芹菜素对3-氯-1,2-丙二醇诱导的大鼠肾损伤及线粒体分裂融合的影响
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摘要
通过研究功能因子芹菜素对食品加工污染物3-氯-1,2-丙二醇(3-chloro 1,2-propanediol,3-MCPD)诱导的大鼠线粒体分裂融合的影响,探讨芹菜素对3-MCPD诱导的大鼠肾损伤的保护机制。将36只雄性SD大鼠随机分成对照组、溶剂(羧甲基纤维素钠)组、3-MCPD组和低、中、高剂量芹菜素组,给实验鼠单独灌胃3-MCPD(30 mg/kg m_b)或3-MCPD联合不同剂量的芹菜素28 d。每天记录大鼠体质量、摄食量,灌胃处理28 d后,麻醉处死,解剖取肾、肝、脑。苏木精-伊红染色后,于显微镜下观察肾脏病理形态的变化,检测肾组织线粒体分裂融合及线粒体转录因子的表达水平。结果表明,芹菜素能缓解3-MCPD诱导的食欲不振、肾组织肿胀、肾脏质量指数的增加以及肾小管、集合管上皮细胞排列不齐,肾小球、肾小囊病变等现象。此外,芹菜素缓解了3-MCPD诱导的线粒体分裂基因FIS1、DRP1的上调表达和线粒体融合基因MFN1、MFN2表达的下调。芹菜素协同处理缓解了3-MCPD导致的线粒体转录因子PGC1、NRF1、TFAM基因表达水平的下降。蛋白表达水平测定结果也证实,芹菜素缓解了3-MCPD诱导的线粒体分裂水平的升高、融合水平的降低以及转录因子NRF2表达的下调。研究结果表明芹菜素通过上调3-MCPD诱导的线粒体转录因子表达水平,调节分裂融合状态,有效缓解3-MCPD导致的肾器官损伤。
To assess the effect of apigenin(API), a functional food factor, on 3-chloro-1,2-propanediol(3-chloro 1,2-propanediol, 3-MCPD)-induced mitochondrial fission and fusion, the protective effect of API on renal injury was investigated. A total of 36 male adult Sprague-Dawley rats were randomly divided into six groups of 6 animals each:control group, solvent control(sodium carboxymethyl cellulose) group, 3-MCPD group, and low-, middle-and high-dose apigenin group. Rats in the experimental groups were administrated via oral gavage with 3-MCPD(30 mg/kg m_b) alone or in combination with apigenin at different doses for 28 days. Body mass and food intake were recorded daily during the experimental period. Finally, the rats were sacrificed to harvest kidney, liver and brain tissues. Rinal tissue sections,stained with hematoxylin and eosin, were observed by microscopy. Renal mitochondrial fission and fusion and transcription factor expression were examined. The results showed that apigenin significantly alleviated the loss of appetite, renal tissue swelling, the increase of kidney/body mass ratio, the irregularity of renal tubular and collecting ducts epithelium and glomerular and renal capsular lesions in rats exposed to 3-MCPD. In addition, apigenin significantly attenuated the up-regulation of DRP1 and FIS1 and the down-regulation of MFN1, MFN2, PGC1, NRF1 and TFAM. At the protein level,apigenin alleviated the increase of mitochondrial fission, the decrease of mitochondrial fusion and the down-regulation of transcription factor NRF2 induced by 3-MCPD. This study suggested that apigenin could protect rats from 3-MCPD induced renal injury via up-regulating the expression of mitochondrial transcription factors and alleviating abnormal mitochondrial fusion and fission.
To assess the effect of apigenin(API), a functional food factor, on 3-chloro-1,2-propanediol(3-chloro 1,2-propanediol, 3-MCPD)-induced mitochondrial fission and fusion, the protective effect of API on renal injury was investigated. A total of 36 male adult Sprague-Dawley rats were randomly divided into six groups of 6 animals each:control group, solvent control(sodium carboxymethyl cellulose) group, 3-MCPD group, and low-, middle-and high-dose apigenin group. Rats in the experimental groups were administrated via oral gavage with 3-MCPD(30 mg/kg m_b) alone or in combination with apigenin at different doses for 28 days. Body mass and food intake were recorded daily during the experimental period. Finally, the rats were sacrificed to harvest kidney, liver and brain tissues. Rinal tissue sections,stained with hematoxylin and eosin, were observed by microscopy. Renal mitochondrial fission and fusion and transcription factor expression were examined. The results showed that apigenin significantly alleviated the loss of appetite, renal tissue swelling, the increase of kidney/body mass ratio, the irregularity of renal tubular and collecting ducts epithelium and glomerular and renal capsular lesions in rats exposed to 3-MCPD. In addition, apigenin significantly attenuated the up-regulation of DRP1 and FIS1 and the down-regulation of MFN1, MFN2, PGC1, NRF1 and TFAM. At the protein level,apigenin alleviated the increase of mitochondrial fission, the decrease of mitochondrial fusion and the down-regulation of transcription factor NRF2 induced by 3-MCPD. This study suggested that apigenin could protect rats from 3-MCPD induced renal injury via up-regulating the expression of mitochondrial transcription factors and alleviating abnormal mitochondrial fusion and fission.
引文
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[12]MASCARAQUE C,GONZáLEZ R,SUáREZ M D,et al.Intestinal anti-inflammatory activity of apigenin K in two rat colitis models induced by trinitrobenzenesulfonic acid and dextran sulphate sodium[J].British Journal of Nutrition,2015,113(4):618-26.DOI:10.1017/S0007114514004292.
[13]药红梅,贾永平,薛铮,等.芹菜素可抑制脂多糖诱导的大鼠血管平滑肌细胞增殖[J].中华心血管病杂志,2017,45(4):323-328.DOI:10.3760/cma.j.issn.0253-3758.2017.04.013.
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[15]VENIGALLA M,GYENGESI E,MNCH G.Curcumin and apigenin:novel and promising therapeutics against chronic neuroinlfammation in Alzheimer’s disease[J].Neural Regeneration Research,2015,10(8):1181-1185.DOI:10.4103/1673-5374.162686.
[16]NABAVI S F,KHAN H,D’ONOFRIO G,et al.Apigenin as Neuroprotective Agent:of mice and men[J].Pharmacological Research,2017,128:359-365.DOI:10.1016/j.phrs.2017.10.008.
[17]阿力木江·买买提江,施海明.线粒体动力学与心肌细胞能量代谢的研究进展[J].复旦学报(医学版),2013,40(5):625-628.DOI:10.3969/j.issn.1672-8467.2013.05.023.
[18]QIN SHUANGLI,DENG Jie,LOU DIDONG,et al.The decreased expression of mitofusin-1 and increased fission-1 together with alterations in mitochondrial morphology in the kidney of rats with chronic fluorosis may involve elevated oxidative stress[J].Journal of Trace Elements in Medicine&Biology,2015,29(1):263-268.DOI:10.1016/j.jtemb.2014.06.001.
[19]GALL J M,WANG Z,BONEGIO R G,et al.Conditional knockout of proximal tubule mitofusin 2 accelerates recovery and improves survival after renal ischemia[J].Journal of the American Society of Nephrology,2015,26(5):1092-1102.DOI:10.1681/ASN.2014010126.
[20]蒋道芳,张晓丽.线粒体损伤与急性肾损伤的研究进展[J].生理科学进展,2017,4 8(4):269-273.DOI:10.3969/j.issn.0559-7765.2017.04.007.
[21]刘炀,刘双全,谭浩,等.糖尿病合并梅毒兔模型的建立及其组织病理损伤的研究[J].实用预防医学,2017,24(9):1025-1031.DOI:10.3969/j.issn.1006-3110.2017.09.001.
[22]梁彩星,刘伟敬,刘华锋,等.纠正线粒体功能障碍对急性肾损伤的治疗作用[J].中国中西医结合肾病杂志,2017,18(5):468-470.DOI:10.3969/j.issn.1009-587X.2017.05.034.
[23]CARELLI V,MARESCA A,CAPORALI L,et al.Mitochondria:biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations[J].International Journal of Biochemistry&Cell Biology,2015,63(6):21-24.DOI:10.1016/j.biocel.2015.01.023.
[24]LIU Q,KRISHNASAMY Y,REHMAN H,et al.Disrupted renal mitochondrial homeostasis after liver transplantation in rats[J].PLoSONE,2015,10(10):e0140906.DOI:10.1371/journal.pone.0140906.
[25]BEREITERHAHN J.Mitochondrial dynamics in aging and disease[J].Progress in Molecular Biology&Translational Science,2014,127:93-131.DOI:10.1016/B978-0-12-394625-6.00004-0.
[26]FOX T D.An MBoC favorite:mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA[J].Molecular Biology of the Cell,2012,23(21):41-44.DOI:10.1091/mbc.8.7.1233.
[27]LEGROS F,LOMBèS A,FRACHON P,et al.Mitochondrial fusion in human cells is efficient,requires the inner membrane potential,and is mediated by mitofusins[J].Molecular Biology of the Cell,2002,13(12):4343-4354.DOI:10.1091/mbc.E02-06-0330.
[28]CHEN H,DETMER S A,EWALD A J,et al.Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J].Journal of Cell Biology,2003,160(2):189-200.DOI:10.1083/jcb.200211046.
[29]YOON Y,KRUEGER E W,OSWALD B J,et al.The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1[J].Molecular&Cellular Biology,2003,23(15):5409-5420.DOI:10.1128/MCB.23.15.5409-5420.2003.
[30]HALES K G,FULLER M T.Developmentally regulated mitochondrial fusion mediated by a conserved,novel,predicted GTPase[J].Cell,1997,90(1):121-129.DOI:10.1016/S0092-8674(00)80319-0.
[31]何惠珍,汤颖,徐安平.线粒体动态学与急性肾损伤[J].岭南急诊医学杂志,2015,20(6):532-533.DOI:10.3969/j.issn.1671-30IX.2015.06.042.
[2]黄明泉,吴继红,孙培培,等.甘油三酯与氯化钠模型反应中3-氯-1,2-丙二醇的形成研究[J].食品科学,2014,35(17):8-11.DOI:10.7506/spkxl002-6630-201417002.
[3]肖颖,周媛,罗仁才,等.3-氯-1,2-丙二醇在大鼠体内的吸收、分布和排泄[J].中华预防医学杂志,2003,37(6):426-428.DOI:10.3760/j:issn:0253-9624.2003.06.009.
[4]VELíSEK J,DAVíDEK J,HAJSLOVáJ,et al.Chlorohydrins in protein hydrolysates[J].Zeitschrift für Lebensmittel-Untersuchung und Forschung,1978,167(4):241-244.DOI:10.1007/BF01135595.
[5]BAER I,CALLE B D L,TAYLOR P.3-MCPD in food other than soy sauce or hydrolysed vegetable protein(HVP)[J].Analytical&Bioanalytical Chemistry,2010,396(1):443-456.DOI:10.1007/s00216-009-3177-y.
[6]BAKHIYA N,ABRAHAM K,GüRTLER R,et al.Toxicological assessment of 3-chloropropane-1,2-diol and glycidol fatty acid esters in food[J].Molecular Nutrition&Food Research,2011,55(4):509-521.DOI:10.1002/mnfr.201000550.Epub2011Feb23.
[7]LEIGH J,MACMAHON S.Occurrence of 3-monochloropropanediol esters and glycidyl esters in commercial infant formulas in the United States[J].Food Additives&Contaminants,2017,34(3):356-370.DOI:10.1080/19440049.2016.1276304.
[8]CASSIDY A,O’REILLYéJ,KAY C,et al.Habitual intake of flavonoid subclasses and incident hypertension in adults[J].American Journal of Clinical Nutrition,2011,93(2):338-347.DOI:10.3945/ajcn.110.006783.
[9]CHO W S,HAN B S,NAM K T,et al.Carcinogenicity study of 3-monochloropropane-1,2-diol in Sprague-Dawley rats[J].Food&Chemical Toxicology,2008,46(9):3172.DOI:10.1016/j.fct.2008.07.003.
[10]杨红霞,孙倩.芹菜素的现代研究进展[J].长治医学院学报,2012,26(5):397-400.DOI:10.3969/j.issn.1006-0588.2012.05.032.
[11]SMOLINSKI A T,PESTKA J J.Modulation of lipopolysaccharideinduced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin(chamomile),ginsenoside Rb(ginseng)and parthenolide(feverfew)[J].Food&Chemical Toxicology,2003,41(10):1381-1390.DOI:10.1016/s0278-6915(03)00146-7.
[12]MASCARAQUE C,GONZáLEZ R,SUáREZ M D,et al.Intestinal anti-inflammatory activity of apigenin K in two rat colitis models induced by trinitrobenzenesulfonic acid and dextran sulphate sodium[J].British Journal of Nutrition,2015,113(4):618-26.DOI:10.1017/S0007114514004292.
[13]药红梅,贾永平,薛铮,等.芹菜素可抑制脂多糖诱导的大鼠血管平滑肌细胞增殖[J].中华心血管病杂志,2017,45(4):323-328.DOI:10.3760/cma.j.issn.0253-3758.2017.04.013.
[14]FU M S,ZHU B J,LUO D W.Apigenin prevents TNF-αinduced apoptosis of primary rat retinal ganglion cells[J].Cellular and Molecular Biology,2014,60(4):37-42.
[15]VENIGALLA M,GYENGESI E,MNCH G.Curcumin and apigenin:novel and promising therapeutics against chronic neuroinlfammation in Alzheimer’s disease[J].Neural Regeneration Research,2015,10(8):1181-1185.DOI:10.4103/1673-5374.162686.
[16]NABAVI S F,KHAN H,D’ONOFRIO G,et al.Apigenin as Neuroprotective Agent:of mice and men[J].Pharmacological Research,2017,128:359-365.DOI:10.1016/j.phrs.2017.10.008.
[17]阿力木江·买买提江,施海明.线粒体动力学与心肌细胞能量代谢的研究进展[J].复旦学报(医学版),2013,40(5):625-628.DOI:10.3969/j.issn.1672-8467.2013.05.023.
[18]QIN SHUANGLI,DENG Jie,LOU DIDONG,et al.The decreased expression of mitofusin-1 and increased fission-1 together with alterations in mitochondrial morphology in the kidney of rats with chronic fluorosis may involve elevated oxidative stress[J].Journal of Trace Elements in Medicine&Biology,2015,29(1):263-268.DOI:10.1016/j.jtemb.2014.06.001.
[19]GALL J M,WANG Z,BONEGIO R G,et al.Conditional knockout of proximal tubule mitofusin 2 accelerates recovery and improves survival after renal ischemia[J].Journal of the American Society of Nephrology,2015,26(5):1092-1102.DOI:10.1681/ASN.2014010126.
[20]蒋道芳,张晓丽.线粒体损伤与急性肾损伤的研究进展[J].生理科学进展,2017,4 8(4):269-273.DOI:10.3969/j.issn.0559-7765.2017.04.007.
[21]刘炀,刘双全,谭浩,等.糖尿病合并梅毒兔模型的建立及其组织病理损伤的研究[J].实用预防医学,2017,24(9):1025-1031.DOI:10.3969/j.issn.1006-3110.2017.09.001.
[22]梁彩星,刘伟敬,刘华锋,等.纠正线粒体功能障碍对急性肾损伤的治疗作用[J].中国中西医结合肾病杂志,2017,18(5):468-470.DOI:10.3969/j.issn.1009-587X.2017.05.034.
[23]CARELLI V,MARESCA A,CAPORALI L,et al.Mitochondria:biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations[J].International Journal of Biochemistry&Cell Biology,2015,63(6):21-24.DOI:10.1016/j.biocel.2015.01.023.
[24]LIU Q,KRISHNASAMY Y,REHMAN H,et al.Disrupted renal mitochondrial homeostasis after liver transplantation in rats[J].PLoSONE,2015,10(10):e0140906.DOI:10.1371/journal.pone.0140906.
[25]BEREITERHAHN J.Mitochondrial dynamics in aging and disease[J].Progress in Molecular Biology&Translational Science,2014,127:93-131.DOI:10.1016/B978-0-12-394625-6.00004-0.
[26]FOX T D.An MBoC favorite:mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA[J].Molecular Biology of the Cell,2012,23(21):41-44.DOI:10.1091/mbc.8.7.1233.
[27]LEGROS F,LOMBèS A,FRACHON P,et al.Mitochondrial fusion in human cells is efficient,requires the inner membrane potential,and is mediated by mitofusins[J].Molecular Biology of the Cell,2002,13(12):4343-4354.DOI:10.1091/mbc.E02-06-0330.
[28]CHEN H,DETMER S A,EWALD A J,et al.Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J].Journal of Cell Biology,2003,160(2):189-200.DOI:10.1083/jcb.200211046.
[29]YOON Y,KRUEGER E W,OSWALD B J,et al.The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1[J].Molecular&Cellular Biology,2003,23(15):5409-5420.DOI:10.1128/MCB.23.15.5409-5420.2003.
[30]HALES K G,FULLER M T.Developmentally regulated mitochondrial fusion mediated by a conserved,novel,predicted GTPase[J].Cell,1997,90(1):121-129.DOI:10.1016/S0092-8674(00)80319-0.
[31]何惠珍,汤颖,徐安平.线粒体动态学与急性肾损伤[J].岭南急诊医学杂志,2015,20(6):532-533.DOI:10.3969/j.issn.1671-30IX.2015.06.042.
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