Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γ expression and inhibition of PI3K/Akt pathway

Guo, Chao; Xu, Lingyuan; He, Qiaoling; Liang, Tao; Duan, Xiaoqun; Li, Rong

doi:10.1016/j.fct.2013.02.051

Cited by 75 publications

(53 citation statements)

References 47 publications

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“…In the current investigation, immunohistochemical reactivity of both PPAR-α and PPAR-γ, increased in omega-3 supplemented rats compared to the only CCl 4 injected animals. Therefore, our results correlate the findings of previous studies [42,65,66] indicating CCl 4 treatment prominently reduce the expression of PPAR-γ, and that omega-3 supplementation has beneficial effects in reducing the development of degenerative changes induced by CCl 4 .…”

Section: Discussionsupporting

confidence: 91%

“…Upon hepatocellular degeneration release of these substances into the circulatory system increases as a result of the loss of membrane integrity. CCl 4 has been previously shown to cause increased serum levels of AST and AlT [1,32,36,42,43] . In the present study, serum AlT and AST levels were significantly higher in CCl 4 given rats as compared to the control.…”

Section: Discussionmentioning

confidence: 98%

“…PPAR-γ overexpression in liver has also been suggested to be important and inhibits the fibrotic changes in liver [34,64] . The number of PPAR-γ expressing cells has also been shown to decrease by CCl 4 treatment [34,42] . In the current investigation, immunohistochemical reactivity of both PPAR-α and PPAR-γ, increased in omega-3 supplemented rats compared to the only CCl 4 injected animals.…”

Section: Discussionmentioning

confidence: 99%

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Salgı

Karaman¹,

Özen²,

Dağ³

et al. 2016

Kafkas Univ Vet Fak Derg

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Omega-3 is a polyunsaturated fatty acid known to have immunomodulatory functions. In the present study, ameliorative potential of omega-3 in experimental carbon tetrachloride (CCl4) toxicity was investigated. Total of 40 adult male Wistar albino rats were allocated into five groups and were subcutaneously given once every two days for 6 weeks the followings: Group 1 (Control): 0.5 ml/kg serum physiologic, Group 2 (Omega): 0.5 g/kg omega-3, Group 3 (Vehicle): 0.5 ml/kg pure olive oil, Group 4 (CCl4): 0.5 ml/kg CCl4, Group 5 (CCl4 + Omega): 0.5 ml/kg CCl4 plus 0.5 g/kg omega-3. At the end of the treatments, blood samples were collected and necropsy was performed for collection of liver tissues. Serum AST, AlT, GGT, TAC, TOC, triglyceride, and visfatin levels were detected. liver morphology and immunoreactivities against TGF-α, TGF-β, PPAR-α, and PPAR-γ were assessed. Serum AST, AlT, GGT, and TOC levels significantly increased while TAC level decreased in CCl4 given animals as compared to the control group. No significant changes were observed in triglyceride and visfatin levels. Immunohistochemical staining revealed increased TGF-α and TGF-β expressions and decreased PPAR-α and PPAR-γ expressions in liver of CCl4 given animals. Omega-3 supplementation has prominent effects in correcting the biochemical and immunohistochemical parameters studied as well as the tissue morphology. The results of the investigation indicated that omega-3 has ameliorative effects on the oxidative tissue degeneration and inflammatory processes induced by CCl4 treatment in rats. Keywords: CCl4, Omega-3, TGF-α, TGF-β, PPAR-α, PPAR-γ Karbon Tetraklorür Toksikasyonunda Omega-3'ün Koruyucu Etkisi ÖzetOmega-3 bağışıklığı düzenleyici fonksiyonları olduğu bilinen çoklu doymamış bir yağ asididir. Bu çalışmada, deneysel karbon tetraklorür (CCl4) toksikasyonunda omega-3'ün koruyucu potansiyel etkisi araştırılmıştır. Toplam 40 adet ergin erkek Wistar albino rat eşit beş gruba ayrıldı ve 6 hafta süresince her iki günde bir olmak üzere subkutan yolla deneklere tarif edilen uygulamalar yapıldı; Grup 1 (kontrol): 0.5 ml/kg serum fizyolojik, Grup 2 (Omega): 0.5 g/kg omega-3, Grup 3 (Taşıt): 0.5 ml/kg saf zeytin yağı, Grup 4 (CCl4): 0.5 ml/kg CCl4, Grup 5 (CCl4 + Omega): 0.5 ml/kg CCl4 artı 0.5 g/kg omega-3. Araştırma süresinin sonunda, kan örnekleri alınan deneklere karaciğer doku örneklerinin toplanması amacıyla nekropsi uygulandı. Serum AST, AlT, GGT, TAC, TOC, trigliserid ve visfatin seviyeleri belirlendi. Karaciğer morfolojisi incelendi ve TGF-α, TGF-β, PPAR-α ve PPAR-γ immunreaktiviteleri tespit edildi. Kontrol grubu ile karşılaştırıldığında CCl4 verilen hayvanlarda serum AST, AlT, GGT ve TOC seviyelerinin anlamlı derecede arttığı, TAC seviyesinin ise azaldığı gözlemlendi. Trigliserid ve visfatin seviyelerinde anlamlı bir değişikliğin olmadığı belirlendi. İmmunohistokimyasal boyamalarda CCl4 verilen hayvanlarda TGF-α ve TGF-β immunreaktiviteleri artarken PPAR-α ve PPAR-γ immunreaktivitelerinde azalma dikkati çekti. Omega-3 takviyesinin incel...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Salgı

Karaman¹,

Özen²,

Dağ³

et al. 2016

Kafkas Univ Vet Fak Derg

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“…The pathological progression of liver fibrosis GO term oxidation reduction 92 LDHA(7) G6PD(5) ACADM(4) GPX1(4) ALDH2(3) response to extracellular stimulus 34 LDHA(7) ALDOB(6) COL1A1(5) G6PD(5) ACADM(4) response to endogenous stimulus 50 LDHA(7) ALDOB(6) COL1A1(5) ACADM(4) GPX1(4) glucose metabolic process 22 LDHA(7) ALDOB(6) G6PD(5) AGL(3) CPS1(3) oxidoreduction coenzyme metabolic process 10 LDHA(7) ALDOB(6) G6PD(5) DCXR(3) HIBADH(3) response to oxidative stress 17 LDHA(7) COL1A1(5) G6PD(5) GPX1(4) GPX3(3) liver development 9 ALDOB(6) ACADM(4) ALDH2(3) ANXA1(3) ASS1(3) cellular response to extracellular stimulus 8 LDHA(7) ALDOB(6) AIF1(4) ASNS(3) ASGR1(2) extracellular matrix organization 9 COL1A1(5) HSD17B12 (3) LGALS3 (2) ANXA2 (2) COL1A2(2) extracellular structure organization 10 COL1A1(5) HSD17B12(3) ANXA2(2) COL1A2(2) DCN(2) actin filament organization 6 AIF1(4) CFL1 (2) PRKCI (2) CORO1A (1) is highly related to the fibrotic response and the proliferation of connective tissue (Guo et al, 2013). In this study, we induced liver lesion and fibrosis using CCl 4 in male Wistar rats, performed the integrative analyses of transcriptomics and proteomics with liver fibrosis tissue compared that of CCl 4 -untreated rat, and identified several important biological process and pathways which enriched by the overlapped differentially expressed genes and proteins.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

et al. 2016

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-The classic toxicity of carbon tetrachloride (CCl 4 ) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl 4 -induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl 4 in liver fibrosis. Wistar rats were treated with CCl 4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl 4 -treated group were significantly higher than that of CCl 4 -untreated group. CCl 4 -treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl 4 treatment. Therefore, the toxicological mechanisms of CCl 4 -induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl 4 detoxication in the liver.

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“…The cell morphological alterations were screened and imaged using a light microscope (CX41-32C02, Olympus, Japan). Furthermore, the diagnostic standard of collagen deposition in the liver was evaluated as previously reported [18] as follows: grade 0, no fibrosis; grade 1, slight fibrosis; grade 2, mild fibrosis; grade 3, moderate fibrosis; and grade 4, severe fibrosis.…”

Section: Measurement Of Collagen Markers In the Livermentioning

confidence: 99%

Anti-Fibrotic Effect of Plumbagin on CCl4-Lesioned Rats

Wei

Huang

Liu

et al. 2015

Cell Physiol Biochem

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Background/Aims: Our previous studies have shown that plumbagin effectively inhibits hepatic stellate cell (HSC) proliferation. Thus, plumbagin-mediated anti-fibrotic effects in vivo merit further investigation. Methods: We used rat models to assess the potential benefits of plumbagin against CCl₄-induced liver fibrosis. Results: The results showed that plumbagin lowered the serum concentrations of liver functional enzymes (ALT, AST, ALB, TBIL) in CCl₄-fibrotic rats while reducing inflammatory cytokine levels (IL-6, TNF-a). As reflected in pathological examinations, rats that were administered plumbagin showed decreased collagen markers (HA, LN, PCIII and CIV) in liver tissues and improved hepatocellular impairments. In addition, plumbagin contributed to down-regulating NF-κB and TLR-4 mRNA in CCl₄-lesioned livers. As revealed in the immunohistochemical assay, plumbagin-administered rats showed reduced levels of a-SMA and TNF-a immunoreactive cells in liver tissue. Conclusion: Collectively, these findings offer appealing evidence that plumbagin may serve as an anti-fibrotic medication through inactivating the NF-κB/TLR-4 pathway that is associated with inflammatory reactions, thereby mitigating liver fibrosis.

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Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γ expression and inhibition of PI3K/Akt pathway

Cited by 75 publications

References 47 publications

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Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

Anti-Fibrotic Effect of Plumbagin on CCl4-Lesioned Rats

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