尿液蛋白生物标志物验证时要考虑的因素
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摘要
生物标志物是和疾病相关的可监测的变化.尿液因其不受人体稳态调节而比血液更富于变化,是早期、敏感的生物标志物来源.尿液由于受到的各种因素的影响,变化极其复杂,一个排除这些影响的方法就是在动物模型上控制其他影响因素,单独观察每个应用因素的作用,找到与疾病直接相关的尿液变化,并且在选择需要验证的疾病候选标志物时应该考虑是不是已经被发现受到一些常见因素的影响,最后再在临床样本上验证找到的尿液标志物线索与人类疾病的关系.本文拟通过列表形式展示疾病候选标志物受影响因素(生理因素、药理因素)影响的情况,提示验证疾病候选标志物时应该慎重考虑这些蛋白,减少验证的成本和精力,以期更有效地建立起人类疾病与其尿液标志物的相对特异的关系.
A biomarker is a measurable change associated with disease.Urine is a source of early,sensitive biomarkers because it is not under homeostatic control; therefore,changes occur more rapidly in urine than in blood.The composition of urine is affected by a variety of factors,and urine is susceptible to complex changes.A way to exclude the impact of multiple factors is to use an animal model in which control over all experimental factors is possible and to observe each factor separately.Additionally,some common effective factors should be considered when choosing disease candidate markers.Finally,during clinical verification,we can discover relationships between urine biomarkers and disease.This article intends to demonstrate the impact of effective factors(physiological and pharmacological) on potential disease markers in tabular form.We suggest that these proteins be carefully considered in the verification of potential disease markers.This should reduce unnecessary costs of clinical verification.We are looking forward to establishing specific relationships between human diseases and their urinary biomarkers more effectively.
A biomarker is a measurable change associated with disease.Urine is a source of early,sensitive biomarkers because it is not under homeostatic control; therefore,changes occur more rapidly in urine than in blood.The composition of urine is affected by a variety of factors,and urine is susceptible to complex changes.A way to exclude the impact of multiple factors is to use an animal model in which control over all experimental factors is possible and to observe each factor separately.Additionally,some common effective factors should be considered when choosing disease candidate markers.Finally,during clinical verification,we can discover relationships between urine biomarkers and disease.This article intends to demonstrate the impact of effective factors(physiological and pharmacological) on potential disease markers in tabular form.We suggest that these proteins be carefully considered in the verification of potential disease markers.This should reduce unnecessary costs of clinical verification.We are looking forward to establishing specific relationships between human diseases and their urinary biomarkers more effectively.
引文
1高友鹤.尿液有可能成为生物标志物的金矿吗?中国科学:生命科学,2013,43:708
2 Cannon W B.Organization for physiological homeostasis.Physiol Rev,1929,9:399–431
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4 Wu J,Gao Y.Physiological conditions can be reflected in human urine proteome and metabolome.Expert Rev Proteomics,2015,12:623–636
5 Gao Y.Are urinary biomarkers from clinical studies biomarkers of disease or biomarkers of medicine?MOJ Proteomics Bioinform,2014,in press,doi:10.15406/mojpb.2014.01.00028
6 Gao Y.Are human biomarker studies always more valuable than animal ones?MOJ Proteomics Bioinform,2015,in press,doi:10 .15406/mojpb.2015.02.00035
7 Gao Y.Roadmap to the Urine Biomarker Era.MOJ Proteomics Bioinform,2014,in press,doi:10.15406/mojpb.2014.01.00005
8 Zhao M,Li M,Li X,et al.Dynamic changes of urinary proteins in a focal segmental glomerulosclerosis rat model.Proteome Sci,2014,12:42
9 Yuan Y,Zhang F,Wu J,et al.Urinary candidate biomarker discovery in a rat unilateral ureteral obstruction model.Sci Rep,2015,5:9314
10 倪艳颖,张繁霜,安满霞,等.细菌性脑膜炎大鼠模型的尿液蛋白质组学变化.生物工程学报,2017,33:1–13
11 Zhang F,Ni Y,Yuan Y.Early urinary candidate biomarker discovery in a rat thioacetamide-induced liver fibrosis model.bioRxiv,2017,in press,doi:10.1101/125120
12 Wu J,Guo Z,Gao Y.Early biomarker discovery in urine of Walker 256 subcutaneous rat model.bioRxiv,2017,in press,doi:10.1101/114611
13 Ni Y,Zhang F,An M,et al.Early candidate biomarkers found from urine of astrocytoma rat before changes in MRI.bioRxiv,2017,in press,doi:10 .1101/117333
14 Wu J,Li X,Gao Y.Early detection in urinary proteome for the effective early treatment of bleomycin-induced pulmonary fibrosis in a rat model.Available from:http://www.paper.edu.cn,doi:10.13140/RG.2.2.15793.99689
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20 Kochhar S,Jacobs D M,Ramadan Z,et al.Probing gender-specific metabolism differences in humans by nuclear magnetic resonance-based metabonomics.Anal Biochem,2006,352:274–281
21 Slupsky C M,Rankin K N,Wagner J,et al.Investigations of the effects of gender,diurnal variation,and age in human urinary metabolomic profiles.Anal Chem,2007,79:6995–7004
22 Psihogios N G,Gazi I F,Elisaf M S,et al.Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics.NMR Biomed,2008,21:195–207
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26 Mamtimin B,Mian Q,Chen C,et al.Gender related metabonomic analysis of serum and urine samples from Xinjiang healthy Han subjects with magnetic resonance.Med Sci,2012,37:1135–1140
27 Zheng H,Yde C C,Arnberg K,et al.NMR-based metabolomic profiling of overweight adolescents:an elucidation of the effects of inter-/intraindividual differences,gender,and pubertal development.Biomed Res Int,2014,2014:1–10
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29 Collino S,Montoliu I,Martin F P J,et al.Metabolic signatures of extreme longevity in northern italian centenarians reveal a complex remodeling of lipids,amino acids,and gut microbiota metabolism.PLoS ONE,2013,8:e56564
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34 May D H,Navarro S L,Ruczinski I,et al.Metabolomic profiling of urine:response to a randomised,controlled feeding study of select fruits and vegetables,and application to an observational study.Br J Nutr,2013,110:1760–1770
35 Llorach R,Medina S,García-Viguera C,et al.Discovery of human urinary biomarkers of aronia-citrus juice intake by HPLC-q-TOF-based metabolomic approach.Electrophoresis,2014,35:1599–1606
36 Garcia-Aloy M,Llorach R,Urpi-Sarda M,et al.Novel multimetabolite prediction of walnut consumption by a urinary biomarker model in a free-living population:the PREDIMED study.J Proteome Res,2014,13:3476–3483
37 Pinto J,Barros A S,Domingues M R M,et al.Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine.J Proteome Res,2015,14:1263–1274
38 Diaz S O,Barros A S,Goodfellow B J,et al.Following healthy pregnancy by nuclear magnetic resonance(NMR)metabolic profiling of human urine.J Proteome Res,2013,12:969–979
39 Trivedi D K,Iles R K.HILIC-MS-based shotgun metabolomic profiling of maternal urine at 9–23 weeks of gestation-establishing the baseline changes in the maternal metabolome.Biomed Chromatogr,2015,29:240–245
40 Lenz E M,Bright J,Wilson I D,et al.A 1H NMR-based metabonomic study of urine and plasma samples obtained from healthy human subjects.J Pharmaceut Biomed Anal,2003,33:1103–1115
41 Saccenti E,Tenori L,Verbruggen P,et al.Of monkeys and men:a metabolomic analysis of static and dynamic urinary metabolic phenotypes in two species.PLoS ONE,2014,9:e106077
42 Kohler M,Franz S,Regeniter A,et al.Comparison of the urinary protein patterns of athletes by 2D-gel electrophoresis and mass spectrometrya a pilot study.Drug Test Anal,2009,1:382–386
43 Kohler M,Walpurgis K,Thomas A,et al.Effects of endurance exercise on the urinary proteome analyzed by 2-D PAGE and Orbitrap MS.Prot Clin Appl,2010,4:568–576
44 Pechlivanis A,Kostidis S,Saraslanidis P,et al.1H NMR-based metabonomic investigation of the effect of two different exercise sessions on the metabolic fingerprint of human urine.J Proteome Res,2010,9:6405–6416
45 Enea C,Seguin F,Petitpas-Mulliez J,et al.1H NMR-based metabolomics approach for exploring urinary metabolome modifications after acute and chronic physical exercise.Anal Bioanal Chem,2010,396:1167–1176
46 Neal C M,Hunter A M,Brennan L,et al.Six weeks of a polarized training-intensity distribution leads to greater physiological and performance adaptations than a threshold model in trained cyclists.J Appl Physiol,2013,114:461–471
47 Krug S,Kastenmüller G,Stückler F,et al.The dynamic range of the human metabolome revealed by challenges.FASEB J,2012,26:2607–2619
48 Mukherjee K,Edgett B A,Burrows H W,et al.Whole blood transcriptomics and urinary metabolomics to define adaptive biochemical pathways of high-intensity exercise in 50–60 year old masters athletes.PLoS ONE,2014,9:e92031
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51 Airoldi L,Magagnotti C,Iannuzzi A R,et al.Effects of cigarette smoking on the human urinary proteome.Biochem Biophys Res Commun,2009,381:397–402
52 Haniff A N,Gam L H.Identification of urinary protein biomarkers for tobacco smoking.Biotech Appl Biochem,2016,63:266–272
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2 Cannon W B.Organization for physiological homeostasis.Physiol Rev,1929,9:399–431
3 Thongboonkerd V,McLeish K R,Arthur J M,et al.Proteomic analysis of normal human urinary proteins isolated by acetone precipitation or ultracentrifugation.Kidney Int,2002,62:1461–1469
4 Wu J,Gao Y.Physiological conditions can be reflected in human urine proteome and metabolome.Expert Rev Proteomics,2015,12:623–636
5 Gao Y.Are urinary biomarkers from clinical studies biomarkers of disease or biomarkers of medicine?MOJ Proteomics Bioinform,2014,in press,doi:10.15406/mojpb.2014.01.00028
6 Gao Y.Are human biomarker studies always more valuable than animal ones?MOJ Proteomics Bioinform,2015,in press,doi:10 .15406/mojpb.2015.02.00035
7 Gao Y.Roadmap to the Urine Biomarker Era.MOJ Proteomics Bioinform,2014,in press,doi:10.15406/mojpb.2014.01.00005
8 Zhao M,Li M,Li X,et al.Dynamic changes of urinary proteins in a focal segmental glomerulosclerosis rat model.Proteome Sci,2014,12:42
9 Yuan Y,Zhang F,Wu J,et al.Urinary candidate biomarker discovery in a rat unilateral ureteral obstruction model.Sci Rep,2015,5:9314
10 倪艳颖,张繁霜,安满霞,等.细菌性脑膜炎大鼠模型的尿液蛋白质组学变化.生物工程学报,2017,33:1–13
11 Zhang F,Ni Y,Yuan Y.Early urinary candidate biomarker discovery in a rat thioacetamide-induced liver fibrosis model.bioRxiv,2017,in press,doi:10.1101/125120
12 Wu J,Guo Z,Gao Y.Early biomarker discovery in urine of Walker 256 subcutaneous rat model.bioRxiv,2017,in press,doi:10.1101/114611
13 Ni Y,Zhang F,An M,et al.Early candidate biomarkers found from urine of astrocytoma rat before changes in MRI.bioRxiv,2017,in press,doi:10 .1101/117333
14 Wu J,Li X,Gao Y.Early detection in urinary proteome for the effective early treatment of bleomycin-induced pulmonary fibrosis in a rat model.Available from:http://www.paper.edu.cn,doi:10.13140/RG.2.2.15793.99689
15 Wijetunge D S S,Karunathilake K H E M,Chaudhari A,et al.Complete nucleotide sequence of pRS218,a large virulence plasmid,that augments pathogenic potential of meningitis-associated Escherichia coli strain RS218.BMC Microbiol,2014,14:203
16 Kim K S.Acute bacterial meningitis in infants and children.Lancet Infect Dis,2010,10:32–42
17 Wu H M,Cordeiro S M,Harcourt B H,et al.Accuracy of real-time PCR,Gram stain and culture for Streptococcus pneumoniae,Neisseria meningitidis and Haemophilus influenzae meningitis diagnosis.BMC Infect Dis,2013,13:26
18 Sun W,Chen Y,Li F,et al.Dynamic urinary proteomic analysis reveals stable proteins to be potential biomarkers.Prot Clin Appl,2009,3:370 –382
19 Castagna A,Olivieri O,Milli A,et al.Female urinary proteomics:new insight into exogenous and physiological hormone-dependent changes.Prot Clin Appl,2011,5:343–353
20 Kochhar S,Jacobs D M,Ramadan Z,et al.Probing gender-specific metabolism differences in humans by nuclear magnetic resonance-based metabonomics.Anal Biochem,2006,352:274–281
21 Slupsky C M,Rankin K N,Wagner J,et al.Investigations of the effects of gender,diurnal variation,and age in human urinary metabolomic profiles.Anal Chem,2007,79:6995–7004
22 Psihogios N G,Gazi I F,Elisaf M S,et al.Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics.NMR Biomed,2008,21:195–207
23 Oh J,Pyo J H,Jo E H,et al.Establishment of a near-standard two-dimensional human urine proteomic map.Proteomics,2004,4:3485–3497
24 Guo Z,Zhang Y,Zou L,et al.A proteomic analysis of individual and gender variations in normal human urine and cerebrospinal fluid using iTRAQ quantification.PLoS ONE,2015,10:e0133270
25 Becker L,Kheirandish-Gozal L,Peris E,et al.Contextualised urinary biomarker analysis facilitates diagnosis of paediatric obstructive sleep apnoea.Sleep Med,2014,15:541–549
26 Mamtimin B,Mian Q,Chen C,et al.Gender related metabonomic analysis of serum and urine samples from Xinjiang healthy Han subjects with magnetic resonance.Med Sci,2012,37:1135–1140
27 Zheng H,Yde C C,Arnberg K,et al.NMR-based metabolomic profiling of overweight adolescents:an elucidation of the effects of inter-/intraindividual differences,gender,and pubertal development.Biomed Res Int,2014,2014:1–10
28 Gu H,Pan Z,Xi B,et al.1H NMR metabolomics study of age profiling in children.NMR Biomed,2009,22:826–833
29 Collino S,Montoliu I,Martin F P J,et al.Metabolic signatures of extreme longevity in northern italian centenarians reveal a complex remodeling of lipids,amino acids,and gut microbiota metabolism.PLoS ONE,2013,8:e56564
30 Li M,Zhao M,Gao Y.Effect of transient blood glucose increases after oral glucose intake on the human urinary proteome.Prot Clin Appl,2015,9 :618–622
31 Wallner-Liebmann S,Gralka E,Tenori L,et al.The impact of free or standardized lifestyle and urine sampling protocol on metabolome recognition accuracy.Genes Nutr,2015,10:441
32 Zheng H,Yde C C,Clausen M R,et al.Metabolomics investigation to shed light on cheese as a possible piece in the french paradox puzzle.J Agric Food Chem,2015,63:2830–2839
33 Medina S,Ferreres F,García-Viguera C,et al.Non-targeted metabolomic approach reveals urinary metabolites linked to steroid biosynthesis pathway after ingestion of citrus juice.Food Chem,2013,136:938–946
34 May D H,Navarro S L,Ruczinski I,et al.Metabolomic profiling of urine:response to a randomised,controlled feeding study of select fruits and vegetables,and application to an observational study.Br J Nutr,2013,110:1760–1770
35 Llorach R,Medina S,García-Viguera C,et al.Discovery of human urinary biomarkers of aronia-citrus juice intake by HPLC-q-TOF-based metabolomic approach.Electrophoresis,2014,35:1599–1606
36 Garcia-Aloy M,Llorach R,Urpi-Sarda M,et al.Novel multimetabolite prediction of walnut consumption by a urinary biomarker model in a free-living population:the PREDIMED study.J Proteome Res,2014,13:3476–3483
37 Pinto J,Barros A S,Domingues M R M,et al.Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine.J Proteome Res,2015,14:1263–1274
38 Diaz S O,Barros A S,Goodfellow B J,et al.Following healthy pregnancy by nuclear magnetic resonance(NMR)metabolic profiling of human urine.J Proteome Res,2013,12:969–979
39 Trivedi D K,Iles R K.HILIC-MS-based shotgun metabolomic profiling of maternal urine at 9–23 weeks of gestation-establishing the baseline changes in the maternal metabolome.Biomed Chromatogr,2015,29:240–245
40 Lenz E M,Bright J,Wilson I D,et al.A 1H NMR-based metabonomic study of urine and plasma samples obtained from healthy human subjects.J Pharmaceut Biomed Anal,2003,33:1103–1115
41 Saccenti E,Tenori L,Verbruggen P,et al.Of monkeys and men:a metabolomic analysis of static and dynamic urinary metabolic phenotypes in two species.PLoS ONE,2014,9:e106077
42 Kohler M,Franz S,Regeniter A,et al.Comparison of the urinary protein patterns of athletes by 2D-gel electrophoresis and mass spectrometrya a pilot study.Drug Test Anal,2009,1:382–386
43 Kohler M,Walpurgis K,Thomas A,et al.Effects of endurance exercise on the urinary proteome analyzed by 2-D PAGE and Orbitrap MS.Prot Clin Appl,2010,4:568–576
44 Pechlivanis A,Kostidis S,Saraslanidis P,et al.1H NMR-based metabonomic investigation of the effect of two different exercise sessions on the metabolic fingerprint of human urine.J Proteome Res,2010,9:6405–6416
45 Enea C,Seguin F,Petitpas-Mulliez J,et al.1H NMR-based metabolomics approach for exploring urinary metabolome modifications after acute and chronic physical exercise.Anal Bioanal Chem,2010,396:1167–1176
46 Neal C M,Hunter A M,Brennan L,et al.Six weeks of a polarized training-intensity distribution leads to greater physiological and performance adaptations than a threshold model in trained cyclists.J Appl Physiol,2013,114:461–471
47 Krug S,Kastenmüller G,Stückler F,et al.The dynamic range of the human metabolome revealed by challenges.FASEB J,2012,26:2607–2619
48 Mukherjee K,Edgett B A,Burrows H W,et al.Whole blood transcriptomics and urinary metabolomics to define adaptive biochemical pathways of high-intensity exercise in 50–60 year old masters athletes.PLoS ONE,2014,9:e92031
49 Sheedy J R,Gooley P R,Nahid A,et al.1H-NMR analysis of the human urinary metabolome in response to an 18-month multi-component exercise program and calcium-vitamin-D3 supplementation in older men.Appl Physiol Nutr Metab,2014,39:1294–1304
50 Daskalaki E,Blackburn G,Kalna G,et al.A study of the effects of exercise on the urinary metabolome using normalisation to individual metabolic output.Metabolites,2015,5:119–139
51 Airoldi L,Magagnotti C,Iannuzzi A R,et al.Effects of cigarette smoking on the human urinary proteome.Biochem Biophys Res Commun,2009,381:397–402
52 Haniff A N,Gam L H.Identification of urinary protein biomarkers for tobacco smoking.Biotech Appl Biochem,2016,63:266–272
53 Bouwman F G,de Roos B,Rubio-Aliaga I,et al.2D-electrophoresis and multiplex immunoassay proteomic analysis of different body fluids and cellular components reveal known and novel markers for extended fasting.BMC Med Genomics,2011,4:24
54 Alfadda A A,Turjoman A A,Moustafa A S,et al.A proteomic analysis of excreted and circulating proteins from obese patients following two different weight-loss strategies.Exp Biol Med(Maywood),2014,239:568–580
55 Rothwell J A,Fillatre Y,Martin J F,et al.New biomarkers of coffee consumption identified by the non-targeted metabolomic profiling of cohort study subjects.PLoS ONE,2014,9:e93474
56 Gibbons H,McNulty B A,Nugent A P,et al.A metabolomics approach to the identification of biomarkers of sugar-sweetened beverage intake.Am J Clin Nutr,2015,101:471–477
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