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FICZ

Catalog No.: GC36043

FICZ (Formyl-indolo [3,2-b] carbazole), as an endogenous ligand for the aryl hydrocarbon receptor (AhR).

FICZ Chemical Structure

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10mM (in 1mL DMSO)
$363.00
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1mg
$116.00
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5mg
$441.00
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10mg
$603.00
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25mg
$1,112.00
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50mg
$1,715.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

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Protocol

Cell experiment [1]:

Cell lines

BMSCs

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.

Reaction Conditions

500 nM; 6h

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]:

Animal models

Male C57BL/6J mice (24-29 g, 10 weeks of age)

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.

Dosage form

5 mg/kg; i.p.,

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.

References:

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.
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.

Background

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].

[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.

Chemical Properties

Cas No. 172922-91-7 SDF
Canonical SMILES O=CC1=C2C(NC3=C2C=CC=C3)=CC4=C1NC5=C4C=CC=C5
Formula C19H12N2O M.Wt 284.31
Solubility DMSO : 10 mg/mL (35.17 mM) Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

Implications of tryptophan photoproduct FICZ in oxidative stress and terminal differentiation of keratinocytes

Ultraviolet B (UVB) irradiation activates aryl hydrocarbon receptor (AHR), generates reactive oxygen species (ROS) and mediates photocarcinogenesis and photoaging. 6-Formylindolo[3,2-b]carbazole (FICZ) is a tryptophan photoproduct generated by UVB exposure. FICZ exhibits similar biological effects to UVB, including AHR ligation and ROS production. FICZ also acts as a potent photosensitizer for UVA and the production of ROS is synergistically augmented in the simultaneous presence of FICZ and UVA. In contrast, FICZ upregulates the expression of terminal differentiation molecules such as filaggrin and loricrin via AHR. In parallel with this, the administration of FICZ inhibits skin inflammation in a murine psoriasis and dermatitis model. In this article, we summarize the harmful and beneficial aspects of FICZ in skin pathology.

How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology

Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity.

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

Endogenous AhR agonist FICZ accumulates in rainbow trout (Oncorhynchus mykiss) alevins exposed to a mixture of two PAHs, retene and fluoranthene

Multiple studies have reported synergized toxicity of PAH mixtures in developing fish larvae relative to the additive effect of the components. From a toxicological perspective, multiple mechanisms are known to contribute to synergism, such as altered toxicodynamics and kinetics, as well as increased oxidative stress. An understudied contributor to synergism is the accumulation of endogenous metabolites, for example: the aryl hydrocarbon receptor 2 (AhR2) agonist and tryptophan metabolite 6-Formylindolo(3,2-b)carbazole (FICZ). Fish larvae exposed to FICZ, alongside knock-down of cytochrome p450 (cyp1a), has been reported to induced symptoms of toxicity similar to those observed following exposure to PAHs or the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin. Here, we explored if FICZ accumulates in newly hatched rainbow trout alevins (Oncorhynchus mykiss) exposed to two PAHs with different properties: retene (potent AhR2 agonist) and fluoranthene (weak AhR2 agonist and Cyp1a inhibitor), either alone or as a binary mixture for 3 and 7 days. We found that exposure to the mixture resulted in accumulation of endogenous FICZ, synergized the blue sac disease index (BSD), and altered the body burden profiles of the PAHs, when compared to the alevins exposed to the individual components. It is thus very plausible that accumulation of endogenously derived FICZ contributed to the synergized BSD index and toxicity in exposed alevins. Accumulation of endogenously derived FICZ is a novel finding that extends our general understanding on PAHs toxicity in developing fish larvae, while at the same time highlighting why environmental risk assessment of PAHs should not be based solely results from the assessment of individual compounds.

Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation

Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment-cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR's role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.

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