Synthetic Imine Resveratrol Analog 2-Methoxyl-3,6-Dihydroxyl-IRA Ameliorates Colitis by Activating Protective Nrf2 Pathway and Inhibiting NLRP3 Expression

Abstract

Resveratrol (RSV) is a naturally occurring polyphenol that exhibits pleiotropic health benefits, including anticolitis and colon cancer-protective activity. Recently, we identified the novel imine RSV analog (IRA), 2-methoxyl-3,6-dihydroxyl-IRA 3,4,5,4-tetramethoxystilbene (C33), as a putative activator of nuclear factor erythroid 2-related factor 2 (Nrf2). The present study was designed to evaluate the ability of C33 to activate the Nrf2 signaling pathway and its anticolitis effect in comparison to RSV. The anticolitis action of C33 was assessed in a mouse model of colitis induced by dextran sulfate sodium (DSS). The effect of C33 on the Nrf2 signaling pathway was examined in vitro and in vivo. Compared to RSV, C33 triggered a more dramatic increase in the expression of genes downstream of Nrf2 in LS174T cells as well as in the small intestine and colon of wild-type (WT) mice. Correlated with its superior ability to activate the cytoprotective Nrf2 pathway, C33 was significantly better in ameliorating DSS-induced colitis by improving the inflammation score, as well as downregulating the markers of inflammation in WT mice. Moreover, induction of the NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome by colitis was also significantly inhibited by the IRA. Nrf2 knockout completely abolished the effects of C33, indicating that Nrf2 is the important mechanistic target of C33 in vivo. In conclusion, the novel IRA, C33, has stronger anticolitis effects than RSV. Further studies are warranted to evaluate C33 as a potential therapeutic agent for inflammatory bowel disease and cancer chemoprevention.

Resveratrol Can Attenuate Astrocyte Activation to Treat Spinal Cord Injury by Inhibiting Inflammatory Responses

“… Antioxidant Anti-inflammatory [ 44 ] Inflammatory bowel diseases (IBD) C57BL/6 WT and Nrf2 −/− mice (induced by dextran sulfate sodium); Human colon cancer LS174T and Caco2 cells Intraperitoneal injection/ Imine RSV Analog 2-Methoxyl-3,6-Dihydroxyl-IRA (C33); RSV (200 mg/kg) The derivative C33 modified by RSV showed stronger anti-inflammatory effect, and effectively improved IBD by activating Nrf2 signaling pathway in-vivo and in-vitro . Anti-inflammatory [ 45 ] Autoimmune encephalomyelitis (AE) C57BL/6 mice Intraperitoneal injection/ RSV (10 mg/kg; 25 mg/kg; 50 mg/kg) RSV reduced oxidative stress and inflammation in EAE mice to protect the integrity of blood-brain barrier. Antioxidant Anti-inflammatory [ 46 ] Neurodegenerative diseases Alzheimer disease (AD) Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs); Tg2576 Swedish transgenic AD mice Passage 3 hUC-MSCs were cultured in media with 2.5 µM RSV, and intravenously delivered the suspension of hUC-MSCs to AD mice (1×106 cells/ 200μl saline solution) RSV-treated hUC-MSCs showed a significant neuroinflammatory inhibitory effect that inhibited MAPKs, p38, and other signal pathways in AD mice by interacting with astrocytes and microglia.…”

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

“…Nrf2 and its target genes NQO1, Trx1, SOD2 and HO-1, especially NQO1, was elevated by cardamonin, which has the effect to depress NLRP3 inflammasome activation in a mouse model ( 69 ). And upregulation of Nrf2 has been detected after treatment of Resveratrol and Hydrogen sulfide (H 2 S) ( 70 , 71 ). ROS is considered as a second messenger in pro-inflammatory responses.…”

Natural products and phytochemical nanoformulations targeting mitochondria in oncotherapy: an updated review on resveratrol

“…However, the accumulating data have shown that the major mechanism for the antioxidant activity of resveratrol is related to its effect on the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Resveratrol, by activation of the Nrf2 signaling pathway, ameliorates oxidative stress [68] to improve colitis [69], arthritis [63], diabetes [70] and non-alcoholic fatty liver disease [71].…”

“…Obviously, mitochondrial dysfunction is associated with a variety of pathological conditions such as NDs [93], hepatic disorders [69] and so on. This is due to the potential role of mitochondria in the induction of apoptotic cell death.…”