The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats

2018 ◽  
Vol 96 (12) ◽  
pp. 1308-1317 ◽  
Author(s):  
Heba M. Mansour ◽  
Abeer A.A. Salama ◽  
Rania M. Abdel-Salam ◽  
Naglaa A. Ahmed ◽  
Noha N. Yassen ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Interleukin 1 ◽  
Health Concern ◽  
Dependent Manner ◽  
Serum Transaminases ◽  
Anti Inflammatory

Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.

scholarly journals Therapeutic Effect of Dunaliella salina Microalgae on Thioacetamide- (TAA-) Induced Hepatic Liver Fibrosis in Rats: Role of TGF-β and MMP9

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Farouk K. El-Baz ◽  
Abeer Salama ◽  
Rania A. A. Salama
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Dunaliella Salina ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Elevated Serum ◽  
Serum Levels ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Liver Histopathology

Liver fibrosis represents a serious global health-care problem and is the outcome of many chronic liver diseases, cirrhosis, hepatitis, and toxin accumulation. The present study aimed to evaluate the antifibrotic curative effect of Dunaliella salina (D. salina) on thioacetamide- (TAA-) induced liver fibrosis in rats. Liver fibrosis was induced by TAA (200mg/kg; i.p.) twice per week for 6 weeks. D. salina was given orally (100 and 200 mg/kg) and silymarin was given orally (100 mg/kg) daily, for 4 weeks after TAA. Serum transaminase activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA significantly (p<0.05) elevated serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum levels of total bilirubin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β) with a reduction in albumin. In addition, TAA increased hepatic contents of collagen I, a-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase (TIMP-1), reduced matrix metalloproteinase 9 (MMP9), and finally produced marked degeneration and fibrosis of hepatocytes. Treatment with D. salina or silymarin improved the histological feature of hepatocytes and ameliorated the deleterious effects of TAA in a dose-dependent manner. Based on these results, it could be concluded that the use of D. salina could be assigned for liver fibrosis treatment via its anti-inflammatory and antifibrotic properties.

scholarly journals Aqueous Date Flesh or Pits Extract Attenuates Liver Fibrosis via Suppression of Hepatic Stellate Cell Activation and Reduction of Inflammatory Cytokines, Transforming Growth Factor-β1 and Angiogenic Markers in Carbon Tetrachloride-Intoxicated Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Nouf M. Al-Rasheed ◽  
Hala A. Attia ◽  
Raeesa A. Mohamad ◽  
Nawal M. Al-Rasheed ◽  
Maha A. Al-Amin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Inflammatory Cytokines ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β1 ◽  
Angiogenic Markers

Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl4(0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl4-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl4-induced expression ofα-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

scholarly journals Local and systemic influence of toxic levels of airborne ozone on the inflammatory response in rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Małgorzata Chmielewska-Krzesińska ◽  
Krzysztof Wąsowicz
Keyword(s):  
Inflammatory Response ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Genes Expression ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Abstract Introduction Ozone is not harmful itself; however, it directly oxidises biomolecules and produces radical-dependent cytotoxicity. Exposure to ozone is by inhalation and therefore the lungs develop the main anti-inflammatory response, while ozone has an indirect impact on the other organs. This study investigated the local and systemic effects of the ozone-associated inflammatory response. Material and Methods Three groups each of 5 Wistar Han rats aged 6 months were exposed for 2h to airborne ozone at 0.5 ppm and a fourth identical group were unexposed controls. Sacrifice was at 3h after exposure for control rats and one experimental group and at 24 h and 48 h for the others. Lung and liver samples were evaluated for changes in expression of transforming growth factor beta 1, anti-inflammatory interleukin 10, pro-inflammatory tumour necrosis factor alpha and interleukin 1 beta and two nuclear factor kappa-light-chain-enhancer of B cells subunit genes. Total RNA was isolated from the samples in spin columns and cDNA was synthesised in an RT-PCR. Expression levels were compared to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and analysed statistically. Results All variables changed non-linearly over time comparing experimental groups to the control. Conspicuous expression changes in the subunit genes and cytokines were observed in both evaluated organs. Conclusion Locally and systemically, inflammation responses to ozone inhalation include regulation of certain genes’ expression. The mechanisms are unalike in lungs and liver but ozone exerts a similar effect in both organs. A broader range of variables influential on ozone response should be studied in the future.

scholarly journals Hierarchical Coculture of Hepatocyte and Hepatic Non-Parenchymal Cells for Liver Fibrosis Studies in vitro

2020 ◽  
Author(s):  
Qiao You Lau ◽  
Fuad Gandhi Torizal ◽  
Marie Shinohara ◽  
Yasuyuki Sakai
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Oxygen Tension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Liver Sinusoidal Endothelial Cell ◽  
Type I ◽  
Parenchymal Cells

During chronic liver injury, inflammation leads to the development of liver fibrosis&mdash; particularly due to the activation of hepatic stellate cells (HSCs). However, the involvement of inflammatory cytokines in HSC activation is unclear. Many existing in vitro liver models do not include these non-parenchymal cells (NPCs), and hence, do not represent the physiological relevance found in vivo. Herein, we demonstrated the hierarchical coculture of primary rat hepatocytes with NPCs such as the human-derived HSC line (LX-2) and the human-derived liver sinusoidal endothelial cell line (TMNK-1). The coculture tissue had higher albumin production and hepatic cytochrome P450 3A4 activity compared to the monoculture. We then further studied the effects of stimulation by both oxygen tension and key pro-fibrogenic cytokines, such as the transforming growth factor beta (TGF-&beta;), on HSC activation. Gene expression analysis revealed that lower oxygen tension and TGF-&beta;1 stimulation enhanced collagen type I, III, and IV, alpha-smooth muscle actin, platelet-derived growth factor, and matrix metallopeptidase expression from LX-2 cells in the hierarchical coculture after fibrogenesis induction. This hierarchical in vitro cocultured liver tissue could, therefore, provide an improved platform as a disease model for elucidating the interactions of various liver cell types and biochemical signals in liver fibrosis studies.

scholarly journals Alpha interferon inhibits translation mediated by the internal ribosome entry site of six different hepatitis C virus genotypes

2005 ◽  
Vol 86 (11) ◽  
pp. 3047-3053 ◽  
Author(s):  
Sidhartha Hazari ◽  
Asha Patil ◽  
Virendra Joshi ◽  
Deborah E. Sullivan ◽  
Cesar D. Fermin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Transforming Growth Factor Beta ◽  
Internal Ribosome Entry Site ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Dependent Manner ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Hcv Genotypes

Certain genotypes of hepatitis C virus (HCV) respond less often than others to treatment with interferon (IFN). The mechanisms for this differential response are not known. In this report antiviral effects of IFN-α2b on translation were examined in a hepatic cell line using chimeric clones of internal ribosome entry site (IRES) sequences from six different HCV genotypes and the green fluorescence protein (GFP) gene. As a control, IFN action at the level of the IRES was examined in the presence of different cytokines. It was determined that IFN-α2b specifically inhibited the translation of GFP mediated by IRES sequences from six major HCV genotypes in a concentration-dependent manner. Other cytokines including tumour necrosis factor alpha, transforming growth factor beta 1, interleukin 1 and interleukin 6 have no inhibitory effect. The inhibition of translation in these experiments was not due to extensive intracellular degradation of IRES-GFP mRNA. These results suggest that the antiviral action of IFN-α2b blocks IRES-mediated translation and this effect is the same among HCVs of other genotypes.

scholarly journals Hepatoprotective Effect and Potential Mechanism of Aqueous Extract from Phyllanthus emblica on Carbon-Tetrachloride-Induced Liver Fibrosis in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Kehuan Yin ◽  
Xuedong Li ◽  
Xiaomin Luo ◽  
Yuru Sha ◽  
Puyang Gong ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Aqueous Extract ◽  
Liver Tissue ◽  
High Performance ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Protein Carbonyl ◽  
Phyllanthus Emblica ◽  
Anti Inflammatory

Liver fibrosis is a pathological variation caused by almost all chronic liver injuries. As an edible and medicinal natural resource, Phyllanthus emblica (PE) has been reported to possess hepatoprotective, antioxidant, and anti-inflammatory activities and may have an ameliorating effect on hepatic fibrosis. To investigate the protective effect of the aqueous extract of PE (AEPE) against liver fibrosis and to uncover its related mechanisms, the chemical profile of AEPE was characterized by high performance liquid chromatography (HPLC) and sulfuric acid-phenol method. Ameliorative effects of different doses of AEPE were investigated in carbon-tetrachloride- (CCl4-) induced liver fibrosis rats by analyzing biochemical markers, morphologic pathology, and related proteins expression in liver tissue. The results indicated that AEPE (1.8, 3.6 g/kg) could significantly reduce levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (Col IV), type III precollagen (PCIII), hyaluronic acid (HA), laminin (LN), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl (PC), tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and hydroxyproline (Hyp) and increase the levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Hematoxylin-eosin (H&E), Sirius red, and Masson staining showed AEPE-treated improved fibrotic lesions and inflammatory cell infiltration. Meanwhile, AEPE treatment also significantly downregulates the expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) in the liver tissue and serum, respectively. In conclusion, AEPE possesses curative efficacy against liver fibrosis through its antioxidant, anti-inflammatory, and antifibrotic effects.

Transforming growth factor beta-induced Foxo3a acts as a profibrotic mediator in hepatic stellate cells

2020 ◽  
Author(s):  
Seung Jung Kim ◽  
Kyu Min Kim ◽  
Ji Hye Yang ◽  
Sam Seok Cho ◽  
Eun Hee Jeong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Forkhead Transcription Factor ◽  
Hepatic Fibrogenesis ◽  
Duct Ligation ◽  
Nuclear Levels

Abstract Hepatic stellate cells (HSCs) are major contributors to hepatic fibrogenesis facilitating liver fibrosis. FoxO3a is a member of the forkhead transcription factor family, which mediates cell proliferation and differentiation. However, the expression and function of FoxO3a during HSC activation remain largely unknown. FoxO3a overexpression was related to fibrosis in patients, and its expression was colocalized with desmin or α-smooth muscle actin, representative HSC markers. We also observed upregulated FoxO3a levels in two animal hepatic fibrosis models, a carbon tetrachloride (CCl4)-injected model and a bile duct ligation model. In addition, TGF-β treatment in mouse primary HSCs or LX-2 cells elevated FoxO3a expression. When FoxO3a was upregulated by TGF-β in LX-2 cells, both the cytosolic and nuclear levels of FoxO3a increased. In addition, we found that the induction of FoxO3a by TGF-β was due to both transcriptional and proteasome-dependent mechanisms. Moreover, FoxO3a overexpression promoted TGF-β-mediated Smad activation. Furthermore, FoxO3a increased fibrogenic gene expression, which was reversed by FoxO3a knockdown. TGF-β-mediated FoxO3a overexpression in HSCs facilitated hepatic fibrogenesis, suggesting that FoxO3a may be a novel target for liver fibrosis prevention and treatment.

scholarly journals Novel IMB16-4 Compound Loaded into Silica Nanoparticles Exhibits Enhanced Oral Bioavailability and Increased Anti-Liver Fibrosis In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1545
Author(s):  
Xia Niu ◽  
Xiaomei Wang ◽  
Bingyu Niu ◽  
Guoqing Li ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Silica Nanoparticles ◽  
Transforming Growth Factor Beta ◽  
Oral Bioavailability ◽  
Transforming Growth Factor ◽  
Mesoporous Silica Nanoparticles ◽  
Smooth Muscle Actin ◽  
Drug Carriers ◽  
Matrix Metalloproteinase 2 ◽  
Scanning Calorimetry

Background: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. Methods: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague–Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. Conclusions: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.

scholarly journals The Effects of New Zealand Grown Ginseng Fractions on Cytokine Production from Human Monocytic THP-1 Cells

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1158
Author(s):  
Wei Chen ◽  
Prabhu Balan ◽  
David G. Popovich
Keyword(s):  
New Zealand ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor Beta ◽  
Inflammatory Cytokine ◽  
Transforming Growth Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Pro-inflammatory cytokines and anti-inflammatory cytokines are important mediators that regulate the inflammatory response in inflammation-related diseases. The aim of this study is to evaluate different New Zealand (NZ)-grown ginseng fractions on the productions of pro-inflammatory and anti-inflammatory cytokines in human monocytic THP-1 cells. Four NZ-grown ginseng fractions, including total ginseng extract (TGE), non-ginsenoside fraction extract (NGE), high-polar ginsenoside fraction extract (HPG), and less-polar ginsenoside fraction extract (LPG), were prepared and the ginsenoside compositions of extracts were analyzed by HPLC using 19 ginsenoside reference standards. The THP-1 cells were pre-treated with different concentrations of TGE, NGE, HPG, and LPG, and were then stimulated with lipopolysaccharide (LPS). The levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and anti-inflammatory cytokines, such as interleukin-10 (IL-10), and transforming growth factor beta-1 (TGF-β1), were determined by enzyme-linked immunosorbent assay (ELISA). TGE at 400 µg/mL significantly inhibited LPS-induced TNF-α and IL-6 productions. NGE did not show any effects on inflammatory secretion except inhibited IL-6 production at a high dose. Furthermore, LPG displayed a stronger effect than HPG on inhibiting pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) productions. Particularly, 100 µg/mL LPG not only significantly inhibited the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, but also remarkably enhanced the production of anti-inflammatory cytokine IL-10. NZ-grown ginseng exhibited anti-inflammatory effects in vitro, which is mainly attributed to ginsenoside fractions (particularly less-polar ginsenosides) rather than non-saponin fractions.

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