Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells

Marra, Fabio; Gentilini, Alessandra; Pinzani, Massimo; Choudhury, Goutam Ghosh; Parola, Maurizio; Herbst, Hermann; Dianzani, Mario U.; Laffi, Giacomo; Abboud, H. E.; Geñtilini, Paolo

doi:10.1016/s0016-5085(97)70144-6

Cited by 193 publications

(187 citation statements)

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“…What is the mechanism underlying this effect? Marra et al 27 have shown that hepatic stellate cell migration is under the dependence of the activity of the phosphatidylinositol 3-kinase. Several flavonoids structurally related to trans-resveratrol are good inhibitors of this enzyme 28 and it is therefore tempting to speculate that this could provide an explanation of our findings.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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Liver myofibroblasts are major actors in the development of liver fibrosis and cancer progression. There is a large interest in drugs that might deactivate these cells. Many studies have shown that the grapevine-derived polyphenol, trans-resveratrol, and other stilbenes have therapeutic potential in some diseases. In this work, we have studied the effect of grapevine polyphenols on cultured human liver myofibroblasts. We have shown that trans-resveratrol profoundly affects myofibroblast phenotype. Trans-resveratrol induced morphological modifications. It markedly reduced proliferation of myofibroblasts in a dose-dependent manner. Trans-resveratrol also decreased the expression of ␣ smooth muscle actin (␣-SMA) without affecting vimentin or ␤-cytoplasmic actin expression. It decreased myofibroblast migration in a monolayer wounding assay. We also showed that trans-resveratrol inhibited the messenger RNA (mRNA) expression of type I collagen. Finally, it decreased the secretion of matrix metalloproteinase 2 (MMP-2). We conclude that trans-resveratrol can deactivate human liver myofibroblasts. In the second part of this study, we have shown that neither trans-piceid (a glycosylated analog) nor trans-piceatannol (a hydroxylated analog) reproduces transresveratrol effects on liver myofibroblasts. We finally show that, although trans-resveratrol decreases the proliferation of skin fibroblast and vascular smooth muscle cells, it does not affect their expression of ␣-SMA, which indicates some cell specificity. (HEPATOLOGY 2000;31:922-931.)

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Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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“…Expression of platelet-derived growth factor (PDGF), a key mitogen and chemoattractant for HSCs 21,22 and of the relative receptor subunits, is markedly up-regulated in human fibrotic liver and correlates with the extent of necroinflammatory and fibrogenic activity. 23 Furthermore, expression of PDGF receptors is a consistent feature of the process of HSC activation in vitro and in vivo.…”

Section: E Xperimental and Clinical Studies Have Indicated Thatmentioning

confidence: 99%

“…22,32 Briefly, the experiments were performed using a modified Boyden chamber technique equipped with 8-mpore polyvinylpyrrolidone-free polycarbonate filters (13-mm diameter). Polycarbonate filters were precoated with 20 g/mL of human type I collagen for 30 minutes at 37°C and placed between the upper and the bottom chamber.…”

Section: Chemotactic Assaymentioning

confidence: 99%

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Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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Background & Aims:Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods & Results: Both NTG and SNAP induced a dosedependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca 2؉ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3 ,5 -cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the ␣ 1 ␤ 1 ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10 -20-fold increase in prostaglandin E 2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3 ,5 -cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen. Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

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“…The phosphatidylinositol 3-kinase (PI3K)/Akt pathway controls a variety of cellular responses involving cell survival and proliferation [6] and is strongly activated in HSCs by the potent mitogen PDGF [7] . Akt indirectly activates mammalian target of rapamycin (mTOR) through inhibition of TSC2 and directly phosphorylates mTOR at S2448 [8] .…”

Section: Introductionmentioning

confidence: 99%

Withagulatin A inhibits hepatic stellate cell viability and procollagen I production through Akt and Smad signaling pathways

et al. 2010

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Aim: To investigate the effects of the natural product Withagulatin A on hepatic stellate cell (HSC) viability and type I procollagen production. The potential mechanism underlying the pharmacological actions was also explored. Methods: The effect of Withagulatin A on cell viability was evaluated in HSC and LX-2 cells using a sulforhodamine B (SRB) assay. Cell cycle distribution was analyzed using flow cytometry. Type I procollagen gene expression was determined using real-time PCR. Regulation of signaling molecules by Withagulatin A was detected using Western blotting. Results: Primary rat HSCs and the human hepatic stellate cell line LX-2 treated with Withagulatin A (0.625-20 μmol/L) underwent a dose-dependent decrease in cell viability, which was associated with S phase arrest and the induction of cell apoptosis. In addition, the natural product decreased phosphorylation of the Akt/mTOR/p70S6K pathway that controls cell proliferation and survival. Furthermore, Withagulatin A (1, 2 μmol/L) inhibited transforming growth factor-β (TGF-β) stimulated type I procollagen gene expression, which was attributable to the suppression of TGF-β stimulated Smad2 and Smad3 phosphorylation. Conclusion: Our results demonstrated that Withagulatin A potently inhibited HSC viability and type I procollagen production, thereby implying that this natural product has potential use in the development of anti-fibrogenic reagents for the treatment of hepatic fibrosis.

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Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells

Cited by 193 publications

References 0 publications

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

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

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Withagulatin A inhibits hepatic stellate cell viability and procollagen I production through Akt and Smad signaling pathways

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