and prepared for biochemical and immunofluorescence studies. |
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Dosage form |
5 mg/kg; i.p., |
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Applications |
Cardiac structure and function were evaluated by cardiac magnetic resonance imaging (CMRI) before and 3 days after Sham or TAC surgery in mice treated with FICZ or with vehicle, and cardiac tissue was used for biochemical studies. CMRI analysis revealed that FICZ improved cardiac function and attenuated cardiac hypertrophy. |
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参考文献: Huang J, et al. Beneficial roles of the AhR ligand FICZ on the regenerative potentials of BMSCs and primed cartilage templates. RSC Adv. 2022 Apr 13;12(18):11505-11516. | |
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