In Vitro and In Vivo Antiglycation Effects of Connarus ruber Extract

Mariko Takenokuchi; Kinuyo Matsumoto; Yuko Nitta; Rumi Takasugi; Yukari Inoue; Michi Iwai; Keiichi Kadoyama; Kazutoshi Yoshida; Hiromi Takano-Ohmuro; Taizo Taniguchi

doi:10.1055/a-1690-3528

Planta Medica, Table of Contents

Planta Med 2022; 88(12): 1026-1035
DOI: 10.1055/a-1690-3528

Biological and Pharmacological Activity

Original Papers

In Vitro and In Vivo Antiglycation Effects of Connarus ruber Extract

Authors

Mariko Takenokuchi

¹Faculty of Pharmacological Sciences, Daiichi University of Pharmacy, Fukuoka, Japan
Kinuyo Matsumoto

²Faculty of Health and Welfare, Kobe Womenʼs University, Kobe, Hyogo, Japan
Yuko Nitta

²Faculty of Health and Welfare, Kobe Womenʼs University, Kobe, Hyogo, Japan
Rumi Takasugi

³Kyodo Byori Inc., Kobe, Hyogo, Japan
Yukari Inoue

⁴Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan
Michi Iwai

⁵Nippi Research Institute of Biomatrix, Toride, Ibaraki, Japan
Keiichi Kadoyama

⁴Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan
Kazutoshi Yoshida

⁶Hyogo Prefectural Institute of Technology, Kobe, Hyogo, Japan
Hiromi Takano-Ohmuro

⁷Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan
Taizo Taniguchi

⁸Research Institute for Human Health Science, Konan University, Kobe, Hyogo, Japan.

⁹Pharmacrea Kobe Co. Ltd., Kobe, Hyogo, Japan

Abstract

Accumulation of advanced glycation end products (AGEs) of the Maillard reaction has been implicated in the pathogenesis of diabetes and its complications. Connarus ruber has been used as a folk remedy for several diseases, including diabetes; however, its underlying mechanism has not yet been investigated. This study investigated the effects of C. ruber extract against glycation on collagen-linked AGEs in vitro and streptozotocin-induced diabetic rats (STZ-DM rats) in vivo. The antiglycation activities of C. ruber extract and aminoguanidine (AG) were examined using a collagen glycation assay kit. Nonfluorescent AGE, N^ε-carboxymethyl lysine (CML), N^ω-carboxymethyl arginine, and N^ε-carboxyethyl lysine levels were measured via electrospray ionization-liquid chromatography-tandem mass spectrometry. The effect of the extract on the cytotoxicity of methylglyoxal (MG), a precursor of AGEs, was examined in HL60 cells. STZ-DM rats were treated with the extract for 4 wk, and the effect was assessed using biochemical markers in the serum and CML-positive cells in renal tissues. C. ruber extract dose-dependently inhibited the glycation of collagen and formation of nonfluorescent AGEs, which was comparable to AG, and it significantly attenuated MG-induced cytotoxicity in HL60 cells. Furthermore, the glycated albumin levels in STZ-DM rats decreased, the increase in serum lipid levels was reversed, and immunohistochemistry demonstrated that CML deposition in the glomerulus of STZ-DM rats significantly decreased. Although further studies are needed, C. ruber could be a potential therapeutic for preventing and progressing many pathological conditions, including diabetes.

Key words

Connarus ruber - Connaraceae - antiglycation - advanced glycation end product - methylglyoxal - diabetes

Full Text

References

References
1 Fournet M, Bonte F, Desmouliere A. Glycation damage: a possible hub for major pathophysiological disorders and aging. Aging Dis 2018; 9: 880-900
2 Uribarri J, del Castillo MD, de la Maza MP, Filip R, Gugliucci A, Luevano-Contreras C, Macias-Cervantes MH, Markowicz Bastos DH, Medrano A, Menini T, Portero-Otin M, Rojas A, Sampaio GR, Wrobel K, Wrobel K, Garay-Sevilla ME. Dietary advanced glycation end products and their role in health and disease. Adv Nutr 2015; 6: 461-473
3 Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct crosslink breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci U S A 2000; 97: 2809-2813
4 Vasan S, Foiles P, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Arch Biochem Biophys 2003; 419: 89-96
5 Gelse K, Poschl E, Aigner T. Collagens–structure, function, and biosynthesis. Adv Drug Deliv Rev 2003; 55: 1531-1546
6 Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med 1986; 314: 403-408
7 Fessel G, Li Y, Diederich V, Guizar-Sicairos M, Schneider P, Sell DR, Monnier VM, Snedeker JG. Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness. PLoS One 2014; 9: e110948
8 Skovgaard D, Svensson RB, Scheijen J, Eliasson P, Mogensen P, Hag AM, Kjaer M, Schalkwijk CG, Schjerling P, Magnusson SP, Couppe C. An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon. Physiol Rep 2017; 5: e13215
9 Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5: 194-222
10 Sassi-Gaha S, Loughlin DT, Kappler F, Schwartz ML, Su B, Tobia AM, Artlett CM. Two dicarbonyl compounds, 3-deoxyglucosone and methylglyoxal, differentially modulate dermal fibroblasts. Matrix Biol 2010; 29: 127-134
11 Antognelli C, Mezzasoma L, Fettucciari K, Talesa VN. A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells. Int J Biochem Cell Biol 2013; 45: 836-844
12 Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med 2002; 251: 87-101
13 Beisswenger PJ, Howell SK, Russell GB, Miller ME, Rich SS, Mauer M. Early progression of diabetic nephropathy correlates with methylglyoxal-derived advanced glycation end products. Diabetes Care 2013; 36: 3234-3239
14 Sun YM, Su Y, Li J, Wang LF. Recent advances in understanding the biochemical and molecular mechanism of diabetic nephropathy. Biochem Biophys Res Commun 2013; 433: 359-361
15 Rakieten N, Rakieten ML, Nadkarni MV. Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemother Rep 1963; 29: 91-98
16 Nakamura T, Ishida Y, Ainai K, Nakamura S, Shirata S, Murayama K, Kurimoto S, Saigo K, Murashige R, Tsuda S, Sasaki YF. Genotoxicity-suppressing effect of aqueous extract of Connarus ruber cortex on cigarette smoke-induced micronuclei in mouse peripheral erythrocytes. Genes Environ 2015; 37: 17
17 Kawaguchi SK, Murashige R, Yamasaki K, Kurimoto SI, Nakamura T, Sasaki YF. Can connarus rubber extract inhibit the induction of insulin resistance by hyperglycemia?. MOJ Toxicology 2020; 6: 6-10
18 Hayashi K, Kojima R, Ito M. Strain differences in the diabetogenic activity of streptozotocin in mice. Biol Pharm Bull 2006; 29: 1110-1119
19 Wang-Fischer Y, Garyantes T. Improving the reliability and utility of streptozotocin-induced rat diabetic model. J Diabetes Res 2018; 2018: 8054073
20 Hirano T. Pathophysiology of diabetic dyslipidemia. J Atheroscler Thromb 2018; 25: 771-782
21 Sompong W, Adisakwattana S. Inhibitory effect of herbal medicines and their trapping abilities against methylglyoxal-derived advanced glycation end-products. BMC Complement Altern Med 2015; 15: 394
22 Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ, Bijlsma JW, Lafeber FP, Baynes JW, TeKoppele JM. Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 2000; 275: 39027-39031
23 Chan WH, Wu HJ, Shiao NH. Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J Cell Biochem 2007; 100: 1056-1069
24 Kim J, Sohn E, Kim CS, Kim JS. Renal podocyte apoptosis in Zucker diabetic fatty rats: Involvement of methylglyoxal-induced oxidative DNA damage. J Comp Pathol 2011; 144: 41-47
25 Kim J, Kim NH, Sohn E, Kim CS, Kim JS. Methylglyoxal induces cellular damage by increasing argpyrimidine accumulation and oxidative DNA damage in human lens epithelial cells. Biochem Biophys Res Commun 2010; 391: 346-351
26 Talukdar D, Chaudhuri BS, Ray M, Ray S. Critical evaluation of toxic versus beneficial effects of methylglyoxal. Biochemistry (Mosc) 2009; 74: 1059-1069
27 Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, Eberhardt NL, Kudva YC. Single dose streptozotocin-induced diabetes: Considerations for study design in islet transplantation models. Lab Anim 2011; 45: 131-140
28 Sakata N, Yoshimatsu G, Tsuchiya H, Egawa S, Unno M. Animal models of diabetes mellitus for islet transplantation. Exp Diabetes Res 2012; 2012: 256707
29 Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015; 239: 483-495
30 Rutledge JC, Ng KF, Aung HH, Wilson DW. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol 2010; 6: 361-370
31 Al-Ani FS, Al-Nimer MS, Ali FS. Dyslipidemia as a contributory factor in etiopathogenesis of diabetic neuropathy. Indian J Endocrinol Metab 2011; 15: 110-114
32 Rondeau P, Bourdon E. The glycation of albumin: structural and functional impacts. Biochimie 2011; 93: 645-658
33 Paroni R, Ceriotti F, Galanello R, Battista Leoni G, Panico A, Scurati E, Paleari R, Chemello L, Quaino V, Scaldaferri L, Lapolla A, Mosca A. Performance characteristics and clinical utility of an enzymatic method for the measurement of glycated albumin in plasma. Clin Biochem 2007; 40: 1398-1405
34 Selvin E, Francis LM, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL, Steffes MW. Nontraditional markers of glycemia: Associations with microvascular conditions. Diabetes Care 2011; 34: 960-967
35 Song SO, Kim KJ, Lee BW, Kang ES, Cha BS, Lee HC. Serum glycated albumin predicts the progression of carotid arterial atherosclerosis. Atherosclerosis 2012; 225: 450-455
36 Hui H, Tang G, Go VL. Hypoglycemic herbs and their action mechanisms. Chin Med 2009; 4: 11
37 Yuan Y, Sun H, Sun Z. Advanced glycation end products (AGEs) increase renal lipid accumulation: A pathogenic factor of diabetic nephropathy (DN). Lipids Health Dis 2017; 16: 126
38 Miyata T, Ueda Y, Horie K, Nangaku M, Tanaka S, van Ypersele de Strihou C, Kurokawa K. Renal catabolism of advanced glycation end products: The fate of pentosidine. Kidney Int 1998; 53: 416-422
39 Wagner Z, Wittmann I, Mazak I, Schinzel R, Heidland A, Kientsch-Engel R, Nagy J. N(epsilon)-(carboxymethyl)lysine levels in patients with type 2 diabetes: Role of renal function. Am J Kidney Dis 2001; 38: 785-791
40 Odani H, Iijima K, Nakata M, Miyata S, Kusunoki H, Yasuda Y, Hiki Y, Irie S, Maeda K, Fujimoto D. Identification of N(omega)-carboxymethylarginine, a new advanced glycation endproduct in serum proteins of diabetic patients: possibility of a new marker of aging and diabetes. Biochem Biophys Res Commun 2001; 285: 1232-1236
41 Delatour T, Fenaille F, Parisod V, Vera FA, Buetler T. Synthesis, tandem MS- and NMR-based characterization, and quantification of the carbon 13-labeled advanced glycation endproduct, 6-N-carboxymethyllysine. Amino Acids 2006; 30: 25-34
42 Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013; 48: 452-458