Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease

Amino Acids

Volumn 48, Issue 5, 2016, Pages 1131-1149

  Baye, Estifanos ^a,b   Ukropcova, Barbara ^c,d   Ukropec, Jozef ^c   Hipkiss, Alan ^e   Aldini, Giancarlo ^f   De Courten, Barbora ^a,g  

^a MONASH UNIVERSITY   (Australia)

^b WOLLO UNIVERSITY   (Ethiopia)

^c INSTITUTE OF EXPERIMENTAL ENDOCRINOLOGY   (Slovakia)

^d Faculty of Medicine of Comenius University and University Hospital Bratislava   (Slovakia)

^e UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^f UNIVERSITY OF MILAN   (Italy)

^g SOUTHERN HEALTH   (Australia)

Author keywords

Atherosclerosis; Carnosine; Cholesterol; Energy expenditure; Insulin resistance; Ischaemia; Obesity; Skeletal muscle; Type 2 diabetes

Indexed keywords

CARNOSINE;

ADRENERGIC SYSTEM; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; BIOLOGICAL ACTIVITY; CARDIOMETABOLIC RISK; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CHELATION; CHRONIC DISEASE; DIET SUPPLEMENTATION; DISEASE ASSOCIATION; DRUG EFFECT; EXERCISE PHYSIOLOGY; HUMAN; INSULIN RESISTANCE; INTERVENTION STUDY; ISCHEMIA; MACROVASCULAR COMPLICATION; MENTAL DISEASE; METABOLIC DISORDER; MICROANGIOPATHY; MORBIDITY; MORTALITY; NEUROLOGIC DISEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PHYSICAL CAPACITY; PHYSICAL PERFORMANCE; PREVALENCE; PRIORITY JOURNAL; PUBLIC HEALTH PROBLEM; REVIEW; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; VASCULAR DISEASE; ANALYSIS; ANIMAL; CARDIOVASCULAR DISEASES; CLINICAL TRIAL (TOPIC); DIETARY SUPPLEMENT; METABOLIC DISEASES;

ANIMALS; CARDIOVASCULAR DISEASES; CARNOSINE; CHRONIC DISEASE; CLINICAL TRIALS AS TOPIC; DIETARY SUPPLEMENTS; HUMANS; METABOLIC DISEASES;

EID: 84961198594     PISSN: 09394451     EISSN: 14382199     Source Type: Journal    
DOI: 10.1007/s00726-016-2208-1     Document Type: Review

References (203)

1. Abe H (2000) Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry-Russia 65(7):757-765
2. Aldini G, Carini M, Beretta G, Bradamante S, Facino RM (2002) Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? Biochem Biophys Res Commun 298(5):699-706
3. Aldini G, Dalle-Donne I, Facino RM, Milzani A, Carini M (2007) Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls. Med Res Rev 27(6):817-868
4. Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli G, Yeum KJ, Negrisoli G, Carini M (2011) The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med 15(6):1339-1354. doi: 10.1111/j.1582-4934.2010.01101.x
5. Aldini G, Vistoli G, Stefek M, Chondrogianni N, Grune T, Sereikaite J, Sadowska-Bartosz I, Bartosz G (2013) Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res 47(Suppl 1):93-137. doi: 10.3109/10715762.2013.792926
6. Aldini G, Carini M, Yeum KJ, Vistoli G (2014) Novel molecular approaches for improving enzymatic and nonenzymatic detoxification of 4-hydroxynonenal: toward the discovery of a novel class of bioactive compounds. Free Radic Biol Med 69:145-156. doi: 10.1016/j.freeradbiomed.2014.01.017
7. Alhamdani MS, Al-Azzawie HF, Abbas FK (2007) Decreased formation of advanced glycation end-products in peritoneal fluid by carnosine and related peptides. Perit Dial Int 27(1):86-89
8. Alkhalaf A, Landman G, van Hateren K, Groenier K, Mooyaart A, De Heer E, Gans R, Navis G, Bakker S, Kleefstra N, Bilo H (2015) Sex specific association between carnosinase gene CNDP1 and cardiovascular mortality in patients with type 2 diabetes (ZODIAC-22). J Nephrol 28:201-207
9. Alpsoy L, Akcayoglu G, Sahin H (2011) Anti-oxidative and anti-genotoxic effects of carnosine on human lymphocyte culture. Hum Exp Toxicol 30(12):1979-1985
10. AlZahrani I, Badawy A, El-Morshedi N (2014) Antioxidant role of carnosine in type-II diabetic Wistar rats. Indian J Appl Res 4(2):13-17
11. Appella E, Robinson EA, Ullrich SJ, Stoppelli MP, Corti A, Cassani G, Blasi F (1987) The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 262(10):4437-4440
12. Arnal N, de Alaniz MJ, Marra CA (2011) Carnosine and neocuproine as neutralizing agents for copper overload-induced damages in cultured human cells. Chem Biol Interact 192(3):257-263
13. Arntfield M, van der Kooy D (2013) The adult mammalian pancreas contains separate precursors of pancreatic and neural crest developmental origins. Stem Cells Dev 22(15):2145-2157
14. Aronson D, Edelman ER (2010) Revascularization for coronary artery disease in diabetes mellitus: angioplasty, stents and coronary artery bypass grafting. Rev Endocr Metab Disord 11(1):75-86. doi: 10.1007/s11154-010-9135-3
15. Artioli GG, Gualano B, Smith A, Stout J, Lancha AH Jr (2010) Role of beta-alanine supplementation on muscle carnosine and exercise performance. Med Sci Sports Exerc 42(6):1162-1173
16. Aydin AF, Kucukgergin C, Ozdemirler-Erata G, Kocak-Toker N, Uysal M (2010a) The effect of carnosine treatment on prooxidant-antioxidant balance in liver, heart and brain tissues of male aged rats. Biogerontology 11(1):103-109
17. Aydin AF, Kusku-Kiraz Z, Dogru-Abbasoglu S, Gulluoglu M, Uysal M, Kocak-Toker N (2010b) Effect of carnosine against thioacetamide-induced liver cirrhosis in rat. Peptides 31(1):67-71
18. Aydin AF, Kusku-Kiraz Z, Dogru-Abbasoglu S, Uysal M (2010c) Effect of carnosine treatment on oxidative stress in serum, apoB-containing lipoproteins fraction and erythrocytes of aged rats. Pharmacol Rep 62(4):733-739
19. Baba SP, Hoetker JD, Merchant M, Klein JB, Cai J, Barski OA, Conklin DJ, Bhatnagar A (2013) Role of aldose reductase in the metabolism and detoxification of carnosine-acrolein conjugates. J Biol Chem 288(39):28163-28179. doi: 10.1074/jbc.M113.504753
20. Babizhayev MA (1989) Antioxidant activity of l-carnosine, a natural histidine-containing dipeptide in crystalline lens. Biochim Biophys Acta 1004(3):363-371
21. Babizhayev MA, Guiotto A, Kasus-Jacobi A (2009) N-Acetylcarnosine and histidyl-hydrazide are potent agents for multitargeted ophthalmic therapy of senile cataracts and diabetic ocular complications. J Drug Target 17(1):36-63
22. Babizhayev MA, Lankin VZ, Savel'Yeva EL, Deyev AI, Yegorov YE (2013) Diabetes mellitus: novel insights, analysis and interpretation of pathophysiology and complications management with imidazole-containing peptidomimetic antioxidants. Recent Pat Drug Deliv Formul 7(3):216-256
23. Baguet A, Reyngoudt H, Pottier A, Everaert I, Callens S, Achten E, Derave W (2009) Carnosine loading and washout in human skeletal muscles. J Appl Physiol 106(3):837-842. doi: 10.1152/japplphysiol.91357.2008
24. Baguet A, Everaert I, Hespel P, Petrovic M, Achten E, Derave W (2011) A new method for non-invasive estimation of human muscle fiber type composition. PLoS One 6(7):e21956. doi: 10.1371/journal.pone.0021956
25. Baguet A, Everaert I, Achten E, Thomis M, Derave W (2012) The influence of sex, age and heritability on human skeletal muscle carnosine content. Amino Acids 43(1):13-20. doi: 10.1007/s00726-011-1197-3
26. Baguet A, Everaert I, Yard B, Peters V, Zschocke J, Zutinic A, De Heer E, Podgorski T, Domaszewska K, Derave W (2014) Does low serum carnosinase activity favor high-intensity exercise capacity? J Appl Physiol 116(5):553-559. doi: 10.1152/japplphysiol.01218.2013
27. Bao Y, Gao C, Hao W, Ji C, Zhao L, Zhang J, Liu T, Ma Q (2015) Effects of dietary l-carnosine and alpha-lipoic acid on growth performance, blood thyroid hormones and lipid profiles in finishing pigs. Asian Australas J Anim Sci 28(10):1465-1470
28. Baran EJ (2000) Metal complexes of carnosine. Biochemistry-Russia 65(7):789-797
29. Baraniuk JN, El-Amin S, Corey R, Rayhan R, Timbol C (2013) Carnosine treatment for gulf war illness: a randomized controlled trial. Global J Health Sci 5(3):69-81
30. Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S (2013) Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 33(6):1162-1170
31. Bauchart C, Savary-Auzeloux I, Patureau Mirand P, Thomas E, Morzel M, Remond D (2007) Carnosine concentration of ingested meat affects carnosine net release into the portal vein of minipigs. J Nutr 137(3):589-593
32. Bauer K (2005) Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochem Res 30(10):1339-1345
33. Bex T, Chung W, Baguet A, Stegen S, Stautemas J, Achten E, Derave W (2014) Muscle carnosine loading by beta-alanine supplementation is more pronounced in trained vs. untrained muscles. J Appl Physiol 116(2):204-209. doi: 10.1152/japplphysiol.01033.2013
34. Blancquaert L, Everaert I, Derave W (2015) Beta-alanine supplementation, muscle carnosine and exercise performance. Curr Opin Clin Nutr Metab Care 18(1):63-70. doi: 10.1097/MCO.0000000000000127
35. Boden G, Homko C, Barrero CA, Stein TP, Chen X, Cheung P, Fecchio C, Koller S, Merali S (2015) Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci Transl Med 7(304):304re307. doi: 10.1126/scitranslmed.aac4765
36. Boldyrev A (2007) Carnosine and oxidative stress in cells and tissues. Nova Science Publishers, New York
37. Boldyrev AA, Gallant SC, Sukhich GT (1999) Carnosine, the protective, anti-aging peptide. Biosci Rep 19(6):581-587
38. Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova N, Bagyeva G, Ivanova-Smolenskaya I, Illarioshkin S (2008) Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. Rejuvenation Res 11(4):821-827. doi: 10.1089/rej.2008.0716
39. Boldyrev AA, Aldini G, Derave W (2013) Physiology and pathophysiology of carnosine. Physiol Rev 93(4):1803-1845. doi: 10.1152/physrev.00039.2012
40. Brown BE, Kim CH, Torpy FR, Bursill CA, McRobb LS, Heather AK, Davies MJ, van Reyk DM (2014) Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis 232(2):403-409. doi: 10.1016/j.atherosclerosis.2013.11.068
41. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813-820
42. Burcham PC, Kaminskas LM, Fontaine FR, Petersen DR, Pyke SM (2002) Aldehyde-sequestering drugs: tools for studying protein damage by lipid peroxidation products. Toxicology 181-182:229-236
43. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52(1):102-110
44. Calder PC, Ahluwalia N, Brouns F, Buetler T, Clement K, Cunningham K, Esposito K, Jonsson LS, Kolb H, Lansink M, Marcos A, Margioris A, Matusheski N, Nordmann H, O'Brien J, Pugliese G, Rizkalla S, Schalkwijk C, Tuomilehto J, Warnberg J, Watzl B, Winklhofer-Roob BM (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106(Suppl 3):S5-78
45. Cartwright SP, Bill RM, Hipkiss AR (2012) l-Carnosine affects the growth of Saccharomyces cerevisiae in a metabolism-dependent manner. PLoS One 7(9):e45006. doi: 10.1371/journal.pone.0045006
46. CDC (2014) National Diabetes Statistics Report: estimates of diabetes and its burden in the United States, 2014. US Department of Health and Human Services, Atlanta. http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html
47. Ceriello A, Motz E (2004) Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24(5):816-823
48. Chengappa KN, Turkin SR, DeSanti S, Bowie CR, Brar JS, Schlicht PJ, Murphy SL, Hetrick ML, Bilder R, Fleet D (2012) A preliminary, randomized, double-blind, placebo-controlled trial of l-carnosine to improve cognition in schizophrenia. Schizophr Res 142(1-3):145-152
49. Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS, Beyreuther K, Tanzi RE, Masters CL, Bush AI (1999) Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion. J Biol Chem 274(33):23223-23228
50. Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J (2002) Double-blind, placebo-controlled study of l-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol 17(11):833-837
51. Chuang CH, Hu ML (2008) l-Carnosine inhibits metastasis of SK-Hep-1 cells by inhibition of matrix metaoproteinase-9 expression and induction of an antimetastatic gene, nm23-H1. Nutr Cancer 60(4):526-533. doi: 10.1080/01635580801911787
52. Cieslak M, Wojtczak A, Cieslak M (2015) Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment. Acta Biochim Pol 62(1):15-21
53. Colagiuri S, Colagiuri R, Conway B, Davey P, Grainger D (2003) DiabCot Australia: assessing the burden of type 2 diabetes in Australia. Diabetes Australia, Canberra
54. Colzani M, Garzon D, Aldini G (2015) Carnosine and derivatives as inhibitors of protein covalent modifications induced by reactive carbonyl species. In: Imidazole dipeptides: chemistry, analysis, function and effects. doi: 10.1039/9781782622611-00139
55. Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, Canzoniero LM, Ciavardelli D, Rizzarelli E, Sensi SL (2011) Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One 6(3):e17971
56. Coughlan MT, Yap FY, Tong DC, Andrikopoulos S, Gasser A, Thallas-Bonke V, Webster DE, Miyazaki J, Kay TW, Slattery RM, Kaye DM, Drew BG, Kingwell BA, Fourlanos S, Groop PH, Harrison LC, Knip M, Forbes JM (2011) Advanced glycation end products are direct modulators of beta-cell function. Diabetes 60(10):2523-2532
57. Dasuri K, Ebenezer P, Fernandez-Kim SO, Zhang L, Gao Z, Bruce-Keller AJ, Freeman LR, Keller JN (2013) Role of physiological levels of 4-hydroxynonenal on adipocyte biology: implications for obesity and metabolic syndrome. Free Radic Res 47(1):8-19. doi: 10.3109/10715762.2012.733003
58. De Courten B, Jakubova M, De Courten M, Kukurova I, Vallova S, Krumpolec P, Valkovic L, Kurdiovac T, Garzon D, Barbaresi S, Teede H, Derave W, Krssak M, Aldini G, Ukropecc J, Ukropcova B (2015a) Effects of carnosine supplementation on glucose metabolism in sedentary individuals with overweight and obesity: pilot clinical trial. Obesity (in press)
59. De Courten B, Kurdiova T, de Courten MP, Belan V, Everaert I, Vician M, Teede H, Gasperikova D, Aldini G, Derave W, Ukropec J, Ukropcova B (2015b) Muscle carnosine is associated with cardiometabolic risk factors in humans. PLoS One 10(10):e0138707. doi: 10.1371/journal.pone.0138707
60. de la Monte S, Wands J (2006) Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2(6):1101-1113
61. Death AK, Fisher EJ, McGrath KC, Yue DK (2003) High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. Atherosclerosis 168(2):263-269
62. del Favero S, Roschel H, Solis MY, Hayashi AP, Artioli GG, Otaduy MC, Benatti FB, Harris RC, Wise JA, Leite CC, Pereira RM, de Sa-Pinto AL, Lancha-Junior AH, Gualano B (2012) Beta-alanine (Carnosyn™) supplementation in elderly subjects (60-80 years): effects on muscle carnosine content and physical capacity. Amino Acids 43(1):49-56
63. Derave W, Ozdemir MS, Harris RC, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E (2007) beta-Alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters. J Appl Physiol 103(5):1736-1743. doi: 10.1152/japplphysiol.00397.2007
64. Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18(6):655-673
65. Diabetes Australia (2013) Diabetes National Election Agenda 2013-2015: type 2 diabetes the 21st century pandemic
66. Dobrota D, Fedorova T, Stvolinsky S, Babusikova E, Likavcanova K, Drgova A, Strapkova A, Boldyrev A (2005) Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect. Neurochem Res 30(10):1283-1288
67. Dolu N, Acer H, Kara AY (2014) Investigation of dose-related effects of carnosine on anxiety with sympathetic skin response and T-maze. Acta Med (Hradec Kralove) 57(3):112-118
68. Dursun N, Taskin E, Ozturk F (2011) Protection against adriamycin-induced cardiomyopathy by carnosine in rats: role of endogenous antioxidants. Biol Trace Elem Res 143(1):412-424
69. Everaert I, Mooyaart A, Baguet A, Zutinic A, Baelde H, Achten E, Taes Y, De Heer E, Derave W (2011) Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans. Amino Acids 40(4):1221-1229. doi: 10.1007/s00726-010-0749-2
70. Everaert I, Taes Y, De Heer E, Baelde H, Zutinic A, Yard B, Sauerhofer S, Vanhee L, Delanghe J, Aldini G, Derave W (2012) Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. Am J Physiol Renal Physiol 302(12):F1537-F1544. doi: 10.1152/ajprenal.00084.2012
71. Feng ZY, Zheng XJ, Wang J (2009) Effects of carnosine on the evoked potentials in hippocampal CA1 region. J Zhejiang Univ Sci B 10(7):505-511. doi: 10.1631/jzus.B0820370
72. Follert P, Cremer H, Béclin C (2014) MicroRNAs in brain development and function: a matter of flexibility and stability. Front Mol Neurosci 7(5):1-8
73. Forbes JM, Sourris KC, de Courten MP, Dougherty SL, Chand V, Lyons JG, Bertovic D, Coughlan MT, Schlaich MP, Soldatos G, Cooper ME, Straznicky NE, Kingwell BA, de Courten B (2014) Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects. Amino Acids 46(2):321-326
74. Forsberg EA, Botusan IR, Wang J, Peters V, Ansurudeen I, Brismar K, Catrina SB (2015) Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1. J Endocrinol 225(3):159-167
75. Fouad AA, El-Rehany MA, Maghraby HK (2007) The hepatoprotective effect of carnosine against ischemia/reperfusion liver injury in rats. Eur J Pharmacol 572(1):61-68
76. Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, Rich SS, Xu J, McDonough C, Janssen B, Yard BA, van der Woude FJ, Bowden DW (2007) A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant 22(4):1131-1135
77. Frohnert BI, Bernlohr DA (2014) Glutathionylated products of lipid peroxidation: a novel mechanism of adipocyte to macrophage signaling. Adipocyte 3(3):224-229. doi: 10.4161/adip.28851
78. Frohnert BI, Long EK, Hahn WS, Bernlohr DA (2014) Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation. Diabetes 63(1):89-100. doi: 10.2337/db13-0777
79. Fujii T, Takaoka M, Muraoka T, Kurata H, Tsuruoka N, Ono H, Kiso Y, Tanaka T, Matsumura Y (2003) Preventive effect of l-carnosine on ischemia/reperfusion-induced acute renal failure in rats. Eur J Pharmacol 474(2-3):261-267
80. Gallant S, Semyonova M, Yuneva M (2000) Carnosine as a potential anti-senescence drug. Biochemistry-Russia 65(7):866-868
81. Gardner ML, Illingworth KM, Kelleher J, Wood D (1991) Intestinal absorption of the intact peptide carnosine in man, and comparison with intestinal permeability to lactulose. J Physiol 439:411-422
82. Gariballa SE, Sinclair AJ (2000) Carnosine: physiological properties and therapeutic potential. Age Ageing 29(3):207-210
83. Giris M, Dogru-Abbasoglu S, Kumral A, Olgac V, Kocak-Toker N, Uysal M (2014) Effect of carnosine alone or combined with alpha-tocopherol on hepatic steatosis and oxidative stress in fructose-induced insulin-resistant rats. J Physiol Biochem 70(2):385-395. doi: 10.1007/s13105-014-0314-7
84. Gopko AV, Kulibin AY, Semenova ML, Zakhidov ST (2005) Carnosine-induced changes in the development of spermatogenic epithelial cells in senescence accelerated SAM mice. Bull Exp Biol Med 140(2):235-237
85. Gordon KJ, Blobe GC (2008) Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 1782(4):197-228. doi: 10.1016/j.bbadis.2008.01.006
86. Gotlib IH, LeMoult J, Colich NL, Foland-Ross LC, Hallmayer J, Joormann J, Lin J, Wolkowitz OM (2015) Telomere length and cortisol reactivity in children of depressed mothers. Mol Psychiatry 20(5):615-620. doi: 10.1038/mp.2014.119
87. Gualano B, Everaert I, Stegen S, Artioli GG, Taes Y, Roschel H, Achten E, Otaduy MC, Junior AH, Harris R, Derave W (2012) Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients. Amino Acids 43(1):21-24
88. Guiotto A, Calderan A, Ruzza P, Borin G (2005) Carnosine and carnosine-related antioxidants: a review. Curr Med Chem 12(20):2293-2315
89. Harris RC, Stellingwerff T (2013) Effect of beta-alanine supplementation on high-intensity exercise performance. Nestle Nutr Inst Workshop Ser 76:61-71. doi: 10.1159/000350258
90. Henle T (2005) Protein-bound advanced glycation endproducts (AGEs) as bioactive amino acid derivatives in foods. Amino Acids 29(4):313-322
91. Hipkiss AR (2007) Could carnosine or related structures suppress Alzheimer's disease? J Alzheimers Dis 11(2):229-240
92. Hipkiss AR (2009) Carnosine, diabetes and Alzheimer's disease. Expert Rev Neurother 9(5):583-585
93. Hipkiss A (2014) Aging risk factors and Parkinson's disease: contrasting roles of common dietary constituents. Neurobiol Aging 35:1469-1472
94. Hipkiss AR (2015) Possible benefit of dietary carnosine towards depressive disorders. Aging Dis 6(5):300-303. doi: 10.14336/ad.2014.1211
95. Hobson RM, Saunders B, Ball G, Harris RC, Sale C (2012) Effects of beta-alanine supplementation on exercise performance: a meta-analysis. Amino Acids 43(1):25-37. doi: 10.1007/s00726-011-1200-z
96. Hoffman J, Landau G, Stout J, Hoffman M, Shavit N, Rosen P, Moran D, Fukuda D, Shelef I, Carmom E, Ostfeld I (2015) β-Alanine ingestion increases muscle carnosine content and combat specific performance in soldiers. Amino Acids 47:627-636
97. Horii Y, Shen J, Fujisaki Y, Yoshida K, Nagai K (2012) Effects of l-carnosine on splenic sympathetic nerve activity and tumor proliferation. Neurosci Lett 510(1):1-5. doi: 10.1016/j.neulet.2011.12.058
98. Huang ES, Basu A, O'Grady M, Capretta JC (2009) Projecting the future diabetes population size and related costs for the U.S. Diabetes Care 32(12):2225-2229
99. IDF (2014) Diabetes Atlas Sixth Edition Update. https://www.idf.org/sites/default/files/Atlas-poster-2014-EN.pdf
100. Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, Kuboki K, Meier M, Rhodes CJ, King GL (1999) Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 103(2):185-195. doi: 10.1172/jci3326
101. Jandeleit-Dahm K, Cooper ME (2008) The role of AGEs in cardiovascular disease. Curr Pharm Des 14(10):979-986
102. Jankovic A, Korac A, Srdic-Galic B, Buzadzic B, Otasevic V, Stancic A, Vucetic M, Markelic M, Velickovic K, Golic I, Korac B (2014) Differences in the redox status of human visceral and subcutaneous adipose tissues-relationships to obesity and metabolic risk. Metabolism 63(5):661-671. doi: 10.1016/j.metabol.2014.01.009
103. Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer C, Rychlik I, Cerna M, Romzova M, de Heer E, Baelde H, Bakker SJ, Zirie M, Rondeau E, Mathieson P, Saleem MA, Meyer J, Koppel H, Sauerhoefer S, Bartram CR, Nawroth P, Hammes HP, Yard BA, Zschocke J, van der Woude FJ (2005) Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 54(8):2320-2327
104. Jia H, Qi X, Fang S, Jin Y, Han X, Wang Y, Wang A, Zhou H (2009) Carnosine inhibits high glucose-induced mesangial cell proliferation through mediating cell cycle progression. Regul Pept 154(1-3):69-76. doi: 10.1016/j.regpep.2008.12.004
105. Jia G, Aroor AR, Martinez-Lemus LA, Sowers JR (2014) Overnutrition, mTOR signaling, and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 307(10):R1198-R1206. doi: 10.1152/ajpregu.00262.2014
106. Kamei J, Ohsawa M, Miyata S, Tanaka S (2008) Preventive effect of l-carnosine on changes in the thermal nociceptive threshold in streptozotocin-induced diabetic mice. Eur J Pharmacol 600(1-3):83-86. doi: 10.1016/j.ejphar.2008.10.002
107. Kemp TM, Barr EL, Zimmet PZ, Cameron AJ, Welborn TA, Colagiuri S, Phillips P, Shaw JE (2005) Glucose, lipid, and blood pressure control in Australian adults with type 2 diabetes: the 1999-2000 AusDiab. Diabetes Care 28(6):1490-1492
108. Kendrick IP, Kim HJ, Harris RC, Kim CK, Dang VH, Lam TQ, Bui TT, Wise JA (2009) The effect of 4 weeks beta-alanine supplementation and isokinetic training on carnosine concentrations in type I and II human skeletal muscle fibres. Eur J Appl Physiol 106(1):131-138. doi: 10.1007/s00421-009-0998-5
109. Kiely A, McClenaghan NH, Flatt PR, Newsholme P (2007) Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta-cell line. J Endocrinol 195(1):113-123
110. Kilhovd BK, Juutilainen A, Lehto S, Ronnemaa T, Torjesen PA, Hanssen KF, Laakso M (2007) Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study. Diabetologia 50(7):1409-1417
111. Kim JE, Chen J (2004) Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53(11):2748-2756
112. Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802(4):396-405. doi: 10.1016/j.bbadis.2009.12.009
113. Kim MY, Kim EJ, Kim YN, Choi C, Lee BH (2011) Effects of alpha-lipoic acid and l-carnosine supplementation on antioxidant activities and lipid profiles in rats. Nutr Res Pract 5(5):421-428. doi: 10.4162/nrp.2011.5.5.421
114. Kim SR, Eom TK, Byun HG (2014) Inhibitory effect of the carnosine-gallic acid synthetic peptide on MMP-2 and MMP-9 in human fibrosarcoma HT1080 cells. J Pept Sci 20(9):716-724. doi: 10.1002/psc.2658
115. Klein R, Lee KE, Knudtson MD, Gangnon RE, Klein BE (2009) Changes in visual impairment prevalence by period of diagnosis of diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 116(10):1937-1942
116. Kohen R, Yamamoto Y, Cundy KC, Ames BN (1988) Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci USA 85(9):3175-3179
117. Koo HY, Wallig MA, Chung BH, Nara TY, Cho BH, Nakamura MT (2008) Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver. Biochim Biophys Acta 1782(5):341-348
118. Koppel H, Riedl E, Braunagel M, Sauerhoefer S, Ehnert S, Godoy P, Sternik P, Dooley S, Yard BA (2011) l-Carnosine inhibits high-glucose-mediated matrix accumulation in human mesangial cells by interfering with TGF-beta production and signalling. Nephrol Dial Transplant 26(12):3852-3858. doi: 10.1093/ndt/gfr324
119. Kresta JY, Oliver JM, Jagim AR, Fluckey J, Riechman S, Kelly K, Meininger C, Mertens-Talcott SU, Rasmussen C, Kreider RB (2014) Effects of 28 days of beta-alanine and creatine supplementation on muscle carnosine, body composition and exercise performance in recreationally active females. J Int Soc Sports Nutr 11(1):55. doi: 10.1186/s12970-014-0055-6
120. Kulebyakin K, Karpova L, Lakonsteva E, Krasavin M, Boldyrev A (2012) Carnosine protects neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. Amino Acids 43(1):91-96
121. Kurdi A, De Meyer GR, Martinet W (2015) Potential therapeutic effects of mTOR inhibition in atherosclerosis. Br J Clin Pharmacol. doi: 10.1111/bcp.12820
122. Lambert EA, Straznicky NE, Dixon JB, Lambert GW (2015) Should the sympathetic nervous system be a target to improve cardiometabolic risk in obesity? Am J Physiol Heart Circ Physiol 309(2):H244-H258. doi: 10.1152/ajpheart.00096.2015
123. LeBlanc J, Soucy J (1994) Effects of carnosine on insulin and glucagon secretion in the dog. Nutr Res 14(11):1655-1660. doi: 10.1016/S0271-5317(05)80320-3
124. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC (2005) Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 513(1-2):145-150
125. Li YF, He RR, Tsoi B, Li XD, Li WX, Abe K, Kurihara H (2012) Anti-stress effects of carnosine on restraint-evoked immunocompromise in mice through spleen lymphocyte number maintenance. PLoS One 7(4):e33190
126. Lim M, Park L, Shin G, Hong H, Kang I, Park Y (2008) Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann N Y Acad Sci 1150:311-315
127. Liu WH, Liu TC, Yin MC (2008) Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Food Chem Toxicol 46(5):1503-1509
128. Liu Y, Cotillard A, Vatier C, Bastard J, Fellahi S, Stévant M, Allatif O, Langlois C, Bieuvelet S, Brochot A, Guilbot A, Clément K, Rizkalla S (2015) A dietary supplement containing cinnamon, chromium and carnosine decreases fasting plasma glucose and increases lean mass in overweight or obese pre-diabetic subjects: a randomized, placebo-controlled trial. PLoS One 10(12)
129. Lombardi C, Carubelli V, Lazzarini V, Vizzardi E, Bordonali T, Ciccarese C, Castrini AI, Dei Cas A, Nodari S, Metra M (2015) Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition 31(1):72-78. doi: 10.1016/j.nut.2014.04.021
130. Luchsinger JA (2012) Type 2 diabetes and cognitive impairment: linking mechanisms. J Alzheimers Dis 30(Suppl 2):S185-S198
131. Ma XY, Jiang ZY, Lin YC, Zheng CT, Zhou GL (2010) Dietary supplementation with carnosine improves antioxidant capacity and meat quality of finishing pigs. J Anim Physiol Anim Nutr 94(6):e286-e295
132. Ma J, Xiong JY, Hou WW, Yan HJ, Sun Y, Huang SW, Jin L, Wang Y, Hu WW, Chen Z (2012) Protective effect of carnosine on subcortical ischemic vascular dementia in mice. CNS Neurosci Ther 18(9):745-753. doi: 10.1111/j.1755-5949.2012.00362.x
133. Mark AB, Poulsen MW, Andersen S, Andersen JM, Bak MK, Ritz C, Holst JJ, Neilson J, de Courten B, Dragsted LO, Bugel S (2013) consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care 37(1):88-95
134. Matfin G (2007) Biomarkers in clinical trials and drug development: measurement of cardiometabolic risk. Br J Diabetes Vasc Dis 7:101-106
135. McDonough CW, Hicks PJ, Lu L, Langefeld CD, Freedman BI, Bowden DW (2009) The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans. Hum Genet 126(2):265-275
136. Miller MW, Sadeh N (2014) Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry 19(11):1156-1162. doi: 10.1038/mp.2014.111
137. Minihane AM, Vinoy S, Russell WR, Baka A, Roche HM, Tuohy KM, Teeling JL, Blaak EE, Fenech M, Vauzour D, McArdle HJ, Kremer BH, Sterkman L, Vafeiadou K, Benedetti MM, Williams CM, Calder PC (2015) Low-grade inflammation, diet composition and health: current research evidence and its translation. Br J Nutr 114(7):999-1012. doi: 10.1017/s0007114515002093
138. Mong MC, Chao CY, Yin MC (2011) Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Eur J Pharmacol 653(1-3):82-88. doi: 10.1016/j.ejphar.2010.12.001
139. Mudgal V, Madaan N, Mudgal A, Singh R, Mishra S (2010) Effect of toxic metals on human health. Open Nutraceuticals J 3:94-99
140. Muslin AJ (2008) MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond) 115(7):203-218. doi: 10.1042/cs20070430
141. Nagai K, Niijima A, Yamano T, Otani H, Okumra N, Tsuruoka N, Nakai M, Kiso Y (2003) Possible role of l-carnosine in the regulation of blood glucose through controlling autonomic nerves. Exp Biol Med 228(10):1138-1145
142. Nagai R, Murray DB, Metz TO, Baynes JW (2012) Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes 61(3):549-559
143. Neidle A, Kandera J (1974) Carnosine - an olfactory bulb peptide. Brain Res 80(2):359-364
144. Niijima A, Okui T, Matsumura Y, Yamano T, Tsuruoka N, Kiso Y, Nagai K (2002) Effects of l-carnosine on renal sympathetic nerve activity and DOCA-salt hypertension in rats. Auton Neurosci Basic Clin 97(2):99-102
145. Orioli M, Aldini G, Benfatto MC, Facino RM, Carini M (2007) HNE Michael adducts to histidine and histidine-containing peptides as biomarkers of lipid-derived carbonyl stress in urines: LC-MS/MS profiling in Zucker obese rats. Anal Chem 79(23):9174-9184. doi: 10.1021/ac7016184
146. Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A (2014) Role of advanced glycation end products in cellular signaling. Redox Biol 2:411-429. doi: 10.1016/j.redox.2013.12.016
147. Palinkas LA, Wingard DL, Barrett-Connor E (1990) Chronic illness and depressive symptoms in the elderly: a population-based study. J Clin Epidemiol 43(11):1131-1141
148. Park YJ, Volpe SL, Decker EA (2005) Quantitation of carnosine in humans plasma after dietary consumption of beef. J Agric Food Chem 53(12):4736-4739
149. Peguero JG, Arenas I, Lamas GA (2014) Chelation therapy and cardiovascular disease: connecting scientific silos to benefit cardiac patients. Trends Cardiovasc Med 24(6):232-240
150. Perry TL, Hansen S, Tischler B, Bunting R, Berry K (1967) Carnosinemia. A new metabolic disorder associated with neurologic disease and mental defect. N Engl J Med 277(23):1219-1227
151. Peters V, Schmitt CP, Zschocke J, Gross ML, Brismar K, Forsberg E (2012) Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids 42(6):2411-2416. doi: 10.1007/s00726-011-1046-4
152. Pfister F, Riedl E, Wang Q, vom Hagen F, Deinzer M, Harmsen MC, Molema G, Yard B, Feng Y, Hammes HP (2011) Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell Physiol Biochem 28(1):125-136
153. Pham-Huy L, He H, Pham-Huy C (2008) Free radicals, antioxidants in disease and health. Int J Biomed Sci 4(2):89-96
154. Quesnele JJ, Laframboise MA, Wong JJ, Kim P, Wells GD (2014) The effects of beta-alanine supplementation on performance: a systematic review of the literature. Int J Sport Nutr Exerc Metab 24(1):14-27
155. Rajanikant GK, Zemke D, Senut MC, Frenkel MB, Chen AF, Gupta R, Majid A (2007) Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke 38(11):3023-3031
156. Rashid I, van Reyk DM, Davies MJ (2007) Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett 581(5):1067-1070
157. Rathmann W, Giani G (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27(10):2568-2569 (author reply 2569)
158. Renner C, Asperger A, Seyffarth A, Meixensberger J, Gebhardt R, Gaunitz F (2010) Carnosine inhibits ATP production in cells from malignant glioma. Neurol Res 32(1):101-105. doi: 10.1179/016164109X12518779082237
159. Riedl E, Koeppel H, Pfister F, Peters V, Sauerhoefer S, Sternik P, Brinkkoetter P, Zentgraf H, Navis G, Henning RH, Van Den Born J, Bakker SJ, Janssen B, van der Woude FJ, Yard BA (2010) N-glycosylation of carnosinase influences protein secretion and enzyme activity: implications for hyperglycemia. Diabetes 59(8):1984-1990
160. Riedl E, Pfister F, Braunagel M, Brinkkotter P, Sternik P, Deinzer M, Bakker SJ, Henning RH, van den Born J, Kramer BK, Navis G, Hammes HP, Yard B, Koeppel H (2011) Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell Physiol Biochem 28(2):279-288
161. Saisho Y, Maruyama T, Hirose H, Saruta T (2007) Relationship between proinsulin-to-insulin ratio and advanced glycation endproducts in Japanese type 2 diabetic subjects. Diabetes Res Clin Pract 78(2):182-188
162. Sale C, Saunders B, Harris RC (2010) Effect of beta-alanine supplementation on muscle carnosine concentrations and exercise performance. Amino Acids 39(2):321-333. doi: 10.1007/s00726-009-0443-4
163. Sale C, Artioli GG, Gualano B, Saunders B, Hobson RM, Harris RC (2013) Carnosine: from exercise performance to health. Amino Acids 44(6):1477-1491. doi: 10.1007/s00726-013-1476-2
164. Sandyk R (1993) The relationship between diabetes mellitus and Parkinson's disease. Int J Neurosci 69(1-4):125-130
165. Sauerhofer S, Yuan G, Braun GS, Deinzer M, Neumaier M, Gretz N, Floege J, Kriz W, van der Woude F, Moeller MJ (2007) l-Carnosine, a substrate of carnosinase-1, influences glucose metabolism. Diabetes 56(10):2425-2432
166. Schaeffer HJ, Weber MJ (1999) Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19(4):2435-2444
167. Sears ME (2013) Chelation: harnessing and enhancing heavy metal detoxification - a review. Sci World J 2013:219840
168. Shalev I, Moffitt TE, Braithwaite AW, Danese A, Fleming NI, Goldman-Mellor S, Harrington HL, Houts RM, Israel S, Poulton R, Robertson SP, Sugden K, Williams B, Caspi A (2014) Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and post-traumatic stress disorder. Mol Psychiatry 19(11):1163-1170. doi: 10.1038/mp.2013.183
169. Sharif R, Thomas P, Zalewski P, Fenech M (2015) Zinc supplementation influences genomic stability biomarkers, antioxidant activity, and zinc transporter genes in an elderly Australian population with low zinc status. Mol Nutr Food Res 59(6):1200-1212. doi: 10.1002/mnfr.201400784
170. Sheinerman KS, Tsivinsky VG, Abdullah L, Crawford F, Umansky SR (2013) Plasma microRNA biomarkers for detection of mild cognitive impairment: biomarker validation study. Aging (Milano) 5(12):925-938
171. Shen J, Yao JF, Tanida M, Nagai K (2008a) Regulation of sympathetic nerve activity by l-carnosine in mammalian white adipose tissue. Neurosci Lett 441(1):100-104. doi: 10.1016/j.neulet.2008.06.027
172. Shen J, Yao JF, Tanida M, Nagai K (2008b) Regulation of sympathetic nerve activity by l-carnosine in mammalian white adipose tissue. Neurosci Lett 441(1):100-104
173. Shen Y, Zhang S, Fu L, Hu W, Chen Z (2008c) Carnosine attenuates mast cell degranulation and histamine release induced by oxygen-glucose deprivation. Cell Biochem Funct 26(3):334-338
174. Son DO, Satsu H, Kiso Y, Shimizu M (2004) Characterization of carnosine uptake and its physiological function in human intestinal epithelial Caco-2 cells. BioFactors 21(1-4):395-398
175. Stegen S, Everaert I, Deldicque L, Vallova S, de Courten B, Ukropcova B, Ukropec J, Derave W (2015) Muscle histidine-containing dipeptides are elevated by glucose intolerance in both rodents and men. PLoS One 10(3):e0121062
176. Stinghen AE, Massy ZA, Vlassara H, Striker GE, Boullier A (2015) Uremic toxicity of advanced glycation end products in CKD. J Am Soc Nephrol. doi: 10.1681/asn.2014101047
177. Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ (2005) Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab 90(11):5998-6005
178. Szczesniak D, Budzen S, Kopec W, Rymaszewska J (2014) Anserine and carnosine supplementation in the elderly: effects on cognitive functioning and physical capacity. Arch Gerontol Geriatr 59(2):485-490
179. Szwergold BS (2005) Carnosine and anserine act as effective transglycating agents in decomposition of aldose-derived Schiff bases. Biochem Biophys Res Commun 336(1):36-41. doi: 10.1016/j.bbrc.2005.08.033
180. Tan CK, Chong HC, Tan EH, Tan NS (2012) Getting 'Smad' about obesity and diabetes. Nutr Diabetes 2:e29. doi: 10.1038/nutd.2012.1
181. Tanida M, Niijima A, Fukuda Y, Sawai H, Tsuruoka N, Shen J, Yamada S, Kiso Y, Nagai K (2005) Dose-dependent effects of l-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats. Am J Physiol Regul Integr Comp Physiol 288(2):R447-R455
182. Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S, Carreau A, Cairns NJ, Carter C, Cowley DJ, Duverger D, Ganzhorn AJ, Guenet C, Heintzelmann B, Laucher V, Sauvage C, Smirnova T (2003) Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem 278(8):6521-6531
183. Thomas MC, Baynes JW, Thorpe SR, Cooper ME (2005) The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Curr Drug Targets 6(4):453-474
184. Thorp AA, Schlaich MP (2015) Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res 2015:341583
185. Tokunaga C, Yoshino K, Yonezawa K (2004) mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun 313(2):443-446
186. Trombley PQ, Horning MS, Blakemore LJ (1998) Carnosine modulates zinc and copper effects on amino acid receptors and synaptic transmission. Neuroreport 9(15):3503-3507
187. Tsai SJ, Kuo WW, Liu WH, Yin MC (2010) Antioxidative and anti-inflammatory protection from carnosine in the striatum of MPTP-treated mice. J Agric Food Chem 58(21):11510-11516
188. Valman HB, Brown RJ, Palmer T, Oberholzer VG, Levin B (1971) Protein intake and plasma amino-acids of infants of low birth weight. Br Med J 4(5790):789-791
189. Vetere A, Choudhary A, Burns SM, Wagner BK (2014) Targeting the pancreatic beta-cell to treat diabetes. Nat Rev Drug Discov 13(4):278-289
190. Vistoli G, Carini M, Aldini G (2012) Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs. Amino Acids 43(1):111-126
191. Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G (2013) Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res 47(Suppl 1):3-27. doi: 10.3109/10715762.2013.815348
192. Wang X, Martindale JL, Liu Y, Holbrook NJ (1998) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J 333(Pt 2):291-300
193. Wanic K, Placha G, Dunn J, Smiles A, Warram JH, Krolewski AS (2008) Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies. Diabetes 57(9):2547-2551
194. Watanabe N, Ikeda U (2004) Matrix metalloproteinases and atherosclerosis. Curr Atheroscler Rep 6(2):112-120
195. Wright E Jr, Scism-Bacon JL, Glass LC (2006) Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia. Int J Clin Pract 60(3):308-314
196. Yamano T, Niijima A, Iimori S, Tsuruoka N, Kiso Y, Nagai K (2001) Effect of l-carnosine on the hyperglycemia caused by intracranial injection of 2-deoxy-d-glucose in rats. Neurosci Lett 313(1-2):78-82
197. Yan H, Harding JJ (2005) Carnosine protects against the inactivation of esterase induced by glycation and a steroid. Biochim Biophys Acta 1741(1-2):120-126
198. Yan H, Guo Y, Zhang J, Ding Z, Ha W, Harding JJ (2008) Effect of carnosine, aminoguanidine, and aspirin drops on the prevention of cataracts in diabetic rats. Mol Vis 14:2282-2291
199. Yan SL, Wu ST, Yin MC, Chen HT, Chen HC (2009) Protective effects from carnosine and histidine on acetaminophen-induced liver injury. J Food Sci 74(8):H259-H265
200. Yuneva M, Bulygina E, Gallant S, Kramarenko G, Stvolinsky S, Semyonova M, Boldyrev A (1999) Effect of carnosine on age-induced changes in senescence-accelerated mice. J Antiaging Med 2(4):337-342
201. Zhang X, Wang Z, Li J, Gu D, Li S, Shen C, Song Z (2013) Increased 4-hydroxynonenal formation contributes to obesity-related lipolytic activation in adipocytes. PLoS One 8(8):e70663. doi: 10.1371/journal.pone.0070663
202. Zhang Z, Miao L, Wu X, Liu G, Peng Y, Xin X, Jiao B, Kong X (2014) Carnosine inhibits the proliferation of human gastric carcinoma cells by retarding Akt/mTOR/p70S6K signaling. J Cancer 5(5):382-389
203. Zhu JM, Wang B, Li J, Chen GM, Fan YG, Feng CC, Pan HF, Ye DQ (2013) D18S880 microsatellite polymorphism of carnosinase gene and diabetic nephropathy: a meta-analysis. Genetic Test Mol Biomarkers 17(4):289-294