和厚朴酚通过激活SIRT1/FOXO1信号通路抵抗小鼠脓毒症脑损伤
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摘要
目的:探究和厚朴酚是否通过激活SIRT1/FOXO1信号通路抵抗小鼠脓毒症脑损伤。方法:通过C57BL/6小鼠盲肠结扎穿孔法建立脓毒症脑损伤模型。小鼠随机分为以下6组:假手术(Sham)组;和厚朴酚处理(HKL)组;盲肠结扎穿孔(CLP)组;盲肠结扎穿孔+和厚朴酚处理(CLP+HKL)组;EX527 (SIRT1特异性抑制剂)预处理+盲肠结扎穿孔+和厚朴酚处理(CLP+HKL+EX527)组;EX527预处理+盲肠结扎穿孔(CLP+EX527)组。盲肠结扎穿孔48 h后检测脑组织内水含量、凋亡率及凋亡相关蛋白Bax、Bcl-2和cleaved Caspase-3的表达情况、炎症相关分子IL-1β与TNF-α、SIRT1信号通路相关蛋白表达情况。结果:与CLP组相比,CLP+HKL组脑组织内SIRT1的表达量及活性、Bcl-2表达量明显增加,而脑组织水含量、凋亡率、Bax、cleaved Caspase-3、IL-1β与TNF-α的表达量明显降低(均P <0.05)。EX527可明显抑制HKL的上述脑保护作用(P <0.05)。结论:和厚朴酚主要通过激活SIRT1/FOXO1信号通路,抑制凋亡与炎症,从而缓解脓毒症脑损伤。
Objective: To elucidate the definite role of silent information regulator 1(SIRT1)/Forkhead box protein O1(FOXO1)signaling pathway in the protective effects of honokiol(HKL) against brain injury in septic mice. Methods: Adult C57 BL/6 mice were subjected to cecal ligation and puncture(CLP) to induce sepsis-associated encephalopathy. The mice were randomly divided into six groups: Sham group, HKL group, CLP group, CLP+HKL group, CLP+HKL+EX527(a selective SIRT1 inhibitor) group and CLP+EX527 group. Forty-eight hours after the surgery, the brain water content, apoptotic ratio and the expression levels of SIRT1,Ac-FOXO1, Bax, Bcl-2, cleaved Caspase-3, IL-1β and TNF-α in each group were measured. Results: Compared with the CLP group,HKL significantly increased the expression level and the deacetylase activity of SIRT1 and the expression level of Bcl-2. HKL reduced brain water content, apoptotic ratio and the expression levels of Bax, cleaved Caspase-3, IL-1β and TNF-α when compared with the CLP group. However, these cerebral-protective effects of honokiol were largely abolished by EX527. Conclusions: HKL attenuates sepsis-associated encephalopathy by reducing apoptosis and inflammation through the activation of SIRT1/FOXO1 signaling pathway.
Objective: To elucidate the definite role of silent information regulator 1(SIRT1)/Forkhead box protein O1(FOXO1)signaling pathway in the protective effects of honokiol(HKL) against brain injury in septic mice. Methods: Adult C57 BL/6 mice were subjected to cecal ligation and puncture(CLP) to induce sepsis-associated encephalopathy. The mice were randomly divided into six groups: Sham group, HKL group, CLP group, CLP+HKL group, CLP+HKL+EX527(a selective SIRT1 inhibitor) group and CLP+EX527 group. Forty-eight hours after the surgery, the brain water content, apoptotic ratio and the expression levels of SIRT1,Ac-FOXO1, Bax, Bcl-2, cleaved Caspase-3, IL-1β and TNF-α in each group were measured. Results: Compared with the CLP group,HKL significantly increased the expression level and the deacetylase activity of SIRT1 and the expression level of Bcl-2. HKL reduced brain water content, apoptotic ratio and the expression levels of Bax, cleaved Caspase-3, IL-1β and TNF-α when compared with the CLP group. However, these cerebral-protective effects of honokiol were largely abolished by EX527. Conclusions: HKL attenuates sepsis-associated encephalopathy by reducing apoptosis and inflammation through the activation of SIRT1/FOXO1 signaling pathway.
引文
[1]A Cabrita J,Pinheiro I,Menezes Falcao L.Rethinking the concept of sepsis and septic shock[J].Eur J Intern Med,2018,54:1-5
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[13]Chen Y,Lei Y,Mo L Q,et al.Electroacupuncture pretreatment with different waveforms prevents brain injury in rats subjected to cecal ligation and puncture via inhibiting microglial activation,and attenuating inflammation,oxidative stress and apoptosis[J].Brain Res Bull,2016,127:248-259
[14]Savio L,Andrade M,de Andrade M P,et al.P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction[J].Mol Neurobiol,2017,54(8):6459-6470
[15]Wang C,Gan D,Wu J,et al.Honokiol exerts antidepressant effects in rats exposed to chronic unpredictable mild stress by regulating brain derived neurotrophic factor level and hypothalamus-pituitary-adrenal axis activity[J].Neurochem Res,2018,43(8):1519-1528
[16]Xian Y F,Ip S P,Mao Q Q,et al.Honokiol improves learning and memory impairments induced by scopolamine in mice[J].Eur JPharmacol,2015,760:88-95
[17]Wang M,Li Y,Ni C,et al.Honokiol Attenuates Oligomeric Amyloid beta1-42-Induced Alzheimer's Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-BSignaling Pathway[J].Cell Physiol Biochem,2017,43(1):69-81
[18]Li N,Xie H,Li L,et al.Effects of honokiol on sepsis-induced acute kidney injury in an experimental model of sepsis in rats[J].Inflammation,2014,37(4):1191-1199
[19]Weng T I,Wu H Y,Kuo C W,et al.Honokiol rescues sepsisassociated acute lung injury and lethality via the inhibition of oxidative stress and inflammation[J].Intensive Care Med,2011,37(3):533-541
[20]Lv H,Wang L,Shen J,et al.Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats[J].Brain Res Bull,2015,115:30-36
[21]Gao J,Zhou R,You X,et al.Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-kappaB pathway[J].Metab Brain Dis,2016,31(4):771-778
[22]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
[23]Zhao L,An R,Yang Y,et al.Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation,apoptosis,and oxidative stress:the role of SIRT1signaling[J].J Pineal Res,2015,59(2):230-239
[2]Messaris E,Betrosian A P,Memos N,et al.Administration of human protein C improves survival in an experimental model of sepsis[J].Crit Care Med,2010,38(1):209-216
[3]Gofton T E,Young G B.Sepsis-associated encephalopathy[J].Nat Rev Neurol,2012,8(10):557-566
[4]Wang H,Liao Z,Sun X,et al.Intravenous administration of honokiol provides neuroprotection and improves functional recovery after traumatic brain injury through cell cycle inhibition[J].Neuropharmacology,2014,86:9-21
[5]Lin C J,Chang Y A,Lin Y L,et al.Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis[J].Phytomedicine,2016,23(5):517-527
[6]Hu Z,Bian X,Liu X,et al.Honokiol protects brain against ischemia-reperfusion injury in rats through disrupting PSD95-nNOSinteraction[J].Brain Res,2013,1491:204-212
[7]Akagi M,Matsui N,Akae H,et al.Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease[J].J Pharmacol Sci,2015,127(2):155-163
[8]Nogueiras R,Habegger K M,Chaudhary N,et al.Sirtuin 1 and sirtuin3:physiological modulators of metabolism[J].Physiol Rev,2012,92(3):1479-1514
[9]Lu H,Wang B.SIRT1 exerts neuroprotective effects by attenuating cerebral ischemia/reperfusion-induced injury via targeting p53/microRNA-22[J].Int J Mol Med,2017,39(1):208-216
[10]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 R ep,2017,16(6):9627-9635
[11]Zhang B,Zhai M,Li B,et al.Honokiol ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by reducing oxidative stress and apoptosis through activating the SIRT1-Nrf2signaling pathway[J].Oxid Med Cell Longev,2018,2018:3159801
[12]Zhu Y,Wang K,Ma Z,et al.SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress[J].Toxicol Appl Pharmacol,2018,363:34-46
[13]Chen Y,Lei Y,Mo L Q,et al.Electroacupuncture pretreatment with different waveforms prevents brain injury in rats subjected to cecal ligation and puncture via inhibiting microglial activation,and attenuating inflammation,oxidative stress and apoptosis[J].Brain Res Bull,2016,127:248-259
[14]Savio L,Andrade M,de Andrade M P,et al.P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction[J].Mol Neurobiol,2017,54(8):6459-6470
[15]Wang C,Gan D,Wu J,et al.Honokiol exerts antidepressant effects in rats exposed to chronic unpredictable mild stress by regulating brain derived neurotrophic factor level and hypothalamus-pituitary-adrenal axis activity[J].Neurochem Res,2018,43(8):1519-1528
[16]Xian Y F,Ip S P,Mao Q Q,et al.Honokiol improves learning and memory impairments induced by scopolamine in mice[J].Eur JPharmacol,2015,760:88-95
[17]Wang M,Li Y,Ni C,et al.Honokiol Attenuates Oligomeric Amyloid beta1-42-Induced Alzheimer's Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-BSignaling Pathway[J].Cell Physiol Biochem,2017,43(1):69-81
[18]Li N,Xie H,Li L,et al.Effects of honokiol on sepsis-induced acute kidney injury in an experimental model of sepsis in rats[J].Inflammation,2014,37(4):1191-1199
[19]Weng T I,Wu H Y,Kuo C W,et al.Honokiol rescues sepsisassociated acute lung injury and lethality via the inhibition of oxidative stress and inflammation[J].Intensive Care Med,2011,37(3):533-541
[20]Lv H,Wang L,Shen J,et al.Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats[J].Brain Res Bull,2015,115:30-36
[21]Gao J,Zhou R,You X,et al.Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-kappaB pathway[J].Metab Brain Dis,2016,31(4):771-778
[22]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
[23]Zhao L,An R,Yang Y,et al.Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation,apoptosis,and oxidative stress:the role of SIRT1signaling[J].J Pineal Res,2015,59(2):230-239