• Korean Journal of Agricultural Science
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• v.39 no.2
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• pp.169-175
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• 2012

To search for the aldose reductase (AR) inhibitors from Korean folk plants, the inhibition of rat lens AR in vitro using the methanol (MeOH) extracts from Korean folk plants was investigated. Among fifty four Korean folk plants tested, the MeOH extract of Cedrela sinensis showed highest inhibition of AR ($IC_{50}$ value, 2.52 ${\mu}g/ml$). The plant C. sinensis has a possibility of new natural resources for the development of AR inhibitor for the prevention of diabetic complications.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.3
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• pp.271-278
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• 2001

Oxidative stress and methylglyoxal (MG), a reactive dicarbonyl metabolites produced by enzymatic and non-enzymatic reaction of normal metabolism, induced aldose reductase (AR) expression in rat aortic smooth muscle cells (SMC). AR expression was induced in a time-dependent manner and reached at a maximum of 4.5-fold in 12 h of MG treatment. This effect of MG was completely abolished by cyclohemide and actinomycin D treatment suggesting AR was synthesized by de novo pathway. Pretreatment of the SMC with N-acetyl-L-cysteine significantly down-regulated the MG-induced AR mRNA. Furthermore, DL-Buthionine-(S,R)-sulfoximine, a reagent which depletes intracellular glutathione levels, increased the levels of MG-induced AR mRNA. These results indicated that MG induces AR mRNA by increasing the intracellular peroxide levels. Aminoguanidine, a scanvenger of dicarbonyl, significantly down-regulated the MG-induced AR mRNA. In addition, the inhibition of AR activities with statil, an AR inhibitor, enhanced the cytotoxic effect of MG on SMC under normal glucose, suggesting a protective role of AR against MG-induced cell damages. These results imply that the induction of AR by MG may contribute to an important cellular detoxification of reactive aldehyde compounds generated under oxidative stress in extrahepatic tissues.

• Preventive Nutrition and Food Science
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• v.6 no.1
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• pp.38-42
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• 2001

The methanol extracts of 25 leguminous seeds in vitro were evaluated for inhibitory activities against lens aldose reductase of Sprague Dawley male rats. The responses varied with both leguminous seed and concentration used. At the concentration of 0.1 mg/mL, the methanol extracts from Amphicaraea edgeworthii, Canavalia lineata, Gylcine max var. solitae, Glycine max var. yagkong, Glycine max var. hooktae, Glycine max var. bangkong, Glycine max var. geumdu, Glycine max var. chungtae, Glycine max var. mejukong, Glycine soja, Phaseolus radiatus var. geodu, Vicia tetrasperma, Vigna angulasis, and Vigna sinensis inhibited enzyme activity by greatertha 60%. In following study, at the concentration of 0.01 mg/mL, the extracts of C. lineata and V. tetraspermahad relatively strong inhibitory activity against aldose reductase. Because of their potent inhibitory activities, the activity of each solvent fraction from C. lineata and V. tetrasperma was determined, and the potent activity was showed from chloroform and hexane fractions, respectively. {TEX}$IC_{50}${/TEX} values of C. lineata and V. tetrasperma were 0.004 and 0.006 mg/mL, respectively. As a naturally occurring therapeutic agent, leguminous seeds described could be useful for developing new agents of antidiabetic complications.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.12
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• pp.4981-4985
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• 2015

Background: Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. Targeting autophagic cell death is emerging as a novel strategy in cancer chemotherapy. Aldose reductase (AR) catalyzes the rate limiting step of the polyol pathway of glucose metabolism; besides reducing glucose to sorbitol, AR reduces lipid peroxidation-derived aldehydes and their glutathione conjugates. A complex interplay between autophagic cell death and/or survival may in turn govern tumor metastasis. This exploratory study aimed to investigate the potential role of AR inhibition using a novel inhibitor Fidarestat in the regulation of autophagy in CRC cells. Materials and Methods: For glucose depletion (GD), HT-29 and SW480 CRC cells were rinsed with glucose-free RPMI-1640, followed by incubation in GD medium +/- Fidarestat ($10{\mu}M$). Proteins were extracted by a RIPA-method followed by Western blotting ($35-50{\mu}g$ of protein; n=3). Results: Autophagic regulatory markers, primarily, microtubule associated protein light chain (LC) 3, autophagy-related gene (ATG) 5, ATG 7 and Beclin-1 were expressed in CRC cells; glyceraldehyde-3 phosphate dehydrogenase (GAPDH) was used as an internal reference. LC3 II (14 kDa) expression was relatively high compared to LC3A/B I levels in both CRC cell lines, suggesting occurrence of autophagy. Expression of non-autophagic markers, high mobility group box (HMG)-1 and Bcl-2, was comparatively low. Conclusions: GD +/- ARI induced autophagy in HT-29 and SW-480 cells, thereby implicating Fidarestat as a promising therapeutic agent for colorectal cancer; future studies with more potent ARIs are warranted to fully dissect the molecular regulatory networks for autophagy in colorectal carcinoma.

• Korean Journal of Pharmacognosy
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• v.41 no.4
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• pp.289-296
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• 2010

Aldose reductase (AR), the principal enzyme of the polyol pathway, has been shown to play an important role in the development of the diabetic complications. Evaluating natural sources for ARI potential may lead to the development of safer and more effective agents against diabetic complications. Sixty four Chinese herbal medicines have been investigated for inhibitory activities on AR. Among them, thirteen herbal medicines, Inula helianthus-aquatilis C. Y. Wu ex Ling. (whole plant), Erigeron breviscapus (Vant.) Hand. Mazz. (whole plant), Lonicera hypoglauca Miq. (leaf, stem), Scutellaria orthocalyx Hang. Mazz. (whole plant), Berchemia floribunda Brongn. (leaf, stem), Michelia alba DC. (flower), Oroxylum indicum (seed), Punica granatum L. (peel), Elsholtzia capituligera (whole plant), Trachelospermum jasminoides (Lindl.) Lem. (whole plant), Elsholtzia strobilifera Benth. (whole plant), Agrimonia pilosa var. nepalensis (D. Don) Nakai (whole plant) and Aster poliothamnus Diels (whole plant) exhibited a significant inhibitory activity against AR. Particularly, Inula helianthus-aquatilis C. Y. Wu ex Ling. showed seven times more potent inhibitory activity than the positive control, 3,3-tetramethyleneglutaric acid (TMG).

• Journal of Applied Biological Chemistry
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• v.61 no.2
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• pp.135-139
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• 2018

The inhibition of aldose reductase (AR) has been shown to prevent the progression of the many complications associated with diabetic hyperglycemia. Several compounds purified from various plant sources have exhibited potent inhibition against AR. In this study, the inhibitory effects of the methanol extracts of the flowers of Synurus excelsus and Weigela subsessilis on AR were determined in vitro. Scopolin and scopoletin are coumarins isolated from the flowers of S. excelsus and W. subsessilis; and quercetin is a known AR inhibitor present in many flowers. To determine and quantify their presence in both plants, HPLC-UV analysis of all three compounds was performed. S. excelsus and W. subsessilis showed potent inhibition against AR having $IC_{50}$ values of 0.17 and $0.14{\mu}g/mL$, respectively. The concentration of scopolin in S. excelsus and W. subsessilis were 34.71 and 174.14 mg/g extract, respectively. Scopoletin was detected in S. excelsus at 3.41 mg/g extract, whereas quercetin was not detected in both plants. This study shows that S. excelsus and W. subsessilis exhibited promising AR inhibitory effects and are both sources of coumarins.

• Natural Product Sciences
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• v.17 no.2
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• pp.130-134
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• 2011

The purpose of this study was to evaluate the therapeutic potential of naturally occurring aldose reductase (AR) inhibitors isolated from Korean native plants. The MeOH extract and stepwise polarity fractions of dandelions were tested on rat lens AR inhibition in vitro. Of these, the EtOAc fractions from the leaves of dandelions (Traxacum coreanum, T. officinale, and T. ohwianum) exhibited an AR inhibitory activity ($IC_{50}$ values, 2.37, 1.73 and 2.68 ${\mu}g/ml$, respectively). A chromatography of the EtOAc fraction from the leaves of T. coreanum led to the further isolation of two flavonoids identified as luteolin and luteolin 7-O-glucopyranoside. These compounds exhibited strong AR inhibitory activity, with $IC_{50}$ values of 0.15 and 1.05 ${\mu}M$, respectively. These results suggested that luteolin is a potent AR inhibitor within dandelions and that it could be a useful lead compound in the development of a novel AR inhibitory agent against diabetic complications.

• Archives of Pharmacal Research
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• v.25 no.3
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• pp.275-279
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• 2002

The crystal structure of byakangelicin, one of furanocoumarin aldose reductase inhibitors, was determined by X-ray diffraction method. The crystal is triclinic, with a=8.114(1), b=10.194(1), $c=11.428(1)\AA,{\;}{\alpha}=111.50(1),{\}{\beta}=95.57(1),{\}{\gamma}=112.52(1)^{circ},{\;}D_x=1.41,{\;}D_m=1.39{\;}g/cm^3$, space group P1 and Z=2. The intensity data were collected by ${\omega}-2{\theta}$ scan method with $CuK_{a}$ radiations. The structure was solved by direct method and refined by full matrix least-squares procedure to the final R-value of 0.056. There are two molecules with different conformations in an asymmetric unit. The molecules are kept by two intermolecular O-HO type hydrogen bonds and van der Waal's forces in the crystal. The absolute configuration of the molecules was estimated to S-form by the 'Eta refinement' procedure.

• Reproductive and Developmental Biology
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• v.29 no.3
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• pp.187-191
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• 2005

This study was designed to investigate the changes of quantity and quality of proteins in medium and cytoplasm during in vitro maturation of bovine oocytes. The total quantity of proteins in medium decreased from 0 to 4.5 hr, but increased from 13.5 to 18 hr after the onset of in vitro maturation. The total quantity of protein in cytoplasm increased from 0 to 4.5 hr, decreased from 4.5 to 9 hr, and increased after 18 hr after the onset of in vitro maturation. A total of 298 protein spots was detected on a gel of 2D SDS-PAGE form maturation medium. Among 28 protein spots expressed significant differences in their quantity, 8 proteins were identified by peptide mass fingerprinting (aldose reductase, alpha enolase, apolipoprotein A-1 precursor, 43kDa collectin precursor, heat shock 27kDa protein, plasminogen activator inhibitor-1 precursor, thrombospondin 1, transitional endoplasmic reticulum ATPase). Among total of 35 protein spots detected on gel of 2D SDS-PACE from oorytes cytoplasm, $\beta$-tubulin was identified by peptide mass fingerprinting.

• Archives of Pharmacal Research
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• v.26 no.8
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• pp.606-611
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• 2003

Byakangelicin, 9-(2,3-dihydroxy-2-methylbutoxy)-4-methoxy-7H- furo[3,2-g][l]benzopyran-7-one (BKG), a component of Angelicae dahuricae Radix, is considered to be an inhibitor of aldose reductase for the treatment of diabetic cataract. An analytical method for the isolation of BKG developed by high-performance liquid chromatography has been reported. No literature on the metabolism of BKG, however, has been found. With the purpose of identifying new metabolites of BKG, BKG (100 mg/kg) was orally administered to Sprague-Dawley rats via a gavage. Using a metabolic cage, urine was collected for 24 h, and the urine samples were extracted by liquid-liquid extraction. For structural identification of new urinary metabolites of BKG, various instrumental analyses were conducted by gas-chromatography/mass spectrometry, high-performance liquid chromatography/diode array detector, liquid chromatography/mass spectroscopy with thermospray interface and $^1H$ nuclear magnetic resonance spectroscopy. Two metabolites produced from the Ο-demethylation or Ο-dealkylation of BKG were newly identified, and another new but unknown metabolite was assumed to be the hydroxylated form of BKG. These results indicate that the major metabolic products of BKG are formed by Ο-demethylation or Ο-dealkylation of BKG side chains.