Nrf2 signaling pathway: Pivotal roles in inflammation.

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper- or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development.

Nrf2, the Master Regulator of Anti-Oxidative Responses

Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury.

Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia-reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches.

Biochanin A protects lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

It has been previously shown that the sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1) can act as a retroviral restriction factor by inhibiting HIV‑1 infection, but whether it has any roles in cancer is still unclear. In the present study, we identified several SAMHD1 splice variants naturally occurring in liver cancer and investigated their roles in regulating drug susceptibility. SAMHD1 variants were identified by sequencing. RT-PCR and western blot analysis were performed to verify the expression level of the polymorphisms. Cell cycle analysis was carried out using flow cytometry, and data were analyzed using Multicycle software. Several deletions of SAMHD1 were identified in both the patients and the healthy controls with no significant difference in respective frequencies, while an insertion in the exon4 occurred at a higher frequency in HBV- and HCV-infected patients (36.4 and 30%, respectively) when compared to the control groups. Following cisplatin treatment and cell cycle analysis, SAMHD1 variants showed different activities in increasing the susceptibility to chemotherapy drugs. The insertion of exon4 correlated with the occurrence of virus infection in the HCC patients. In conclusion, analysis of the different activities of SAMHD1 splice variants in regulating drug sensitivity implied that the exon4 insertion might act as an indicator of the occurrence of liver cancer.

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Tuo Wang

Papers

Biochanin A protects lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

Identification of natural splice variants of SAMHD1 in virus-infected HCC.