medigraphic.com
Órgano Oficial de la Asociación Mexicana de Hepatología

2018, Number 2

<< Back Next >>

Ann Hepatol 2018; 17 (2)

Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress, Inflammation and TGF-β /Smad Inhibition in Rats

Said MM, Azab SS, Saeed NM, El-Demerdash E

Language: English
References: 53
Page: 307-317
PDF size: 673.76 Kb.


ABSTRACT

Introduction. The present study aimed to elucidate the potential antifibrotic effects of pinocembrin (PIN), a flavanone found abundantly in honey and propolis, by studying its effect on different oxidative stress, inflammatory and fibrosis markers in an experimental model of CCl4-induced liver fibrosis. Material and methods. PIN (20 mg/kg) was given orally 3 times/week for 6 consecutive weeks alternating with CCl4 (0.5 mL/kg, 1:1 mixture with corn oil, i. p.) twice weekly. Different hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Results. PIN significantly restored liver transaminases and total cholesterol to normal levels. Also, PIN ameliorated oxidative stress injury evoked by CCl4 as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme superoxide dismutase (SOD). Further, PIN upregulated the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective enzyme hemeoxygenase-1 (HO-1). Moreover, PIN alleviated pro-inflammatory cytokines such as TNF-α via inhibiting nuclear factor-κB (NF-κB) activation. As markers of fibrosis, collagen and α-SMA expression increased markedly in the CCl4 group and PIN prevented these alterations. In addition, PIN down-regulated TGFβ1 and p-Smad2/3, thereby inhibiting TGFβ1/Smad signaling pathway. Conclusion. These results suggest that PIN possess potent antifibrotic effects that can be explained on its antioxidant properties. It ameliorates oxidative stress and inflammation during induction of fibrogenesis via its ability to augment cellular antioxidant defenses, activating Nrf2-mediated HO-1 expression and modulating NF-κB and TGF-β1/Smad signaling pathway.


REFERENCES

  1. Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214: 199-210.

  2. Chu Ps, Nakamoto N, Ebinuma H, Usui S, Saeki K, Matsumoto A, Mikami Y, et al. C?C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology 2013; 58: 337-50.

  3. Ahmad A, Ahmad R. Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches. Saudi J Gastroenterol 2012; 18: 155.

  4. Gressner O, Weiskirchen R, Gressner A. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cel Mol Med 2007; 11: 1031-51.

  5. Henderson N, Iredale J. Liver fibrosis: cellular mechanisms of progression and resolution. Clinical Science 2007; 112: 265-80.

  6. Dooley S, Streckert M, Delvoux B, Gressner AM. Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts. Biochemical and Biophysical Research Communications 2001; 283: 554-62.

  7. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol 2012:13:616-30.

  8. Ten Dijke P, Hill CS. New insights into TGF-β-Smad signalling. Trends in Biochemical Sciences 2004; 29: 265-73.

  9. Ghatak S, Biswas A, Dhali GK, Chowdhury A, Boyer JL, Santra A. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice. Toxicology and Applied Pharmacology 2011; 251: 59-69.

  10. Cong M, Liu T, Wang P, Fan X, Yang A, Bai Y, Peng Z, et al. Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis. Am J Pathol 2013; 182: 1607-16.

  11. Yang J-J, Tao H, Huang C, Li J. Nuclear erythroid 2-related factor 2: A novel potential therapeutic target for liver fibrosis. Food and Chemical Toxicology 2013; 59: 421-7.

  12. Jaganathan SK, Mandal M. Antiproliferative effects of honey and of its polyphenols: a review. Journal of Biomedicine and Biotechnology 2009: 2009.

  13. Gao M, Liu R, Zhu S-Y, Du G-H. Acute neurovascular unit protective action of pinocembrin against permanent cerebral ischemia in rats. Journal of Asian Natural Products Research 2008; 10: 551-8.

  14. Liu R, Gao M, Yang Z-H, Du G-H. Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemiareperfusion both in vivo and in vitro. Brain Research 2008: 1216: 104-15.

  15. Soromou LW, Chu X, Jiang L, Wei M, Huo M, Chen N, Guan S, et al. In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses. International Immunopharmacology 2012; 14: 66-74.

  16. Kapoor S. Comment on isolation and identification of compounds from Penthorum chinense Pursh with antioxidant and antihepatocarcinoma properties: Pinocembrin and its rapidly emerging neuroprotective effects. Journal of Agricultural and Food Chemistry 2013; 61: 1416-16.

  17. Yu Y-S, Hsu C-L, Yen G-C. Anti-inflammatory effects of the roots of Alpinia pricei Hayata and its phenolic compounds. Journal of Agricultural and Food Chemistry 2009; 57: 7673-80.

  18. Chen C-S, Wu C-H, Lai Y-C, Lee W-S, Chen H-M, Chen R-J, Chen L-C, et al. NF-κB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis. Toxicology 2008; 246: 148-57.

  19. Catchpole O, Mitchell K, Bloor S, Davis P, Suddes A. Antiproliferative activity of New Zealand propolis and phenolic compounds vs human colorectal adenocarcinoma cells. Fitoterapia 2015; 106: 167-74.

  20. Jin X, Liu Q, Jia L, Li M, Wang X. Pinocembrin attenuates 6- OHDA-induced neuronal cell death through Nrf2/ARE pathway in SH-SY5Y cells. Cellular and molecular neurobiology 2015; 35: 323-33.

  21. Kao H-F, Chang-Chien P-W, Chang W-T, Yeh T-M, Wang J-Y. Propolis inhibits TGF-β1-induced epithelial-mesenchymal transition in human alveolar epithelial cells via PPARγ activation. International Immunopharmacology 2013; 15: 565-74.

  22. Shalaby N, Abd-Alla H, Hamed M, Al-Ghamdi S, Jambi S. Flavones composition and therapeutic potential of Dodonaea viscosa against liver fibrosis. International Journal of Phytomedicine 2012; 4: 27-39.

  23. Olsson I, Lantz M, Nilsson E, Peetre C, Thysell H, Grubb A, Adolf G. Isolation and characterization of a tumor necrosis factor binding protein from urine. Eur J Haematol 1989; 42: 270-5.

  24. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic acids research 2001; 29: e45-e45.

  25. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 1976; 72: 248-54.

  26. Bahcecioglu IH, Koca SS, Poyrazoglu OK, Yalniz M, Ozercan IH, Ustundag B, Sahin K, et al. Hepatoprotective effect of infliximab, an anti-TNF-α agent, on carbon tetrachloride-induced hepatic fibrosis. Inflammation 2008; 31: 215-21.

  27. Yachi R, Igarashi O, Kiyose C. Protective effects of vitamin E analogs against carbon tetrachloride-induced fatty liver in rats. J Clin Biochem Nutrit 2010; 47: 148-54.

  28. Fujii T, Fuchs BC, Yamada S, Lauwers GY, Kulu Y, Goodwin JM, Lanuti M, et al. Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterology 2010; 10: 79.

  29. Recknagel RO, Glende EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacology & Therapeutics 1989; 43: 139-54.

  30. Ungvari Z, Sonntag WE, de Cabo R, Baur JA, Csiszar A. Mitochondrial protection by resveratrol. Exercise and Sport Sciences Reviews 2011; 39: 128-32.

  31. He X, Wang L, Szklarz G, Bi Y, Ma Q. Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway. Journal of Pharmacology and Experimental Therapeutics 2012; 342: 81-90.

  32. Na H-K, Surh Y-J. Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food and Chemical Toxicology 2008; 46: 1271-8.

  33. Yeh CT, Chiu HF, Yen GC. Protective effect of sulforaphane on indomethacin-induced cytotoxicity via heme oxygenase-1 expression in human intestinal Int 407 cells. Molecular Nutrition & Food Research 2009; 53: 1166-76.

  34. Lee B-H, Hsu W-H, Chang Y-Y, Kuo H-F, Hsu Y-W, Pan T-M. Ankaflavin: a natural novel PPARγ agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo. Free Radical Biology and Medicine 2012; 53: 2008-16.

  35. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, Taguchi K, et al. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicological Sciences 2008: 104: 218-27.

  36. Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N'-nitrosodimethylamineinduced liver fibrosis via restraining oxidative damage. Chemico-Biological Interactions 2014; 221: 1-12.

  37. Mohamed MR, Emam MA, Hassan NS, Mogadem AI. Umbelliferone and daphnetin ameliorate carbon tetrachloride-induced hepatotoxicity in rats via nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1 expression. Environmental Toxicology and Pharmacology 2014; 38: 531-41.

  38. Huang C-S, Lii C-K, Lin A-H, Yeh Y-W, Yao H-T, Li C-C, Wang T-S, et al. Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Archives of Toxicology 2013; 87: 167-78.

  39. Mani M, Golmohammadi T, Khaghani S, Zamani Z, Azadmanesh K, Meshkani R, Pasalar P. Homocysteine Induces Heme Oxygenase-1 Expression via Transcription Factor Nrf2 Activation in HepG2 Cells. Iranian Biomedical Journal 2013; 17: 93-100.

  40. Wang J-Q, Chen X, Zhang C, Tao L, Zhang Z-H, Liu X-Q, Xu Y-B, et al. Phenylbutyric acid protects against carbon tetrachloride- induced hepatic fibrogenesis in mice. Toxicology and Applied Pharmacology 2013; 266: 307-16.

  41. Shim J-Y, Kim M-H, Kim H-D, Ahn J-Y, Yun Y-S, Song J-Y. Protective action of the immunomodulator ginsan against carbon tetrachloride-induced liver injury via control of oxidative stress and the inflammatory response. Toxicology and Applied Pharmacology 2010; 242: 318-25.

  42. Shin D-S, Kim KW, Chung HY, Yoon S, Moon J-O. Effect of sinapic acid against carbon tetrachloride-induced acute hepatic injury in rats. Archives of Pharmacal Research 2013; 36: 626-33.

  43. Ma J-Q, Liu C-M, Qin Z-H, Jiang J-H, Sun Y-Z. Ganoderma applanatum terpenes protect mouse liver against benzo (α) pyren-induced oxidative stress and inflammation. Environmental Toxicology and Pharmacology 2011; 31: 460-8.

  44. Kong D, Zhang F, Wei D, Zhu X, Zhang X, Chen L, Lu Y, et al. Paeonol inhibits hepatic fibrogenesis via disrupting nuclear factor-κB pathway in activated stellate cells: In vivo and in vitro studies. J Gastroenterol Hepatol 2013; 28: 1223-33.

  45. Park KC, Park JH, Jeon JY, Kim SY, Kim JM, Lim CY, Lee TH, et al. A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. Brit J Pharmacol 2014; 171: 4820-30.

  46. Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. Journal of Biological Chemistry 2000; 275: 2247-50.

  47. Ahmad R, Ahmed S, Khan NU, Hasnain A-U. Operculina turpethum attenuates N-nitrosodimethylamine induced toxic liver injury and clastogenicity in rats. Chemico-Biological Interactions 2009; 181: 145-53.

  48. Liu Y, Wang Z, Kwong SQ, Lui EL, Friedman SL, Li FR, Lam RW, et al. Inhibition of PDGF, TGF-beta, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr- Abl tyrosine kinase antagonist Nilotinib. J Hepatol 2011; 55: 612-25.

  49. Deng Y-R, Ma H-D, Tsuneyama K, Yang W, Wang Y-H, Lu FT, Liu C-H, et al. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. Journal of Autoimmunity 2013; 46: 25-34.

  50. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003; 425: 577-84.

  51. Inagaki Y, Okazaki I. Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut 2007; 56: 284-92.

  52. Liu R-M, Pravia KG. Oxidative stress and glutathione in TGF- β-mediated fibrogenesis. Free Radical Biology and Medicine 2010; 48: 1-15.

  53. Liu X, Hu H, Yin JQ. Therapeutic strategies against TGF-β signaling pathway in hepatic fibrosis. Liver International 2006; 26: 8-22.




2020     |     www.medigraphic.com