Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC50 of SA for inhibition of AR activity was 213.17？μg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC. 1. Introduction Increasing population senescence due to improved living standards and diet has increased the incidence rate of diabetic cataract, a frequent cause of vision impairment and blindness [1]. A complex pathogenic mechanism underlies diabetic cataract. Though the exact mechanism remains uncertain, a large body of research indicates that aldose reductase (AR) is a key enzyme involved in DC development [2]. In order to reduce diabetic cataract incidence and slow the progression of diabetic cataract in current patients, further understanding of the mechanistic involvement of AR in diabetic cataract development and progression is required. In diabetic patients, AR activation increases polyalcohol metabolism rates. As a result, glucitol accumulation in the eye caused increased osmotic pressure, alterations to cell membrane permeability, edema, and damage to cells of the optical lens. These changes block the passage of nutrients into the lens, further resulting in reduced amino acid levels accompanied by protein denaturation and polymerization. The end result of this process is cataract formation and progression [3]. Previous studies of the experimental aldose reductase inhibitors GP-1447 and KIOM-79 have demonstrated a relationship between AR
A. Pollreisz and U. Schmidt-Erfurth, “Diabetic cataract-pathogenesis, epidemiology and treatment,” Journal of Ophthalmology, vol. 2010, Article ID 608751, 5 pages, 2010.
A. B. M. Reddy, R. Tammali, R. Mishra, S. Srivastava, S. K. Srivastava, and K. V. Ramana, “Aldose reductase deficiency protects sugar-induced lens opacification in rats,” Chemico-Biological Interactions, vol. 191, no. 1–3, pp. 346–350, 2011.
K. Kawakubo, A. Mori, K. Sakamoto, T. Nakahara, and K. Ishii, “GP-1447, an inhibitor of aldose reductase, prevents the progression of diabetic cataract in rats,” Biological and Pharmaceutical Bulletin, vol. 35, no. 6, pp. 866–872, 2012.
J. Kim, C.-S. Kim, E. Sohn, Y. M. Lee, and J. S. Kim, “KIOM-79 inhibits aldose reductase activity and cataractogenesis in Zucker diabetic fatty rats,” Journal of Pharmacy and Pharmacology, vol. 63, no. 10, pp. 1301–1308, 2011.
N. Hotta, Y. Akanuma, R. Kawamori et al., “Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative aldose reductase inhibitor-diabetes complications trial,” Diabetes Care, vol. 29, no. 7, pp. 1538–1544, 2006.
S. Misawa, S. Kuwabara, K. Kanai et al., “Aldose reductase inhibition alters nodal Na+ currents and nerve conduction in human diabetics,” Neurology, vol. 66, no. 10, pp. 1545–1549, 2006.
D. K. Patel, R. Kumar, D. Laloo, and S. Hemalatha, “Evaluation of phytochemical and antioxidant activities of the different fractions of Hybanthus enneaspermus (Linn.) F. Muell. (Violaceae),” Asian Pacific Journal of Tropical Medicine, vol. 4, no. 5, pp. 391–396, 2011.
R. N. Gacche and N. A. Dhole, “Aldose reductase inhibitory, anti-cataract and antioxidant potential of selected medicinal plants from the Marathwada region, India,” Natural Product Research, vol. 25, no. 7, pp. 760–763, 2011.
J. Lee, D. S. Jang, N. H. Kim, Y. M. Lee, J. Kim, and J. S. Kim, “Galloyl glucoses from the seeds of Cornus officinalis with inhibitory activity against protein glycation, aldose reductase, and cataractogenesis ex vivo,” Biological and Pharmaceutical Bulletin, vol. 34, no. 3, pp. 443–446, 2011.
Commission of Chinese Pharmacopoeia, Pharmacopoeia of the People’s Republic of China, China Medical Science and Technology Press, Beijing, China, pp. 264–265, 2010.
J. I. Song, Y. J. Kang, H.-Y. Yong, Y. C. Kim, and A. Moon, “Denbinobin, a phenanthrene from Dendrobium nobile, inhibits invasion and induces apoptosis in SNU-484 human gastric cancer cells,” Oncology Reports, vol. 27, no. 3, pp. 813–818, 2012.
M. Y. Yoon, J. H. Hwang, J. H. Park et al., “Neuroprotective effects of SG-168 against oxidative stress-induced apoptosis in PC12 cells,” Journal of Medicinal Food, vol. 14, no. 1-2, pp. 120–127, 2011.
Y. Li, F. Li, Q. Gong, Q. Wu, and J. Shi, “Inhibitory effects of dendrobium alkaloids on memory impairment induced by lipopolysaccharide in rats,” Planta Medica, vol. 77, no. 2, pp. 117–121, 2011.
J. S. Hwang, S. A. Lee, S. S. Hong et al., “Phenanthrenes from Dendrobium nobile and their inhibition of the LPS-induced production of nitric oxide in macrophage RAW 264.7 cells,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 12, pp. 3785–3787, 2010.
A. Luo, X. He, S. Zhou, Y. Fan, T. He, and Z. Chun, “In vitro antioxidant activities of a water-soluble polysaccharide derived from Dendrobium nobile Lindl. extracts,” International Journal of Biological Macromolecules, vol. 45, no. 4, pp. 359–363, 2009.
A. Meissner and T. Noack, “Proliferation of human lens epithelial cells (HLE-B3) is inhibited by blocking of voltage-gated calcium channels,” Pflugers Archiv European Journal of Physiology, vol. 457, no. 1, pp. 47–59, 2008.
M. Azuma, T. R. Shearer, T. Matsumoto, L. L. David, and T. Murachi, “Calpain II in two in vivo models of sugar cataract,” Experimental Eye Research, vol. 51, no. 4, pp. 393–401, 1990.
Ganeshpurkar, S. S. Bhadoriya, P. Pardhi, A. P. Jain, and G. Rai, “In vitro prevention of cataract by Oyster Mushroom Pleurotus florida extract on isolated goat eye lens,” Indian Journal of Pharmacology, vol. 43, pp. 667–670, 2011.
M. M. Bradford, “A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding,” Analytical Biochemistry, vol. 72, no. 1-2, pp. 248–254, 1976.
P. K. Sahoo and P. Behera, “Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors,” European Journal of Medicinal Chemistry, vol. 45, no. 3, pp. 909–914, 2010.
N. Halder, S. Joshi, and S. K. Gupta, “Lens aldose reductase inhibiting potential of some indigenous plants,” Journal of Ethnopharmacology, vol. 86, no. 1, pp. 113–116, 2003.
Z. Wang, B. Ling, R. Zhang et al., “Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase,” Journal of Molecular Graphics and Modelling, vol. 28, no. 2, pp. 162–169, 2009.
C. Koukoulitsa, F. Bailly, K. Pegklidou, V. J. Demopoulos, and P. Cotelle, “Evaluation of aldose reductase inhibition and docking studies of 6′-nitro and 6′,6′-dinitrorosmarinic acids,” European Journal of Medicinal Chemistry, vol. 45, no. 4, pp. 1663–1666, 2010.
H. Steuber, M. Zentgraf, C. Gerlach, C. A. Sotriffer, A. Heine, and G. Klebe, “Expect the unexpected or caveat for drug designers: multiple structure determinations using aldose reductase crystals treated under varying soaking and co-crystallisation conditions,” Journal of Molecular Biology, vol. 363, no. 1, pp. 174–187, 2006.
R. Maccari, R. Ciurleo, M. Giglio et al., “Identification of new non-carboxylic acid containing inhibitors of aldose reductase,” Bioorganic and Medicinal Chemistry, vol. 18, no. 11, pp. 4049–4055, 2010.
R. Maccari, R. Ottanà, R. Ciurleo et al., “Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives,” Bioorganic and Medicinal Chemistry, vol. 16, no. 11, pp. 5840–5852, 2008.
J. Y. Xu, L. Y. Wu, X. Q. Zheng, J. L. Lu, M. Y. Wu, and Y. R. Liang, “Green tea polyphenols attenuating ultraviolet B-induced damage to human retinal pigment epithelial cells in vitro,” Investigative Ophthalmology and Visual Science, vol. 51, no. 12, pp. 6665–6670, 2010.
Z. Kyselova, M. Stefek, and V. Bauer, “Pharmacological prevention of diabetic cataract,” Journal of Diabetes and its Complications, vol. 18, no. 2, pp. 129–140, 2004.
Z. Hashim and S. Zarina, “Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes,” Journal of Diabetes and Its Complications, vol. 26, no. 4, pp. 275–279, 2012.
M. L. Mulhern, C. J. Madson, A. Danford, K. Ikesugi, P. F. Kador, and T. Shinohara, “The unfolded protein response in lens epithelial cells from galactosemic rat lenses,” Investigative Ophthalmology and Visual Science, vol. 47, no. 9, pp. 3951–3959, 2006.
D. C. Kosegarten and T. J. Maher, “Use of guinea pigs as model to study galactose-induced cataract formation,” Journal of Pharmaceutical Sciences, vol. 67, no. 10, pp. 1478–1479, 1978.
P. Suryanarayana, K. Krishnaswamy, and G. Bhanuprakash Reddy, “Effect of curcumin on galactose-induced cataractogenesis in rats,” Molecular Vision, vol. 9, pp. 223–230, 2003.
Y. S. Kim, N. H. Kim, Y. M. Lee, and J. S. Kim, “Preventive effect of chlorogenic acid on lens opacity and cytotoxicity in human lens epithelial cells,” Biological and Pharmaceutical Bulletin, vol. 34, no. 6, pp. 925–928, 2011.
