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http://dx.doi.org/10.14348/molcells.2021.2245

Cucurbitacin B Suppresses Hyperglycemia Associated with a High Sugar Diet and Promotes Sleep in Drosophila melanogaster  

Sang, Jiun (Department of Bio and Fermentation Convergence Technology, Kookmin University)
Dhakal, Subash (Department of Bio and Fermentation Convergence Technology, Kookmin University)
Lee, Youngseok (Department of Bio and Fermentation Convergence Technology, Kookmin University)
Abstract
Secondary metabolites enable plants to protect themselves from herbivorous insects. Among these, cucurbitacin B (cuc-B) is a bitter-tasting compound with promising pharmacological potential. Dietary exposure to cuc-B lowered the hemolymph glucose levels of Drosophila melanogaster fed with a high carbohydrate diet, which is homologous to high blood glucose in humans, and its effect was comparable to that of metformin, a well-known glucose-lowering drug. Furthermore, cuc-B reduced tissue sugar levels and glycogen levels, as well as triacylglycerol levels. Our results thus highlight the potential applicability of this compound to treat chronic metabolic diseases such as diabetes and obesity. Additionally, we analyzed sleep quality and taste-associative memory enhancement after cuc-B and metformin treatment. Both supplements increased nighttime bout length and metformin increased memory consolidation. Therefore, discarded shell of Cucurbitaceae could be processed into health supplements.
Keywords
cucurbitacin B; hypoglycemia; memory; metformin; sleep;
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1 Adeyemi, M.H. (2010). The potential of secondary metabolites in plant material as deterents against insect pests: a review. Afr. J. Pure Appl. Chem. 4, 243-246.
2 Bailey, C.J. (2017). Metformin: historical overview. Diabetologia 60, 1566-1576.   DOI
3 Campbell, S.S. and Tobler, I. (1984). Animal sleep: a review of sleep duration across phylogeny. Neurosci. Biobehav. Rev. 8, 269-300.   DOI
4 Catterson, J.H., Knowles-Barley, S., James, K., Heck, M.M., Harmar, A.J., and Hartley, P.S. (2010). Dietary modulation of Drosophila sleep-wake behaviour. PLoS One 5, e12062.   DOI
5 Chen, J.C., Chiu, M.H., Nie, R.L., Cordell, G.A., and Qiu, S.X. (2005). Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat. Prod. Rep. 22, 386-399.   DOI
6 Chen, X., Bao, J., Guo, J., Ding, Q., Lu, J., Huang, M., and Wang, Y. (2012). Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anticancer Drugs 23, 777-787.   DOI
7 Collier, C.A., Bruce, C.R., Smith, A.C., Lopaschuk, G., and Dyck, D.J. (2006). Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 291, E182-E189.   DOI
8 Dus, M., Min, S., Keene, A.C., Lee, G.Y., and Suh, G.S. (2011). Taste-independent detection of the caloric content of sugar in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 108, 11644-11649.   DOI
9 De Truchis, P., Kirstetter, M., Perier, A., Meunier, C., Zucman, D., Force, G., Doll, J., Katlama, C., Rozenbaum, W., and Masson, H. (2007). Reduction in triglyceride level with N-3 polyunsaturated fatty acids in HIV-infected patients taking potent antiretroviral therapy: a randomized prospective study. J. Acquir. Immune Defic. Syndr. 44, 278-285.   DOI
10 Duca, F.A., Cote, C.D., Rasmussen, B.A., Zadeh-Tahmasebi, M., Rutter, G.A., Filippi, B.M., and Lam, T.K. (2015). Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat. Med. 21, 506.   DOI
11 Hendricks, J.C., Finn, S.M., Panckeri, K.A., Chavkin, J., Williams, J.A., Sehgal, A., and Pack, A.I. (2000). Rest in Drosophila is a sleep-like state. Neuron 25, 129-138.   DOI
12 Hundal, R.S., Krssak, M., Dufour, S., Laurent, D., Lebon, V., Chandramouli, V., Inzucchi, S.E., Schumann, W.C., Petersen, K.F., and Landau, B.R. (2000). Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49, 2063-2069.   DOI
13 Kim, Y.C., Choi, D., Cha, A., Lee, Y.G., Baek, N.I., Rimal, S., Sang, J., Lee, Y., and Lee, S. (2020). Critical enzymes for biosynthesis of cucurbitacin derivatives in watermelon and their biological significance. Commun. Biol. 3, 1-11.   DOI
14 Ikeda, T., Iwata, K., and Murakami, H. (2000). Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Biochem. Pharmacol. 59, 887-890.   DOI
15 Kajbaf, F., Fendri, S., Basille-Fantinato, A., Diouf, M., Rose, D., Jounieaux, V., and Lalau, J.D. (2014). The relationship between metformin therapy and sleep quantity and quality in patients with Type 2 diabetes referred for potential sleep disorders. Diabet. Med. 31, 577-580.   DOI
16 Kaushik, U., Aeri, V., and Mir, S.R. (2015). Cucurbitacins-an insight into medicinal leads from nature. Pharmacogn. Rev. 9, 12.   DOI
17 Kim, K.H., Lee, I.S., Park, J.Y., Kim, Y., An, E.J., and Jang, H.J. (2018). Cucurbitacin b induces hypoglycemic effect in diabetic mice by regulation of amp-activated protein kinase alpha and glucagon-like peptide-1 via bitter taste receptor signaling. Front. Pharmacol. 9, 1071.   DOI
18 Kim, S.H., Lee, Y., Akitake, B., Woodward, O.M., Guggino, W.B., and Montell, C. (2010). Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. Proc. Natl. Acad. Sci. U. S. A. 107, 8440-8445.   DOI
19 Kirkhart, C. and Scott, K. (2015). Gustatory learning and processing in the Drosophila mushroom bodies. J. Neurosci. 35, 5950-5958.   DOI
20 Lee, Y., Kang, M.J., Shim, J., Cheong, C.U., Moon, S.J., and Montell, C. (2012). Gustatory receptors required for avoiding the insecticide L-canavanine. J. Neurosci. 32, 1429-1435.   DOI
21 Lee, Y., Kim, S.H., and Montell, C. (2010). Avoiding DEET through insect gustatory receptors. Neuron 67, 555-561.   DOI
22 Molyneux, R.J., Lee, S.T., Gardner, D.R., Panter, K.E., and James, L.F. (2007). Phytochemicals: the good, the bad and the ugly? Phytochemistry 68, 2973-2985.   DOI
23 Lee, Y., Moon, S.J., and Montell, C. (2009). Multiple gustatory receptors required for the caffeine response in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 106, 4495-4500.   DOI
24 Lin, H.Z., Yang, S.Q., Chuckaree, C., Kuhajda, F., Ronnet, G., and Diehl, A.M. (2000). Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med. 6, 998-1003.   DOI
25 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., and MacDonald, M.J. (2014). Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546.   DOI
26 Masek, P., Worden, K., Aso, Y., Rubin, G.M., and Keene, A.C. (2015). A dopamine-modulated neural circuit regulating aversive taste memory in Drosophila. Curr. Biol. 25, 1535-1541.   DOI
27 Meunier, N., Belgacem, Y.H., and Martin, J.R. (2007). Regulation of feeding behaviour and locomotor activity by takeout in Drosophila. J. Exp. Biol. 210, 1424-1434.   DOI
28 Moon, S.J., Lee, Y., Jiao, Y., and Montell, C. (2009). A Drosophila gustatory receptor essential for aversive taste and inhibiting male-to-male courtship. Curr. Biol. 19, 1623-1627.   DOI
29 Ohadoma, S. and Michael, H. (2011). Effects of co-administration of methanol leaf extract of Catharanthus roseus on the hypoglycemic activity of metformin and glibenclamide in rats. Asian Pac. J. Trop. Med. 4, 475-477.   DOI
30 Oliveira, D.T.d., Fernandes, I.d.C., Sousa, G.G.d., Santos, T.A.P.d., Paiva, N.C.N.d., Carneiro, C.M., Evangelista, E.A., Barboza, N.R., and Guerra-Sa, R. (2020). High-sugar diet leads to obesity and metabolic diseases in ad libitum-fed rats irrespective of caloric intake. Arch. Endocrinol. Metab. 64, 71-81.   DOI
31 Rimal, S., Sang, J., Dhakal, S., and Lee, Y. (2020). Cucurbitacin B activates bitter-sensing gustatory receptor neurons via gustatory receptor 33a in Drosophila melanogaster. Mol. Cells 43, 530.   DOI
32 Park, J.H. and Kwon, J.Y. (2011). A systematic analysis of Drosophila gustatory receptor gene expression in abdominal neurons which project to the central nervous system. Mol. Cells 32, 375.   DOI
33 Pintana, H., Apaijai, N., Pratchayasakul, W., Chattipakorn, N., and Chattipakorn, S.C. (2012). Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci. 91, 409-414.   DOI
34 Poudel, S. and Lee, Y. (2018). Impaired taste associative memory and memory enhancement by feeding omija in Parkinson's disease fly model. Mol. Cells 41, 646.   DOI
35 Pulito, C., Sanli, T., Rana, P., Muti, P., Blandino, G., and Strano, S. (2013). Metformin: on ongoing journey across diabetes, cancer therapy and prevention. Metabolites 3, 1051-1075.   DOI
36 Rimal, S. and Lee, Y. (2019). Molecular sensor of nicotine in taste of Drosophila melanogaster. Insect Biochem. Mol. Biol. 111, 103178.   DOI
37 Rovenko, B.M., Kubrak, O.I., Gospodaryov, D.V., Perkhulyn, N.V., Yurkevych, I.S., Sanz, A., Lushchak, V., and Lushchak, V.I. (2015). High sucrose consumption promotes obesity whereas its low consumption induces oxidative stress in Drosophila melanogaster. J. Insect Physiol. 79, 42-54.   DOI
38 Rowan, J.A., Hague, W.M., Gao, W., Battin, M.R., and Moore, M.P. (2008). Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med. 358, 2003-2015.   DOI
39 Sang, J., Rimal, S., and Lee, Y. (2019). Gustatory receptor 28b is necessary for avoiding saponin in Drosophila melanogaster. EMBO Rep. 20, e47328.
40 Seetharaman, S. (2016). The influences of dietary sugar and related metabolic disorders on cognitive aging and dementia. In Molecular Basis of Nutrition and Aging, M. Malavolta, ed. (San Diego: Elsevier), pp. 331-344.
41 Shaw, P.J., Cirelli, C., Greenspan, R.J., and Tononi, G. (2000). Correlates of sleep and waking in Drosophila melanogaster. Science 287, 1834-1837.   DOI
42 Slack, C., Foley, A., and Partridge, L. (2012). Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila. PLoS One 7, e47699.   DOI
43 Thimmappa, R., Geisler, K., Louveau, T., O'Maille, P., and Osbourn, A. (2014). Triterpene biosynthesis in plants. Annu. Rev. Plant Biol. 65, 225-257.   DOI
44 Vanderheyden, W.M., Gerstner, J.R., Tanenhaus, A., Yin, J.C., and Shaw, P.J. (2013). ERK phosphorylation regulates sleep and plasticity in Drosophila. PLoS One 8, e81554.   DOI
45 Vella, S., Buetow, L., Royle, P., Livingstone, S., Colhoun, H., and Petrie, J. (2010). The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 53, 809-820.   DOI
46 Wigglesworth, V. (1949). The utilization of reserve substances in Drosophila during flight. J. Exp. Biol. 26, 150-163.   DOI
47 Yeh, S.H.H., Shie, F.S., Liu, H.K., Yao, H.H., Kao, P.C., Lee, Y.H., Chen, L.M., Hsu, S.M., Chao, L.J., and Wu, K.W. (2020). A high-sucrose diet aggravates Alzheimer's disease pathology, attenuates hypothalamic leptin signaling, and impairs food-anticipatory activity in APPswe/PS1dE9 mice. Neurobiol. Aging 90, 60-74.   DOI
48 Zou, C., Liu, G., Liu, S., Liu, S., Song, Q., Wang, J., Feng, Q., Su, Y., and Li, S. (2018). Cucurbitacin B acts a potential insect growth regulator by antagonizing 20-hydroxyecdysone activity. Pest Manag. Sci. 74, 1394-1403.   DOI