Phloridzin Highly Accumulated in Malus rockii Rehder and Its Structure Revision and Hypolipidemic Activity

Abstract

Phloridzin is a lead compound of the prestigious antidiabetic gliflozins. The present study found that phloridzin highly accumulated in Malus rockii Rehder. The content of phloridzin in M. rockii was the highest among wild plants, with the percentage of 15.54% in the dry leaves. The structure of phloridzin was revised by proton exchange experiments and extensive 2D NMR spectra. Phloridzin exhibited significant hypolipidemic activity in golden Syrian hamsters maybe by increasing the expression of CYP7A1, at the doses of 50 mg/kg and 200 mg/kg. The total performance of anti-hyperlipidemic effect of phloridzin may be superior to that of lovastatin, though lovastatin was more active than phloridzin. In addition, phloridzin exhibited moderate antimalarial activity with inhibition ratio of 31.3 ± 10.9% at a dose of 25 mg/kg/day, and showed moderate analgesic activity with 28.0% inhibition at a dose of 50 mg/kg.

Key words

Malus rockii - Rosaceae - phloridzin - hypolipidemic activity - antimalarial activity - analgesic activity

• References

• 1 Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41: 111-188
• 2 Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, Ferranti SD, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation 2019; 139: e1082-e1143
• 3 Abdullah SM, Defina LF, Leonard D, Barlow CE, Radford NB, Willis BL, Rohatgi A, Mcguire DK, De Lemos JA, Grundy SM, Berry JD, Khera A. Long-term association of low-density lipoprotein cholesterol with cardiovascular mortality in individuals at low 10-year risk of atherosclerotic cardiovascular disease. Circulation 2018; 138: 2315-2325
• 4 Goldstein JL, Brown MS. A century of cholesterol and coronaries: From plaques to genes to statins. Cell 2015; 161: 161-172
• 5 Vasan RS, Pan S, Larson MG, Mitchell GF, Xanthakis V. Arteriosclerosis, atherosclerosis, and cardiovascular health: Joint relations to the incidence of cardiovascular disease. Hypertension 2021; 78: 1232-1240
• 6 Defilippis AP, Trainor PJ, Thanassoulis G, Brumback LC, Post WS, Tsai MY, Tsimikas S. Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis. Eur Heart J 2021;
• 7 World Health Organization. Cardiovascular diseases (CVDs). Accessed September 28, 2021 at: https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
• 8 The Writing Committee of the Report on Cardiovascular Health and Diseases in China. Report on cardiovascular health and diseases burden in China: An updated summary of 2020. Chin Circ J 2021; 36: 521-545
• 9 Zhao D, Liu J, Wang M, Zhang X, Zhou M. Epidemiology of cardiovascular disease in China: Current features and implications. Nat Rev Cardiol 2019; 16: 203-212
• 10 Stevens W, Peneva D, Li JZ, Liu LZ, Liu G, Gao R, Lakdawalla DN. Estimating the future burden of cardiovascular disease and the value of lipid and blood pressure control therapies in China. BMC Health Serv Res 2016; 16: 175
• 11 Lu Y, Zhang H, Lu J, Ding Q, Li X, Wang X, Sun D, Tan L, Mu L, Liu J, Feng F, Yang H, Zhao H, Schulz WL, Krumholz HM, Pan X, Li J. Prevalence of dyslipidemia and availability of lipid-lowering medications among primary health care settings in China. JAMA Netw Open 2021; 4: e2127573
• 12 Mangravite LM, Engelhardt BE, Medina MW, Smith JD, Brown CD, Chasman DI, Mecham BH, Howie B, Shim H, Naidoo D, Feng Q, Rieder MJ, Chen YDI, Rotter JI, Ridker PM, Hopewell JC, Parish S, Armitage J, Collins R, Wilke RA, Nickerson DA, Stephens M, Krauss RM. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 2013; 502: 377-380
• 13 Benes LB, Bassi NS, Davidson MH. The risk of hepatotoxicity, new onset diabetes and rhabdomyolysis in the era of high-intensity statin therapy: does statin type matter?. Prog Cardiovasc Dis 2016; 59: 145-152
• 14 Curfman G. Statin-associated myopathy–an elusive clinical problem. JAMA Intern Med 2018; 178: 1230
• 15 Attar A. Response to statin therapy in the real world. Eur J Prev Cardiol 2020;
• 16 Marta KL, Anna G, Jakub M, Juliusz P. Genetic and non-genetic determinants of the pharmacological activity of statins. Curr Drug Metab 2016; 17: 877-896
• 17 Jia MR, Zhang Y. Dictionary of Chinese Ethnic Medicine. Beijing: China Medical Science and Technology Press; 2016: 518
• 18 Dao PTA, Quan TL, Mai TT. Antioxidant constituents from the stem of Tetrastigma erusbescense Planch. (Vitaceae). Nat Prod Sci 2014; 20: 22-28
• 19 Rui-Lin N, Tanaka T, Zhou J, Tanaka O. Phlorizin and trilobatin, sweet dihydrochalcone-glucosides from leaves of Lithocarpus litseifolius (Hance) Rehd. (Fagaceae). Agric Biol Chem 1982; 46: 1933-1934
• 20 Gosch C, Halbwirth H, Stich K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry 2010; 71: 838-843
• 21 Guo DY, Wang X, Qin HE, Li Z, Du X, Wang JZ. Quality analysis of Malus hupehensis at different altitudes and growth stages. J Chin Med Mater 2013; 36: 1238-1240
• 22 Li MQ, Fan YK, Li X, Liu XY, Li XY. Determination of LD₅₀ of phloridzin and phloridzin in mice. China Pharm 2013; 16: 466-468
• 23 Chiang JYL. Bile acid metabolism and signaling. Compr Physiol 2013; 3: 1191-1212
• 24 Shen Y, Cui SJ, Chen H, Shen L, Wang M, Dong X, Xiao CJ, Jiang B. Antimalarial eudesmane sesquiterpenoids from Dobinea delavayi . J Nat Prod 2020; 83: 927-936
• 25 Shen Y, Chen H, Shen L, Li HX, Dong X, Xiao CJ, Jiang B. Dodelates A–E: five dimeric eudesmane sesquiterpenoids from Dobinea delavayi . Bioorg Chem 2020; 95: 103488
• 26 Qiu L, Xiao CJ, Shen Y, Xu W, Liu XB, Dong X, Jiang B. Bioactive hydroxypropionylated glucose derivatives from Astragalus bhotanensis . Nat Prod Res 2021; 35: 5066-5074
• 27 Li HX, Xiao CJ, Wang M, Cui SJ, Li HF, Wang KL, Dong X, Jiang B. Four new phenylethanoid glycosides from Ternstroemia gymnanthera and their analgesic activities. Phytochem Lett 2019; 34: 25-29
• 28 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
• 29 Zhang L, Haddouti EM, Beckert H, Biehl R, Pariyar S, Rüwald JM, Li X, Jaenisch M, Burger C, Wirtz DC, Kabir K, Schildberg FA. Investigation of cytotoxicity, oxidative stress, and inflammatory responses of tantalum nanoparticles in THP-1-derived macrophages. Mediat Inflamm 2020; 2020: 3824593
• 30 Forbes-Hernandez TY, Giampieri F, Gasparrini M, Afrin S, Mazzoni L, Cordero MD, Mezzetti B, Quiles JL, Battino M. Lipid accumulation in HepG2 cells is attenuated by strawberry extract through AMPK activation. Nutrients 2017; 9: 621
• 31 Zeng H, Chen P, Chang Q, Zheng B, Zhang Y. Hypolipidemic effect of polysaccharides from Fortunella margarita (Lour.) Swingle in hyperlipidemic rats. Food Chem Toxicol 2019; 132: 110663