Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor β1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation

Ikeda, Remina; Ishii, Kyoko; Hoshikawa, Yasushi; Azumi, Junya; Arakaki, Yuta; Yasui, Toshihiro; Matsuura, Shizuka; Matsumi, Yoshiaki; Kono, Yohei; Yusuke, Mizuta; Kurimasa, Akihiro; Hisatome, Ichiro; Friedman, Scott L.; Kawasaki, Hironaka; Shiota, Goshi

doi:10.1007/s00011-011-0309-6

Cited by 24 publications

(19 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, those findings were accompanied by the inhibition of α- SMA expression and of the activation of Akt and p38MAPK, which have been reported to be involved in LX-2 myofibroblastic transformation. Thus, our findings would suggest that both Akt and p38MAPK could play a role in the intracellular pathway leading to α- SMA inhibition in LX-2 treated with supernatants of Huh7.5 [40, 41]. The co-culture experiments would confirm the importance of the cross talk between Huh7.5 and LX-2 in mediating liver progression towards fibrosis and in eliciting the protective effects of 17 β estradiol and genistein.…”

Section: Discussionsupporting

confidence: 52%

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Surico¹,

Ercoli²,

Farruggio

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: estrogens and phytoestrogens exert hepatoprotection through mechanisms not clearly examined yet. Here, we investigated the protective effects exerted by 17β-estradiol and genistein against oxidative stress in hepatocytes and hepatic stellate cells (HSCs) and the involvement of specific receptors and the intracellular signalling. Methods: Huh7.5 and LX-2, alone or in co-culture with Huh7.5, were treated with 17β-estradiol and genistein alone or in the presence of menadione and of estrogen receptors (ERs) and G protein-coupled-estrogenic-receptors (GPER) blockers. Cell viability, mitochondrial membrane potential and oxidant/antioxidant system were measured by specific kits. Western Blot was used for the analysis of Akt and p38-mitogen-activated-protein kinases (MAPK) activation and α-smooth-muscle actin expression. Results: In Huh7.5, 17β-estradiol and genistein prevented the effects of peroxidation by modulating Akt and p38MAPK activation. Similar antioxidant and protective findings were obtained in LX-2 of co-culture experiments, only. ERs and GPER blockers were able to prevent the effects of 17β-estradiol and genistein. Conclusion: In Huh7.5 and LX-2, 17β-estradiol and genistein counteract the effects of peroxidation through the involvement of ERs and GPER and by an intracellular signalling related to Akt and p38MAPK. As concerning LX-2, paracrine factors released by Huh7.5 play a key role in protection against oxidative stress.

show abstract

Section: Discussionsupporting

confidence: 52%

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Surico¹,

Ercoli²,

Farruggio

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…NASH development in these mice is similar, but not identical to that seen in humans. For example, NOX4 induction is a major event in human NASH-associated fibrosis [46]. NOX4, however, is not induced by the WD in LDLR -/- mice.…”

Section: Discussionmentioning

confidence: 99%

A Metabolomic Analysis of Omega-3 Fatty Acid-Mediated Attenuation of Western Diet-Induced Nonalcoholic Steatohepatitis in LDLR-/- Mice

et al. 2013

View full text Add to dashboard Cite

BackgroundNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice.MethodsUsing livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. ResultsLivers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. ConclusionDHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice.

show abstract

“…Only one of these variants was active as assessed by ROS production, but the mechanisms by which this variant generates ROS remain unclear as it lacks most of the transmembrane regions and part of the FAD binding region. Nox4 was originally identified in the kidney (Geiszt et al, 2000; Shiose et al, 2001) and in addition to cardiovascular tissues discussed below, it is expressed in hematopoietic stem cells (Piccoli et al, 2005), osteoclasts (Yang et al, 2001, 2004), keratinocytes (Chamulitrat et al, 2004), melanoma cells (Brar et al, 2002), neurons (Vallet et al, 2005; Kleinschnitz et al, 2010), adipocyte (Kanda et al, 2011), embryonic stem cells (Bartsch et al, 2011), chondrocytes (Grange et al, 2006; Kim et al, 2010), hepatic stellate cells (Ikeda et al, 2011), epithelial cells (Carnesecchi et al, 2011), and podocytes (Piwkowska et al, 2011). Using the human Nox4 standard gene sequence for comparison, approximately 2385 single nucleotide polymorphism (SNP) sites were found in the genomic DNA region of Nox4, and 45 SNP sites in the gene coding region.…”

Section: Nox4 Variants Expression and Genetic Variationmentioning

confidence: 99%

From form to function: the role of Nox4 in the cardiovascular system

Chen¹,

Haigh²,

Barman³

et al. 2012

Front. Physio.

136

123

View full text Add to dashboard Cite

The NADPH oxidase (Nox) family of proteins is comprised of seven members, including Noxes1–5 and the Duoxes 1 and 2. Nox4 is readily distinguished from the other Nox isoforms by its high level of expression in cardiovascular tissues and unique enzymatic properties. Nox4 is constitutively active and the amount of reactive oxygen species (ROS) contributed by Nox4 is primarily regulated at the transcriptional level although there is recent evidence for post-translational control. Nox4 emits a different pattern of ROS and its subcellular localizations, tissue distribution and influence over signaling pathways is different from the other Nox enzymes. Previous investigations have revealed that Nox4 is involved in oxygen sensing, vasomotor control, cellular proliferation, differentiation, migration, apoptosis, senescence, fibrosis, and angiogenesis. Elevated expression of Nox4 has been reported in a number of cardiovascular diseases, including atherosclerosis, pulmonary fibrosis, and hypertension, cardiac failure and ischemic stroke. However, many important questions remain regarding the functional significance of Nox4 in health and disease, including the role of Nox4 subcellular localization and its downstream targets. The goal of this review is to summarize the recent literature on the genetic and enzymatic regulation, subcellular localization, signaling pathways, and the role of Nox4 in cardiovascular disease states.

show abstract

Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor β1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation

Abstract: These results suggest that ROS and Nox4 induced by TGFβ1 are the therapeutic targets of PPC in the suppression of human hepatic stellate cell activation.

Cited by 24 publications

References 23 publications

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

A Metabolomic Analysis of Omega-3 Fatty Acid-Mediated Attenuation of Western Diet-Induced Nonalcoholic Steatohepatitis in LDLR-/- Mice

From form to function: the role of Nox4 in the cardiovascular system

Contact Info

Product

Resources

About