Effect of antioxidants, resveratrol, quercetin, andN-acetylcysteine, on the functions of cultured rat hepatic stellate cells and kupffer cells

Abstract

Effects of antioxidants, resveratrol, quercetin, and N-acetylcysteine (NAC) on the functions of cultured rat hepatic stellate cells and Kupffer cells were studied. These compounds dose-dependently suppressed serum-dependent proliferation of stellate cells as determined by [ 3 H]thymidine and 5-bromo-2Ј-deoxyuridine uptake. Expression of smooth muscle ␣-actin was suppressed by a high dose of resveratrol and quercetin. These phenolic compounds also suppressed inositol phosphate metabolism, tyrosine phosphorylation, and mitogen-activated protein (MAP) kinase activation in platelet-derived growth factor/BB-stimulated stellate cells. Moreover, the phenolic compounds selectively reduced the level of cell cycle protein cyclin D1 in stellate cells. Thus, resveratrol and quercetin might inhibit stellate cell activation by perturbing signal transduction pathway and cell cycle protein expression, whereas mechanism of potent antiproliferative effect of NAC remains to be elucidated. On the other hand, kinetic analysis showed that production of nitric oxide (NO) and tumor necrosis factor ␣ (TNF-␣) by lipopolysaccharide-stimulated Kupffer cells was strongly inhibited by resveratrol and quercetin but not by NAC. Although expression of messenger RNAs for inducible NO synthase and TNF-␣ was not affected by the phenolic compounds, cellular levels of inducible NO synthase and TNF-␣ secretion were suppressed significantly, indicating the posttranscriptional process of generating these proteins might be affected predominantly by these phenolic compounds. Thus, NAC and these phenolic compounds may have therapeutic potential against liver injury by regulating functions of hepatic stellate cells and Kupffer

Cellular redox state alters recombinant adeno-associated virus transduction through tyrosine phosphatase pathways

“…18 To evaluate whether ROIs might be a common mediator responsible for augmentation of rAAV transduction by HU and UV treatment, we evaluated the ability of N-acetyl-L-cysteine (NAC), a known redox scavenger of H0 · radicals and H 2 O 2 , to attenuate UV and HU augmentation of rAAV transduction. 19 Results from these studies demonstrate that 50 mm NAC completely blocks the augmentation of rAAV transduction following H 2 O 2 , UV and HU treatment (Figure 1c, d and e). Inhibition was maximal at 50 mm NAC, but a dose-response of inhibition in rAAV transduction was seen at intermediate concentrations.…”

Deactivation of cultured human liver myofibroblasts byTrans-resveratrol, a grapevine-derived polyphenol

“…On the other hand, several reports have shown that trans-resveratrol inhibits several types of cellular kinases, either tyrosine kinases 24 or serine/threonine kinases. 25 In their report, Kawada et al 21 show that trans-resveratrol decreases the activation of the MAPK ERK1 and ERK2 and suggest that this could be secondary to a decreased activation of the platelet-derived growth factor receptor by its ligand. We also found that trans-resveratrol decreased the activation of MAPK in human liver myofibroblasts when the cells were stimulated by HS.…”

“…This was not a nonspecific inhibitory effect on protein synthesis because trans-resveratrol failed to affect the expression of vimentin or ␤-cytoplasmic actin, other cytoskeletal proteins. Kawada et al 21 have shown that transresveratrol could partially prevent the culture-induced expression of ␣-SMA during the first few days of culture. However, trans-resveratrol lost its effect after 5 days of culture.…”

Hepatoprotective Effect of Quercetin Pretreatment Against Paracetamol-Induced Liver Damage and Partial Hepatectomy in Rats

“…Other studies with different models of carbon tetrachloride-induced toxic hepatitis 9,18 or a model of methionine-choline deficient diet 19 or studies of arsenite-induced lesions 15 describe attenuation of fibrosis by quercetin. Kawada et al 20 showed that quercetin and other natural phenolics inhibit stellate cell activation by disturbing signal transduction pathways and cell protein expression, thus interrupting the differentiation of stellate cells into myofibroblasts, and the consequent production of collagen type I and II. Figure 5 shows that animals treated with a high dose of paracetamol presented a great reduction in glycogen and other 1,2-glycols (PAS-positive inclusions) in the centrilobular region.…”