白藜芦醇通过SIRT1减轻蛛网膜下腔出血大鼠神经系统炎症反应
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摘要
目的:白藜芦醇(RSV)对蛛网膜下腔出血(SAH)大鼠神经系统沉默信息调节因子同源蛋白1(SIRT1)的表达及炎症反应的影响。方法:48只成年雄性SD大鼠分为对照组(Control)、蛛网膜下腔出血组(SAH)、RSV治疗组(RSV)和RSV联合组SIRT1抑制剂EX 527处理组(RSV+EX 527),利用自身血液注射法制备SAH大鼠模型,神经功能缺损评分检测大鼠神经功能变化,Western Blot检测SIRT1表达水平变化,免疫荧光染色观察小胶质细胞表面标记CD11b的表达变化,利用ELISA检测神经系统炎性细胞因子TNF-α和IL-1β变化。结果:与正常对照组相比,SAH大鼠神经功能受损明显(P <0. 05),中枢神经系统SIRT1表达降低(P <0. 05),小胶质细胞活化明显(P <0. 05),TNF-α和IL-1β均显著升高(P <0. 05);经过RSV治疗后,与SAH大鼠相比,治疗组大鼠神经功能明显得到改善(P <0. 05),神经系统SIRT1表达增加(P <0. 05),小胶质细胞活化受到抑制(P <0. 05),炎性细胞因子TNF-α和IL-1β水平下降(P <0. 05);使用EX 527处理后,RSV的神经保护作用受到抑制,表现为SAH大鼠神经功能恢复不明显,中枢神经系统小胶质细胞持续活化,细胞因子TNF-α和IL-1β水平维持在较高水平。结论:RSV通过促进SIRT1表达抑制炎症反应发挥对SAH大鼠中枢神经系保护作用。
Objective: To investigate the effects of resveratrol( RSV) on the expression of silent mating type information regulation 2 homolog 1 SIRT1 and inflammatory response in the central nervous system of subarachnoid hemorrhage( SAH) rats. Methods: 48 adult male SD rats were divided into Control group,SAH group,RSV group,and RSV + EX 527 group. SAH model were prepared by using their own blood injections in rats. Neurological function defect scale test was performed at 7 thday after surgery. The expression of SIRT1 was detected by Western Blot. The expression of glial cell surface markers CD11 b was detected by immunofluorescence staining. The levels of TNF-α and IL-1β were detected by ELISA. Results: Compared with control group,SAH caused neurological dysfunction( P <0. 05),SIRT1 down regulation( P < 0. 05),microglia activation( P < 0. 05),TNF-α and IL-1β up regulation( P <0. 05) in brain tissue. RSV treatment resulted the neurological function of the rats in the treatment group was significantly improved( P < 0. 05),SIRT1 up regulation( P < 0. 05),inhibition microglia cell activation( P < 0. 05),TNF-αand IL-1β levels down regulation( P < 0. 05). After the treatment with EX 527,the neuroprotective effects of RSV was inhibited,which showed that the neurological function of SAH rats was not restored,the microglias in the central nervous system were continuously activated,and the levels of TNF-α and IL-1β were maintained at a high level. Conclusion: RSV plays a protective role in the central nervous system of SAH rats by promoting the expression of SIRT1 and inhibiting the inflammatory response.
Objective: To investigate the effects of resveratrol( RSV) on the expression of silent mating type information regulation 2 homolog 1 SIRT1 and inflammatory response in the central nervous system of subarachnoid hemorrhage( SAH) rats. Methods: 48 adult male SD rats were divided into Control group,SAH group,RSV group,and RSV + EX 527 group. SAH model were prepared by using their own blood injections in rats. Neurological function defect scale test was performed at 7 thday after surgery. The expression of SIRT1 was detected by Western Blot. The expression of glial cell surface markers CD11 b was detected by immunofluorescence staining. The levels of TNF-α and IL-1β were detected by ELISA. Results: Compared with control group,SAH caused neurological dysfunction( P <0. 05),SIRT1 down regulation( P < 0. 05),microglia activation( P < 0. 05),TNF-α and IL-1β up regulation( P <0. 05) in brain tissue. RSV treatment resulted the neurological function of the rats in the treatment group was significantly improved( P < 0. 05),SIRT1 up regulation( P < 0. 05),inhibition microglia cell activation( P < 0. 05),TNF-αand IL-1β levels down regulation( P < 0. 05). After the treatment with EX 527,the neuroprotective effects of RSV was inhibited,which showed that the neurological function of SAH rats was not restored,the microglias in the central nervous system were continuously activated,and the levels of TNF-α and IL-1β were maintained at a high level. Conclusion: RSV plays a protective role in the central nervous system of SAH rats by promoting the expression of SIRT1 and inhibiting the inflammatory response.
引文
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[10]Ramachandran S,Loganathan S,Cheeran V,et al. Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes[J]. Leuk Res Rep. 2018,9:28-35. DOI:10. 1016/j. lrr. 2018. 02. 001.
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[15]Peng Y,Jin J,Fan L,et al. Rolipram attenuates early brain injury following experimental subarachnoid hemorrhage in rats:possibly via regulating the SIRT1/NF-κB pathway[J]. Neurochem Res,2018,43(4):785-795. DOI:10. 1007/s11064-018-2480-4.
[16]Zhou XM,Zhang X,Zhang XS,et al. SIRT1 inhibition by sirtinol aggravates brain edema after experimental subarachnoid hemorrhage[J]. J Neurosci Res,2014,92(6):714-722. DOI:10. 1002/jnr. 23359.
[17]Di Emidio G,Santini SJ,D’Alessandro AM,et al. SIRT1 participates in the response to methylglyoxal-dependent glycative stress in mouse oocytes and ovary[J]. Biochim Biophys Acta Mol Basis Dis.2019,pii:S0925-4439(19)30063-8. DOI:10. 1016/j. bbadis. 2019. 02. 011.
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[19]Zhang T,Chi Y,Ren Y,et al. Resveratrol reduces oxidative stress and apoptosis in podocytes via Sir2-related enzymes, Sirtuins1(SIRT1)/Peroxisome proliferator-activated receptorγCo-activator1α(PGC-1α)axis[J]. Med Sci Monit,2019,25:1220-1231.DOI:10. 12659/MSM. 911714.
[20]Fourny N,Lan C,Sérée E,et al. Protective effect of resveratrol against ischemia-reperfusion injury via enhanced high energy compounds and e NOS-SIRT1 expression in type 2 diabetic female rat heart[J]. Nutrients. 2019,11(1). pii:E105. DOI:10. 3390/nu11010105.
[21]Cheang WS,Wong WT,Wang L,et al. Resveratrol ameliorates endothelial dysfunction in diabetic and obese mice through sirtuin 1and peroxisome proliferator-activated receptorδ[J]. Pharmacol Res. 2019,139:384-394. DOI:10. 1016/j. phrs. 2018. 11. 041.
[22] Laudati G,Mascolo L,Guida N,et al. Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway[J]. Neurotoxicology. 2018,71(1):6-15. DOI:10. 1016/j. neuro. 2018. 11. 009.
[23]Guo S,Liao H,Liu J,et al. Regulation of Sirt1[J]. Cell Physiol Biochem. 2018; 50(4):1346-1360. DOI:10. 1159/000494593.
[24]Zou P,Liu X,Li G,et al. Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1[J]. Mol Med Rep. 2018,17(2):3212-3217.DOI:10. 3892/mmr. 2017. 8241.
[25]Guo Y,Li JX,Mao TY,et al. Targeting Sirt1 in a rat model of high-fat diet-induced non-alcoholic fatty liver disease:Comparison of Gegen Qinlian decoction and resveratrol[J]. Exp Ther Med.2017,4(5):4279-4287. DOI:10. 3892/etm. 2017. 5076.
[26]Zhang XS,Wu Q,Wu LY,et al. Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats[J]. Cell Death Dis. 2016,7(10):e2416. DOI:10.1038/cddis. 2016. 292.
[27]Sebori R,Kuno A,Hosoda R,et al. Resveratrol decreases oxidative stress by restoring mitophagy and improves the pathophysiology of dystrophin-deficient mdx mice[J]. Oxid Med Cell Longev. 2018,2018:9179270. DOI:10. 1155/2018/9179270.
[2]Li Z,Han X. Resveratrol alleviates early brain injury following subarachnoid hemorrhage:possible involvement of the AMPK/SIRT1/autophagy signaling pathway[J]. Biol Chem. 2018,399(11):1339-1350. DOI:10. 1515/hsz-2018-0269.
[3]Zhang X,Lu Y,Wu Q,et al. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway[J]. FASEB J. 2019 Jan,33(1):722-737. DOI:10. 1096/fj. 201800642RR.
[4]Zhao Z,Yao M,Wei L,et al. Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice[J]. Nutr Neurosci. 2019,1-12. DOI:10. 1080/1028415X.2019. 1581460.
[5]Zhang X,Wu Q,Lu Y,et al. Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2-and SIRT1-dependent pathways[J]. Free Radic Biol Med,2018,124:504-516. DOI:10. 1016/j. freeradbiomed. 2018. 06. 035.
[6]Shi HJ,Xu C,Liu MY,et al. Resveratrol improves the energy sensing and glycolipid metabolism of blunt snout bream megalobrama amblycephala fed high-carbohydrate diets by activating the AMPKSIRT1-PGC-1αnetwork[J]. Front Physiol. 2018,9:1258. DOI:10. 3389/fphys. 2018. 01258.
[7]Huang B,Zhang W,Wei L,et al. Resveratrol down-regulates endothelin type B receptors in vascular smooth muscle cells via Sirt1/ERK1/2/NF-кB signaling pathways[J]. Eur J Pharmacol. 2018,840:44-49. DOI:10. 1016/j. ejphar. 2018. 09. 022.
[8] Sener TE,Tavukcu HH,Atasoy BM,et al. Resveratrol treatment may preserve the erectile function after radiotherapy by restoring antioxidant defence mechanisms,SIRT1 and NOS protein expressions[J]. Int J Impot Res. 2018,30(4):179-188. DOI:10. 1038/s41443-018-0042-6.
[9]Agrahari G,Sah SK,Kim TY. Superoxide dismutase 3 protects mesenchymal stem cells through enhanced autophagy and regulation of Fox O3a trafficking[J]. BMB Rep. 2018,51(7):344-349.
[10]Ramachandran S,Loganathan S,Cheeran V,et al. Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes[J]. Leuk Res Rep. 2018,9:28-35. DOI:10. 1016/j. lrr. 2018. 02. 001.
[11]Li Q,Peng Y,Fan L,et al. Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway[J]. Biomed Pharmacother.2018,99:947-955. DOI:10. 1016/j. biopha. 2018. 01. 093.
[12]赵忠惠,邹正,毛崇丹,等.睫状神经营养因子对大鼠脑缺血后髓鞘再生的影响[J].神经解剖学杂志,2019,35(1):47-51. DOI:10. 16557/j. cnki. 1000-7547. 2019. 01. 008.
[13]Qian C,Jin J,Chen J,et al. SIRT1 activation by resveratrol reduces brain edema and neuronal apoptosis in an experimental rat subarachnoid hemorrhage model[J]. Mol Med Rep,2017,16(6):9627-9635. DOI:10. 3892/mmr. 2017. 7773.
[14]Zhao L,Liu H,Yue L,et al. Melatonin attenuates early brain injury via the melatonin receptor/Sirt1/NF-κB signaling pathway following subarachnoid hemorrhage in mice[J]. Mol Neurobiol. 2017,54(3):1612-1621. DOI:10. 1007/s12035-016-9776-7.
[15]Peng Y,Jin J,Fan L,et al. Rolipram attenuates early brain injury following experimental subarachnoid hemorrhage in rats:possibly via regulating the SIRT1/NF-κB pathway[J]. Neurochem Res,2018,43(4):785-795. DOI:10. 1007/s11064-018-2480-4.
[16]Zhou XM,Zhang X,Zhang XS,et al. SIRT1 inhibition by sirtinol aggravates brain edema after experimental subarachnoid hemorrhage[J]. J Neurosci Res,2014,92(6):714-722. DOI:10. 1002/jnr. 23359.
[17]Di Emidio G,Santini SJ,D’Alessandro AM,et al. SIRT1 participates in the response to methylglyoxal-dependent glycative stress in mouse oocytes and ovary[J]. Biochim Biophys Acta Mol Basis Dis.2019,pii:S0925-4439(19)30063-8. DOI:10. 1016/j. bbadis. 2019. 02. 011.
[18]Xie J,Li X,Zhou Y,et al. Resveratrol abrogates hypoxia-induced up-regulation of exosomal Amyloid-βpartially by inhibiting CD147[J]. Neurochem Res,2019,DOI:10. 1007/s11064-019-02742-3.
[19]Zhang T,Chi Y,Ren Y,et al. Resveratrol reduces oxidative stress and apoptosis in podocytes via Sir2-related enzymes, Sirtuins1(SIRT1)/Peroxisome proliferator-activated receptorγCo-activator1α(PGC-1α)axis[J]. Med Sci Monit,2019,25:1220-1231.DOI:10. 12659/MSM. 911714.
[20]Fourny N,Lan C,Sérée E,et al. Protective effect of resveratrol against ischemia-reperfusion injury via enhanced high energy compounds and e NOS-SIRT1 expression in type 2 diabetic female rat heart[J]. Nutrients. 2019,11(1). pii:E105. DOI:10. 3390/nu11010105.
[21]Cheang WS,Wong WT,Wang L,et al. Resveratrol ameliorates endothelial dysfunction in diabetic and obese mice through sirtuin 1and peroxisome proliferator-activated receptorδ[J]. Pharmacol Res. 2019,139:384-394. DOI:10. 1016/j. phrs. 2018. 11. 041.
[22] Laudati G,Mascolo L,Guida N,et al. Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway[J]. Neurotoxicology. 2018,71(1):6-15. DOI:10. 1016/j. neuro. 2018. 11. 009.
[23]Guo S,Liao H,Liu J,et al. Regulation of Sirt1[J]. Cell Physiol Biochem. 2018; 50(4):1346-1360. DOI:10. 1159/000494593.
[24]Zou P,Liu X,Li G,et al. Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1[J]. Mol Med Rep. 2018,17(2):3212-3217.DOI:10. 3892/mmr. 2017. 8241.
[25]Guo Y,Li JX,Mao TY,et al. Targeting Sirt1 in a rat model of high-fat diet-induced non-alcoholic fatty liver disease:Comparison of Gegen Qinlian decoction and resveratrol[J]. Exp Ther Med.2017,4(5):4279-4287. DOI:10. 3892/etm. 2017. 5076.
[26]Zhang XS,Wu Q,Wu LY,et al. Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats[J]. Cell Death Dis. 2016,7(10):e2416. DOI:10.1038/cddis. 2016. 292.
[27]Sebori R,Kuno A,Hosoda R,et al. Resveratrol decreases oxidative stress by restoring mitophagy and improves the pathophysiology of dystrophin-deficient mdx mice[J]. Oxid Med Cell Longev. 2018,2018:9179270. DOI:10. 1155/2018/9179270.