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| Curcumin antagonized CCl4-induced liver fibrosis in mice by activating SIRT1 |
| SHEN Changjun1 ZHANG Shuai1 LI Haopeng2 HOU Chen3 CHEN Jie4 |
1.The Second Ward of General Surgery, Yan′an People′s Hospital, Shannxi Province, Yan′an 716000, China;
2.Department of Orthopedics, the Second Affiliated Hospital of Xi′an Jiaotong University, Shannxi Province, Xi′an 710032, China;
3.the Third Department of Neurology, the Third Affiliated Hospital of Xi′an Jiaotong University Shaanxi Provincial People′s Hospital, Shannxi Province, Xi′an 710032, China;
4.Department of Burns and Cutaneous Surgery, the Second Affiliated Hospital of Xi′an Medical College Xijing Hosptital, Air Force Medical University, Shannxi Province, Xi′an 710032, China |
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Abstract Objctive To investigate the activity of silencing information regulator 1 (SIRT1) in the liver of carbon tetrachloride (CCl4) induced liver fibrosis in mice, and to investigate the effect of curcumin on liver fibrosis and its molecular mechanism. Methods Twenty-four C57BL/6 mice were randomly divided into normal group, model group and Curcumin treatment group, with 8 mice in each group. Hepatic fibrosis model was prepared by intraperitoneal injection of CCl4. After the modeling, the curcumin treatment group was given 0.5% Carboxymethyl Cellulose Sodium Curcumin Suspension by gavage. The model group and the normal group were given 0.5% Sodium Carboxymethyl Cellulose by gavage, the mice were killed after 6 weeks. HE staining was used to detect the pathological changes of mouse liver. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and activity of SIRT1 were detected. Transforming growth factor β1 (TGF -β1), α-smooth muscle actin (α-SMA), collagen typeⅠ (Coll Ⅰ) mRNA expression, and Cleaved - caspase3, Coll Ⅰ protein expression. Results The expression levels of ALT, AST, IL-6 and TNF-α in serum of the model group were all significant higher than those of the normal group (all P ＜ 0.01). The expression levels of ALT, AST, IL-6 and TNF-α in the treatment group were all lower than those in the model group, and the differences were highly statistically significant (all P ＜ 0.01). The enzyme activity of SIRT1 in the liver cells of the model group was lower than that of the normal group, and the difference was highly statistically significant (P ＜ 0.01). The enzyme activity of SIRT1 in the treatment group was significantly higher than that in the model group, and the difference was highly statistically significant (P ＜ 0.01). Model group in the liver tissue, TGF-β1, α-SMA mRNA and Coll Ⅰ expression of amount of expression were significantly higher than those of normal group, Cleaved-caspase3 was significantly lower than that of normal group, with highly statistically significant differences (all P ＜ 0.01). The mRNA expression of TGF-β1, α-SMA and Coll Ⅰ expression quantity in the treatment group were lower than those in the model group, Cleaved-caspase3 was significantly higher than that of model group, with highly statistically significant differences (all P ＜ 0.01). Conclusion Curcumin has an inhibitory effect on CCl4-induced liver fibrosis, and the mechanism may be to up-regulate the activity of SIRT1, thereby reducing the inflammatory response, inhibiting the activation of hepatic stellate cells, and antagonizing liver fibrosis.
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[1] Kao NJ，Hu JY，Wu CS，et al. Curcumin represses the activity of inhibitor-κB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation [J]. Int Immunopharmacol，2016，38：1-7.
[2] Su TH，Kao JH，Liu CJ. Molecular mechanism and treatment of viral hepatitis-related liver fibrosis [J]. Int J Mol Sci，2014，15（6）：10578-10604.
[3] Hu YB，Ye XT，Zhou QQ，et al. Sestrin 2 Attenuates Rat Hepatic Stellate Cell （HSC） Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism [J]. Cell Physiol Biochem，2018：2111-2122.
[4] O′Reilly S，Ciechomska M，Cant R，et al. Interleukin-6 （IL-6） trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β （TGF-β） signaling promoting SMAD3 activation and fibrosis via Gremlin protein [J]. J Biol Chem，2014，289（14）：9952-9960.
[5] Khanizadeh S，Ravanshad M，Hosseini S，et al. Blocking of SMAD4 expression by shRNA effectively inhibits fibrogenesis of human hepatic stellate cells [J]. Gastroenterol Hepatol Bed Bench，2015，8（4）：262-269.
[6] Kisseleva T，Brenner DA. The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis [J]. J Hepatol，2012，56（4）：965-972.
[7] Inagaki Y，Nemoto T，Kushida M，et al. Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice [J]. Hepatology，2003， 38（4）：890-899.
[8] Gu L，Tao X，Xu Y，et al. Dioscin alleviates BDL-and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway [J]. Toxicol Appl Pharmacol，2016，292：19-29.
[9] Sodhi K，Puri N，Favero G，et al. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet [J]. PLoS One，2015，10（6）：e0128648.
[10] Li M，Hong W，Hao C，et al. SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice [J]. FASEB J，2018，32（1）：500-511.
[11] Cappetta D，Esposito G，Piegari E. SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy [J]. Int J Cardiol，2016，205：99-110.
[12] Zhao XA，Chen G，Liu Y，et al. Curcumin reduces Ly6Chi，monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion [J]. Biomed Pharmacother，2018，106：868-878.
[13] Sica A，Invernizzi P，Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology [J]. Hepatology，2014，59（5）：2034-2042.
[14] Zheng J，Wu C，Lin Z，et al. Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation--a novel mechanism suppressing liver fibrosis [J]. FEBS J，2014，281（1）：88-103.
[15] Bellet MM，Masri S，Astarita G，et al. Histone Deacetylase SIRT1 Controls Proliferation，Circadian Rhythm，and Lipid Metabolism during Liver Regeneration in Mice [J]. J Biol Chem，2016，291（44）：23318-23329.
[16] Mccubrey JA，Lertpiriyapong K，Steelman LS，et al. Effects of resveratrol，curcumin，berberine and other nutraceuticals on aging，cancer development，cancer stem cells and microRNAs [J]. Aging，2017，9（6）：1477-1536.
[17] Lee DE，Lee SJ，Kim SJ，et al. Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation [J]. Nutrients，2019，11（11）：E2702.
[18] Ding RB，Bao J，Deng CX. Emerging roles of SIRT1 in fatty liver diseases [J]. Int J Biol Sci，2017，13（7）：852-867.
[19] Yin H，Hu M，Liang X，et al. Deletion of SIRT1 From Hepatocytes in Mice Disrupts Lipin-1 Signaling and Aggravates Alcoholic Fatty Liver [J]. Gastroenterol，2014， 146（3）：801-811.
[20] Marengo A，Rosso C，Bugianesi E. Liver Cancer：Connections with Obesity，Fatty Liver，and Cirrhosis [J]. Annu Rev Med，2016，67：103-117.
[21] Unalp-Arida A，Ruhl CE. PNPLA3 I148M and liver fat and fibrosis scores predict liver disease mortality in the United States population [J]. Hepatology，2019，31032. |
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