臺灣博碩士論文加值系統

慢性腎臟病的盛行率逐年上升，而暴露於鉛環境會增加罹患慢性腎臟病之風險。由於現今腎功能指標不足以診斷鉛誘導腎損傷，故相關生物標記仍需進一步被開發和研究。二甲雙胍（metformin，Met）為第二型糖尿病第一線用藥，過去研究指出可用於改善腎損傷，但詳細機轉仍須進一步探討。本研究首先以標靶式代謝體學探討二甲雙胍用於治療鉛誘導腎損傷之可能性，並透過非標靶式尿液代謝體學找尋鉛誘導腎損傷之早期生物標記，並探討不同劑量之二甲雙胍腎保護機轉之相關機轉。雄性Wistar大鼠以含鉛飲用水（250 ppm Pb(NO3)2）誘導腎損傷，而二甲雙胍經口投與50或100 mg/kg/d作為腎保護藥物，持續投與28天。本研究以NMR搭配多變量分析進行非標靶式尿液代謝體學研究，並將七個潛在的生物標記進行定量。研究結果顯示，250 ppm鉛誘導腎損傷於臨床生化檢驗並無明顯之變化，但腎組織於近端腎小管處有明顯損傷。相較於對照組，鉛損傷組大鼠之腎臟甲基乙二醛（methylglyoxal）（control vs. Pb, 36.40 ± 5.69 vs. 56.86 ± 17.47 μg/mg protein, p < 0.01）和尿中D-乳酸（D-lactate）（Pb vs. Pb+Met, 0.32 ± 0.13 vs. 0.68 ± 0.28 μmol/mg creatinine, p < 0.01）皆顯著性地上升。合併投與二甲雙胍（50 mg/kg/d）可顯著地降低腎臟甲基乙二醛（Pb vs. Pb+Met, 56.86 ± 17.47 vs. 39.91 ± 4.00 μg/mg protein, p < 0.05）和尿中D-乳酸（Pb vs. Pb+Met, 0.68 ± 0.28 vs. 0.32 ± 0.08 μmol/mg creatinine, p < 0.01），來延緩腎損傷。接著，尿液代謝體學中將七個潛在的代謝物進行定量分析，結果顯示除了尿中D-乳酸之外，尿中胍乙酸（guanidinoacecitc acid）（control vs. Pb, 19.35 ± 4.74 vs. 26.31 ± 5.40 μg/mg creatinine, p < 0.05）和δ-胺基乙醯丙酸（δ-aminolevulinic acid）（control vs. Pb, 0.55 ± 0.11 vs. 24.25 ± 6.55 μg/mg creatinine, p < 0.01）在鉛腎損傷下有顯著性地上升。合併投與二甲雙胍發現低劑量二甲雙胍之腎臟保護效果優於高劑量。本研究首次提出腎臟甲基乙二醛以及尿中D-乳酸、尿中胍乙酸以及δ-胺基乙醯丙可望成為早期鉛誘導腎損傷之生物標記，此外，透過標靶式以及非標靶式代謝體學亦發現尿中D-乳酸於鉛誘導腎損傷下有顯著性地上升。二甲雙胍腎保護效果主要透過降低甲基乙二醛及其代謝物D-乳酸來達到改善鉛誘導腎損傷。研究成果將可望應用於診斷早期鉛誘導腎損傷，了解二甲雙胍劑量對於延緩鉛誘導腎損傷之差異。根據研究結果推測，投與二甲雙胍（600 mg/day）於成人（60 kg）可能可有效地延緩低濃度鉛誘導之腎損傷，特別是早期且非高血糖之腎損傷。

The prevalence of chronic kidney disease is increased year by year. Heavy metal (Pb) is one of the environmental pollutant. Expose to Pb is one of the risk factor that leads to chronic kidney disease. Due to current biomarkers are not sensitive to diagnosis of Pb-induced renal injury, novel biomarkers need to be discovered. Metformin is first-line oral therapy for type II diabetic mellitus. Our studies demonstrated that metformin could attenuate renal injury, but mechanism of its action is need to be elucidated. First of all, we want to investigating the reno-protection of metformin effect on Pb-induced nephrotoxicty in rats with targeted metabolomics. Then, non-targeted urinary metabolomics is applied for discovery the early biomarkers of Pb-induced renal injury and investigating the mechanism of reno-protection of metformin. Male Wistar rats were received 250 ppm Pb(NO3)2 in drinking water, and orally administered metformin (50 or 100 mg/kg/d) for consecutive 28 days. Non-targeted urinary metabolomics were carried out with NMR coupled with multivariate analysis. The seven potential biomarkers were further quantification. The results showed that Pb induced renal injury at proximal tubule without alteration of clinical chemistry. Compared with the control group, renl methylglyoxal (36.40 ± 5.69 vs. 56.86 ± 17.47 μg/mg protein, p < 0.01) and urinary D-lactate (0.32 ± 0.13 vs. 0.68 ± 0.28 μmol/mg creatinine, p < 0.01) were significantly increased in Pb rats. After cotreated with metformin (50 mg/kg/d), renal injury were attenuated, and renal methylglyoxal (56.86 ± 17.47 vs. 39.91 ± 4.00 μg/mg protein, p < 0.05) and urinary D-lactate (0.68 ± 0.28 vs. 0.32 ± 0.08 μmol/mg creatinine, p < 0.01) were signficantly decreased compared with the Pb-treated group. After urinary metabolomics analysis, potential biomarkers were quantified. The results showed that urinary guanidinoacetic acid (19.35 ± 4.74 vs. 26.31 ± 5.40 μg/mg creatinine, p < 0.05), urinary δ-aminolevulinic acid (0.55 ± 0.11 vs. 24.25 ± 6.55 μg/mg creatinine, p < 0.01) and urinary D-lactate were significantly increased in the Pb group compared with the control group. After co-treated with metformin, low-dose metformin (50 mg/kg/d) had better renoprotective ability than high-dose (100 mg/kg/d) one. This is the first study demonstrating that renal methylglyoxal and urinary D-lactate, guanidinoacetic acid and δ-aminolevulinic acid are potential biomarkers of early diagnosis of Pb-induced renal injury. In addition, urinary D-lactate was signficantlty increased in Pb-induced nephrotixcity rats in both targeted and non-targeted metabolomics. The reno-protection of metformin is attributable to decrease methylglyoxal and its metabolite, D-lactate. Our study provides sensitive biomarkers to early diagnosis of low-level Pb-induced renal injury and reno-protective effect of metformin. Based on our results, we speculated that administration of metformin (600 mg/day) might possibly attenuate low-level Pb-induced renal injury in adults (60 kg), especially in the early stage of renal injury without hyperglycemia.

目錄
目錄 I
圖目錄 IV
表目錄 VI
附錄表 VII
縮寫表 VIII
摘要 XII
Abstract XIV
第一章 緒論 1
第二章 文獻回顧 4
2.1 代謝體學 4
2.2 甲基乙二醛 9
2.2.1 甲基乙二醛之來源 11
2.2.2 甲基乙二醛之代謝 12
2.2.3 甲基乙二醛之致病機轉與相關疾病 15
2.3 乳酸 16
2.3.1 乳酸來源 17
2.3.2 乳酸代謝與排泄 19
2.3.3 乳酸中毒與相關疾病 20
2.3.4 乳酸之分析方法 22
2.4 重金屬－鉛 24
2.4.1 鉛之吸收、分布、代謝及排泄 24
2.4.2 鉛誘導腎損傷之流行病學 24
2.4.3 鉛誘導腎損傷之相關機轉 25
2.4.3 鉛中毒之臨床特徵與診斷鉛誘導腎損傷之生物標記 26
2.4.4暴露於鉛之代謝體學研究 29
2.4.5臨床治療鉛中毒 30
2.5 二甲雙胍 32
2.5.1 二甲雙胍之藥物動力學 33
2.5.2 二甲雙胍之藥效動力學 34
2.5.3 二甲雙胍之乳酸中毒 34
2.5.4 二甲雙胍臨床應用 35
第三章 研究目的 37
第四章 研究材料與方法 38
4.1 研究材料 38
4.2 研究方法 42
4.2.1 動物實驗 42
4.2.2 生物檢品採樣與前處理 43
4.2.3 血液生化分析 43
4.2.4 腎臟蛋白質定量分析 43
4.2.5 尿蛋白定量分析 44
4.2.6 腎臟組織學量化評估 45
4.2.7 尿中肌酸酐定量分析 45
4.2.8 生物檢品之甲基乙二醛定量分析 46
4.2.9 生物檢品之D-與L-乳酸定量分析 49
4.2.10 腎臟與血清之乳酸脫氫酵素活性測定 53
4.2.11 尿液代謝體學分析 54
4.2.12 尿中N-acetyl--D-glucosaminidase定量分析 58
4.2.13 尿中δ-aminolevulinic acid定量分析 60
4.2.14 尿中Guanidinoacetic acid、Hippurica acid和Indoleacetic acid定量分析 63
4.2.15 統計分析 65
第五章 結果與討論 67
第一節 二甲雙胍對鉛誘導腎損傷大鼠之影響與標靶式代謝體學研究 67
5.1.1 實驗動物體重、飲水量和臨床生化指標之影響 67
5.1.2 腎組織病理學評估與量化 71
5.1.3 生物檢品之甲基乙二醛含量變化 71
5.1.4 生物檢品之D-和L-LA含量變化 75
5.1.5 腎臟與血清中乳酸脫氫酶活性之變化 75
5.1.6 討論 81
第二節 不同劑量之二甲雙胍對鉛誘導腎損傷大鼠之非標靶式尿液代謝體學 85
5.2.1 實驗動物體重、飲水量以及臨床生化指標之變化 85
5.2.2 腎臟與肝臟組織學與損傷量化分析 88
5.2.3 NMR-based尿液代謝體學搭配多變量分析之結果 91
5.2.4 驗證尿中潛在生物標記之含量變化 106
5.2.5 討論 113
第六章 結論 120
第七章 未來展望 120
參考文獻 122
附錄 147

圖目錄
Figure 1. Nephritis, nephritic syndrome and nephrosis ranked within ten of leading causes of death in Taiwan in 1994-2016. 1
Figure 2. Metabolomics events from 1980 onwards. 6
Figure 3. Publications of NMR- or MS-based metabolomics between 2002 to 2017. 7
Figure 4. The chemical structure of methylglyoxal. 11
Figure 5. The formation of methylglyoxal from glucose, triglyceride, amino acids, and β-hydroxybutyrate. 13
Figure 6. The metabolic pathways involved in MG detoxification. 14
Figure 7. The chemical structures of L- and D-lactate. 16
Figure 8. Methylglyoxal converts it into D-lactate through glyoxalase system. 17
Figure 9. The formation of L-lactate from pyruvate and L-alanine. 18
Figure 10. The structure of 2,1,3-benzoxadiazole backbone and derivatization reagent of NBD-PZ. 23
Figure 11. Blood Pb level and its related physiological functions in children and adults. 27
Figure 12. The structure of metformin. 32
Figure 13. Relevant structures for the metformin−methylglyoxal reaction. 36
Figure 14. Derivatization scheme of methylglyoxla with DDP. 47
Figure 15. Derivatization scheme of D- and L-lactate with NBD-PZ. 51
Figure 16. The stationary phase of Chiralpak AD-RH. 52
Figure 17. Schematic diagram for the enzymatic assay of NAG activity. 59
Figure 18. Derivatization scheme of δ-aminolevulinic acid with acetylacetone and formaldehyde 62
Figure 19. Metformin’s effect of final body weight and daily drinking water volume on Pb-induced nephrotoxicity rats. 68
Figure 20. Metformin’s effect of clinical chemistry on Pb-induced nephrotoxicity rats. 69
Figure 21. Metformin’s effect of urinalysis on Pb-induced nephrotoxicity rats. 70
Figure 22. Evaluation of renal architecture with hematoxylin and eosin stain and the sum of the tubulointerstitial histological score were obtained from rat kidneys. 72
Figure 23. Chromatograms of methylglyoxal from standard solution and biological samples. 73
Figure 24. Determination of methylglyoxal levels in rat urine, kidney and serum. 74
Figure 25. Chromatograms of D-, and L-lactate from standard solution using column-switching system. 76
Figure 26. Chromatograms of NBD-D,L-lactate and quantitative results from rat urine. 77
Figure 27. Chromatograms of NBD-D,L-lactate and quantitative results from rat serum. 78
Figure 28. Chromatograms of NBD-D,L-lactate and quantitative results from rat kidney. 79
Figure 29. Different doses of metformin’s effect of body weight and water intake on Pb-induced nephrotoxicity rats. 86
Figure 30. Metformin’s effect of renal histological examination on Pb-induced nephrotoxicity in rats. 89
Figure 31. Metformin’s effect of hepatic histological examination on Pb-induced toxicity in rats. 90
Figure 32. 1H-NMR spectra of urinary metabolomics in Pb-induced nephrotoxicity rats co-treated with metformin. 93
Figure 33. PCA of score plot and loading plot. 96
Figure 34. PLS-DA of score plot and loading plot. 97
Figure 35. PLS-DA of LOOCV and permutation test. 98
Figure 36. Pathway analysis. 104
Figure 37. The chemical structure of guanidinoacetic acid, hippuric acid and indoleacetic acid. 105
Figure 38. The chromatogram of δ-aminolevulinic acid in standard solution and rat urine. 108
Figure 39. Metformin’s effects on potential biomarkers of Pb-induced nephrotoxicity in rat urine. 110
Figure 40. Hypothesis of metformin’s effect on low-level Pb-induced nephrotoxicity in rats with metformin treatment. 119
Figure 41. Metformin’s effect of renal and urinary metabolites on low-level Pb-induced nephrotoxicity in rats with metformin treatment. 121

 
表目錄
Table 1. Comparison between the GC-MS, LC-MS and NMR-based metabolomics. 8
Table 2. The advantages and disadvantages of non-targeted and targeted metabolomics. 8
Table 3. The alteration of D- or L-lactate in different diseases. 21
Table 4. Current biomarkers of Pb-induced nephrotoxicity. 28
Table 5. Chelation therpay for symptomatic or asymptomatic patients 31
Table 6. List of selected multiple reaction monitoring parameters for each analyte and internal standard. 66
Table 7. Metformin’s effect on the lactate dehydrogenase (LDH) activity in Pb-induced nephrotoxic rats. 80
Table 8. Different doses of metformin’s effect of clinical chemistry and urinalysis on Pb-induced nephrotoxicity rats. 87
Table 9. The significant alteration peaks in 1H-NMR spectra between the five groups. 94
Table 10. Identified metabolites from 1D and 2D-NMR spectra. 99
Table 11. The pathway analysis of significant altered metabolites. 104
Table 12. Metformin’s effects on potential biomarkers of Pb-induced nephrotoxicity in rat urine. 107
Table 13. Precision and accuracy of determination of δ-aminolevulinic acid in rat urine using HPLC with fluorescence detector. 109
Table 14. Precision and accuracy of determination of guanidinoacetic acid, indoleacetic acid, and hippuric acid in standard solution using LC-MS/MS. 111
Table 15. Precision, accuracy, recovery and matrix effect for determination of guanidinoacetic acid, indoleacetic acid, and hippuric acid in rat urine using LC-MS/MS. 112

Aatsinki, S. M., Buler, M., Salomäki, H., Koulu, M., Pavek, P., & Hakkola, J. (2014). Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions. British Journal of Pharmacology, 171(9), 2351-2363.
Adeva-Andany, M., Lopez-Ojen, M., Funcasta-Calderon, R., Ameneiros-Rodriguez, E., Donapetry-Garcia, C., Vila-Altesor, M., & Rodriguez-Seijas, J. (2014). Comprehensive review on lactate metabolism in human health. Mitochondrion, 17, 76-100.
Agadjanyan, Z. S., Dmitriev, L. F., & Dugin, S. F. (2005). A new role of phosphoglucose isomerase. Involvement of the glycolytic enzyme in aldehyde metabolism. Biochemistry (Moscow), 70(11), 1251-1255.
Alarcon, W. A. (2016). Elevated Blood Lead Levels Among Employed Adults - United States, 1994-2013. MMWR Morb Mortal Wkly Rep, 63(55), 59-65.
Allaman, I., Bélanger, M., & Magistretti, P. J. (2015). Methylglyoxal, the dark side of glycolysis. Frontiers in Neuroscience, 9(FEB).
Andrade, F., Rodriguez-Soriano, J., Prieto, J. A., Aguirre, M., Ariceta, G., Lage, S., Azcona, I., Prado, C., Sanjurjo, P., & Aldamiz-Echevarria, L. (2011). Methylation cycle, arginine-creatine pathway and asymmetric dimethylarginine in paediatric renal transplant. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association 26(1), 328-336.
Andrade, V., Mateus, M. L., Batoreu, M. C., Aschner, M., & dos Santos, A. P. (2013). Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese. Neurotoxicology, 38, 33-41.
Angeloni, C., Zambonin, L., & Hrelia, S. (2014). Role of methylglyoxal in Alzheimer''s disease. BioMed Research International, 2014, 238485.
Ansari, M. A., Maayah, Z. H., Bakheet, S. A., El-Kadi, A. O., & Korashy, H. M. (2013). The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model. Toxicology, 306, 40-49.
Araki, S., Aono, H., Yokoyama, K., & Murata, K. (1986). Filterable plasma concentration, glomerular filtration, tubular balance, and renal clearance of heavy metals and organic substances in metal workers. Archives of Environmental Health, 41(4), 216-221.
Aschenbrenner, D. S. (2016). The FDA Revises Restrictions on Metformin Use in Kidney Impairment. Am J Nurs, 116(8), 22-23.
ATSDR. (2017). Lead Toxicity. from https://www.atsdr.cdc.gov/csem/csem.asp?csem=34&po=0
Baba, S. P., Hellmann, J., Srivastava, S., & Bhatnagar, A. (2011). Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE). Chemico-Biological Interactions, 191(1-3), 357-363.
Bachmakov, I., Glaeser, H., Fromm, M. F., & König, J. (2008). Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters. Diabetes, 57(6), 1463-1469.
Bailey, C. J., & Day, C. (2004). Metformin: its botanical background. Practical Diabetes International, 21(3), 115-117.
Bakker, J. (1999). Blood lactate levels. Current Opinion in Critical Care, 5(3), 234.
Barbier, O., Jacquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the kidney. Nephron-Physiology, 99(4), p105-p110.
Barker, M., & Rayens, W. (2003). Partial least squares for discrimination. Journal of Chemometrics, 17(3), 166-173.
Barskova, V. G., Eliseev, M. S., Nasonov, E. L., Volkov, A. V., Tsapina, T. N., Zilov, A. V., Iakunina, I. A., Il''inykh, E. V., & Kudaeva, F. M. (2005). [Use of metformin (siofor) in patients with gout and insulin resistance (pilot 6-month results)]. Terapevticheskii Arkhiv, 77(12), 44-49.
Bartel, J., Krumsiek, J., & Theis, F. J. (2013). Statistical methods for the analysis of high-throughput metabolomics data. Computational and Structural Biotechnology Journal, 4, e201301009.
Bax, A., & Davis, D. G. (1985). MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy. Journal of Magnetic Resonance (1969), 65(2), 355-360.
Bechara, E. J. H. (1996). Oxidative stress in acute intermittent porphyria and lead poisoning may be triggered by 5-aminolevulinic acid. Brazilian Journal of Medical and Biological Research, 29(7), 841-851.
Beisswenger, B. G., Delucia, E. M., Lapoint, N., Sanford, R. J., & Beisswenger, P. J. (2005). Ketosis leads to increased methylglyoxal production on the Atkins diet. Annals of the New York Academy of Sciences, 1043, 201-210.
Beisswenger, P. J., Howell, S. K., Touchette, A. D., Lal, S., & Szwergold, B. S. (1999). Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes, 48(1), 198-202.
Benton, C. M., Couchman, L., Marsden, J. T., Rees, D. C., Moniz, C., & Lim, C. K. (2012). Direct and simultaneous determination of 5-aminolaevulinic acid and porphobilinogen in urine by hydrophilic interaction liquid chromatography-electrospray ionisation/tandem mass spectrometry. Biomedical Chromatography, 26(8), 1033-1040.
Bodmer, M., Meier, C., Krahenbuhl, S., Jick, S. S., & Meier, C. R. (2008). Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care, 31(11), 2086-2091.
Bouatra, S., Aziat, F., Mandal, R., Guo, A. C., Wilson, M. R., Knox, C., Bjorndahl, T. C., Krishnamurthy, R., Saleem, F., Liu, P., Dame, Z. T., Poelzer, J., Huynh, J., Yallou, F. S., Psychogios, N., Dong, E., Bogumil, R., Roehring, C., & Wishart, D. S. (2013). The Human Urine Metabolome. PLOS ONE, 8(9), e73076.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248-254.
Brandt, R. B., Siegel, S. A., Waters, M. G., & Bloch, M. H. (1980). Spectrophotometric assay for D-(-)-lactate in plasma. Analytical Biochemistry, 102(1), 39-46.
Breton, J., Daniel, C., Vignal, C., Body-Malapel, M., Garat, A., Plé, C., & Foligné, B. (2016). Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecology. Scientific Reports, 6, 19200.
Brewster, U. C., & Perazella, M. A. (2004). A review of chronic lead intoxication: an unrecognized cause of chronic kidney disease. Am J Med Sci, 327(6), 341-347.
Caglayan, F., Cakmak, M., Caglayan, O., & Cavusoglu, T. (2003). Plasma D-lactate levels in diagnosis of appendicitis. Journal of Investigative Surgery 16(4), 233-237.
Cano, N. (2002). Bench-to-bedside review: glucose production from the kidney. Crit Care, 6(4), 317-321.
Capati, A., Ijare, O. B., & Bezabeh, T. (2017). Diagnostic Applications of Nuclear Magnetic Resonance-Based Urinary Metabolomics. Magn Reson Insights, 10, 1178623x17694346.
Carpenter, L., & Halestrap, A. P. (1994). The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich-Lettre tumour cells studied with the intracellular pH indicator BCECF. Biochemical Journal, 304(Pt 3), 751-760.
Casazza, J. P., Felver, M. E., & Veech, R. L. (1984). The metabolism of acetone in rat. Journal of Biological Chemistry, 259(1), 231-236.
Case, E. M., & Cook, R. P. (1931). The occurrence of pyruvic acid and methylglyoxal in muscle metabolism. Biochemical Journal, 25(4), 1319-1335.
Chen, K. H., Lin, J. L., Lin-Tan, D. T., Hsu, H. H., Hsu, C. W., Hsu, K. H., & Yen, T. H. (2012). Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation 60(4), 530-538.
Chou, C. K., Chen, S. M., Li, Y. C., Huang, T. C., & Lee, J. A. (2015). Low-molecular-weight chitosan scavenges methylglyoxal and N (epsilon)-(carboxyethyl)lysine, the major factors contributing to the pathogenesis of nephropathy. SpringerPlus, 4, 312.
Chou, C. K., Lee, Y. T., Chen, S. M., Hsieh, C. W., Huang, T. C., Li, Y. C., & Lee, J. A. (2015). Elevated urinary D-lactate levels in patients with diabetes and microalbuminuria. Journal of Pharmaceutical and Biomedical Analysis, 116, 65-70.
Chou, C. K., Li, Y. C., Chen, S. M., Shih, Y. M., & Lee, J. A. (2015). Chitosan prevents gentamicin-induced nephrotoxicity via a carbonyl stress-dependent pathway. BioMed Research International, 2015.
Christensen, M. M., Brasch-Andersen, C., Green, H., Nielsen, F., Damkier, P., Beck-Nielsen, H., & Brosen, K. (2011). The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenetics and genomics, 21(12), 837-850.
Clift, F. P., & Cook, R. P. (1932). A method of determination of some biologically important aldehydes and ketones, with special reference to pyruvic acid and methylglyoxal. Biochemical Journal, 26(6), 1788-1799.
Conger, J. D. (1990). Acute uric acid nephropathy. Med Clin North Am, 74(4), 859-871.
Connor, H., Woods, H. F., & Ledingham, J. G. (1983). Comparison of the kinetics and utilisation of D(-)-and L(+)-sodium lactate in normal man. Annals of nutrition & metabolism, 27(6), 481-487.
Cramer, K., Goyer, R. A., Jagenburg, R., & Wilson, M. H. (1974). Renal ultrastructure, renal function, and parameters of lead toxicity in workers with different periods of lead exposure. British Journal of Industrial Medicine, 31(2), 113-127.
Dakin, H. D., & Dudley, H. W. (1913). An Enzyme concerned with the formation of hydroxy acids from ketonic aldehydes. Journal of Biological Chemistry, 14(2), 155-157.
Dangprapai, Y., & Wright, S. H. (2011). Interaction of H + with the extracellular and intracellular aspects of hMATE1. American Journal of Physiology - Renal Physiology, 301(3), F520-F528.
Dawson, D. M., Goodfriend, T. L., & Kaplan, N. O. (1964). Lactic dehydrogenases: functions of the two types rates of synthesis of the two major forms can be correlated with metabolic differentiation. Science (New York, N.Y.) 143(3609), 929-933.
De Broe, M. E., Kajbaf, F., & Lalau, J. D. (2018). Renoprotective Effects of Metformin. Nephron, 138(4), 261-274.
Deng, Y., & Yu, P. H. (1999). Simultaneous determination of formaldehyde and methylglyoxal in urine: involvement of semicarbazide-sensitive amine oxidase-mediated deamination in diabetic complications. J Chromatogr Sci, 37(9), 317-322.
Desai, K. M., Chang, T., Wang, H., Banigesh, A., Dhar, A., Liu, J., Untereiner, A., & Wu, L. (2010). Oxidative stress and aging: is methylglyoxal the hidden enemy? Canadian Journal of Physiology and Pharmacology, 88(3), 273-284.
Dudka, I., Kossowska, B., Senhadri, H., Latajka, R., Hajek, J., Andrzejak, R., Antonowicz-Juchniewicz, J., & Gancarz, R. (2014). Metabonomic analysis of serum of workers occupationally exposed to arsenic, cadmium and lead for biomarker research: a preliminary study. Environ Int, 68, 71-81.
Dunn, W. B., Broadhurst, D., Ellis, D. I., Brown, M., Halsall, A., O''Hagan, S., Spasic, I., Tseng, A., & Kell, D. B. (2008). A GC-TOF-MS study of the stability of serum and urine metabolomes during the UK Biobank sample collection and preparation protocols. International Journal of Epidemiology 37 Suppl 1, i23-30.
Duong, J. K., Roberts, D. M., Furlong, T. J., Kumar, S. S., Greenfield, J. R., Kirkpatrick, C. M., Graham, G. G., Williams, K. M., & Day, R. O. (2012). Metformin therapy in patients with chronic kidney disease. Diabetes Obes Metab, 14(10), 963-965.
Edelstein, C. L. (2008). Biomarkers of acute kidney injury. Advances in Chronic Kidney Disease, 15(3), 222-234.
Eikawa, S., Nishida, M., Mizukami, S., Yamazaki, C., Nakayama, E., & Udono, H. (2015). Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proceedings of the National Academy of Sciences, 112(6), 1809-1814.
Eisenhardt, S., Schwarzmann, N., Henschel, V., Germeyer, A., von Wolff, M., Hamann, A., & Strowitzki, T. (2006). Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial. The Journal of Clinical Endocrinology and Metabolism, 91(3), 946-952.
Ekstrom, N., Schioler, L., Svensson, A. M., Eeg-Olofsson, K., Miao Jonasson, J., Zethelius, B., Cederholm, J., Eliasson, B., & Gudbjornsdottir, S. (2012). Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open, 2(4).
El-Mir, M. Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000). Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. Journal of Biological Chemistry, 275(1), 223-228.
Ellis, J. K., Athersuch, T. J., Thomas, L. D. K., Teichert, F., Pérez-Trujillo, M., Svendsen, C., Spurgeon, D. J., Singh, R., Järup, L., Bundy, J. G., & Keun, H. C. (2012). Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population. BMC Medicine, 10(1), 61.
Emwas, A.-H. M., Salek, R. M., Griffin, J. L., & Merzaban, J. (2013). NMR-based metabolomics in human disease diagnosis: applications, limitations, and recommendations. Metabolomics, 9(5), 1048-1072.
Eriksson L, Byrne T, Johansson E, Trygg J, & C, W. (2013). Multi- and Megavariate Data Analysis Basic Principles and Applications (3st ed.). Malmö: Umetrics Academy.
Espinosa-Mansilla, A., Durán-Merás, I., Cañada, F. C., & Márquez, M. P. (2007). High-performance liquid chromatographic determination of glyoxal and methylglyoxal in urine by prederivatization to lumazinic rings using in serial fast scan fluorimetric and diode array detectors. Analytical Biochemistry, 371(1), 82-91.
Evans, M., & Elinder, C. G. (2011). Chronic renal failure from lead: myth or evidence-based fact? Kidney International, 79(3), 272-279.
Evenepoel, P., Meijers, B. K., Bammens, B. R., & Verbeke, K. (2009). Uremic toxins originating from colonic microbial metabolism. Kidney Int Suppl(114), S12-19.
Ewaschuk, J. B., Naylor, J. M., & Zello, G. A. (2005). D-lactate in human and ruminant metabolism. Journal of Nutrition, 135(7), 1619-1625.
Flick, M. J., & Konieczny, S. F. (2002). Identification of putative mammalian D-lactate dehydrogenase enzymes. Biochemical and Biophysical Research Communications, 295(4), 910-916.
Flora, S. J., Bhattacharya, R., & Vijayaraghavan, R. (1995). Combined therapeutic potential of meso-2,3-dimercaptosuccinic acid and calcium disodium edetate on the mobilization and distribution of lead in experimental lead intoxication in rats. Fundam Appl Toxicol, 25(2), 233-240.
Flora, S. J. S., & Pachauri, V. (2010). Chelation in Metal Intoxication. International Journal of Environmental Research and Public Health, 7(7), 2745-2788.
Fujioka, K., & Shibamoto, T. (2006). Determination of toxic carbonyl compounds in cigarette smoke. Environmental Toxicology and Chemistry, 21(1), 47-54.
Fukushima, T., Lee, J. A., Korenaga, T., Ichihara, H., Kato, M., & Imai, K. (2001). Simultaneous determination of D-lactic acid and 3-hydroxybutyric acid in rat plasma using a column-switching HPLC with fluorescent derivatization with 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ). Biomedical Chromatography, 15(3), 189-195.
Gavaghan, C. L., Holmes, E., Lenz, E., Wilson, I. D., & Nicholson, J. K. (2000). An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk:ApfCD mouse. FEBS Letters, 484(3), 169-174.
Gladden, L. B. (1989). Lactate uptake by skeletal muscle. Exerc Sport Sci Rev, 17, 115-155.
Glinghammar, B., Rafter, I., Lindstrom, A. K., Hedberg, J. J., Andersson, H. B., Lindblom, P., Berg, A. L., & Cotgreave, I. (2009). Detection of the mitochondrial and catalytically active alanine aminotransferase in human tissues and plasma. Int J Mol Med, 23(5), 621-631.
Gomes, R. A., Vicente Miranda, H., Silva, M. S., Graça, G., Coelho, A. V., Ferreira, A. E., Cordeiro, C., & Freire, A. P. (2006). Yeast protein glycation in vivo by methylglyoxal: Molecular modification of glycolytic enzymes and heat shock proteins. FEBS Journal, 273(23), 5273-5287.
Gong, L., Goswami, S., Giacomini, K. M., Altman, R. B., & Klein, T. E. (2012). Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics, 22(11), 820-827.
Gowda, G. A., & Djukovic, D. (2014). Overview of mass spectrometry-based metabolomics: opportunities and challenges. Methods in Molecular Biology, 1198, 3-12.
Gowda, S., Desai, P. B., Hull, V. V., Math, A. A., Vernekar, S. N., & Kulkarni, S. S. (2009). A review on laboratory liver function tests. Pan Afr Med J, 3, 17.
Graham, G. G., Punt, J., Arora, M., Day, R. O., Doogue, M. P., Duong, J., Furlong, T. J., Greenfield, J. R., Greenup, L. C., Kirkpatrick, C. M., Ray, J. E., Timmins, P., & Williams, K. M. (2011). Clinical Pharmacokinetics of Metformin. Clinical Pharmacokinetics, 50(2), 81-98.
Gu, L., Wang, X., Zhang, Y., Jiang, Y., Lu, H., Bi, K., & Chen, X. (2014). Determination of 12 potential nephrotoxicity biomarkers in rat serum and urine by liquid chromatography with mass spectrometry and its application to renal failure induced by Semen Strychni. Journal of Separation Science, 37(9-10), 1058-1066.
Hai-Lei, M., Min, X., Bin, W., Hui-Min, W., Xiao-Ming, D., & Dong-Hai, L. (2007). Evaluation of Filtering Effects of Orthogonal Signal Correction on Metabonomic Analysis of Healthy Human Serum 1H NMR Spectra. Acta Chimica Sinica, 65(2), 152-158.
Halperin, M. L., & Kamel, K. S. (1996). D-lactic acidosis: turning sugar into acids in the gastrointestinal tract. Kidney International, 49(1), 1-8.
Henry, H., Marmy Conus, N., Steenhout, P., Beguin, A., & Boulat, O. (2012). Sensitive determination of D-lactic acid and L-lactic acid in urine by high-performance liquid chromatography-tandem mass spectrometry. Biomedical Chromatography, 26(4), 425-428.
Hippisley-Cox, J., & Coupland, C. (2016). Diabetes treatments and risk of amputation, blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia: open cohort study in primary care. BMJ (Clinical research ed.), 352, i1450.
Hocher, B., & Adamski, J. (2017). Metabolomics for clinical use and research in chronic kidney disease. Nat Rev Nephrol, 13(5), 269-284.
Honek, J. F. (2015). Glyoxalase biochemistry. Biomol Concepts, 6(5-6), 401-414.
Hong, C. D., Hanenson, I. B., Lerner, S., Hammond, P. B., Pesce, A. J., & Pollak, V. E. (1980). Occupational exposure to lead: Effects on renal function. Kidney International, 18(4), 489-494.
Hsu, C. C., Hwang, S. J., Wen, C. P., Chang, H. Y., Chen, T., Shiu, R. S., Horng, S. S., Chang, Y. K., & Yang, W. C. (2006). High prevalence and low awareness of CKD in Taiwan: a study on the relationship between serum creatinine and awareness from a nationally representative survey. American Journal of Kidney Diseases, 48(5), 727-738.
Hsu, C. C., Wahlqvist, M. L., Lee, M. S., & Tsai, H. N. (2011). Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. Journal of Alzheimers Disease, 24(3), 485-493.
Huang, T. C., Chen, S. M., Li, Y. C., & Lee, J. A. (2013). Urinary D-lactate levels reflect renal function in aristolochic acid-induced nephropathy in mice. Biomedical Chromatography, 27(9), 1100-1106.
Huang, T. C., Chen, S. M., Li, Y. C., & Lee, J. A. (2014). Increased renal semicarbazide-sensitive amine oxidase activity and methylglyoxal levels in aristolochic acid-induced nephrotoxicity. Life Sciences, 114(1), 4-11.
Huang, Y. S., Li, Y. C., Tsai, P. Y., Lin, C. E., Chen, C. M., Chen, S. M., & Lee, J. A. (2017). Accumulation of methylglyoxal and D-lactate in Pb-induced nephrotoxicity in rats. Biomedical Chromatography, 31(5).
Hung, A. M., Roumie, C. L., Greevy, R. A., Liu, X., Grijalva, C. G., Murff, H. J., & Griffin, M. R. (2013). Kidney function decline in metformin versus sulfonylurea initiators: assessment of time-dependent contribution of weight, blood pressure, and glycemic control. Pharmacoepidemiology and Drug Safety, 22(6), 623-631.
Hung, S. C., Chang, Y. K., Liu, J. S., Kuo, K. L., Chen, Y. H., Hsu, C. C., & Tarng, D. C. (2015). Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol, 3(8), 605-614.
Inoue, Y., Shinka, T., Ohse, M., Ikawa, H., & Kuhara, T. (2006). Application of optical isomer analysis by diastereomer derivatization GC/MS to determine the condition of patients with short bowel syndrome. Journal of Chromatography B, 838(1), 37-42.
Inzucchi, S. E., Lipska, K. J., Mayo, H., Bailey, C. J., & McGuire, D. K. (2014). Metformin in patients with type 2 diabetes and kidney disease: a systematic review. The Journal of the American Medical Association, 312(24), 2668-2675.
Irshaid, F., Mansi, K., Bani-Khaled, A., & Aburjia, T. (2012). Hepatoprotetive, Cardioprotective and Nephroprotective Actions of Essential Oil Extract of Artemisia sieberi in Alloxan Induced Diabetic Rats. Iranian Journal of Pharmaceutical Research, 11(4), 1227-1234.
Irving, B. A., & Spielmann, G. (2016). Does Citrulline Sit at the Nexus of Metformin''s Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes? Diabetes, 65(12), 3537-3540.
Ito, S., Kusuhara, H., Yokochi, M., Toyoshima, J., Inoue, K., Yuasa, H., & Sugiyama, Y. (2012). Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther, 340(2), 393-403.
Kajbaf, F., & Lalau, J. D. (2013). The criteria for metformin-associated lactic acidosis: the quality of reporting in a large pharmacovigilance database. Diabet Med, 30(3), 345-348.
Kajiwara, M., Hara, K., Takatori, K., & Matsumoto, K. (1993). Revised structure of a delta-aminolevulinic acid derivative. Clinical Chemistry, 39(9), 1867-1871.
Kalapos, M. P. (1999). Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicology Letters, 110(3), 145-175.
Kang, H. G., Jeong, S. H., Cho, M. R., Cho, J. H., & Bischoff, K. (2009). Time-dependent changes in lead and delta-aminolevulinic acid after subchronic lead exposure in rats. Human & Experimental Toxicology, 28(10), 647-654.
Kay, L., Keifer, P., & Saarinen, T. (1992). Pure absorption gradient enhanced heteronuclear single quantum correlation spectroscopy with improved sensitivity. Journal of the American Chemical Society, 114(26), 10663-10665.
Khalil-Manesh, F., Gonick, H. C., & Cohen, A. H. (1993). Experimental model of lead nephropathy. III. Continuous low-level lead administration. Archives of Environmental Health, 48(4), 271-278.
Khattab, S., Mohsen, I. A., Foutouh, I. A., Ramadan, A., Moaz, M., & Al-Inany, H. (2006). Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecological Endocrinology, 22(12), 680-684.
Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Kohler, A., Glossmann, H., Schneider, R., Sutherland, C., & Schweiger, S. (2010). Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21830-21835.
Kiersztan, A., Modzelewska, A., Jarzyna, R., Jagielska, E., & Bryla, J. (2002). Inhibition of gluconeogenesis by vanadium and metformin in kidney-cortex tubules isolated from control and diabetic rabbits. Biochemical Pharmacology, 63(7), 1371-1382.
Kinsky, O. R., Hargraves, T. L., Anumol, T., Jacobsen, N. E., Dai, J., Snyder, S. A., Monks, T. J., & Lau, S. S. (2016). Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans. Chemical Research in Toxicology, 29(2), 227-234.
Kisfalvi, K., Eibl, G., Sinnett-Smith, J., & Rozengurt, E. (2009). Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Research, 69(16), 6539-6545.
Klaassen, C.D. Heavy metals and heavy metal antagonists. In The Pharmacological Basis of Therapeutics; Goodman, L., Gilman, A., Eds.; McGraw Hill, Medical Publishing Division: New York, NY, USA, 2006; pp. 1825-1872.Kodama, S., Yamamoto, A., Matsunaga, A., Soga, T., & Minoura, K. (2000). Direct chiral resolution of lactic acid in food products by capillary electrophoresis. Journal of Chromatography A, 875(1–2), 371-377.
Kondoh, Y., Kawase, M., Kawakami, Y., & Ohmori, S. (1992). Concentrations of D-lactate and its related metabolic intermediates in liver, blood, and muscle of diabetic and starved rats. Research in Experimental Medicine. Zeitschrift Fur Die Gesamte Experimentelle Medizin Einschliesslich Experimenteller Chirurgie, 192(6), 407-414.
Koritzinsky, M. (2015). Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy. International Journal of Radiation Oncology, Biology, Physics, 93(2), 454-464.
Kosnett, M. J., Wedeen, R. P., Rothenberg, S. J., Hipkins, K. L., Materna, B. L., Schwartz, B. S., Hu, H., & Woolf, A. (2007). Recommendations for Medical Management of Adult Lead Exposure. Environmental Health Perspectives, 115(3), 463-471.
Krishnan, E., Lingala, B., & Bhalla, V. (2012). Low-level lead exposure and the prevalence of gout: An observational study. Annals of Internal Medicine, 157(4), 233-241.
Kruk, J., Doskocz, M., Jodłowska, E., Zacharzewska, A., Łakomiec, J., Czaja, K., & Kujawski, J. (2017). NMR Techniques in Metabolomic Studies: A Quick Overview on Examples of Utilization. Applied Magnetic Resonance, 48(1), 1-21.
Kuo, H. W., Tsai, S. S., Tiao, M. M., & Yang, C. Y. (2007). Epidemiological features of CKD in Taiwan. American Journal of Kidney Diseases, 49(1), 46-55.
Kuwagaki, Y., & Sudo, J. (1989). Interrelation of urinary and plasma levels of guanidinoacetic acid with alteration in renal activity of glycine amidinotransferase in acute renal failure rats. Chem Pharm Bull (Tokyo), 37(3), 781-784.
Lalau, J. D., Vermersch, A., Hary, L., Andrejak, M., Isnard, F., & Quichaud, J. (1990). Type 2 diabetes in the elderly: an assessment of metformin (metformin in the elderly). International journal of clinical pharmacology, therapy, and toxicology, 28(8), 329-332.
Langer, S., Kreutz, R., & Eisenreich, A. (2016). Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions. Journal of Nephrology, 29(6), 765-773.
Lauwerys, R., Buchet, J. P., Roels, H. A., & Materne, D. (1974). Relationship between urinary delta-aminolevulinic acid excretion and the inhibition of red cell delta-aminolevulinate dehydratase by lead. Clinical Toxicology, 7(4), 383-388.
Le Bras, G., & Garel, J. R. (1991). Properties of D-lactate dehydrogenase from Lactobacillus bulgaricus: a possible different evolutionary origin for the D- and L-lactate dehydrogenases. FEMS Microbiol Lett, 63(1), 89-93.
Lee, H., & Ko, G. (2014). Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol, 80(19), 5935-5943.
Lee, J. A., Tsai, Y. C., Chen, H. Y., Wang, C. C., Chen, S. M., Fukushima, T., & Imai, K. (2005). Fluorimetric determination of D-lactate in urine of normal and diabetic rats by column-switching high-performance liquid chromatography. Analytica Chimica Acta, 534(2), 185-191.
Li, C.-Y., Song, H.-T., Wang, X.-X., Wan, Y.-Y., Ding, X.-S., Liu, S.-J., Dai, G.-L., Liu, Y.-H., & Ju, W.-Z. (2017). Urinary metabolomics reveals the therapeutic effect of HuangQi Injections in cisplatin-induced nephrotoxic rats. Scientific Reports, 7(1), 3619.
Li, M., Wang, B., Zhang, M., Rantalainen, M., Wang, S., Zhou, H., Zhang, Y., Shen, J., Pang, X., Zhang, M., Wei, H., Chen, Y., Lu, H., Zuo, J., Su, M., Qiu, Y., Jia, W., Xiao, C., Smith, L. M., Yang, S., Holmes, E., Tang, H., Zhao, G., Nicholson, J. K., Li, L., & Zhao, L. (2008). Symbiotic gut microbes modulate human metabolic phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 2117-2122.
Li, Y. C., Shih, Y. M., & Lee, J. A. (2013). Gentamicin caused renal injury deeply related to methylglyoxal and Ne-(carboxyethyl)lysine (CEL). Toxicology Letters, 219(1), 85-92.
Li, Y. C., Tsai, S. H., Chen, S. M., Chang, Y. M., Huang, T. C., Huang, Y. P., Chang, C. T., & Lee, J. A. (2012). Aristolochic acid-induced accumulation of methylglyoxal and N ε-(carboxymethyl)lysine: An important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy. Biochemical and Biophysical Research Communications, 423(4), 832-837.
Lin, J. L., Lin-Tan, D. T., Hsu, K. H., & Yu, C. C. (2003). Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. The New England Journal of Medicine, 348(4), 277-286.
Lin, M. H., Chen, H. Y., Liao, T. H., Huang, T. C., Chen, C. M., & Lee, J. A. (2011). Determination of time-dependent accumulation of D-lactate in the streptozotocin-induced diabetic rat kidney by column-switching HPLC with fluorescence detection. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 879(29), 3214-3219.
Linko-Löppönen, S. (1986). Fluorometric measurement of urinary N-acetyl-β-D-glucosaminidase and its correlation to uremia. Clinica Chimica Acta, 160(2), 123-127.
Liu, C.-M., Ma, J.-Q., & Sun, Y.-Z. (2012). Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. Toxicology and Applied Pharmacology, 258(3), 330-342.
Liu, G., Wang, Z. K., Wang, Z. Y., Yang, D. B., Liu, Z. P., & Wang, L. (2016). Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead. Archives of Toxicology, 90(5), 1193-1209.
Liu, Y., Chen, H., Lu, J., Jiang, Y., Yang, R., Gao, S., Dong, X., & Chen, W. (2017). Urinary metabolomics of complete Freund''s adjuvant-induced hyperalgesia in rats. Biomedical Chromatography, 31(6).
Loghman-Adham, M. (1997). Renal Effects of Environmental and Occupational Lead Exposure. Environmental Health Perspectives, 105(9), 928-938.
Luke, R. G. (1981). Uremia and the BUN. The New England Journal of Medicine, 305(20), 1213-1215.
Luo, Q., Wang, S., Sun, L.-N., & Wang, H. (2017). Metabolic profiling of root exudates from two ecotypes of Sedum alfredii treated with Pb based on GC-MS. Scientific Reports, 7, 39878.
Mack, D. R. (2004). D(-)-lactic acid-producing probiotics, D(-)-lactic acidosis and infants. Canadian Journal of Gastroenterology, 18(11), 671-675.
Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., Jurczak, M. J., Camporez, J.-P., Lee, H.-Y., Cline, G. W., Samuel, V. T., Kibbey, R. G., & Shulman, G. I. (2014). Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature, 510, 542.
Marescau, B., Nagels, G., Possemiers, I., De Broe, M. E., Becaus, I., Billiouw, J. M., Lornoy, W., & De Deyn, P. P. (1997). Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism: Clinical and Experimental
46(9), 1024-1031.
Marsilio, R., Dall''Amico, R., Giordano, G., Murer, L., Montini, G., Ros, M., Bacelle, L., Plebani, M., Dussini, N., & Zacchello, G. (1999). Rapid determination of creatinine in serum and urine by ion-pair high-performance liquid chromatography. International Journal of Clinical and Laboratory Research, 29(3), 103-109.
Martinez-Alfaro, M., Ramirez-Garcia, G., Gutierrez-Granados, S., Alcaraz-Contreras, Y., Gallegos-Corona, M. A., de Larrea, G. Z., & Carabez-Trejo, A. (2013). Melatonin attenuates the effects of sub-acute administration of lead on kidneys in rats without altering the lead-induced reduction in nitric oxide. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 27(4), 364-369.
Mason, L. H., Harp, J. P., & Han, D. Y. (2014). Pb neurotoxicity: neuropsychological effects of lead toxicity. BioMed Research International, 2014, 840547.
Masterjohn, C., Mah, E., Park, Y., Pei, R., Lee, J., Manautou, J. E., & Bruno, R. S. (2013). Acute glutathione depletion induces hepatic methylglyoxal accumulation by impairing its detoxification to D-lactate. Exp Biol Med (Maywood), 238(4), 360-369.
Matafome, P., Rodrigues, T., Sena, C., & Seica, R. (2017). Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises. Medicinal Research Reviews, 37(2), 368-403.
Matafome, P., Sena, C., & Seica, R. (2013). Methylglyoxal, obesity, and diabetes. Endocrine, 43(3), 472-484.
McKinney, G. R., & Gocke, D. J. (1956). Determination of glyoxalase activity. Journal of Biological Chemistry, 219(2), 605-610.
McLachlin, J. R., Goyer, R. A., & Cherian, M. G. (1980). Formation of lead-induced inclusion bodies in primary rat kidney epithelial cell cultures: Effect of actinomycin D and cycloheximide. Toxicology and Applied Pharmacology, 56(3), 418-431.
McLellan, A. C., Phillips, S. A., & Thornalley, P. J. (1992). Fluorimetric assay of D-lactate. Analytical Biochemistry, 206(1), 12-16.
Miao, P., Sheng, S., Sun, X., Liu, J., & Huang, G. (2013). Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life, 65(11), 904-910.
Minematsu, T., & Giacomini, K. M. (2011). Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Molecular Cancer Therapeutics, 10(3), 531-539.
Miyauchi, S., Gopal, E., Fei, Y. J., & Ganapathy, V. (2004). Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. The Journal of Biological Chemistry, 279(14), 13293-13296.
Moree-Testa, P., & Saint-Jalm, Y. (1981). Determination of α-dicarbonyl compounds in cigarette smoke. Journal of Chromatography A, 217(Supplement C), 197-208.
Mortada, W. I., Sobh, M. A., El-Defrawy, M. M., & Farahat, S. E. (2001). Study of lead exposure from automobile exhaust as a risk for nephrotoxicity among traffic policemen. American Journal of Nephrology, 21(4), 274-279.
Mudipalli, A. (2007). Lead hepatotoxicity & potential health effects. Indian Journal of Medical Research, 126(6), 518-527.
Muntner, P., Menke, A., DeSalvo, K. B., Rabito, F. A., & Batuman, V. (2005). Continued decline in blood lead levels among adults in the united states: The national health and nutrition examination surveys. Archives of Internal Medicine, 165(18), 2155-2161.
Nagao, M., Fujita, Y., Wakabayashi, K., Nukaya, H., Kosuge, T., & Sugimura, T. (1986). Mutagens in coffee and other beverages. Environmental Health Perspectives, 67, 89-91.
Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm, 7(2), 27-31.
Navarro-Moreno, L. G., Quintanar-Escorza, M. A., González, S., Mondragón, R., Cerbón-Solorzáno, J., Valdés, J., & Calderón-Salinas, J. V. (2009). Effects of lead intoxication on intercellular junctions and biochemical alterations of the renal proximal tubule cells. Toxicology in Vitro, 23(7), 1298-1304.
Nemet, I., Varga-Defterdarovic, L., & Turk, Z. (2006). Methylglyoxal in food and living organisms. Mol Nutr Food Res, 50(12), 1105-1117.
Neuberg, C. (1913). Weitere Untersuchung über die biochemische Umwandlung von Methylglyoxal in Milchsäure nebst Bemerkung über die Entstehung der verschiedenen Milchsäuren in der Natur. Biochemische Zeitschrift, 51, 484-508.
Nicholson, J. K., Lindon, J. C., & Holmes, E. (1999). ''Metabonomics'': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 29(11), 1181-1189.
Niemann, C. U., & Serkova, N. J. (2007). Biochemical mechanisms of nephrotoxicity: application for metabolomics. Expert Opin Drug Metab Toxicol, 3(4), 527-544.
Nies, A. T., Hofmann, U., Resch, C., Schaeffeler, E., Rius, M., & Schwab, M. (2011). Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PLOS ONE, 6(7), e22163.
Norton, D., Crow, B., Bishop, M., Kovalcik, K., George, J., & Bralley, J. A. (2007). High performance liquid chromatography–tandem mass spectrometry (HPLC/MS/MS) assay for chiral separation of lactic acid enantiomers in urine using a teicoplanin based stationary phase. Journal of Chromatography B, 850(1–2), 190-198.
Odani, H., Asami, J., Ishii, A., Oide, K., Sudo, T., Nakamura, A., Miyata, N., Otsuka, N., Maeda, K., & Nakagawa, J. (2008). Suppression of Renal α-Dicarbonyl Compounds Generated following Ureteral Obstruction by Kidney-Specific α-Dicarbonyl/l-Xylulose Reductase. Annals of the New York Academy of Sciences, 1126(1), 320-324.
Odigie, I. P., Ladipo, C. O., Ettarh, R., & Izegbu, M. C. (2004). Effect Of Chronic Exposure To Low Levels Of Lead On Renal Function And Renal Ultrastructure In SD Rats. Nigerian Journal of Physiological Sciences 19, 19(1-2), 27- 32.
Ogihara, T., Tamai, I., & Tsuji, A. (2000). In situ and in vitro evidence for stereoselective and carrier-mediated transport of monocarboxylic acids across intestinal epithelial tissue. Biological and Pharmaceutical Bulletin, 23(7), 855-859.
Oh, M. S., Uribarri, J., Alveranga, D., Lazar, I., Bazilinski, N., & Carroll, H. J. (1985). Metabolic utilization and renal handling of D-lactate in men. Metabolism, 34(7), 621-625.
Oishi, H., Nomiyama, H., Nomiyama, K., & Tomokuni, K. (1996). Fluorometric HPLC determination of delta-aminolevulinic acid (ALA) in the plasma and urine of lead workers: biological indicators of lead exposure. Journal of Analytical Toxicology, 20(2), 106-110.
Osaki, T., Yokoe, I., Takahashi, K., Inoue, K., Ishizuka, M., Tanaka, T., Azuma, K., Murahata, Y., Tsuka, T., Itoh, N., Imagawa, T., & Okamoto, Y. (2017). Metformin enhances the cytotoxicity of 5-aminolevulinic acid-mediated photodynamic therapy in vitro. Oncol Lett, 14(1), 1049-1053.
Oskarsson, A., & Hellström-Lindahl, E. (1988). Increased lead uptake and inhibition of ALAD-activity in isolated rat hepatocytes incubated with lead-diethyldithiocarbamate complex. Chemico-Biological Interactions, 67(1-2), 59-70.
Owen, M. R., Doran, E., & Halestrap, A. P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal, 348(3), 607-614.
Pallister, T., Jackson, M. A., Martin, T. C., Zierer, J., Jennings, A., Mohney, R. P., MacGregor, A., Steves, C. J., Cassidy, A., Spector, T. D., & Menni, C. (2017). Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome. Scientific Reports, 7(1), 13670.
Palmer, A. G., Cavanagh, J., Wright, P. E., & Rance, M. (1991). Sensitivity improvement in proton-detected two-dimensional heteronuclear correlation NMR spectroscopy. Journal of Magnetic Resonance (1969), 93(1), 151-170.
Patil, A. J., Bhagwat, V. R., Patil, J. A., Dongre, N. N., Ambekar, J. G., & Das, K. K. (2007). Occupational lead exposure in battery manufacturing workers, silver jewelry workers, and spray painters in Western Maharashtra (India): Effect on liver and kidney function. Journal of Basic and Clinical Physiology and Pharmacology, 18(2), 87-100.
Patti, G. J., Yanes, O., & Siuzdak, G. (2012). Metabolomics: the apogee of the omic triology. Nature reviews. Molecular cell biology, 13(4), 263-269.
Perry, M. C., Hoagland, H., & Wagoner, R. D. (1976). Uric acid nephropathy. The Journal of the American Medical Association, 236(8), 961-962.
Phillips, S. A., & Thornalley, P. J. (1993). The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. European Journal of Biochemistry, 212(1), 101-105.
Piotto, M., Saudek, V., & Sklenar, V. (1992). Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. Journal of Biomolecular NMR, 2(6), 661-665.
Pirkle, W. H., & Pochapsky, T. C. (1989). Considerations of chiral recognition relevant to the liquid chromatography separation of enantiomers. Chemical Reviews, 89(2), 347-362.
Pronicka, E., Mielniczuk, Z., Rowińska, E., Ksiazyk, J., Szczygielska-Kozak, M., Wieczorek, E., & Kulczycka, H. (1991). Urinary succinylacetone presence and delta-aminolaevulinic acid excretion in patients with type I tyrosinaemia during treatment. Materia Medica Polona, 23(2), 136-138.
Psihogios, N. G., Kalaitzidis, R. G., Dimou, S., Seferiadis, K. I., Siamopoulos, K. C., & Bairaktari, E. T. (2007). Evaluation of Tubulointerstitial Lesions'' Severity in Patients with Glomerulonephritides:  An NMR-Based Metabonomic Study. Journal of Proteome Research, 6(9), 3760-3770.
Rabbani, N., & Thornalley, P. J. (2008). Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochemical Society Transactions, 36(Pt 5), 1045-1050.
Rabbani, N., & Thornalley, P. J. (2014). Glyoxalase Centennial conference: introduction, history of research on the glyoxalase system and future prospects. Biochemical Society Transactions, 42(2), 413-418.
Rabbani, N., & Thornalley, P. J. (2015). Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochemical and Biophysical Research Communications, 458(2), 221-226.
Rachmani, R., Slavachevski, I., Levi, Z., Zadok, B., Kedar, Y., & Ravid, M. (2002). Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. European Journal of Internal Medicine, 13(7), 428.
Rastogi, S. K. (2008). Renal effects of environmental and occupational lead exposure. Indian Journal of Occupational and Environmental Medicine, 12(3), 103-106.
Ray, S., & Ray, M. (1981). Isolation of methylglyoxal synthase from goat liver. The Journal of Biological Chemistry, 256(12), 6230-6233.
Reddy, Y. A., Chalamaiah, M., Ramesh, B., Balaji, G., & Indira, P. (2014). Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats. Journal of Food Science and Technology, 51(5), 908-914.
Rei, M., Hiroshi, M., Masaaki, U., & Teruaki, M. (1971). Peptide Synthesis by Oxidation-Reduction Condensation. II. The Use of Disulfide as an Oxidant. Bulletin of the Chemical Society of Japan, 44(5), 1373-1378.
Richard, J. P. (1984). Acid-base catalysis of the elimination and isomerization reactions of triose phosphates. Journal of the American Chemical Society, 106(17), 4926-4936.
Richard, J. P. (1991). Kinetic parameters for the elimination reaction catalyzed by triosephosphate isomerase and an estimation of the reaction''s physiological significance. Biochemistry, 30(18), 4581-4585.
Robergs, R. A., Ghiasvand, F., & Parker, D. (2004). Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol, 287(3), R502-516.
Roberts, L. D., Souza, A. L., Gerszten, R. E., & Clish, C. B. (2012). Targeted Metabolomics. Current Protocols in Molecular Biology, CHAPTER, Unit30.32-Unit30.32.
Ruan, P., Gong, Z. J., & Zhang, Q. R. (2004). Changes of plasma D(-)-lactate, diamine oxidase and endotoxin in patients with liver cirrhosis. Hepatobiliary & Pancreatic Diseases International, 3(1), 58-61.
Rubingh, C. M., Bijlsma, S., Derks, E. P., Bobeldijk, I., Verheij, E. R., Kochhar, S., & Smilde, A. K. (2006). Assessing the performance of statistical validation tools for megavariate metabolomics data. Metabolomics : Official journal of the Metabolomic Society, 2(2), 53-61.
Ruggiero-Lopez, D., Lecomte, M., Moinet, G., Patereau, G., Lagarde, M., & Wiernsperger, N. (1999). Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. Biochemical Pharmacology, 58(11), 1765-1773.
Sa, I., da Costa, M. J., & Cunha, E. M. (2012). Lead hepatotoxicology: a study in an animal model. Toxicology and Industrial Health, 28(2), 108-113.
Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: heavy metal nephrotoxicity. Nefrologia, 32(3), 279-286.
Sabatino, A., Regolisti, G., Brusasco, I., Cabassi, A., Morabito, S., & Fiaccadori, E. (2015). Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol Dial Transplant, 30(6), 924-933.
Sabolic, I. (2006). Common mechanisms in nephropathy induced by toxic metals. Nephron Physiology, 104(3), p107-114.
Santosh Kumar, B., & Raja, R. (2014). Metabolite Identification in NMR-based Metabolomics. Current Metabolomics, 2(3), 163-173.
Sapin, V., Nicolet, L., Aublet-Cuvelier, B., Sangline, F., Roszyk, L., Dastugue, B., Gazuy, N., Deteix, P., & Souweine, B. (2006). Rapid decrease in plasma D-lactate as an early potential predictor of diminished 28-day mortality in critically ill septic shock patients. Clinical Chemistry and Laboratory Medicine, 44(4), 492-496.
Sato, N., Takahashi, D., Chen, S. M., Tsuchiya, R., Mukoyama, T., Yamagata, S., Ogawa, M., Yoshida, M., Kondo, S., Satoh, N., & Ueda, S. (2004). Acute nephrotoxicity of aristolochic acids in mice. The Journal of pharmacy and pharmacology, 56(2), 221-229.
Sato, T., Toyoshima, A., Hiraki, T., Ohta, Y., Katayama, K., Arai, T., & Tazaki, H. (2011). Effects of metformin on plasma concentrations of glucose and mannose, g6pase and pepck activity, and mrna expression in the liver and kidney of chickens. British Poultry Science, 52(2), 273-277.
Schück, O. (1984). Uric Acid Excretion Examination of Kidney Function (pp. 243-251). Dordrecht, Provincie Zuid-Holland: Springer Netherlands.
Scheijen, J. L., Hanssen, N. M., van de Waarenburg, M. P., Jonkers, D. M., Stehouwer, C. D., & Schalkwijk, C. G. (2012). L(+) and D(-) lactate are increased in plasma and urine samples of type 2 diabetes as measured by a simultaneous quantification of L(+) and D(-) lactate by reversed-phase liquid chromatography tandem mass spectrometry. Experimental Diabetes Research, 2012, 234812.
Schleucher, J., Schwendinger, M., Sattler, M., Schmidt, P., Schedletzky, O., Glaser, S. J., Sorensen, O. W., & Griesinger, C. (1994). A general enhancement scheme in heteronuclear multidimensional NMR employing pulsed field gradients. Journal of Biomolecular NMR, 4(2), 301-306.
Seheult, J., Fitzpatrick, G., & Boran, G. (2017). Lactic acidosis: an update. Clinical Chemistry and Laboratory Medicine, 55(3), 322-333.
Serkova, N. J., & Niemann, C. U. (2006). Pattern recognition and biomarker validation using quantitative 1H-NMR-based metabolomics. Expert Review of Molecular Diagnostics, 6(5), 717-731.
Shackelford, C., Long, G., Wolf, J., Okerberg, C., & Herbert, R. (2002). Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol, 30(1), 93-96.
Shefa, S. T., & Heroux, P. (2017). Both physiology and epidemiology support zero tolerable blood lead levels. Toxicology Letters, 280, 232-237.
Sklenar, V., Piotto, M., Leppik, R., & Saudek, V. (1993). Gradient-Tailored Water Suppression for 1H-15N HSQC Experiments Optimized to Retain Full Sensitivity. Journal of Magnetic Resonance, Series A, 102(2), 241-245.
Smith, E. A., & Macfarlane, G. T. (1997). Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine. Microb Ecol, 33(3), 180-188.
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., & Klenk, D. C. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry, 150(1), 76-85.
Sommar, J. N., Svensson, M. K., Björ, B. M., Elmståhl, S. I., Hallmans, G., Lundh, T., Schön, S. M., Skerfving, S., & Bergdahl, I. A. (2013). End-stage renal disease and low level exposure to lead, cadmium and mercury; a population-based, prospective nested case-referent study in Sweden. Environmental Health, 12(1), 9.
Somogyi, A., Stockley, C., Keal, J., Rolan, P., & Bochner, F. (1987). Reduction of metformin renal tubular secretion by cimetidine in man. British Journal of Clinical Pharmacology, 23(5), 545-551.
Sousa, C. A., & Soares, E. V. (2014). Mitochondria are the main source and one of the targets of Pb (lead)-induced oxidative stress in the yeast Saccharomyces cerevisiae. Applied Microbiology and Biotechnology, 98(11), 5153-5160.
Souza, J. B., Rocha, J. B. T., Nogueira, C. W., Borges, V. C., Kaizer, R. R., Morsch, V. M., Dressler, V. L., Martins, A. F., Flores, É. M. M., & Schetinger, M. R. C. (2007). Delta-aminolevulinate dehydratase (δ-ALA-D) activity in diabetes and hypothyroidism. Clinical Biochemistry, 40(5), 321-325.
Star, R. A. (1998). Treatment of acute renal failure. Kidney International, 54(6), 1817-1831.
Staudinger, K. C., & Roth, V. S. (1998). Occupational lead poisoning. American Family Physician, 57(4), 719-726, 731-712.
Strife, C. F., Zuroweste, E. L., Emmett, E. A., Finelli, V. N., Petering, H. G., & Berry, H. K. (1977). Tyrosinemia with acute intermittent porphyria: aminolevulinic acid dehydratase deficiency related to elevated urinary aminolevulinic acid levels. The Journal of Pediatrics, 90(3), 400-404.
Suh, K. S., Choi, E. M., Rhee, S. Y., & Kim, Y. S. (2014). Methylglyoxal induces oxidative stress and mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. Free Radical Research, 48(2), 206-217.
Sybilska, D., Żukowski, J., & Bojarski, J. (1986). Resolution of mephenytoin and some chiral barbiturates into enantiomers by reversed phase high performance liquid chromatography via β-cyclodextrin inclusion complexes. Journal of liquid chromatography, 9(2-3), 591-606.
Takiar, V., Nishio, S., Seo-Mayer, P., King, J. D., Jr., Li, H., Zhang, L., Karihaloo, A., Hallows, K. R., Somlo, S., & Caplan, M. J. (2011). Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proceedings of the National Academy of Sciences of the United States of America, 108(6), 2462-2467.
Tang, R., Ding, C., Ma, Y., Wang, J., Zhang, T., & Wang, X. (2017). Metabolic Responses of Eisenia Fetida to Individual Pb and Cd Contamination in Two Types of Soils. Scientific Reports, 7, 13110.
Tanihara, Y., Masuda, S., Sato, T., Katsura, T., Ogawa, O., & Inui, K. i. (2007). Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters. Biochemical Pharmacology, 74(2), 359-371.
Thurn, J. R., Pierpont, G. L., Ludvigsen, C. W., & Eckfeldt, J. H. (1985). D-lactate encephalopathy. The American Journal of Medicine, 79(6), 717-721.
Todoroki, K., Goto, K., Nakano, T., Ishii, Y., Min, J. Z., Inoue, K., & Toyo''oka, T. (2014). 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as an enantioseparation enhancer for fluorescence chiral derivatization-liquid chromatographic analysis of dl-lactic acid. Journal of Chromatography. A, 1360, 188-195.
Tofuku, Y., Muramoto, H., Kuroda, M., & Takeda, R. (1985). Impaired metabolism of guanidinoacetic acid in uremia. Nephron, 41(2), 174-178.
Toyo''oka, T., Ishibashi, M., Takeda, Y., Nakashima, K., Akiyama, S., Uzu, S., & Imai, K. (1991). Precolumn fluorescence tagging reagent for carboxylic acids in high-performance liquid chromatography: 4-substituted-7-aminoalkylamino-2,1,3-benzoxadiazoles. J Chromatogr, 588(1-2), 61-71.
Toyo''oka, T., Ishibashi, M., & Terao, T. (1992). Fluorescent chiral derivatization reagents for carboxylic acid enantiomers in high-performance liquid chromatography. Analyst, 117(4), 727-733.
Tsai, Y. C., Liao, T. H., & Lee, J. A. (2003). Identification of L-3-hydroxybutyrate as an original ketone body in rat serum by column-switching high-performance liquid chromatography and fluorescence derivatization. Analytical Biochemistry, 319(1), 34-41.
Tsutsui, H., Mochizuki, T., Maeda, T., Noge, I., Kitagawa, Y., Min, J. Z., Todoroki, K., Inoue, K., & Toyo''oka, T. (2012). Simultaneous determination of DL-lactic acid and DL-3-hydroxybutyric acid enantiomers in saliva of diabetes mellitus patients by high-throughput LC-ESI-MS/MS. Analytical and Bioanalytical Chemistry, 404(6-7), 1925-1934.
Tubbs, P. K. (1965). The metabolism of D-alpha-hydroxy acids in animal tissues. Annals of the New York Academy of Sciences, 119(3), 920-926.
Tulpan, D., Leger, S., Belliveau, L., Culf, A., & Cuperlovic-Culf, M. (2011). MetaboHunter: an automatic approach for identification of metabolites from 1H-NMR spectra of complex mixtures. BMC Bioinformatics, 12, 400.
U.S.FDA. (2016). FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. from https://www.fda.gov/
Uchiyama, S., Santa, T., Okiyama, N., Fukushima, T., & Imai, K. (2001). Fluorogenic and fluorescent labeling reagents with a benzofurazan skeleton. Biomedical Chromatography, 15(5), 295-318.
Urakami, Y., Kimura, N., Okuda, M., & Inui, K. I. (2004). Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharmaceutical Research, 21(6), 976-981.
Uribarri, J., Oh, M. S., & Carroll, H. J. (1998). D-Lactic Acidosis: A Review of Clinical Presentation, Biochemical Features, and Pathophysiologic Mechanisms. Medicine, 77(2), 73-82.
van der Greef, J., Bouwman, J., Odink, J., Schrijver, J., & C., T. N. d. B. M. (1984). Evaluation of field desorption mass spectrometric profiles by quotient weighting. Biomedical Mass Spectrometry, 11(10), 535-538.
van der Greef, J., van Wietmarschen, H., van Ommen, B., & Verheij, E. (2013). Looking back into the future: 30 years of metabolomics at TNO. Mass Spectrometry Reviews, 32(5), 399-415.
Viollet, B., Guigas, B., Sanz Garcia, N., Leclerc, J., Foretz, M., & Andreelli, F. (2012). Cellular and molecular mechanisms of metformin: an overview. Clinical Science (London, England : 1979), 122(6), 253-270.
Wang, J., Yang, Z., Lin, L., Zhao, Z., Liu, Z., & Liu, X. (2012). Protective effect of naringenin against lead-induced oxidative stress in rats. Biological Trace Element Research, 146(3), 354-359.
Wang, M., Weng, X., Guo, J., Chen, Z., Jiang, G., & Liu, X. (2016). Metformin alleviated EMT and fibrosis after renal ischemia-reperfusion injury in rats. Renal Failure, 38(4), 614-621.
Wang, Q., Zhao, H.-H., Chen, J.-W., Hao, Q.-L., Gu, K.-D., Zhu, Y.-X., Zhou, Y.-K., & Ye, L.-X. (2010). δ-Aminolevulinic acid dehydratase activity, urinary δ-aminolevulinic acid concentration and zinc protoporphyrin level among people with low level of lead exposure. International Journal of Hygiene and Environmental Health, 213(1), 52-58.
Warren, M. J., Cooper, J. B., Wood, S. P., & Shoolingin-Jordan, P. M. (1998). Lead poisoning, haem synthesis and 5-aminolaevulinic acid dehydratase. Trends in Biochemical Sciences, 23(6), 217-221.
Wedeen, R. P., Batuman, V., & Landy, E. (1983). The safety of the EDTA lead-mobilization test. Environmental Research, 30(1), 58-62.
Wen, C. P., Cheng, T. Y., Tsai, M. K., Chang, Y. C., Chan, H. T., Tsai, S. P., Chiang, P. H., Hsu, C. C., Sung, P. K., Hsu, Y. H., & Wen, S. F. (2008). All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet, 371(9631), 2173-2182.
Westerhuis, J. A., Hoefsloot, H. C. J., Smit, S., Vis, D. J., Smilde, A. K., Van Velzen, E. J. J., Van Duijnhoven, J. P. M., & Van Dorsten, F. A. (2008). Assessment of PLSDA cross validation. Metabolomics, 4(1), 81-89.
Williams, B. J., Hejtmancik, M. R., Jr., & Abreu, M. (1983). Cardiac effects of lead. Federation Proceedings, 42(13), 2989-2993.
Winiarska-Mieczan, A. (2014). Cumulative rate and distribution of Cd and Pb in the organs of adult male Wistar rats during oral exposure. Environmental Toxicology and Pharmacology, 38(3), 751-760.
Winiarska-Mieczan, A., & Kwiecien, M. (2016). The Effect of Exposure to Cd and Pb in the Form of a Drinking Water or Feed on the Accumulation and Distribution of These Metals in the Organs of Growing Wistar Rats. Biological Trace Element Research, 169(2), 230-236.
Wishart, D. S. (2010). Computational approaches to metabolomics. In R. Matthiesen (Ed.), Methods in Molecular Biology (2009/12/04 ed., Vol. 593, pp. 283-313). United States, New York: Humana Press.
Worley, B., & Powers, R. (2016). PCA as a practical indicator of OPLS-DA model reliability. Current Metabolomics, 4(2), 97-103.
Xia, J., Bjorndahl, T. C., Tang, P., & Wishart, D. S. (2008). MetaboMiner – semi-automated identification of metabolites from 2D NMR spectra of complex biofluids. BMC Bioinformatics, 9(1), 507.
Xia, J., Psychogios, N., Young, N., & Wishart, D. S. (2009). MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Research, 37(Web Server issue), W652-W660.
Xia, J., & Wishart, D. S. (2016). Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis. Curr Protoc Bioinformatics, 55, 14.10.11-14.10.91.
Xiao, C., Hao, F., Qin, X., Wang, Y., & Tang, H. (2009). An optimized buffer system for NMR-based urinary metabonomics with effective pH control, chemical shift consistency and dilution minimization. Analyst, 134(5), 916-925.
Yang, X., Ding, H., Qin, Z., Zhang, C., Qi, S., Zhang, H., Yang, T., He, Z., Yang, K., Du, E., Liu, C., Xu, Y., & Zhang, Z. (2016). Metformin Prevents Renal Stone Formation through an Antioxidant Mechanism In Vitro and In Vivo. Oxidative Medicine and Cellular Longevity, 2016, 4156075.
Yu, C. C., Lin, J. L., & Lin-Tan, D. T. (2004). Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study. Journal of the American Society of Nephrology, 15(4), 1016-1022.
Yurekli, M., Esrefoglu, M., Doĝru, M. I., Doĝru, A., Gul, M., & Whidden, M. (2009). Adrenomedullin reduces antioxidant defense system and enhances kidney tissue damage in cadmium and lead exposed rats. Environmental Toxicology, 24(3), 279-286.
Zhai, Q., Li, T., Yu, L., Xiao, Y., Feng, S., Wu, J., Zhao, J., Zhang, H., & Chen, W. (2017). Effects of subchronic oral toxic metal exposure on the intestinal microbiota of mice. Science Bulletin, 62(12), 831-840.
Zhang, H. H., & Guo, X. L. (2016). Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemotherapy and Pharmacology, 78(1), 13-26.
Zhang, X., Zhao, Y., Xu, J., Xue, Z., Zhang, M., Pang, X., Zhang, X., & Zhao, L. (2015). Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Scientific Reports, 5, 14405.
Zhang, Y., Guan, M., Zheng, Z., Zhang, Q., Gao, F., & Xue, Y. (2013). Effects of Metformin on CD133+ Colorectal Cancer Cells in Diabetic Patients. PLOS ONE, 8(11), e81264.
Zhang, Y., Hu, H., Shi, Y., Yang, X., Cao, L., Wu, J., Asweto, C. O., Feng, L., Duan, J., & Sun, Z. (2017). 1H NMR-based metabolomics study on repeat dose toxicity of fine particulate matter in rats after intratracheal instillation. Science of the Total Environment, 589, 212-221.
Zhang, Z., Gao, X., Guo, M., Jiang, H., Cao, Y., & Zhang, N. (2017). The Protective Effect of Baicalin Against Lead-Induced Renal Oxidative Damage in Mice. Biological Trace Element Research, 175(1), 129-135.
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J., & Moller, D. E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation, 108(8), 1167-1174.
Zhou, R., Xu, Y., Shen, J., Han, L., Chen, X., Feng, X., & Kuang, X. (2016). Urinary KIM-1: a novel biomarker for evaluation of occupational exposure to lead. Scientific Reports, 6, 38930.
李淩堯. (2011). D-乳酸於Gentamicin誘導大鼠腎病變下投與Atorvastatin之研究. 臺北醫學大學. 碩士論文. 台北.
施懿?. (2013). Meformin對腎損傷齧齒類動物組織中D-乳酸的影響. 臺北醫學大學. 台北.
財團法人國家衛生研究院. (2015). 臺灣慢性腎臟病臨床診療指引.
莊明正. (2011). 四氯化碳誘導肝臟發炎動物模式中D-乳酸之探討. 臺北醫學大學. 藥學系碩士班. 碩士論文. 台北.
黃國旭. (2014). 玉山薊對四氯化碳誘導肝損傷大鼠血清及組織中甲基乙二醛及D-乳酸的影響. 臺北醫學大學. 台北.
蔡牧承. (2014). 人參皂苷Rg1與N-乙醯半胱胺酸對於順氯氨鉑引發腎毒性之純系小鼠腎組織中甲基乙二醛及D-乳酸的影響. 臺北醫學大學. 台北.