Abstract
Millions of people worldwide have diabetes, which is diagnosed by fasting blood glucose levels exceeding 126 mg/dL. Regardless of the type of diabetes, prolonged hyperglycemia is damaging to several organs including eyes, kidneys, nerve, and/or heart. The damages are associated with a high risk of morbidity and mortality. Diabetes has been implicated in ischemia in the microvasculature of the target tissues, which occurs due to the insufficient perfusion of tissues. The resulting occlusion and pain affect the quality of life. Multiple therapeutic approaches have been proposed for a long time to overcome these vascular complications. Apart from systemically controlling high glucose levels, other therapeutic strategies are not well understood. In this review, we summarize the recent literature for biochemical/cellular targets that are being utilized for the treatment of diabetic microvascular diseases. These targets, which are closely associated with mitochondrial dysfunction, include the polyol and diacylglycerol-protein kinase C pathways, oxidative stress, non-enzymatic glycation and the formation of advanced glycation end products, and immune dysregulation/inflammation.
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References
Ahad A, Mujeeb M, Ahsan H, Siddiqui WA (2014) Prophylactic effect of baicalein against renal dysfunction in type 2 diabetic rats. Biochimie 106:101–110
Al-Onazi AS, Al-Rasheed NM, Attia HA, Al-Rasheed NM, Ahmed RM, Al-Amin MA, Poizat C (2016) Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-beta1/Smad and GRAP pathways. J Pharm Pharmacol 68:219–232
Alter ML, Ott IM, Von Websky K, Tsuprykov O, Sharkovska Y, Krause-Relle K, Raila J, Henze A, Klein T, Hocher B (2012) DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res 36:119–130
Avogaro A, Fadini GP (2014) The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care 37:2884–2894
Bansal D, Badhan Y, Gudala K, Schifano F (2013) Ruboxistaurin for the treatment of diabetic peripheral neuropathy: a systematic review of randomized clinical trials. Diabetes Metab J 37:375–384
Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BEK, Hughes TM, Craft S, Freedman BI, Bowden DW, Vinik AI, Casellini CM (2017) Diabetic microvascular disease: an endocrine society scientific statement. J Clin Endocrinol Metab 102:4343–4410
Bourhill T, Narendran A, Johnston RN (2017) Enzastaurin: a lesson in drug development. Crit Rev Oncol Hematol 112:72–79
Brahma MK, Pepin ME, Wende AR (2017) My sweetheart is broken: role of glucose in diabetic cardiomyopathy. Diabetes Metab J 41:1–9
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820
Buck MD, O’sullivan D, Klein GRI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, Van Der Windt GJ, Chen Q, Huang SC, O’neill CM, Edelson BT, Pearce EJ, Sesaki H, Huber TB, Rambold AS, Pearce EL (2016) Mitochondrial dynamics controls t cell fate through metabolic programming. Cell 166:63–76
Calderon GD, Juarez OH, Hernandez GE, Punzo SM, De La Cruz ZD (2017) Oxidative stress and diabetic retinopathy: development and treatment. Eye (Lond) 31:1122–1130
Campochiaro PA, Group CPS (2004) Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci 45:922–931
Cheng YS, Chao J, Chen C, Lv LL, Han YC, Liu BC (2018) The PKCbeta-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy. J Pharm Pharmacol. https://doi.org/10.1111/jphp.13043
Chin MP, Bakris GL, Block GA, Chertow GM, Goldsberry A, Inker LA, Heerspink HJL, O’grady M, Pergola PE, Wanner C, Warnock DG, Meyer CJ (2018) Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol 47:40–47
Clermont A, Chilcote TJ, Kita T, Liu J, Riva P, Sinha S, Feener EP (2011) Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats. Diabetes 60:1590–1598
De Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, Mcmurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM, Investigators BT (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 369:2492–2503
Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97:12222–12226
Du Y, Miller CM, Kern TS (2003) Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med 35:1491–1499
Durpes MC, Morin C, Paquin-Veillet J, Beland R, Pare M, Guimond MO, Rekhter M, King GL, Geraldes P (2015) PKC-beta activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis. Cardiovasc Res 106:303–313
Eid AA, Ford BM, Block K, Kasinath BS, Gorin Y, Ghosh-Choudhury G, Barnes JL, Abboud HE (2010) AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes. J Biol Chem 285:37503–37512
Ertunc ME, Hotamisligil GS (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099–2114
Fakhruddin S, Alanazi W, Jackson KE (2017) Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J Diabetes Res 2017:8379327
Forbes JM, Coughlan MT, Cooper ME (2008) Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57:1446–1454
Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070
Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605
Gorin Y, Wauquier F (2015) Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease. Mol Cells 38:285–296
Hotamisligil GS (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177–185
Hotamisligil GS, Davis RJ (2016) Cell signaling and stress responses. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a006072
Hou Y, Shi Y, Han B, Liu X, Qiao X, Qi Y, Wang L (2018) The antioxidant peptide SS31 prevents oxidative stress, downregulates CD36 and improves renal function in diabetic nephropathy. Nephrol Dial Transplant 33:1908–1918
Isakov N (2018) Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Semin Cancer Biol 48:36–52
Ito A, Hong C, Oka K, Salazar JV, Diehl C, Witztum JL, Diaz M, Castrillo A, Bensinger SJ, Chan L, Tontonoz P (2016) Cholesterol accumulation in CD11c(+) immune cells is a causal and targetable factor in autoimmune disease. Immunity 45:1311–1326
Jha JC, Gray SP, Barit D, Okabe J, El-Osta A, Namikoshi T, Thallas-Bonke V, Wingler K, Szyndralewiez C, Heitz F, Touyz RM, Cooper ME, Schmidt HH, Jandeleit-Dahm KA (2014) Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol 25:1237–1254
Jha JC, Thallas-Bonke V, Banal C, Gray SP, Chow BS, Ramm G, Quaggin SE, Cooper ME, Schmidt HH, Jandeleit-Dahm KA (2016) Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy. Diabetologia 59:379–389
Jung GS, Jeon JH, Choe MS, Kim SW, Lee IK, Kim MK, Park KG (2016) Renoprotective effect of gemigliptin, a dipeptidyl peptidase-4 inhibitor, in streptozotocin-induced type 1 diabetic mice. Diabetes Metab J 40:211–221
Jung SB, Choi MJ, Ryu D, Yi HS, Lee SE, Chang JY, Chung HK, Kim YK, Kang SG, Lee JH, Kim KS, Kim HJ, Kim CS, Lee CH, Williams RW, Kim H, Lee HK, Auwerx J, Shong M (2018) Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat Commun 9:1551
Kanasaki K (2018) The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin. Clin Sci (Lond) 132:489–507
Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, Ishigaki Y, Kitada M, Srivastava SP, Koya D (2014) Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 63:2120–2131
Kawanami D, Matoba K, Sango K, Utsunomiya K (2016) Incretin-based therapies for diabetic complications: basic mechanisms and clinical evidence. Int J Mol Sci. https://doi.org/10.3390/ijms17081223
Kiritoshi S, Nishikawa T, Sonoda K, Kukidome D, Senokuchi T, Matsuo T, Matsumura T, Tokunaga H, Brownlee M, Araki E (2003) Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52:2570–2577
Kita T, Clermont AC, Murugesan N, Zhou Q, Fujisawa K, Ishibashi T, Aiello LP, Feener EP (2015) Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema. Diabetes 64:3588–3599
Koya D, King GL (1998) Protein kinase C activation and the development of diabetic complications. Diabetes 47:859–866
Kumar B, Gupta SK, Srinivasan BP, Nag TC, Srivastava S, Saxena R, Jha KA (2013) Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 87:65–74
Lassegue B, San Martin A, Griendling KK (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110:1364–1390
Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80:780–787
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184
Mahmoodnia L, Aghadavod E, Beigrezaei S, Rafieian-Kopaei M (2017) An update on diabetic kidney disease, oxidative stress and antioxidant agents. J Renal Inj Prev 6:153–157
Mannucci E, Dicembrini I, Lauria A, Pozzilli P (2013) Is glucose control important for prevention of cardiovascular disease in diabetes? Diabetes Care 36(Suppl 2):S259–263
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsboll T, Investigators S- (2016a) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, Committee LS, Investigators LT (2016b) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322
Mclaughlin T, Ackerman SE, Shen L, Engleman E (2017) Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest 127:5–13
Meenatchi P, Purushothaman A, Maneemegalai S (2017) Antioxidant, antiglycation and insulinotrophic properties of Coccinia grandis (L.) in vitro: possible role in prevention of diabetic complications. J Tradit Complement Med 7:54–64
Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, Tourlomousis P, Dabritz JHM, Gottlieb E, Latorre I, Corr SC, Mcmanus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O’neill LA (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167(457–470):e413
Nebbioso M, Pranno F, Pescosolido N (2013) Lipoic acid in animal models and clinical use in diabetic retinopathy. Expert Opin Pharmacother 14:1829–1838
Nenna A, Nappi F, Avtaar Singh SS, Sutherland FW, Di Domenico F, Chello M, Spadaccio C (2015) Pharmacologic approaches against advanced glycation end products (AGEs) in diabetic cardiovascular disease. Res Cardiovasc Med 4:e26949
Noh H, King GL (2007) The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl 106:S49–53
Nuzzo E, Berg KM, Andersen LW, Balkema J, Montissol S, Cocchi MN, Liu X, Donnino MW (2015) Pyruvate dehydrogenase activity is decreased in the peripheral blood mononuclear cells of patients with sepsis. A prospective observational trial. Ann Am Thorac Soc 12:1662–1666
Ola MS, Ahmed MM, Abuohashish HM, Al-Rejaie SS, Alhomida AS (2013) Telmisartan ameliorates neurotrophic support and oxidative stress in the retina of streptozotocin-induced diabetic rats. Neurochem Res 38:1572–1579
Ono Y, Mizuno K, Takahashi M, Miura Y, Watanabe T (2013) Suppression of advanced glycation and lipoxidation end products by angiotensin II type-1 receptor blocker candesartan in type 2 diabetic patients with essential hypertension. Fukushima J Med Sci 59:69–75
Orr JW, Newton AC (1992) Interaction of protein kinase C with phosphatidylserine. 2. Specificity and regulation. Biochemistry 31:4667–4673
Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436–2443
Park S, Bivona BJ, Ford SM Jr, Xu S, Kobori H, De Garavilla L, Harrison-Bernard LM (2013) Direct evidence for intrarenal chymase-dependent angiotensin II formation on the diabetic renal microvasculature. Hypertension 61:465–471
Park S, Jeon JH, Min BK, Ha CM, Thoudam T, Park BY, Lee IK (2018) Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism. Diabetes Metab J 42:270–281
Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO (2016) Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354:481–484
Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG, Investigators BS (2011) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 365:327–336
Phan AT, Doedens AL, Palazon A, Tyrakis PA, Cheung KP, Johnson RS, Goldrath AW (2016) Constitutive glycolytic metabolism supports CD8(+) T cell effector memory differentiation during viral infection. Immunity 45:1024–1037
Pollack RM, Donath MY, Leroith D, Leibowitz G (2016) Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabetes Care 39(Suppl 2):S244–252
Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25:502–508
Rhee SY, Kim YS (2018) The role of advanced glycation end products in diabetic vascular complications. Diabetes Metab J 42:188–195
Ryan DG, O’neill LJ (2017) Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett 591:2992–3006
Sasaki S, Inoguchi T (2012) The role of oxidative stress in the pathogenesis of diabetic vascular complications. Diabetes Metab J 36:255–261
Schrauwen P, Hesselink MK (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53:1412–1417
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R, Komuro I (2016) HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 7:11635
Sharkia I, Hadad Erlich T, Landolina N, Assayag M, Motzik A, Rachmin I, Kay G, Porat Z, Tshori S, Berkman N, Levi-Schaffer F, Razin E (2017) Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor. J Allergy Clin Immunol 140(204–214):e208
Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha-Vaz J, Shahri N, Berg PH, MBDL, and MBCU Groups (2013) The effect of the oral PKC beta inhibitor ruboxistaurin on vision loss in two phase 3 studies. Invest Ophthalmol Vis Sci 54:1750–1757
Sifuentes-Franco S, Pacheco-Moises FP, Rodriguez-Carrizalez AD, Miranda-Diaz AG (2017) The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy. J Diabetes Res 2017:1673081
Soufi FG, Mohammad-Nejad D, Ahmadieh H (2012) Resveratrol improves diabetic retinopathy possibly through oxidative stress—nuclear factor kappaB—apoptosis pathway. Pharmacol Rep 64:1505–1514
Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci 1147:37–52
Steven S, Oelze M, Hanf A, Kroller-Schon S, Kashani F, Roohani S, Welschof P, Kopp M, Godtel-Armbrust U, Xia N, Li H, Schulz E, Lackner KJ, Wojnowski L, Bottari SP, Wenzel P, Mayoux E, Munzel T, Daiber A (2017) The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol 13:370–385
Tan Z, Xie N, Cui H, Moellering DR, Abraham E, Thannickal VJ, Liu G (2015) Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194:6082–6089
Tan SMQ, Chiew Y, Ahmad B, Kadir KA (2018) Tocotrienol-rich vitamin E from palm oil (tocovid) and its effects in diabetes and diabetic nephropathy: a pilot phase II clinical trial. Nutrients. https://doi.org/10.3390/nu10091315
Thoudam T, Jeon JH, Ha CM, Lee IK (2016) Role of mitochondria-associated endoplasmic reticulum membrane in inflammation-mediated metabolic diseases. Mediators Inflamm 2016:1851420
Tuttle KR, Mcgill JB, Bastyr EJ 3rd, Poi KK, Shahri N, Anderson PW (2015) Effect of ruboxistaurin on albuminuria and estimated GFR in people with diabetic peripheral neuropathy: results from a randomized trial. Am J Kidney Dis 65:634–636
Ulrich P, Cerami A (2001) Protein glycation, diabetes, and aging. Recent Prog Horm Res 56:1–21
Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306:F194–204
Van Den Bossche J, Baardman J, Otto NA, Van Der Velden S, Neele AE, Van Den Berg SM, Luque-Martin R, Chen HJ, Boshuizen MC, Ahmed M, Hoeksema MA, De Vos AF, De Winther MP (2016) Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep 17:684–696
Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z, Zou MH (2017) Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 66:193–205
Wanner C (2017) EMPA-REG OUTCOME: the nephrologist’s point of view. Am J Med 130:S63–S72
Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, Woerle HJ, Broedl UC, Von Eynatten M, Zinman B, Investigators E-RO (2018) Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation 137:119–129
Wiley J, Westbrook M, Long J, Greenfield JR, Day RO, Braithwaite J (2014) Diabetes education: the experiences of young adults with type 1 diabetes. Diabetes Ther 5:299–321
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, Mcguire DK, Wilding JPH, Ruff CT, IaM Gause-Nilsson, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS, Investigators D-T (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380:347–357
Acknowledgements
This work was supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1501), Basic Science Research Program through the National Research Foundation (NRF) of Korea (NRF-2017R1A2B3006406), Bio & Medical Technology Development Program of the NRF & funded by the Korean government (MSIP&MOHW) (NRF-2016M3A9B6902872) and NRF grant funded by the Korean government (MSIT) (NRF-2017R1C1B5077060). The illustrations were made with the help of Dr.Hyo-Jeong Lee at Research Institute of Aging and Metabolism, Kyungpook national university and Na-Young Kwon at Guam middle school, Daegu, Republic of Korea.
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Park, S., Kang, HJ., Jeon, JH. et al. Recent advances in the pathogenesis of microvascular complications in diabetes. Arch. Pharm. Res. 42, 252–262 (2019). https://doi.org/10.1007/s12272-019-01130-3
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DOI: https://doi.org/10.1007/s12272-019-01130-3