Indole-3-Carbinol

Cerebral ischaemia is the primary cause of stroke. The restoration of blood flow, known as reperfusion, has been observed to exacerbate the pathological changes caused by ischaemia and lead to a significant increase in the formation of reactive oxygen species. Cellular defense against reactive molecules is facilitated by the antioxidant system. The nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor is considered to be the primary regulator of this system. One of the exogenous antioxidants that has the potential to enhance the redox status in tissues experiencing oxidative stress is indole-3-carbinol (I3C). The objective of the present study was to analyze the transcriptional regulation of antioxidant enzyme functioning under conditions of I3C administration to rats with cerebral ischaemia/reperfusion injury (CIRI). The findings of this study demonstrated that the administration of I3C to rats with CIRI resulted in the normalization of the lactate/pyruvate ratio and the reduction of brain tissue damage. These outcomes could be attributed to the improvement of the redox status caused by the tested compound. Furthermore, I3C altered the activity of antioxidant enzymes and the number of Nrf2-positive neurons, leading to a shift towards control values. It has been demonstrated that I3C is also capable of restoring chaperone activity. This capacity may play a pivotal role in correcting dysfunction in the proteostasis system and in maintaining adequate protein folding during the course of a disease. Consequently, I3C demonstrated a neuroprotective effect in CIRI by normalizing oxidative status, regulating Nrf2-mediated antioxidant response, and enhancing chaperone activity.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and immunotherapy has demonstrated significant therapeutic benefit in HCC. Indole-3-carbinol (I3C), a naturally occurring ingredient of cruciferous vegetables, significantly inhibits the growth of a wide range of tumors. However, its mechanism of action has not been fully elucidated.

This study aims to verify and explore the immunomodulatory effect of I3C in HCC models, and to investigate the specific role and mechanism by which I3C affects PD-L1 expression through the ubiquitination of NF-κB p105.

In vitro, I3C was treated with HepG2 cells and relevant indicators were analyzed. In vivo, the mouse HCC model was established and the effect of I3C on tumors and immune function was evaluated. Subsequently, the downstream target of I3C was found through target prediction, molecular docking, and molecular dynamics simulation. Finally, combined therapy was used to further investigate the effect of I3C on mouse HCC tumors.

We observed that I3C resulted in decreased programmed cell death ligand 1 (PD-L1) expression in HepG2 cells and increased CD8 T cell infiltration in tissues. Subsequently, target prediction and molecular docking demonstrated that I3C was able to efficiently bind to NF-κB p105. In addition, overexpression of NF-κB p105 upregulated PD-L1 expression and almost completely eliminated the inhibitory effect of I3C. Notably, the combination of I3C and PD-L1 monoclonal antibodies showed synergistic anti-tumor effects in the mouse HCC model.

This study demonstrated that I3C inhibits PD-L1-mediated immune evasion in HCC via suppressing NF-κB p105 ubiquitination. The role of I3C in tumors deserves further investigation and provides the foundation for the future development of novel immunotherapeutic drugs.