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Volumn 290, Issue 43, 2015, Pages 26235-26248

Isolation of positive modulator of glucagon-like peptide-1 Signaling from trigonella foenum-graecum (Fenugreek) seed

Author keywords

[No Author keywords available]

Indexed keywords

BIOCHEMISTRY; BIOLOGY;

EID: 84944916912     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.672097     Document Type: Article
Times cited : (35)

References (50)
  • 1
    • 84878808238 scopus 로고    scopus 로고
    • Pharmacology, physiology, and mechanisms of incretin hormone action
    • Campbell, J. E., and Drucker, D. J. (2013) Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819-837.
    • (2013) Cell Metab. , vol.17 , pp. 819-837
    • Campbell, J.E.1    Drucker, D.J.2
  • 3
    • 84897848470 scopus 로고    scopus 로고
    • Central effects of GLP-1: New opportunities for treatments of neurodegenerative diseases
    • Hölscher, C. (2014) Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J. Endocrinol. 221, T31-T41.
    • (2014) J. Endocrinol. , vol.221 , pp. T31-T41
    • Hölscher, C.1
  • 6
    • 53249142132 scopus 로고    scopus 로고
    • Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority study
    • Duration-1 Study Group
    • Drucker, D. J., Buse, J. B., Taylor, K., Kendall, D. M., Trautmann, M., Zhuang, D., Porter, L., and DURATION-1 Study Group. (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority study. Lancet 372, 1240-1250.
    • (2008) Lancet , vol.372 , pp. 1240-1250
    • Drucker, D.J.1    Buse, J.B.2    Taylor, K.3    Kendall, D.M.4    Trautmann, M.5    Zhuang, D.6    Porter, L.7
  • 7
    • 78650753885 scopus 로고    scopus 로고
    • Incretin-based therapies for type 2 diabetes mellitus: Properties, functions, and clinical implications
    • Nauck, M. A. (2011) Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am. J. Med. 124, S3-S18.
    • (2011) Am. J. Med , vol.124 , pp. S3-S18
    • Nauck, M.A.1
  • 8
    • 33644618433 scopus 로고    scopus 로고
    • The biology of incretin hormones
    • Drucker, D. J. (2006) The biology of incretin hormones. Cell Metab. 3, 153-165.
    • (2006) Cell Metab , vol.3 , pp. 153-165
    • Drucker, D.J.1
  • 9
    • 84870054636 scopus 로고    scopus 로고
    • GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus
    • Meier, J. J. (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728-742.
    • (2012) Nat. Rev. Endocrinol , vol.8 , pp. 728-742
    • Meier, J.J.1
  • 10
    • 1442350411 scopus 로고    scopus 로고
    • Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects
    • Meier, J. J., Nauck, M. A., Kranz, D., Holst, J. J., Deacon, C. F., Gaeckler, D., Schmidt, W. E., and Gallwitz, B. (2004) Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53, 654-662.
    • (2004) Diabetes , vol.53 , pp. 654-662
    • Meier, J.J.1    Nauck, M.A.2    Kranz, D.3    Holst, J.J.4    Deacon, C.F.5    Gaeckler, D.6    Schmidt, W.E.7    Gallwitz, B.8
  • 11
    • 84876715030 scopus 로고    scopus 로고
    • Glucagon-like peptide-1 in the rat brain: Distribution of expression and functional implication
    • Gu, G., Roland, B., Tomaselli, K., Dolman, C. S., Lowe, C., and Heilig, J. S. (2013) Glucagon-like peptide-1 in the rat brain: distribution of expression and functional implication. J. Comp. Neurol. 521, 2235-2261.
    • (2013) J. Comp. Neurol. , vol.521 , pp. 2235-2261
    • Gu, G.1    Roland, B.2    Tomaselli, K.3    Dolman, C.S.4    Lowe, C.5    Heilig, J.S.6
  • 12
    • 79952310049 scopus 로고    scopus 로고
    • Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: What is up, what is down?
    • Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J., and Meier, J. J. (2011) Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54, 10-18.
    • (2011) Diabetologia , vol.54 , pp. 10-18
    • Nauck, M.A.1    Vardarli, I.2    Deacon, C.F.3    Holst, J.J.4    Meier, J.J.5
  • 13
    • 84876475252 scopus 로고    scopus 로고
    • Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: Systematic review and meta-analyses of clinical studies
    • Calanna, S., Christensen, M., Holst, J. J., Laferrère, B., Gluud, L. L., Vilsbøll, T., and Knop, F. K. (2013) Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 56, 965-972.
    • (2013) Diabetologia , vol.56 , pp. 965-972
    • Calanna, S.1    Christensen, M.2    Holst, J.J.3    Laferrère, B.4    Gluud, L.L.5    Vilsbøll, T.6    Knop, F.K.7
  • 15
    • 67651173077 scopus 로고    scopus 로고
    • Incretin-based therapies for type 2 diabetes mellitus
    • Lovshin, J. A., and Drucker, D. J. (2009) Incretin-based therapies for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 5, 262-269.
    • (2009) Nat. Rev. Endocrinol. , vol.5 , pp. 262-269
    • Lovshin, J.A.1    Drucker, D.J.2
  • 16
    • 84878185729 scopus 로고    scopus 로고
    • A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe?
    • Butler, P. C., Elashoff, M., Elashoff, R., and Gale, E. A. (2013) A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 36, 2118-2125.
    • (2013) Diabetes Care , vol.36 , pp. 2118-2125
    • Butler, P.C.1    Elashoff, M.2    Elashoff, R.3    Gale, E.A.4
  • 17
    • 0035487327 scopus 로고    scopus 로고
    • Classical and new roles of β-arrestins in the regulation of G-protein-coupled receptors
    • Pierce, K. L., and Lefkowitz, R. J. (2001) Classical and new roles of β-arrestins in the regulation of G-protein-coupled receptors. Nat. Rev. Neurosci. 2, 727-733.
    • (2001) Nat. Rev. Neurosci , vol.2 , pp. 727-733
    • Pierce, K.L.1    Lefkowitz, R.J.2
  • 18
    • 0028342447 scopus 로고
    • Signal transduction by the cloned glucagon-like peptide-1 receptor: Comparison with signaling by the endogenous receptors of beta cell lines
    • Widmann, C., Bürki, E., Dolci, W., and Thorens, B. (1994) Signal transduction by the cloned glucagon-like peptide-1 receptor: comparison with signaling by the endogenous receptors of beta cell lines. Mol. Pharmacol. 45, 1029-1035.
    • (1994) Mol. Pharmacol. , vol.45 , pp. 1029-1035
    • Widmann, C.1    Bürki, E.2    Dolci, W.3    Thorens, B.4
  • 19
    • 84930660533 scopus 로고    scopus 로고
    • Modulation of glucagon-like peptide-1 (GLP-1) potency by endocannabinoid- like lipids represents a novel mode of regulating GLP-1 receptor signaling
    • Cheng, Y. H., Ho, M. S., Huang, W. T., Chou, Y. T., and King, K. (2015) Modulation of glucagon-like peptide-1 (GLP-1) potency by endocannabinoid- like lipids represents a novel mode of regulating GLP-1 receptor signaling. J. Biol. Chem. 290, 14302-14313.
    • (2015) J. Biol. Chem. , vol.290 , pp. 14302-14313
    • Cheng, Y.H.1    Ho, M.S.2    Huang, W.T.3    Chou, Y.T.4    King, K.5
  • 20
    • 84893468344 scopus 로고    scopus 로고
    • Fenugreek use in patients with diabetes mellitus
    • Haber, S. L., and Keonavong, J. (2013) Fenugreek use in patients with diabetes mellitus. Am. J. Health Syst. Pharm. 70, 1196.
    • (2013) Am. J. Health Syst. Pharm , vol.70 , pp. 1196
    • Haber, S.L.1    Keonavong, J.2
  • 21
    • 84881490316 scopus 로고    scopus 로고
    • A novel insight on chronic AlCl3 neurotoxicity through IL-6 and GFAP expressions: Modulating effect of functional food fenugreek seeds
    • Belaïd-Nouira, Y., Bakhta, H., Samoud, S., Trimech, M., Haouas, Z., and Ben Cheikh, H. (2013) A novel insight on chronic AlCl3 neurotoxicity through IL-6 and GFAP expressions: modulating effect of functional food fenugreek seeds. Nutr. Neurosci. 16, 218-224.
    • (2013) Nutr. Neurosci. , vol.16 , pp. 218-224
    • Belaïd-Nouira, Y.1    Bakhta, H.2    Samoud, S.3    Trimech, M.4    Haouas, Z.5    Ben Cheikh, H.6
  • 22
    • 84906881291 scopus 로고    scopus 로고
    • Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis
    • Al-Okbi, S. Y. (2014) Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis. Toxicol. Ind. Health 30, 738-749.
    • (2014) Toxicol. Ind. Health , vol.30 , pp. 738-749
    • Al-Okbi, S.Y.1
  • 23
    • 84870300620 scopus 로고    scopus 로고
    • Antiallergic effect of trigonella foenum-graecum L. Extracts on allergic skin inflammation induced by trimellitic anhydride in BALB/c mice
    • Bae, M. J., Shin, H. S., Choi, D. W., and Shon, D. H. (2012) Antiallergic effect of Trigonella foenum-graecum L. extracts on allergic skin inflammation induced by trimellitic anhydride in BALB/c mice. J. Ethnopharmacol. 144, 514-522.
    • (2012) J. Ethnopharmacol , vol.144 , pp. 514-522
    • Bae, M.J.1    Shin, H.S.2    Choi, D.W.3    Shon, D.H.4
  • 24
    • 0033527663 scopus 로고    scopus 로고
    • Association of β-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization
    • Oakley, R. H., Laporte, S. A., Holt, J. A., Barak, L. S., and Caron, M. G. (1999) Association of β-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization. J. Biol. Chem. 274, 32248-32257.
    • (1999) J. Biol. Chem. , vol.274 , pp. 32248-32257
    • Oakley, R.H.1    Laporte, S.A.2    Holt, J.A.3    Barak, L.S.4    Caron, M.G.5
  • 25
    • 33750837563 scopus 로고    scopus 로고
    • High-content screening of knownGprotein-coupled receptors by arrestin translocation
    • Hudson, C. C., Oakley, R. H., Sjaastad, M. D., and Loomis, C. R. (2006) High-content screening of knownGprotein-coupled receptors by arrestin translocation. Methods Enzymol. 414, 63-78.
    • (2006) Methods Enzymol , vol.414 , pp. 63-78
    • Hudson, C.C.1    Oakley, R.H.2    Sjaastad, M.D.3    Loomis, C.R.4
  • 26
    • 0037028924 scopus 로고    scopus 로고
    • A highly enantioselective amino acid-catalyzed route to functionalized α-amino acids
    • Córdova, A., Notz, W., Zhong, G., Betancort, J. M., and Barbas, C. F. 3rd (2002) A highly enantioselective amino acid-catalyzed route to functionalized α-amino acids. J. Am. Chem. Soc. 124, 1842-1843.
    • (2002) J. Am. Chem. Soc. , vol.124 , pp. 1842-1843
    • Córdova, A.1    Notz, W.2    Zhong, G.3    Betancort, J.M.4    Barbas, C.F.5
  • 27
    • 0027209447 scopus 로고
    • Binding specificity and signal transduction of receptors for glucagon- like peptide-1(7-36)amide and gastric inhibitory polypeptide on RINm5F insulinoma cells
    • Gallwitz, B., Witt, M., Fölsch, U. R., Creutzfeldt, W., and Schmidt, W. E. (1993) Binding specificity and signal transduction of receptors for glucagon- like peptide-1(7-36)amide and gastric inhibitory polypeptide on RINm5F insulinoma cells. J. Mol. Endocrinol. 10, 259-268.
    • (1993) J. Mol. Endocrinol , vol.10 , pp. 259-268
    • Gallwitz, B.1    Witt, M.2    Fölsch, U.R.3    Creutzfeldt, W.4    Schmidt, W.E.5
  • 28
    • 0024114396 scopus 로고
    • The entero-insular axis: The new incretin candidate glucagon-like peptide-1(7-36)amide (GLP-1(7-36))amide
    • Göke, R., Göke, B., Richter, G., and Arnold, R. (1988) The entero-insular axis: The new incretin candidate glucagon-like peptide-1(7-36)amide (GLP-1(7-36))amide. Z. Gastroenterol. 26, 715-719.
    • (1988) Z. Gastroenterol , vol.26 , pp. 715-719
    • Göke, R.1    Göke, B.2    Richter, G.3    Arnold, R.4
  • 29
    • 84875966088 scopus 로고    scopus 로고
    • Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes
    • Fu, Z., Gilbert, E. R., and Liu, D. (2013) Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 9, 25-53.
    • (2013) Curr. Diabetes Rev. , vol.9 , pp. 25-53
    • Fu, Z.1    Gilbert, E.R.2    Liu, D.3
  • 30
    • 0036132087 scopus 로고    scopus 로고
    • Medium-dependence of the secondary structure of exendin-4 and glucagon- like-peptide-1
    • Andersen, N. H., Brodsky, Y., Neidigh, J. W., and Prickett, K. S. (2002) Medium-dependence of the secondary structure of exendin-4 and glucagon- like-peptide-1. Bioorg. Med. Chem. 10, 79-85.
    • (2002) Bioorg. Med. Chem. , vol.10 , pp. 79-85
    • Andersen, N.H.1    Brodsky, Y.2    Neidigh, J.W.3    Prickett, K.S.4
  • 31
    • 0025266913 scopus 로고
    • Glucagon-like peptide-I analogs: Effects on insulin secretion and adenosine 3', 5' -monophosphate formation
    • Gefel, D., Hendrick, G. K., Mojsov, S., Habener, J., and Weir, G. C. (1990) Glucagon-like peptide-I analogs: effects on insulin secretion and adenosine 3', 5' -monophosphate formation. Endocrinology 126, 2164-2168.
    • (1990) Endocrinology , vol.126 , pp. 2164-2168
    • Gefel, D.1    Hendrick, G.K.2    Mojsov, S.3    Habener, J.4    Weir, G.C.5
  • 32
    • 0023025947 scopus 로고
    • Effect of fenugreek seeds and leaves on blood glucose and serum insulin responses in human subjects
    • Sharma, R. D. (1986) Effect of fenugreek seeds and leaves on blood glucose and serum insulin responses in human subjects. Nutr. Res. 6, 1353-1364.
    • (1986) Nutr. Res. , vol.6 , pp. 1353-1364
    • Sharma, R.D.1
  • 33
    • 84892468157 scopus 로고    scopus 로고
    • Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: A meta-analysis of clinical trials
    • Neelakantan, N., Narayanan, M., de Souza, R. J., and van Dam, R. M. (2014) Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: A meta-analysis of clinical trials. Nutr. J. 13, 7.
    • (2014) Nutr. J. , vol.13 , pp. 7
    • Neelakantan, N.1    Narayanan, M.2    De Souza, R.J.3    Van Dam, R.M.4
  • 34
    • 0023872236 scopus 로고
    • Glucose-lowering effect of fenugreek in non-insulin dependent diabetics
    • Madar, Z., Abel, R., Samish, S., and Arad, J. (1988) Glucose-lowering effect of fenugreek in non-insulin dependent diabetics. Eur. J. Clin. Nutr. 42, 51-54.
    • (1988) Eur. J. Clin. Nutr , vol.42 , pp. 51-54
    • Madar, Z.1    Abel, R.2    Samish, S.3    Arad, J.4
  • 35
    • 34248563781 scopus 로고    scopus 로고
    • Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain
    • Runge, S., Schimmer, S., Oschmann, J., Schiødt, C. B., Knudsen, S. M., Jeppesen, C. B., Madsen, K., Lau, J., Thøgersen, H., and Rudolph, R. (2007) Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain. Biochemistry 46, 5830-5840.
    • (2007) Biochemistry , vol.46 , pp. 5830-5840
    • Runge, S.1    Schimmer, S.2    Oschmann, J.3    Schiødt, C.B.4    Knudsen, S.M.5    Jeppesen, C.B.6    Madsen, K.7    Lau, J.8    Thøgersen, H.9    Rudolph, R.10
  • 36
    • 84860532030 scopus 로고    scopus 로고
    • Converting peptides into drug leads by lipidation
    • Zhang, L., and Bulaj, G. (2012) Converting peptides into drug leads by lipidation. Curr. Med. Chem. 19, 1602-1618.
    • (2012) Curr. Med. Chem. , vol.19 , pp. 1602-1618
    • Zhang, L.1    Bulaj, G.2
  • 38
    • 37849026464 scopus 로고    scopus 로고
    • Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: Importance of fatty acid length, polarity, and bulkiness
    • Madsen, K., Knudsen, L. B., Agersoe, H., Nielsen, P. F., Thøgersen, H., Wilken, M., and Johansen, N. L. (2007) Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J. Med. Chem. 50, 6126-6132.
    • (2007) J. Med. Chem , vol.50 , pp. 6126-6132
    • Madsen, K.1    Knudsen, L.B.2    Agersoe, H.3    Nielsen, P.F.4    Thøgersen, H.5    Wilken, M.6    Johansen, N.L.7
  • 39
    • 77956249652 scopus 로고    scopus 로고
    • Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway- selective manner: Implications for drug screening
    • Koole, C., Wootten, D., Simms, J., Valant, C., Sridhar, R., Woodman, O. L., Miller, L. J., Summers, R. J., Christopoulos, A., and Sexton, P. M. (2010) Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway- selective manner: implications for drug screening. Mol. Pharmacol. 78, 456-465.
    • (2010) Mol. Pharmacol , vol.78 , pp. 456-465
    • Koole, C.1    Wootten, D.2    Simms, J.3    Valant, C.4    Sridhar, R.5    Woodman, O.L.6    Miller, L.J.7    Summers, R.J.8    Christopoulos, A.9    Sexton, P.M.10
  • 43
    • 47649122375 scopus 로고    scopus 로고
    • Review of selected Chinese herbal medicines in the treatment of type 2 diabetes
    • Wang, E., and Wylie-Rosett, J. (2008) Review of selected Chinese herbal medicines in the treatment of type 2 diabetes. Diabetes Educ. 34, 645-654.
    • (2008) Diabetes Educ , vol.34 , pp. 645-654
    • Wang, E.1    Wylie-Rosett, J.2
  • 44
    • 83455194630 scopus 로고    scopus 로고
    • The potential of fenugreek (Trigonella foenum-graecum) as a functional food and nutraceutical and its effects on glycemia and lipidemia
    • Roberts, K. T. (2011) The potential of fenugreek (Trigonella foenum-graecum) as a functional food and nutraceutical and its effects on glycemia and lipidemia. J. Med. Food 14, 1485-1489.
    • (2011) J. Med. Food , vol.14 , pp. 1485-1489
    • Roberts, K.T.1
  • 45
    • 70350447051 scopus 로고    scopus 로고
    • Effect of fenugreek fiber on satiety, blood glucose and insulin response and energy intake in obese subjects
    • Mathern, J. R., Raatz, S. K., Thomas, W., and Slavin, J. L. (2009) Effect of fenugreek fiber on satiety, blood glucose and insulin response and energy intake in obese subjects. Phytother. Res. 23, 1543-1548.
    • (2009) Phytother. Res. , vol.23 , pp. 1543-1548
    • Mathern, J.R.1    Raatz, S.K.2    Thomas, W.3    Slavin, J.L.4
  • 46
    • 34047254102 scopus 로고    scopus 로고
    • Soluble dietary fibre fraction of trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action
    • Hannan, J. M., Ali, L., Rokeya, B., Khaleque, J., Akhter, M., Flatt, P. R., and Abdel-Wahab, Y. H. (2007) Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action. Br. J. Nutr. 97, 514-521.
    • (2007) Br. J. Nutr , vol.97 , pp. 514-521
    • Hannan, J.M.1    Ali, L.2    Rokeya, B.3    Khaleque, J.4    Akhter, M.5    Flatt, P.R.6    Abdel-Wahab, Y.H.7
  • 47
    • 41749109134 scopus 로고    scopus 로고
    • Clinical observation on trigonella foenum-graecum L. Total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus
    • Lu, F. R., Shen, L., Qin, Y., Gao, L., Li, H., and Dai, Y. (2008) Clinical observation on trigonella foenum-graecum L. total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus. Chin. J. Integr. Med. 14, 56-60.
    • (2008) Chin. J. Integr. Med , vol.14 , pp. 56-60
    • Lu, F.R.1    Shen, L.2    Qin, Y.3    Gao, L.4    Li, H.5    Dai, Y.6
  • 48
    • 84863746781 scopus 로고    scopus 로고
    • Trigonelline: A plant alkaloid with therapeutic potential for diabetes and central nervous system disease
    • Zhou, J., Chan, L., and Zhou, S. (2012) Trigonelline: A plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Curr. Med. Chem. 19, 3523-3531.
    • (2012) Curr. Med. Chem , vol.19 , pp. 3523-3531
    • Zhou, J.1    Chan, L.2    Zhou, S.3


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