Nrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis

Abstract

It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We first found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers. Curcumin dose-dependently ameliorated hepatocyte necroptosis and alleviated alcohol-caused decrease in hepatic Nrf2 expression in alcoholic mice. Then Nrf2 shRNA lentivirus was introduced to generate Nrf2-knockdown mice. Our results indicated that Nrf2 knockdown aggravated the effects of alcohol on liver injury and necroptosis and even abrogated the inhibitory effect of curcumin on necroptosis. Further, activated Nrf2 by curcumin inhibited p53 expression in both livers and cultured hepatocytes under alcohol stimulation. The next in vitro experiments, similar to in vivo ones, revealed that although Nrf2 knockdown abolished the suppression of curcumin on necroptosis of hepatocytes exposed to ethanol, p53 siRNA could clearly rescued the relative effect of curcumin. In summary, for the first time, we concluded that curcumin attenuated alcohol-induced hepatocyte necroptosis in a Nrf2/p53-dependent mechanism. These findings make curcumin an excellent candidate for ALD treatment and advance the understanding of ALD mechanisms associated with hepatocyte necroptosis.

Curcumin Protects Human Trophoblast HTR8/SVneo Cells from H2O2-Induced Oxidative Stress by Activating Nrf2 Signaling Pathway

“…Nrf2 nuclear translocation was also observed in the H 2 O 2 treatment group. In addition, previous researchers have made great effort to prove that curcumin activates Nrf2 and HO-1 signaling leading to protection against oxidative stress in different cell types [17,19,52,53]. In accordance with these findings, pre-treatment with curcumin induced a more obvious Nrf2 nuclear translocation than the H 2 O 2 treatment alone.…”

The in vivo evidence for regulated necrosis

“…133 Other groups reported RIPK1 and RIPK3 expression levels to be elevated upon chronic ethanol feeding. 134,135 Along similar lines, the liver-specific deletion of caspase-8 in hepatocytes resulted in non-apoptotic liver injury 136 ; interestingly, these caspase-8-deficient hepatocytes exhibited accelerated liver regeneration. 137 Concomitantly, pharmacological RIPK1 inhibition decreased ASH=alcoholic steatohepatitis) do exist some contradictory data, which might be solved within the next years with more knowledge about ferroptotic involvement.…”

Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate

“…Moreover, St-PGA-CL-BDMC treatment also inhibited these and other NF-κB-dependent responses in FA-AKI mice concomitant to repression of NF-κB/p65 upregulation and nuclear translocation. Whereas lower levels of HO-1, Lcn2 and PCNA in a context of preserved function may reflect the milder renal injury 55 , the inhibition of FA-AKI-induced Fn14 expression and Klotho suppression could also contribute to the downregulation of AKI-associated inflammation, thus preventing the amplification of injury. In this regard, Fn14 targeting decreases the severity of FA-AKI and limits kidney inflammation and necroptosis 9 , while Klotho has anti-inflammatory, tissue-protective, and anti-fibrotic properties 56 .…”