叶黄素对D-半乳糖模型小鼠肝氧化损伤及相关基因的影响
摘要
目的：氧化应激是机体氧化和抗氧化体系失衡,导致机体损伤的状态,与多种疾病的发生发展紧密相关。叶黄素是一种天然类胡萝卜素,其特殊的分子结构使其具有抗氧化特性,在预防黄斑变性、白内障、心血管疾病、肿瘤,保护皮肤和视力等方面有着重要的作用。本研究应用D-半乳糖(D-galactose,D-gal)小鼠模型,探讨叶黄素对氧化应激的缓解作用及其可能机制。
方法：昆明种雄性小鼠随机分为D-gal模型对照组、叶黄素低剂量组、叶黄素高剂量组和正常对照组。D-gal 120mg/kg.d腹腔注射制作小鼠氧化应激模型,叶黄素低、高剂量组分别灌胃给予叶黄素10,40mg/kg. d,持续6w。6w后观察小鼠肝组织活性氧(reactive oxygen species,ROS)、丙二醛(malonaldehyde, MDA)、一氧化氮(nitric oxide,NO)含量,超氧化物歧化酶(superoxide dismutase,SOD)、总一氧化氮合酶(total nitricoxide synthase,TNOS)、诱导型一氧化氮合酶(induced nitricoxide synthase,iNOS)、结构型一氧化氮合酶(constitutive nitricoxide synthase,cNOS)、线粒体ATP酶(mitochondria ATPase)活性和血清谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)水平,RT-PCR法检测血红素氧合酶(heme oxygenase-1,HO-1)mRNA、toll样受体4(toll like receptor,TLR4)mRNA、诱导型一氧化氮合酶mRNA表达水平。
结果：(1)模型组小鼠肝组织ROS、MDA含量以及血清ALT、AST水平显著高于正常对照组,肝组织SOD、线粒体Na+-K+-ATPase、Ca2+ -ATPase活性显著低于正常对照组,差异均有显著性(P<0.05)。与模型组比较,叶黄素高、低剂量组小鼠肝组织ROS、MDA含量、ALT、AST水平显著降低,高剂量组SOD活性、线粒体各ATPase活性显著升高,差异均有显著性(P<0.05)。
(2)模型组小鼠肝组织NO含量、TNOS、iNOS、cNOS活性显著高于正常对照组(P<0.05)。与模型组相比,叶黄素高剂量组小鼠肝组织NO含量、iNOS、cNOS活性显著降低；叶黄素高、低剂量组TNOS活性显著降低(P<0.05)。
(3)模型组小鼠肝脏HO-1 mRNA表达显著低于正常对照组,TLR4 mRNA、iNOS mRNA表达显著高于正常对照组(P<0.01)；而叶黄素高剂量组肝脏HO-1 mRNA表达高于模型组(P<0.05),叶黄素高、低剂量组肝脏TLR4 mRNA、iNOS mRNA表达显著低于模型组(P<0.05)。
结论：
叶黄素可缓解D-半乳糖模型小鼠体内氧化应激状态,减轻肝细胞损伤。其作用机制可能与叶黄素的下列效应有关：
(1)清除氧自由基,提高SOD酶、线粒体Na+-K+-ATPase、Ca2+-ATPase活性,保护线粒体。
(2)抑制NO/NOS系统,下调iNOS的表达,减少NO的含量。
(3)提高HO-1的表达,下调TLR4表达,平衡机体氧化应激和免疫炎症反应失衡状态。
Objective:Lutein is one kind of natural carotenoid, its unique molecular structure have guaranted its antioxidant properties,it also has an important role in the prevention of macular degeneration, cataracts, and development of tumors,cardiovascular diseases,skin and eye protection.Oxidative stress is the imbalance state of oxidative and antioxidative system, will cause body injury,and related with some kind of diseases.In this study, We use D-gal mice model to investigate the mitigation of lutein on oxidative stress and its possible mechanism.
Method:Kunming strain male mice were randomized into 4 groups:high lutein dose group (HL) and low lutein dose group(LL) 40,10 mg/kg. d, control group and model group. After 6 weeks,the content of reactive oxygen species (ROS),malondialdehyde (MDA),nitric oxide (NO) and activity of superoxide dismutase (SOD),total nitric oxide synthase (TNOS), inducable nitric oxide synthase(iNOS),constitutive nitric oxide synthase(cNOS)and mitochondrial Na+-K+-ATP ase,Ca2+-ATP ase in liver tissue and aspartate aminotransferase (AST),alanine aminotransferase (ALT) in serum were determined.The levels of toll-like receptor-4(TLR4) mRNA and hemeoxygenase-1(HO-1)mRNA, inducable nitric oxide synthase (iNOS)mRNA in hepatic tissue were determined using reverse transcription polymerase chain reaction(RT-PCR)technique.
Results:(1)Model group ROS、MDA、serum ALT, AST content significantly higher than control group. Activities of SOD、Na+-K+-ATP ase,Ca2+-ATP ase significantly lower than control group. LL and HL group tissue ROS、MDA content、serum ALT,AST content level compared with model group were significantly decreased(p<0.05);HL group's activities of SOD、Na+-K+-ATP ase、Ca2+-ATP ase compared with model group were significantly increased(P<0.05).
(2)Model group activities of TNOS and iNOS,cNOS and content of tissue NO were significantly increased (P<0.05);Activities of iNOS,cNOS and content of tissue NO in high lutein dose group compared with model group were significantly decreased respectively (P<0.05);Activities of TNOS in lutein groups compared with model group were significantly decreased (P<0.05).
(3)Model group's HO-1 mRNA was significantly decreased, High lutein group's HO-1 mRNA level compared with model group was significantly increased(P<0.05).Model group's TLR4,iNOS mRNA level were significantly increased(P<0.05).TLR4,iNOS mRNA level of lutein dose groups was significantly decreased (P<0.05).
Conclusion:
Lutein can alleviate D-galactose induced oxidative stress in mice, reduce liver cell injury. The mechanism may be related to the effects of lutein in the following:
(1)Scavenge oxygen free radicals,increase SOD enzyme,mitochondrial Na+-K+-ATPase,Ca2+-ATPase activity,protect mitochondria.
(2) Lutein can inhibit the NO/NOS system, reduced the expression of iNOS and reduce NO levels.
(3)Lutein can increase the expression of HO-1,reduce the expression of TLR4.Balance the body's oxidative stress state and inflammatory immune response.
方法：昆明种雄性小鼠随机分为D-gal模型对照组、叶黄素低剂量组、叶黄素高剂量组和正常对照组。D-gal 120mg/kg.d腹腔注射制作小鼠氧化应激模型,叶黄素低、高剂量组分别灌胃给予叶黄素10,40mg/kg. d,持续6w。6w后观察小鼠肝组织活性氧(reactive oxygen species,ROS)、丙二醛(malonaldehyde, MDA)、一氧化氮(nitric oxide,NO)含量,超氧化物歧化酶(superoxide dismutase,SOD)、总一氧化氮合酶(total nitricoxide synthase,TNOS)、诱导型一氧化氮合酶(induced nitricoxide synthase,iNOS)、结构型一氧化氮合酶(constitutive nitricoxide synthase,cNOS)、线粒体ATP酶(mitochondria ATPase)活性和血清谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)水平,RT-PCR法检测血红素氧合酶(heme oxygenase-1,HO-1)mRNA、toll样受体4(toll like receptor,TLR4)mRNA、诱导型一氧化氮合酶mRNA表达水平。
结果：(1)模型组小鼠肝组织ROS、MDA含量以及血清ALT、AST水平显著高于正常对照组,肝组织SOD、线粒体Na+-K+-ATPase、Ca2+ -ATPase活性显著低于正常对照组,差异均有显著性(P<0.05)。与模型组比较,叶黄素高、低剂量组小鼠肝组织ROS、MDA含量、ALT、AST水平显著降低,高剂量组SOD活性、线粒体各ATPase活性显著升高,差异均有显著性(P<0.05)。
(2)模型组小鼠肝组织NO含量、TNOS、iNOS、cNOS活性显著高于正常对照组(P<0.05)。与模型组相比,叶黄素高剂量组小鼠肝组织NO含量、iNOS、cNOS活性显著降低；叶黄素高、低剂量组TNOS活性显著降低(P<0.05)。
(3)模型组小鼠肝脏HO-1 mRNA表达显著低于正常对照组,TLR4 mRNA、iNOS mRNA表达显著高于正常对照组(P<0.01)；而叶黄素高剂量组肝脏HO-1 mRNA表达高于模型组(P<0.05),叶黄素高、低剂量组肝脏TLR4 mRNA、iNOS mRNA表达显著低于模型组(P<0.05)。
结论：
叶黄素可缓解D-半乳糖模型小鼠体内氧化应激状态,减轻肝细胞损伤。其作用机制可能与叶黄素的下列效应有关：
(1)清除氧自由基,提高SOD酶、线粒体Na+-K+-ATPase、Ca2+-ATPase活性,保护线粒体。
(2)抑制NO/NOS系统,下调iNOS的表达,减少NO的含量。
(3)提高HO-1的表达,下调TLR4表达,平衡机体氧化应激和免疫炎症反应失衡状态。
Objective:Lutein is one kind of natural carotenoid, its unique molecular structure have guaranted its antioxidant properties,it also has an important role in the prevention of macular degeneration, cataracts, and development of tumors,cardiovascular diseases,skin and eye protection.Oxidative stress is the imbalance state of oxidative and antioxidative system, will cause body injury,and related with some kind of diseases.In this study, We use D-gal mice model to investigate the mitigation of lutein on oxidative stress and its possible mechanism.
Method:Kunming strain male mice were randomized into 4 groups:high lutein dose group (HL) and low lutein dose group(LL) 40,10 mg/kg. d, control group and model group. After 6 weeks,the content of reactive oxygen species (ROS),malondialdehyde (MDA),nitric oxide (NO) and activity of superoxide dismutase (SOD),total nitric oxide synthase (TNOS), inducable nitric oxide synthase(iNOS),constitutive nitric oxide synthase(cNOS)and mitochondrial Na+-K+-ATP ase,Ca2+-ATP ase in liver tissue and aspartate aminotransferase (AST),alanine aminotransferase (ALT) in serum were determined.The levels of toll-like receptor-4(TLR4) mRNA and hemeoxygenase-1(HO-1)mRNA, inducable nitric oxide synthase (iNOS)mRNA in hepatic tissue were determined using reverse transcription polymerase chain reaction(RT-PCR)technique.
Results:(1)Model group ROS、MDA、serum ALT, AST content significantly higher than control group. Activities of SOD、Na+-K+-ATP ase,Ca2+-ATP ase significantly lower than control group. LL and HL group tissue ROS、MDA content、serum ALT,AST content level compared with model group were significantly decreased(p<0.05);HL group's activities of SOD、Na+-K+-ATP ase、Ca2+-ATP ase compared with model group were significantly increased(P<0.05).
(2)Model group activities of TNOS and iNOS,cNOS and content of tissue NO were significantly increased (P<0.05);Activities of iNOS,cNOS and content of tissue NO in high lutein dose group compared with model group were significantly decreased respectively (P<0.05);Activities of TNOS in lutein groups compared with model group were significantly decreased (P<0.05).
(3)Model group's HO-1 mRNA was significantly decreased, High lutein group's HO-1 mRNA level compared with model group was significantly increased(P<0.05).Model group's TLR4,iNOS mRNA level were significantly increased(P<0.05).TLR4,iNOS mRNA level of lutein dose groups was significantly decreased (P<0.05).
Conclusion:
Lutein can alleviate D-galactose induced oxidative stress in mice, reduce liver cell injury. The mechanism may be related to the effects of lutein in the following:
(1)Scavenge oxygen free radicals,increase SOD enzyme,mitochondrial Na+-K+-ATPase,Ca2+-ATPase activity,protect mitochondria.
(2) Lutein can inhibit the NO/NOS system, reduced the expression of iNOS and reduce NO levels.
(3)Lutein can increase the expression of HO-1,reduce the expression of TLR4.Balance the body's oxidative stress state and inflammatory immune response.
引文
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