人参皂苷Rg1、Rb1的药效及作用机制研究进展
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摘要
综述了人参皂苷Rg1、Rb1对神经系统疾病(阿尔茨海默病、帕金森病、脑缺血)、肿瘤、糖尿病及其并发症的药理作用,对比分析了人参皂苷Rg1、Rb1的潜在治疗优势。研究发现,Rg1和Rb1均表现出相似的神经保护作用和抗肿瘤活性,并对糖尿病及其并发症具有改善效果;但Rg1和Rb1的治疗靶点及作用相关信号通路有所不同,这与Rg1、Rb1分别是原人参三醇型和原人参二醇型代表类皂苷,且具有不同结构有关。理解人参皂苷Rg1和Rb1的药效及作用机制的异同将为其进一步的药理研究、相关疾病的治疗以及Rg1和Rb1的联合开发用药研究提供新的思路。
This paper reviews the pharmacological effects of ginsenoside Rg1 and Rb1 on neurological diseases(Alzheimer's disease, Parkinson's disease, and cerebral ischemia), tumors, diabetes and its complications, and analyzes the potential treatment advantages of ginsenoside Rg1 and Rb1 on these major diseases. It is found that both Rg1 and Rb1 show similar neuroprotective effect and anti-tumor activity, and have improved effect on diabetes and its complications. However, the therapeutic targets and effect-related signaling pathways of Rg1 and Rb1 are different, which is related to the fact that Rg1 and Rb1 are respectively original ginseng triol type and original ginseng diol type representing saponins and have different structures. Understanding the differences and similarities of the pharmacodynamics and mechanism of ginsenoside Rg1 and Rb1 will provide new ideas for further pharmacological research, treatment of related diseases, and drug research for the joint development of Rg1 and Rb1.
This paper reviews the pharmacological effects of ginsenoside Rg1 and Rb1 on neurological diseases(Alzheimer's disease, Parkinson's disease, and cerebral ischemia), tumors, diabetes and its complications, and analyzes the potential treatment advantages of ginsenoside Rg1 and Rb1 on these major diseases. It is found that both Rg1 and Rb1 show similar neuroprotective effect and anti-tumor activity, and have improved effect on diabetes and its complications. However, the therapeutic targets and effect-related signaling pathways of Rg1 and Rb1 are different, which is related to the fact that Rg1 and Rb1 are respectively original ginseng triol type and original ginseng diol type representing saponins and have different structures. Understanding the differences and similarities of the pharmacodynamics and mechanism of ginsenoside Rg1 and Rb1 will provide new ideas for further pharmacological research, treatment of related diseases, and drug research for the joint development of Rg1 and Rb1.
引文
[1]李蕾,谢丽娟,王国明,等.人参、西洋参不同部位提取物中14种皂苷含量比较[J].人参研究,2018,30(3):11-13. DOI:10.19403/j.cnki.1671-1521.2018.03.003.LI L,XIE L J,WANG G M,et al. Comparison of 14 saponin contents in extracts from different parts of ginseng and American ginseng[J]. Ginseng Research,2018,30(3):11-13. DOI:10.19403/j.cnki.1671-1521.2018.03.003(Ch).
[2]张于,程伟.中西医治疗阿尔兹海默病的研究现状[J].中医临床研究,2012,4(13):115-117. DOI:10.3969/j.issn.1674-7860. 2012.13.069.ZHANG Y,CHENG W. Research status on treating AD in the integrative medicine[J]. Clinical Journal of Chinese Medicine,2012,4(13):115-117. DOI:10.3969/j.issn.1674-7860.2012.13.069(Ch).
[3] QUAN Q K,WANG J,LI X,et al. Ginsenoside Rg1 decreases Aβ1–42 level by upregulating PPARγand IDE expression in the hippocampus of a rat model of Alzheimer's disease[J]. PloS One,2013,8(3):e59155. DOI:10.1371/journal.pone.0059155.
[4] FANG F,CHEN X C,HUANG T W,et al. Multifaced neuroprotective effects of ginsenoside Rg1 in an Alzheimer mouse model[J]. Biochim Biophys Acta,2012,1822(2):286-292. DOI:10.1016/j.bbadis.2011.10.004.
[5] CHEN L M,LIN Z Y,ZHU Y G,et al. Ginsenoside Rg1attenuatesβ-amyloid generation via suppressing PPARγ-regulated BACE1 activity in N2a-APP695 cells[J].European Journal of Pharmacology,2012,675(1):15-21.DOI:10.1016/j.ejphar.2011.11.039.
[6] HUANG T W,FANG F,CHEN L M,et al. Ginsenoside Rg1 attenuates oligomeric Aβ1-42-induced mitochondrial dysfunction[J]. Current Alzheimer Research,2012,9(3):388-395. DOI:10.2174/156720512800107636.
[7] LI W,CHU Y Q,ZHANG L,et al. Ginsenoside Rg1prevents SK-N-SH neuroblastoma cell apoptosis induced by supernatant from Aβ1-40-stimulated THP-1 monocytes[J]. Brain Research Bulletin,2012,88(5):501-506. DOI:10.1016/j.brainresbull.2012.05.002.
[8] WU J Y,YANG H Y,ZHAO Q W,et al. Ginsenoside Rg1 exerts a protective effect against Aβ25-35-induced toxicity in primary cultured rat cortical neurons through the NF-κB/NO pathway[J]. International Journal of Molecular Medicine,2016,37(3):781-788. DOI:10.3892/ijmm.2016.2485.
[9] GONG L,LI S L,LI H,et al. Ginsenoside Rg1 protects primary cultured rat hippocampal neurons from cell apoptosis induced byβ-amyloid protein[J]. Pharmaceutical Biology,2011,49(5):501-507. DOI:10.3109/13880209.2010.521514.
[10] WU J Y,PAN Z F,WANG Z Q,et al. Ginsenoside Rg1protection againstβ-amyloid peptide-induced neuronal apoptosis via estrogen receptorαand glucocorticoid receptor-dependent anti-protein nitration pathway[J]. Neuropharmacology,2012,63(3):349-361. DOI:10.1016/j.neuropharm.2012.04.005.
[11] ZHAO B S,LIU Y,GAO X Y,et al. Effects of ginsenoside Rg1 on the expression of toll-like receptor 3,4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line[J]. Molecules,2014,19(10):16925-16936. DOI:10.3390/molecules191016925.
[12] GU W J,LIU D,ZHANG M R,et al. Effect of ginsenoside Rb1 on insulin signal transduction pathway in hippocampal neurons of high-glucose-fed rats[J]. China Journal of Chinese Materia Medica,2014,39(6):1064-1068.
[13] ZHAO R P,ZHANG Z X,SONG Y J,et al. Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3βpathway in ginsenoside Rb1’s attenuation of beta-amyloidinduced neurotoxicity and Tau phosphorylation[J]. Journal of Ethnopharmacology,2011,133(3):1109-1116. DOI:10.1016/j.jep.2010.11.054.
[14] QIAN Y H,HAN H,HU X D,et al. Protective effect of ginsenoside Rb1 on beta-amyloid protein(1-42)-induced neurotoxicity in cortical neurons[J]. Neurological Research,2009,31(7):663-667. DOI:10.1179/174313209X385572.
[15] WANG Y H,DU G H. Ginsenoside Rg1 inhibits betasecretase activity in vitro and protects against Abetainduced cytotoxicity in PC12 cells[J]. Journal of Asian Natural Products Research, 2009,11(7):604-612.DOI:10.1080/10286020902843152.
[16] LIANG H,LIU L F,LIU J,et al. Ginsenoside Rg1 protects against neurodegeneration by inducing neurite outgrowth in cultured hippocampal neurons[J]. Neural Regeneration Research,2016,11(2):319-325. DOI:10.4103/1673-5374.177741.
[17] WANG Q,SUN L H,JIA W,et al. Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice[J]. Phytotherapy Research,2010,24(12):1748-1754. DOI:10.1002/ptr.3130.
[18] ZHAO H H,DI J,LIU W S,et al. Involvement of GSK3and PP2A in ginsenoside Rb1’s attenuation of aluminuminduced Tau hyperphosphorylation[J]. Behavioural Brain Research,2013,241(1):228-234. DOI:10.1016/j.bbr.2012.11.037.
[19] CHEN X C,HUANG T W,ZHANG J,et al. Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1’s attenuation of beta-amyloid peptide25-35-induced Tau hyperphosphorylation in cortical neurons[J]. Brain Research,2008,1200:99-106. DOI:10.1016/j.brainres.2007.12.029.
[20] WANG Y,FENG Y,FU Q Y,et al. Panax notoginsenoside Rb1 ameliorates Alzheimer’s disease by upregulating brainderived neurotrophic factor and downregulating Tau protein expression[J]. Experimental&Therapeutic Medicine,2013,6(3):826-830. DOI:10.3892/etm.2013.1215.
[21]李玺,刘颖,袁海峰,等.人参皂苷Rg1对冈田酸所致大鼠脑片Tau蛋白磷酸化的影响[J].中西医结合学报,2010,8(10):955-960. DOI:10.3736/jcim20101007.LI X,LIU Y,YUAN H F,et al. Effects of gensenoside Rg1on Tau protein phosphorylation induced by okadaic acid in rat brain slices[J]. Journal of Chinese Integrative Medicine,2010,8(10):955-960. DOI:10.3736/jcim20101007(Ch).
[22]李玺,张欣,袁海峰,等.人参皂苷Rg1对AD模型大鼠脑片P-Tau,caspase-3表达的影响[J].中国中药杂志,2010,35(3):369-372. DOI:10.4268/cjcmm20100325.LI X,ZHANG X,YUAN H F,et al. Experimental research on effect of gensenoside Rg1 on expressions of PTau and caspase-3 in brain slices from AD model rats[J].China Journal of Chinese Materia Medica,2010,35(3):369-372. DOI:10.4268/cjcmm20100325(Ch).
[23] ZHOU T T,ZU G,WANG X,et al. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of Parkinson’s disease[J]. International Immunopharmacology,2015,29(2):334-343.DOI:10.1016/j.intimp.2015.10.032.
[24] ZHOU T T,ZU G,ZHANG X G,et al. Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson’s disease[J]. Neuropharmacology,2016,101:480-489. DOI:10.1016/j.neuropharm.2015.10.024.
[25] HENG Y,ZHANG Q S,MU Z,et al. Ginsenoside Rg1attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced Parkinsonism mouse model by targetingα-synuclein abnormalities in the substantia nigra[J]. Toxicology Letters,2016,243:7-21. DOI:10.1016/j.toxlet.2015.12.005.
[26] REN X F,CHEN L,GAO X Q,et al. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra[J]. Journal of Steroid Biochemistry&Molecular Biology,2016,155:94-103. DOI:10.1016/j.jsbmb.2015.09.040.
[27] XU L,CHEN W F,WONG M S. Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson’s disease through the IGF-I receptor signalling pathway[J]. British Journal of Pharmacology,2010,158(3):738-748. DOI:10.1111/j.1476-5381.2009.00361.x.
[28] XU H M,JIANG H,WANG J,et al. Rg1 protects the MPP-treated MES23.5 cells via attenuating DMT1 upregulation and cellular iron uptake[J]. Neuropharmacology,2010,58(2):488-494. DOI:10.1016/j.neuropharm.2009.09.002.
[29] WANG J,XU H M,YANG H D,et al. Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins[J]. Neurochemistry International,2009,54(1):43-48. DOI:10.1016/j.neuint.2008.10.003.
[30] ZHANG Y L,LIU Y,KANG X P,et al. Ginsenoside Rb1confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson’s disease[J]. Neuropharmacology,2017,131:223-237. DOI:10.1016/j.neuropharm.2017.12.012.
[31] YANG Y D,LI X,ZHANG L M,et al. Ginsenoside Rg1 suppressed infammation and neuron apoptosis by activating PPARγ/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury[J]. International Journal of Clinical&Experimental Pathology,2015,8(3):2484-2494.
[32] XIE C L,LI J H,WANG W W,et al. Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression[J]. Life Sciences,2015,121:145-151. DOI:10.1016/j.lfs.2014.12.002.
[33]王巧云,刘凤,吴峰阶,等.人参皂苷Rg1对局灶性脑缺血再灌注损伤大鼠海马p-ERK1/2与p-JNK表达的影响[J].中国中西医结合杂志,2013,33(2):229-234.WANG Q Y,LIU F,WU F J,et al. Effects of ginsenoside Rg1 on the expressions of p-eRK1/2 and p-JNK in local cerebral ischemia/reperfusion injury rats[J]. Chinese Journal of Integrated Traditional&Western Medicine,2013,33(2):229-234(Ch).
[34] WANG L,ZHAO H,ZHAI Z Z,et al. Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia-reperfusion injury in mice[J]. Biomedicine&Pharmacotherapy,2018,99:876-882. DOI:10.1016/j.biopha.2018.01.136.
[35] ZHU J,JIANG Y,WU L,et al. Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia[J]. Neuroscience,2012,202(2):342-351. DOI:10.1016/j.neuroscience.2011.11.070.
[36] DONG X,ZHENG L,LU S J,et al. Neuroprotective effects of pretreatment of ginsenoside Rb1 on severe cerebral ischemia-induced injuries in aged mice:Involvement of anti-oxidant signaling[J]. Geriatrics&Gerontology International,2017,17(2):338-345. DOI:10.1111/ggi.12699.
[37] WANG S Y,LI M H,GUO Y,et al. Effects of Panax notoginseng ginsenoside Rb1 on abnormal hippocampal microenvironment in rats[J]. Journal of Ethnopharmacology,2017,202:138-146. DOI:10.1016/j.jep.2017.01.005.
[38]黄小平,王蓓,邱咏园,等.黄芪甲苷、人参皂苷Rg1、Rb1和三七皂苷R1抗小鼠脑缺血再灌注氧化应激损伤和促进能量代谢的配伍研究[J].湖南中医药大学学报,2014,34(7):5-11. DOI:10.3969/j. issn. 1674-070X.2014.07.002.005.07.HUANG X P,WANG B,QIU Y Y,et al. The combination study of astragalosideⅣ,ginsenosides Rg1,Rb1 and notoginsenoside R1 on antagonizing oxidative stress injury and promoting energy metabolism after ischemia-reperfusion in mice[J]. Journal of Traditional Chinese Medicine University of Hunan,2014,34(7):5-11. DOI:10.3969/j.issn.1674-070X.2014.07.002.005.07(Ch).
[39]柯大智,王红宁,陈地龙,等.人参皂苷Rg1抑制白血病细胞K562增殖并诱导分化的分子机制[J].第三军医大学学报,2014,36(2):125-129. DOI:10.16016/j.1000-5404.2014.02.003.KE D Z,WANG H N,CHEN D L,et al. Molecular mechanism of ginsenoside Rg1 in inhibiting proliferation and inducing differentiation in chronic myelocytic leukemia K562 cells[J]. Acta Academiae Medicinae Militaris Tertiae,2014,36(2):125-129. DOI:10.16016/j. 1000-5404.2014.02.003(Ch).
[40]王国红.人参皂甙Rg1、肉桂酸、丹参酮ⅡA及其组合对人成骨肉瘤MG-63细胞终末分化的诱导研究[D].厦门:厦门大学,2005.WANG G H. Study on the Terminal Differentiation of Human Osteosarcoma MG-63 Cells Induced by Ginsenoside Rg1,Cinnamic Acid,TanshinoneⅡA and Their Combinations[D]. Xiamen:Xiamen University,2005(Ch).
[41]张龙江,周二付.人参皂苷Rg1对结肠癌肿瘤体外和体内的增殖抑制作用[J].世界华人消化杂志,2014(30):4599-4603. DOI:10.11569/wcjd.v22.i30.4599.ZHANG L J,ZHOU E F. In vitro and in vivo inhibitory effects of ginsenoside Rg1 on proliferation of colon cancer cells[J]. World Chinese Journal of Digestology,2014(30):4599-4603. DOI:10.11569/wcjd.v22.i30.4599(Ch).
[42]王红宁,左国伟,陈地龙,等.人参皂苷Rb1、Rg1、Re对白血病细胞株KG1α增殖的影响[J].生物技术,2010,20(2):56-58. DOI:10.16519/j.cnki.1004-311x.2010.02.031.WANG H N,ZUO G W,CHEN D L,et al. Effects of ginsenoside Rb1,Rg1,Re on proliferation of KG1αcells[J].Biotechnology,2010,20(2):56-58. DOI:10.16519/j.cnki.1004-311x.2010.02.031(Ch).
[43]崔金刚,王晓燕,熊敏琪,等.人参皂苷Rg1与Rb1在心肌缺血复合肿瘤病理环境下的作用研究[J].上海中医药大学学报,2014,28(4):58-63. DOI:10.16306/j.1008-861x.2014.04.020.CUI J G,WANG X Y,XIONG M Q,et al. Effects of ginsenosides Rg1 and Rb1 in myocardial ischemia complex pathological environment of neoplasia[J]. Journal of Shanghai University of Traditional Chinese Medicine,2014,28(4):58-63. DOI:10.16306/j.1008-861x.2014.04.020(Ch).
[44]刘嘉.肿瘤多药耐药机制及其逆转方案的研究进展[J].中国肿瘤外科杂志,2010,2(3):174-178. DOI:10.3969/j.issn.1674-4136.2010.03.012.LIU J. Advances in research on multidrug resistance mechanism of tumor and its reversal program[J]. Chinese Journal of Surgical Oncology,2010,2(3):174-178. DOI:10.3969/j.issn.1674-4136.2010.03.012(Ch).
[45]王婷.三七总皂苷Rb1对肿瘤耐药逆转作用的实验研究[D].昆明:昆明医学院,2011.WANG T. PNS-Rb1 Reverse Effect on Tumor Multidrugresistance in vivo Study[D]. Kunming:Kunming Medical College,2011(Ch).
[46] WANG Y,LIU Y,ZHANG X Y,et al. Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways[J]. International Immunopharmacology,2014,23(1):77-84. DOI:10.1016/j. intimp.2014.07.028.
[47]武文华.人参皂苷Rg1在裸鼠抗肿瘤治疗中免疫调节作用的研究[D].长春:吉林大学,2017.WU W H. Immunomodulatory Effects of Ginsenoside Rg1in Nude Mice with Antitumor Therapy[D]. Changchun:Jilin University,2017.
[48] DE S B G,MENASCHE G,FISCHER A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules[J]. Nature Reviews Immunology,2010,10(8):568-579. DOI:10.1038/nri2803.
[49]金岩,曲婷婷,柳越冬,等.人参皂苷Rb1、Rg1与5-氟脲嘧啶对地塞米松诱导S180荷瘤小鼠脾淋巴细胞凋亡影响的实验研究[J].中华中医药学刊,2006,24(7):1272-1273.DOI:10.13193/j.archtcm.2006.07.90.jiny.038.JIN Y,QU T T,LIU Y D,et al. Effect of ginsenoside Rb1,Rg1 and 5-fluorouracil on apoptosis of spleen lymphocytes in S180 tumor-bearing mice induced by dexamethasone[J].Chinese Archives of Traditional Chinese Medicine,2006,24(7):1272-1273. DOI:10.13193/j.archtcm.2006.07.90.jiny.038(Ch).
[50]曲婷婷,金岩,柳越冬,等.人参皂苷Rb1、Rg1与5-氟脲嘧啶对荷瘤小鼠免疫功能的影响[J].中医研究,2006,19(5):16-18.QU T T,JIN Y,LIU Y D,et al. Effects of ginsenoside Rb1,Rg1 and 5-fluorouracil on immune function of tumor-bearing mice[J]. Traditional Chinese Medicinal Research,2006,19(5):16-18(Ch).
[51] LI J,WEI Q,ZUO G W,et al. Ginsenoside Rg1 induces apoptosis through inhibition of the EpoR-mediated JAK2/STAT5 signalling pathway in the TF-1/Epo human leukemia cell line[J]. Asian Pacific Journal of Cancer Prevention Apjcp,2014,15(6):2453-2459. DOI:10.7314/APJCP.2014.15.6.2453.
[52] HWANG J W,OH J H,YOO H S,et al. Mountain ginseng extract exhibits antilung cancer activity by inhibiting the nuclear translocation of NF-κB[J]. American Journal of Chinese Medicine,2012,40(1):187-202. DOI:10.1142/S0192415X12500152.
[53] YU M L,YU X B,GUO D H,et al. Ginsenoside Rg1attenuates invasion and migration by inhibiting transforming growth factor-β1-induced epithelial to mesenchymal transition in HepG2 cells[J]. Molecular Medicine Reports,2015,11(4):3167-3173. DOI:10.3892/mmr.2014.3098.
[54] LI L I,WANG Y,BENQUAN Q I,et al. Suppression of PMA-induced tumor cell invasion and migration by ginsenoside Rg1 via the inhibition of NF-κB-dependent MMP-9 expression[J]. Oncology Reports, 2014,32(5):1779-1786. DOI:10.3892/or.2014.3422.
[55] NADKARNI P,CHEPURNY O G,HOLZ G G. Chapter two—regulation of glucose homeostasis by GLP-1[J].Progress in Molecular Biology&Translational Science,2014,121(121):23-65. DOI:10.1016/B978-0-12-800101-1.00002-8.
[56] RONDAS D,D’HERTOG W,OVERBERGH L,et al.Glucagon-like peptide-1:Modulator ofβ-cell dysfunction and death[J]. Diabetes Obesity&Metabolism,2013,15(s3):185-192. DOI:10.1111/dom.12165.
[57] LIU C,ZHANG M,HU M Y,et al. Increased glucagonlike peptide-1 secretion may be involved in antidiabetic effects of ginsenosides[J]. Journal of Endocrinology,2013,217(2):185-196. DOI:10.1530/JOE-12-0502.
[58] YU X Z,YE L F,ZHANG H,et al. Ginsenoside Rb1ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice[J]. Journal of Ginseng Research,2015,39(3):199-205. DOI:10.1016/j.jgr.2014.11.004.
[59] AKIYAMA N,AKIYAMA Y,KATO H,et al. Pharmacological evaluation of adipose dysfunction via 11β-hydroxysteroid dehydrogenase type 1 in the development of diabetes in diet-induced obese mice with cortisone pellet implantation[J]. Journal of Pharmacology&Experimental Therapeutics,2014,349(1):66-74. DOI:10.1124/jpet.113.210716.
[60] SONG B,DING L,ZHANG H,et al. Ginsenoside Rb1increases insulin sensitivity through suppressing 11β-hydroxysteroid dehydrogenase type I[J]. American Journal of Translational Research,2017,9(3):1049-1057.
[61] LECLERCQ I A,SILVA MORAIS A D,SCHROYEN B,et al. Insulin resistance in hepatocytes and sinusoidal liver cells:Mechanisms and consequences[J]. Journal of Hepatology,2007,47(1):142-156. DOI:10.1016/j.jhep.2007.04.002.
[62] COOL B,ZINKER B,CHIOU W,et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome[J]. Cell Metabolism,2006,3(6):403-416. DOI:10.1016/j.cmet.2006.05.005.
[63] ZHANG B B,ZHOU G C,LI C. AMPK:An emerging drug target for diabetes and the metabolic syndrome[J].Cell Metabolism,2009,9(5):407-416. DOI:10.1016/j.cmet.2009.03.012.
[64] LIU Q,ZHANG F G,ZHANG W S,et al. Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through Akt-FoxO1 interaction[J]. Science Foundation in China,2017,7(4):4001-4012. DOI:10.7150/thno.18788.
[65]尚文斌,郭超,赵娟,等.人参皂苷Rb1通过上调脂肪组织葡萄糖转运体促进葡萄糖消耗[J].中国中药杂志,2014,39(22):4448-4452. DOI:10.4268/cjcmm20142232.SHANG W B,GUO C,ZHAO J,et al. Ginsenoside Rb1 upregulates expressions of GLUTs to promote glucose consumption in adiopcytes[J]. China Journal of Chinese Materia Medica,2014,39(22):4448-4452. DOI:10.4268/cjcmm20142232(Ch).
[66] DYER J,WOOD I S,PALEJWALA A,et al. Expression of monosaccharide transporters in intestine of diabetic humans[J]. The American Journal of Physiology-Gastrointestinal and Liver Physiology,2002,282(2):G241.DOI:10.1152/ajpgi.00310.2001.
[67] DOMINGUEZ R J A,CHIRASANI V R,HERMANN K,et al. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice[J]. Laboratory Investigation,2016,96(1):98-111. DOI:10.1038/labinvest.2015.129.
[68] WANG C W,SU S C,HUANG S F,et al. An essential role of cAMP response element binding protein in ginsenoside Rg1-mediated inhibition of Na+/glucose cotransporter 1 gene expression[J]. Molecular Pharmacology,2015,88(6):1072-1083. DOI:10.1124/mol.114.097352.
[69] LACKEY D E,OLEFSKY J M. Regulation of metabolism by the innate immune system[J]. Nature Reviews Endocrinology,2015,12(1):15-28. DOI:10.1038/nrendo.2015.189.
[70] WU Y Z,YU Y H,SZABO A,et al. Central inflammation and leptin resistance are attenuated by ginsenoside Rb1treatment in obese mice fed a high-fat diet[J]. PloS One,2014,9(3):e92618. DOI:10.1371/journal.pone.0092618.
[71] PARK B K,LEE E A,KIM H Y,et al. Fatty liver and insulin resistance in the liver-specific knockout mice of mitogen inducible gene-6[J]. Journal of Diabetes Research,2016:1-9. DOI:10.1155/2016/1632061.
[72] HUANG C N,WANG C J,LEE Y J,et al. Active subfractions of abelmoschus esculentus substantially prevent free fatty acid-induced beta cell apoptosis via inhibiting dipeptidyl peptidase-4[J]. PLoS One,2017,12(7):e0180285. DOI:10.1371/journal.pone.0180285.
[73] TIAN W,CHEN L,ZHANG L,et al. Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats[J]. Genetics&Molecular Research,2017,16(1):gmr16019463. DOI:10.4238/gmr16019463.
[74]李鑫.人参皂苷Rg1对2型糖尿病大鼠肝损伤保护作用[J].中国公共卫生,2015,31(5):612-614. DOI:10.11847/zgggws2015-31-05-21.LI X. Protective effect of ginsenoside Rg1 on liver injury in rats with type 2 diabetes[J]. Chinese Journal of Public Health, 2015,31(5):612-614. DOI:10.11847/zgggws2015-31-05-21(Ch).
[75] HUANG Q,WANG T,YANG L,et al. Ginsenoside Rb2 alleviates hepatic lipid accumulation by restoring autophagy via induction of sirt1 and activation of AMPK[J].International Journal of Molecular Sciences,2017,18(5):1063. DOI:10.3390/ijms18051063.
[76]赵宗江,张学凯,张新雪,等. Rg1、Rb1对糖尿病肾病大鼠肾脏保护作用及其对肾组织TGF-β1 mRNA与蛋白表达的影响[J].北京中医药大学学报,2008,31(6):373-377.ZHAO Z J,ZHANG X K,ZHANG X X,et al. Protective effect of Rg1 and Rb1 on kidney in rats with diabetic nephropathy and their influences on expressions of TGF-β1 mRNA and protein of renal tissue[J]. Journal of Beijing University of Traditional Chinese Medicine,2008,31(6):373-377(Ch).
[77]张丽娜,陈晖,尤冠巧,等.人参皂甙Rg1对糖尿病肾病大鼠肾皮质中MMP-2、9和Ⅳ型胶原表达的影响[J].世界最新医学信息文摘,2015,15(60):103-104. DOI:10.3969/j.issn.1671-3141.2015.60.093.ZHANG L N,CHEN H,YOU G Q,et al. Effects of ginsenoside Rg1 on the expression of MMP-2,9 and IV collagen in renal cortex of diabetic nephropathy rats[J].World Latest Medicine Information,2015,15(60):103-104. DOI:10.3969/j.issn.1671-3141.2015.60.093(Ch).
[78]张丽娜,谢席胜,左川,等.人参皂甙Rg1对糖尿病肾病大鼠TNF-α、MCP-1表达的影响[J].四川大学学报(医学版),2009,40(3):466-471.ZHANG L N,XIE X S,ZUO C,et al. Effect of ginsenoside Rgl on the expression of TNF-αand MCP-1 in rats with diabetic nephropathy[J]. Journal of Sichuan University(Medical Science Edition),2009,40(3):466-471(Ch).
[79] YU H T,ZHEN J,YANG Y,et al. Ginsenoside Rg1ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model[J]. Journal of Cellular&Molecular Medicine,2016,20(4):623-631. DOI:10.1111/jcmm.12739.
[80] PUTAALA J,LIEBKIND R,GORDIN D,et al. Diabetes mellitus and ischemic stroke in the young:Clinical features and long-term prognosis[J]. Neurology,2011,76(21):1831-1837. DOI:10.1212/WNL.0b013e31821cccc2.
[81] SHEN J,ZHAO Z,SHANG W,et al. Ginsenoside Rg1nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction[J]. International Journal of Nanomedicine,2017,12:6477-6486. DOI:10.2147/IJN.S139602.
[82] LIU D,ZHANG H,GU W J,et al. Ginsenoside Rb1protects hippocampal neurons from high glucose-induced neurotoxicity by inhibiting GSK3β-mediated CHOP induction[J]. Molecular Medicine Reports,2014,9(4):1434-1438. DOI:10.3892/mmr.2014.1958.
[2]张于,程伟.中西医治疗阿尔兹海默病的研究现状[J].中医临床研究,2012,4(13):115-117. DOI:10.3969/j.issn.1674-7860. 2012.13.069.ZHANG Y,CHENG W. Research status on treating AD in the integrative medicine[J]. Clinical Journal of Chinese Medicine,2012,4(13):115-117. DOI:10.3969/j.issn.1674-7860.2012.13.069(Ch).
[3] QUAN Q K,WANG J,LI X,et al. Ginsenoside Rg1 decreases Aβ1–42 level by upregulating PPARγand IDE expression in the hippocampus of a rat model of Alzheimer's disease[J]. PloS One,2013,8(3):e59155. DOI:10.1371/journal.pone.0059155.
[4] FANG F,CHEN X C,HUANG T W,et al. Multifaced neuroprotective effects of ginsenoside Rg1 in an Alzheimer mouse model[J]. Biochim Biophys Acta,2012,1822(2):286-292. DOI:10.1016/j.bbadis.2011.10.004.
[5] CHEN L M,LIN Z Y,ZHU Y G,et al. Ginsenoside Rg1attenuatesβ-amyloid generation via suppressing PPARγ-regulated BACE1 activity in N2a-APP695 cells[J].European Journal of Pharmacology,2012,675(1):15-21.DOI:10.1016/j.ejphar.2011.11.039.
[6] HUANG T W,FANG F,CHEN L M,et al. Ginsenoside Rg1 attenuates oligomeric Aβ1-42-induced mitochondrial dysfunction[J]. Current Alzheimer Research,2012,9(3):388-395. DOI:10.2174/156720512800107636.
[7] LI W,CHU Y Q,ZHANG L,et al. Ginsenoside Rg1prevents SK-N-SH neuroblastoma cell apoptosis induced by supernatant from Aβ1-40-stimulated THP-1 monocytes[J]. Brain Research Bulletin,2012,88(5):501-506. DOI:10.1016/j.brainresbull.2012.05.002.
[8] WU J Y,YANG H Y,ZHAO Q W,et al. Ginsenoside Rg1 exerts a protective effect against Aβ25-35-induced toxicity in primary cultured rat cortical neurons through the NF-κB/NO pathway[J]. International Journal of Molecular Medicine,2016,37(3):781-788. DOI:10.3892/ijmm.2016.2485.
[9] GONG L,LI S L,LI H,et al. Ginsenoside Rg1 protects primary cultured rat hippocampal neurons from cell apoptosis induced byβ-amyloid protein[J]. Pharmaceutical Biology,2011,49(5):501-507. DOI:10.3109/13880209.2010.521514.
[10] WU J Y,PAN Z F,WANG Z Q,et al. Ginsenoside Rg1protection againstβ-amyloid peptide-induced neuronal apoptosis via estrogen receptorαand glucocorticoid receptor-dependent anti-protein nitration pathway[J]. Neuropharmacology,2012,63(3):349-361. DOI:10.1016/j.neuropharm.2012.04.005.
[11] ZHAO B S,LIU Y,GAO X Y,et al. Effects of ginsenoside Rg1 on the expression of toll-like receptor 3,4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line[J]. Molecules,2014,19(10):16925-16936. DOI:10.3390/molecules191016925.
[12] GU W J,LIU D,ZHANG M R,et al. Effect of ginsenoside Rb1 on insulin signal transduction pathway in hippocampal neurons of high-glucose-fed rats[J]. China Journal of Chinese Materia Medica,2014,39(6):1064-1068.
[13] ZHAO R P,ZHANG Z X,SONG Y J,et al. Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3βpathway in ginsenoside Rb1’s attenuation of beta-amyloidinduced neurotoxicity and Tau phosphorylation[J]. Journal of Ethnopharmacology,2011,133(3):1109-1116. DOI:10.1016/j.jep.2010.11.054.
[14] QIAN Y H,HAN H,HU X D,et al. Protective effect of ginsenoside Rb1 on beta-amyloid protein(1-42)-induced neurotoxicity in cortical neurons[J]. Neurological Research,2009,31(7):663-667. DOI:10.1179/174313209X385572.
[15] WANG Y H,DU G H. Ginsenoside Rg1 inhibits betasecretase activity in vitro and protects against Abetainduced cytotoxicity in PC12 cells[J]. Journal of Asian Natural Products Research, 2009,11(7):604-612.DOI:10.1080/10286020902843152.
[16] LIANG H,LIU L F,LIU J,et al. Ginsenoside Rg1 protects against neurodegeneration by inducing neurite outgrowth in cultured hippocampal neurons[J]. Neural Regeneration Research,2016,11(2):319-325. DOI:10.4103/1673-5374.177741.
[17] WANG Q,SUN L H,JIA W,et al. Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine-induced learning and memory impairment in mice[J]. Phytotherapy Research,2010,24(12):1748-1754. DOI:10.1002/ptr.3130.
[18] ZHAO H H,DI J,LIU W S,et al. Involvement of GSK3and PP2A in ginsenoside Rb1’s attenuation of aluminuminduced Tau hyperphosphorylation[J]. Behavioural Brain Research,2013,241(1):228-234. DOI:10.1016/j.bbr.2012.11.037.
[19] CHEN X C,HUANG T W,ZHANG J,et al. Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1’s attenuation of beta-amyloid peptide25-35-induced Tau hyperphosphorylation in cortical neurons[J]. Brain Research,2008,1200:99-106. DOI:10.1016/j.brainres.2007.12.029.
[20] WANG Y,FENG Y,FU Q Y,et al. Panax notoginsenoside Rb1 ameliorates Alzheimer’s disease by upregulating brainderived neurotrophic factor and downregulating Tau protein expression[J]. Experimental&Therapeutic Medicine,2013,6(3):826-830. DOI:10.3892/etm.2013.1215.
[21]李玺,刘颖,袁海峰,等.人参皂苷Rg1对冈田酸所致大鼠脑片Tau蛋白磷酸化的影响[J].中西医结合学报,2010,8(10):955-960. DOI:10.3736/jcim20101007.LI X,LIU Y,YUAN H F,et al. Effects of gensenoside Rg1on Tau protein phosphorylation induced by okadaic acid in rat brain slices[J]. Journal of Chinese Integrative Medicine,2010,8(10):955-960. DOI:10.3736/jcim20101007(Ch).
[22]李玺,张欣,袁海峰,等.人参皂苷Rg1对AD模型大鼠脑片P-Tau,caspase-3表达的影响[J].中国中药杂志,2010,35(3):369-372. DOI:10.4268/cjcmm20100325.LI X,ZHANG X,YUAN H F,et al. Experimental research on effect of gensenoside Rg1 on expressions of PTau and caspase-3 in brain slices from AD model rats[J].China Journal of Chinese Materia Medica,2010,35(3):369-372. DOI:10.4268/cjcmm20100325(Ch).
[23] ZHOU T T,ZU G,WANG X,et al. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of Parkinson’s disease[J]. International Immunopharmacology,2015,29(2):334-343.DOI:10.1016/j.intimp.2015.10.032.
[24] ZHOU T T,ZU G,ZHANG X G,et al. Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson’s disease[J]. Neuropharmacology,2016,101:480-489. DOI:10.1016/j.neuropharm.2015.10.024.
[25] HENG Y,ZHANG Q S,MU Z,et al. Ginsenoside Rg1attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced Parkinsonism mouse model by targetingα-synuclein abnormalities in the substantia nigra[J]. Toxicology Letters,2016,243:7-21. DOI:10.1016/j.toxlet.2015.12.005.
[26] REN X F,CHEN L,GAO X Q,et al. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra[J]. Journal of Steroid Biochemistry&Molecular Biology,2016,155:94-103. DOI:10.1016/j.jsbmb.2015.09.040.
[27] XU L,CHEN W F,WONG M S. Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson’s disease through the IGF-I receptor signalling pathway[J]. British Journal of Pharmacology,2010,158(3):738-748. DOI:10.1111/j.1476-5381.2009.00361.x.
[28] XU H M,JIANG H,WANG J,et al. Rg1 protects the MPP-treated MES23.5 cells via attenuating DMT1 upregulation and cellular iron uptake[J]. Neuropharmacology,2010,58(2):488-494. DOI:10.1016/j.neuropharm.2009.09.002.
[29] WANG J,XU H M,YANG H D,et al. Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins[J]. Neurochemistry International,2009,54(1):43-48. DOI:10.1016/j.neuint.2008.10.003.
[30] ZHANG Y L,LIU Y,KANG X P,et al. Ginsenoside Rb1confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson’s disease[J]. Neuropharmacology,2017,131:223-237. DOI:10.1016/j.neuropharm.2017.12.012.
[31] YANG Y D,LI X,ZHANG L M,et al. Ginsenoside Rg1 suppressed infammation and neuron apoptosis by activating PPARγ/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury[J]. International Journal of Clinical&Experimental Pathology,2015,8(3):2484-2494.
[32] XIE C L,LI J H,WANG W W,et al. Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression[J]. Life Sciences,2015,121:145-151. DOI:10.1016/j.lfs.2014.12.002.
[33]王巧云,刘凤,吴峰阶,等.人参皂苷Rg1对局灶性脑缺血再灌注损伤大鼠海马p-ERK1/2与p-JNK表达的影响[J].中国中西医结合杂志,2013,33(2):229-234.WANG Q Y,LIU F,WU F J,et al. Effects of ginsenoside Rg1 on the expressions of p-eRK1/2 and p-JNK in local cerebral ischemia/reperfusion injury rats[J]. Chinese Journal of Integrated Traditional&Western Medicine,2013,33(2):229-234(Ch).
[34] WANG L,ZHAO H,ZHAI Z Z,et al. Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia-reperfusion injury in mice[J]. Biomedicine&Pharmacotherapy,2018,99:876-882. DOI:10.1016/j.biopha.2018.01.136.
[35] ZHU J,JIANG Y,WU L,et al. Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia[J]. Neuroscience,2012,202(2):342-351. DOI:10.1016/j.neuroscience.2011.11.070.
[36] DONG X,ZHENG L,LU S J,et al. Neuroprotective effects of pretreatment of ginsenoside Rb1 on severe cerebral ischemia-induced injuries in aged mice:Involvement of anti-oxidant signaling[J]. Geriatrics&Gerontology International,2017,17(2):338-345. DOI:10.1111/ggi.12699.
[37] WANG S Y,LI M H,GUO Y,et al. Effects of Panax notoginseng ginsenoside Rb1 on abnormal hippocampal microenvironment in rats[J]. Journal of Ethnopharmacology,2017,202:138-146. DOI:10.1016/j.jep.2017.01.005.
[38]黄小平,王蓓,邱咏园,等.黄芪甲苷、人参皂苷Rg1、Rb1和三七皂苷R1抗小鼠脑缺血再灌注氧化应激损伤和促进能量代谢的配伍研究[J].湖南中医药大学学报,2014,34(7):5-11. DOI:10.3969/j. issn. 1674-070X.2014.07.002.005.07.HUANG X P,WANG B,QIU Y Y,et al. The combination study of astragalosideⅣ,ginsenosides Rg1,Rb1 and notoginsenoside R1 on antagonizing oxidative stress injury and promoting energy metabolism after ischemia-reperfusion in mice[J]. Journal of Traditional Chinese Medicine University of Hunan,2014,34(7):5-11. DOI:10.3969/j.issn.1674-070X.2014.07.002.005.07(Ch).
[39]柯大智,王红宁,陈地龙,等.人参皂苷Rg1抑制白血病细胞K562增殖并诱导分化的分子机制[J].第三军医大学学报,2014,36(2):125-129. DOI:10.16016/j.1000-5404.2014.02.003.KE D Z,WANG H N,CHEN D L,et al. Molecular mechanism of ginsenoside Rg1 in inhibiting proliferation and inducing differentiation in chronic myelocytic leukemia K562 cells[J]. Acta Academiae Medicinae Militaris Tertiae,2014,36(2):125-129. DOI:10.16016/j. 1000-5404.2014.02.003(Ch).
[40]王国红.人参皂甙Rg1、肉桂酸、丹参酮ⅡA及其组合对人成骨肉瘤MG-63细胞终末分化的诱导研究[D].厦门:厦门大学,2005.WANG G H. Study on the Terminal Differentiation of Human Osteosarcoma MG-63 Cells Induced by Ginsenoside Rg1,Cinnamic Acid,TanshinoneⅡA and Their Combinations[D]. Xiamen:Xiamen University,2005(Ch).
[41]张龙江,周二付.人参皂苷Rg1对结肠癌肿瘤体外和体内的增殖抑制作用[J].世界华人消化杂志,2014(30):4599-4603. DOI:10.11569/wcjd.v22.i30.4599.ZHANG L J,ZHOU E F. In vitro and in vivo inhibitory effects of ginsenoside Rg1 on proliferation of colon cancer cells[J]. World Chinese Journal of Digestology,2014(30):4599-4603. DOI:10.11569/wcjd.v22.i30.4599(Ch).
[42]王红宁,左国伟,陈地龙,等.人参皂苷Rb1、Rg1、Re对白血病细胞株KG1α增殖的影响[J].生物技术,2010,20(2):56-58. DOI:10.16519/j.cnki.1004-311x.2010.02.031.WANG H N,ZUO G W,CHEN D L,et al. Effects of ginsenoside Rb1,Rg1,Re on proliferation of KG1αcells[J].Biotechnology,2010,20(2):56-58. DOI:10.16519/j.cnki.1004-311x.2010.02.031(Ch).
[43]崔金刚,王晓燕,熊敏琪,等.人参皂苷Rg1与Rb1在心肌缺血复合肿瘤病理环境下的作用研究[J].上海中医药大学学报,2014,28(4):58-63. DOI:10.16306/j.1008-861x.2014.04.020.CUI J G,WANG X Y,XIONG M Q,et al. Effects of ginsenosides Rg1 and Rb1 in myocardial ischemia complex pathological environment of neoplasia[J]. Journal of Shanghai University of Traditional Chinese Medicine,2014,28(4):58-63. DOI:10.16306/j.1008-861x.2014.04.020(Ch).
[44]刘嘉.肿瘤多药耐药机制及其逆转方案的研究进展[J].中国肿瘤外科杂志,2010,2(3):174-178. DOI:10.3969/j.issn.1674-4136.2010.03.012.LIU J. Advances in research on multidrug resistance mechanism of tumor and its reversal program[J]. Chinese Journal of Surgical Oncology,2010,2(3):174-178. DOI:10.3969/j.issn.1674-4136.2010.03.012(Ch).
[45]王婷.三七总皂苷Rb1对肿瘤耐药逆转作用的实验研究[D].昆明:昆明医学院,2011.WANG T. PNS-Rb1 Reverse Effect on Tumor Multidrugresistance in vivo Study[D]. Kunming:Kunming Medical College,2011(Ch).
[46] WANG Y,LIU Y,ZHANG X Y,et al. Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways[J]. International Immunopharmacology,2014,23(1):77-84. DOI:10.1016/j. intimp.2014.07.028.
[47]武文华.人参皂苷Rg1在裸鼠抗肿瘤治疗中免疫调节作用的研究[D].长春:吉林大学,2017.WU W H. Immunomodulatory Effects of Ginsenoside Rg1in Nude Mice with Antitumor Therapy[D]. Changchun:Jilin University,2017.
[48] DE S B G,MENASCHE G,FISCHER A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules[J]. Nature Reviews Immunology,2010,10(8):568-579. DOI:10.1038/nri2803.
[49]金岩,曲婷婷,柳越冬,等.人参皂苷Rb1、Rg1与5-氟脲嘧啶对地塞米松诱导S180荷瘤小鼠脾淋巴细胞凋亡影响的实验研究[J].中华中医药学刊,2006,24(7):1272-1273.DOI:10.13193/j.archtcm.2006.07.90.jiny.038.JIN Y,QU T T,LIU Y D,et al. Effect of ginsenoside Rb1,Rg1 and 5-fluorouracil on apoptosis of spleen lymphocytes in S180 tumor-bearing mice induced by dexamethasone[J].Chinese Archives of Traditional Chinese Medicine,2006,24(7):1272-1273. DOI:10.13193/j.archtcm.2006.07.90.jiny.038(Ch).
[50]曲婷婷,金岩,柳越冬,等.人参皂苷Rb1、Rg1与5-氟脲嘧啶对荷瘤小鼠免疫功能的影响[J].中医研究,2006,19(5):16-18.QU T T,JIN Y,LIU Y D,et al. Effects of ginsenoside Rb1,Rg1 and 5-fluorouracil on immune function of tumor-bearing mice[J]. Traditional Chinese Medicinal Research,2006,19(5):16-18(Ch).
[51] LI J,WEI Q,ZUO G W,et al. Ginsenoside Rg1 induces apoptosis through inhibition of the EpoR-mediated JAK2/STAT5 signalling pathway in the TF-1/Epo human leukemia cell line[J]. Asian Pacific Journal of Cancer Prevention Apjcp,2014,15(6):2453-2459. DOI:10.7314/APJCP.2014.15.6.2453.
[52] HWANG J W,OH J H,YOO H S,et al. Mountain ginseng extract exhibits antilung cancer activity by inhibiting the nuclear translocation of NF-κB[J]. American Journal of Chinese Medicine,2012,40(1):187-202. DOI:10.1142/S0192415X12500152.
[53] YU M L,YU X B,GUO D H,et al. Ginsenoside Rg1attenuates invasion and migration by inhibiting transforming growth factor-β1-induced epithelial to mesenchymal transition in HepG2 cells[J]. Molecular Medicine Reports,2015,11(4):3167-3173. DOI:10.3892/mmr.2014.3098.
[54] LI L I,WANG Y,BENQUAN Q I,et al. Suppression of PMA-induced tumor cell invasion and migration by ginsenoside Rg1 via the inhibition of NF-κB-dependent MMP-9 expression[J]. Oncology Reports, 2014,32(5):1779-1786. DOI:10.3892/or.2014.3422.
[55] NADKARNI P,CHEPURNY O G,HOLZ G G. Chapter two—regulation of glucose homeostasis by GLP-1[J].Progress in Molecular Biology&Translational Science,2014,121(121):23-65. DOI:10.1016/B978-0-12-800101-1.00002-8.
[56] RONDAS D,D’HERTOG W,OVERBERGH L,et al.Glucagon-like peptide-1:Modulator ofβ-cell dysfunction and death[J]. Diabetes Obesity&Metabolism,2013,15(s3):185-192. DOI:10.1111/dom.12165.
[57] LIU C,ZHANG M,HU M Y,et al. Increased glucagonlike peptide-1 secretion may be involved in antidiabetic effects of ginsenosides[J]. Journal of Endocrinology,2013,217(2):185-196. DOI:10.1530/JOE-12-0502.
[58] YU X Z,YE L F,ZHANG H,et al. Ginsenoside Rb1ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice[J]. Journal of Ginseng Research,2015,39(3):199-205. DOI:10.1016/j.jgr.2014.11.004.
[59] AKIYAMA N,AKIYAMA Y,KATO H,et al. Pharmacological evaluation of adipose dysfunction via 11β-hydroxysteroid dehydrogenase type 1 in the development of diabetes in diet-induced obese mice with cortisone pellet implantation[J]. Journal of Pharmacology&Experimental Therapeutics,2014,349(1):66-74. DOI:10.1124/jpet.113.210716.
[60] SONG B,DING L,ZHANG H,et al. Ginsenoside Rb1increases insulin sensitivity through suppressing 11β-hydroxysteroid dehydrogenase type I[J]. American Journal of Translational Research,2017,9(3):1049-1057.
[61] LECLERCQ I A,SILVA MORAIS A D,SCHROYEN B,et al. Insulin resistance in hepatocytes and sinusoidal liver cells:Mechanisms and consequences[J]. Journal of Hepatology,2007,47(1):142-156. DOI:10.1016/j.jhep.2007.04.002.
[62] COOL B,ZINKER B,CHIOU W,et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome[J]. Cell Metabolism,2006,3(6):403-416. DOI:10.1016/j.cmet.2006.05.005.
[63] ZHANG B B,ZHOU G C,LI C. AMPK:An emerging drug target for diabetes and the metabolic syndrome[J].Cell Metabolism,2009,9(5):407-416. DOI:10.1016/j.cmet.2009.03.012.
[64] LIU Q,ZHANG F G,ZHANG W S,et al. Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through Akt-FoxO1 interaction[J]. Science Foundation in China,2017,7(4):4001-4012. DOI:10.7150/thno.18788.
[65]尚文斌,郭超,赵娟,等.人参皂苷Rb1通过上调脂肪组织葡萄糖转运体促进葡萄糖消耗[J].中国中药杂志,2014,39(22):4448-4452. DOI:10.4268/cjcmm20142232.SHANG W B,GUO C,ZHAO J,et al. Ginsenoside Rb1 upregulates expressions of GLUTs to promote glucose consumption in adiopcytes[J]. China Journal of Chinese Materia Medica,2014,39(22):4448-4452. DOI:10.4268/cjcmm20142232(Ch).
[66] DYER J,WOOD I S,PALEJWALA A,et al. Expression of monosaccharide transporters in intestine of diabetic humans[J]. The American Journal of Physiology-Gastrointestinal and Liver Physiology,2002,282(2):G241.DOI:10.1152/ajpgi.00310.2001.
[67] DOMINGUEZ R J A,CHIRASANI V R,HERMANN K,et al. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice[J]. Laboratory Investigation,2016,96(1):98-111. DOI:10.1038/labinvest.2015.129.
[68] WANG C W,SU S C,HUANG S F,et al. An essential role of cAMP response element binding protein in ginsenoside Rg1-mediated inhibition of Na+/glucose cotransporter 1 gene expression[J]. Molecular Pharmacology,2015,88(6):1072-1083. DOI:10.1124/mol.114.097352.
[69] LACKEY D E,OLEFSKY J M. Regulation of metabolism by the innate immune system[J]. Nature Reviews Endocrinology,2015,12(1):15-28. DOI:10.1038/nrendo.2015.189.
[70] WU Y Z,YU Y H,SZABO A,et al. Central inflammation and leptin resistance are attenuated by ginsenoside Rb1treatment in obese mice fed a high-fat diet[J]. PloS One,2014,9(3):e92618. DOI:10.1371/journal.pone.0092618.
[71] PARK B K,LEE E A,KIM H Y,et al. Fatty liver and insulin resistance in the liver-specific knockout mice of mitogen inducible gene-6[J]. Journal of Diabetes Research,2016:1-9. DOI:10.1155/2016/1632061.
[72] HUANG C N,WANG C J,LEE Y J,et al. Active subfractions of abelmoschus esculentus substantially prevent free fatty acid-induced beta cell apoptosis via inhibiting dipeptidyl peptidase-4[J]. PLoS One,2017,12(7):e0180285. DOI:10.1371/journal.pone.0180285.
[73] TIAN W,CHEN L,ZHANG L,et al. Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats[J]. Genetics&Molecular Research,2017,16(1):gmr16019463. DOI:10.4238/gmr16019463.
[74]李鑫.人参皂苷Rg1对2型糖尿病大鼠肝损伤保护作用[J].中国公共卫生,2015,31(5):612-614. DOI:10.11847/zgggws2015-31-05-21.LI X. Protective effect of ginsenoside Rg1 on liver injury in rats with type 2 diabetes[J]. Chinese Journal of Public Health, 2015,31(5):612-614. DOI:10.11847/zgggws2015-31-05-21(Ch).
[75] HUANG Q,WANG T,YANG L,et al. Ginsenoside Rb2 alleviates hepatic lipid accumulation by restoring autophagy via induction of sirt1 and activation of AMPK[J].International Journal of Molecular Sciences,2017,18(5):1063. DOI:10.3390/ijms18051063.
[76]赵宗江,张学凯,张新雪,等. Rg1、Rb1对糖尿病肾病大鼠肾脏保护作用及其对肾组织TGF-β1 mRNA与蛋白表达的影响[J].北京中医药大学学报,2008,31(6):373-377.ZHAO Z J,ZHANG X K,ZHANG X X,et al. Protective effect of Rg1 and Rb1 on kidney in rats with diabetic nephropathy and their influences on expressions of TGF-β1 mRNA and protein of renal tissue[J]. Journal of Beijing University of Traditional Chinese Medicine,2008,31(6):373-377(Ch).
[77]张丽娜,陈晖,尤冠巧,等.人参皂甙Rg1对糖尿病肾病大鼠肾皮质中MMP-2、9和Ⅳ型胶原表达的影响[J].世界最新医学信息文摘,2015,15(60):103-104. DOI:10.3969/j.issn.1671-3141.2015.60.093.ZHANG L N,CHEN H,YOU G Q,et al. Effects of ginsenoside Rg1 on the expression of MMP-2,9 and IV collagen in renal cortex of diabetic nephropathy rats[J].World Latest Medicine Information,2015,15(60):103-104. DOI:10.3969/j.issn.1671-3141.2015.60.093(Ch).
[78]张丽娜,谢席胜,左川,等.人参皂甙Rg1对糖尿病肾病大鼠TNF-α、MCP-1表达的影响[J].四川大学学报(医学版),2009,40(3):466-471.ZHANG L N,XIE X S,ZUO C,et al. Effect of ginsenoside Rgl on the expression of TNF-αand MCP-1 in rats with diabetic nephropathy[J]. Journal of Sichuan University(Medical Science Edition),2009,40(3):466-471(Ch).
[79] YU H T,ZHEN J,YANG Y,et al. Ginsenoside Rg1ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model[J]. Journal of Cellular&Molecular Medicine,2016,20(4):623-631. DOI:10.1111/jcmm.12739.
[80] PUTAALA J,LIEBKIND R,GORDIN D,et al. Diabetes mellitus and ischemic stroke in the young:Clinical features and long-term prognosis[J]. Neurology,2011,76(21):1831-1837. DOI:10.1212/WNL.0b013e31821cccc2.
[81] SHEN J,ZHAO Z,SHANG W,et al. Ginsenoside Rg1nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction[J]. International Journal of Nanomedicine,2017,12:6477-6486. DOI:10.2147/IJN.S139602.
[82] LIU D,ZHANG H,GU W J,et al. Ginsenoside Rb1protects hippocampal neurons from high glucose-induced neurotoxicity by inhibiting GSK3β-mediated CHOP induction[J]. Molecular Medicine Reports,2014,9(4):1434-1438. DOI:10.3892/mmr.2014.1958.