Pharmacologically Tested Aldose Reductase Inhibitors Isolated from Plant Sources—A Concise Report

Chinese Journal of Natural Chinese Journal of Natural Medicines 2012, 10(5): 0388−0340 Medicines

doi: 10.3724/SP.J.1009.2012.00388

Pharmacologically tested aldose reductase inhibitors isolated from plant sources—A concise report

D. K. Patel, R. Kumar, K. Sairam, S. Hemalatha*

Pharmacognosy Research Laboratory, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Vara- nasi-221005, India Available online Sep. 2012

[ABSTRACT] Aldose reductase (AR), a cytosolic, monomeric oxidoreductase, is a key enzyme in the polyol pathway which controls the conversion of glucose to sorbitol. The accumulation of sorbitol by the activation of AR enzymes in lens, retina, and sciatic nerves leads to the cause of diabetic defects resulting in various secondary complications, viz. retinopathy, neuropathy, nephropathy and Alz- heimer’s disease. Thus, reduction of the polyol pathway flux by AR inhibitors could be a potential therapeutic opening in the treatment and prevention of diabetic complications. At present, the AR inhibitors belong to two different chemical classes. One is the hydantoin derivatives, such as Sorbinil, Dilantin, and Minalrestat, and the other is the carboxylic acid derivatives, such as Epalrestat, Alrestatin, and Tolrestat. However, it is known that most of these synthethic compounds have unacceptable side-effects. Well known medicinal plants like Chrysanthemum indicum, Chrysanthemum morifolium, Prunus mume, Myrcia multiflora, Centella asiatica, and Salacia reticulata, Salacia oblonga, and Salacia chinensis exhibited potent AR inhibitory activity. The present review summarizes the list of plant material, and their isolated phytoconstituents which have been tested for their AR inhibitory activity. This litreature review covers the period to 2011, and a total of 72 plants are listed. [KEY WORDS] Aldose reductase; Cataracts; Enzyme; Human recombinant AR; Medicinal plants; Phytoconstituents; Polyol pathway; Rat lens AR; Rat lens [CLC Number] R96 [Document code] A [Article ID] 1672-3651(2012)05-0388-13

1 Introduction diabetic complications, including retinopathy, neuropathy, nephropathy and Alzheimer’s disease [1-3]. In normal tissue, Aldose reductase (AR) is a key enzyme in the polyol aldose reductase has low substrate affinity for glucose, how- pathway that controls the conversion of glucose to sorbitol. ever, in diabetes mellitus, the increased availability of glu- AR is found in almost all mammalian cells, but organs such cose in insulin-insensitive tissues such as the lens, nerve, and as the lens, retina, and sciatic nerves, which are affected by retina leads to the increased formation of sorbitol through the diabetic complications were found to contain the maximum polyol pathway [4]. Oxidative stress is also another factor accumulation of AR enzymes. Increased polyol pathway flux involved in the development of diabetes related complica- cause accumulation of sorbitol in the lens fiber, which, in tions and disorders [5]. turn, causes an increased influx of water and the generation Natural components like flavonoids have health beneficial of osmotic stress thereby leading to cataract formation which properties due to inhibition of certain enzymes, such as xan- is regarded as the main cause of blindness worldwide. Due to thine oxidase, aldose reductase, and antioxidant activity [6-7]. the poor penetration across membranes and inefficient me- Several flavonoids, such as quercitrin, guaijaverin and des- tabolism, sorbitol and its metabolites accumulate in the manthin have been tested and proven for its inhibitory activ- nerves, retina, and kidneys resulting in the development of ity against aldose reductase [8]. Flavonoids are commonly ingested from fruits and vegetables in the diet, although they have no nutritive value, they are capable of exerting various [Received on] 17-Sep.-2011 pharmacological activities, including antioxidative, supero- [Research funding] This project was supported by University Grants [9] Commission, New Delhi. xide-scavenging, and aldose reductase inhibitory activity . [*Corresponding author] S. Hemalatha: E-mail: shemalatha.phe@ Several well-known, natural occurring medicines, medicinal itbhu.ac.in, Mobile No. +91 9415256481 food stuffs and plant such as Chrysanthemum indicum, These authors have no any conflict of interest to declare. Chrysanthemum morifolium, Prunus mume, Myrcia multi-

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 flora, Centella asiatica, Salacia reticulata, Salacia oblonga, and the generation or enhancement of oxidative stress, were and Salacia chinensis exhibited potent inhibitory activity considered as the main culprit which lead to the various dia- against rat lens aldose reductase [4]. A number of structurally betic-related complications, such as cataracts. Sorbitol is an diverse naturally occurring and synthetic AR and advanced alcohol, polyhydroxylated, and strongly hydrophilic, and glycosylation end product (AGEs) inhibitors have been stud- therefore does not diffuse readily through cell membranes ied in vivo, and were reported to be effective for the preven- and accumulates intracellularly with possible osmotic conse- tion of diabetic complications in experimental animals, as quences particularly leading to osmotic stress and finally [5] well as in clinical trials . Natural antioxidants, which are causes diabetic lesions [13]. The intracellular accumulation of ubiquitous in fruits, tea, vegetables, cereals, and medicinal sorbitol also leads to locally hyperosmotic conditions respon- plants, have their importance for the prevention and treatment sible for the loss of clarity in the lens. The usage of NAD by of various diseases caused by oxidative damage, and for im- sorbitol dehydrogenase leads to an increased ratio of proving the shelf life of food products, and they have re- NADH/NAD+, which has been termed “pseudohypoxia” and ceived great attention [10-11]. Thus, reduction of the hypergly- linked to a multitude of metabolic and signaling changes cemia-induced polyol pathway flux by AR inhibitors could be known to alter cell function [14]. Under hyperglycemic condi- a potential therapeutic opening in the treatment and prevention, as much as 30% of the glucose is channeled in to the tion of diabetic complications such as cataract formation. polyol pathway causing a substantial depletion of NADPH This review mainly focuses on the aldose reductase inhibitory and consequently a significant decrease in the glutathione activity of the phytoconstituents isolated from different plant (GSH) level. Thus, during hyperglycemia, AR activity di- source, which were scientifically tested and validated, either [15-16] in vitro or in vivo on animal models. minishes the cellular antioxidant capacity . Oxidation of sorbitol to fructose by sorbitol dehydrogenase (SDH) causes 2 Role of aldose reductase in polyol pathway oxidative stress because its co-factor NAD is converted to leading to various health defects NADH in the process, and NADH is the substrate for NADH oxidase to generate reactive oxygen species (ROS) [17]. Al- The polyol pathway is usually a two-step metabolic though the polyol pathway causes oxidative stress in both the process through which glucose is reduced to sorbitol, which lens and the nerve, its role in the development of diabetic is further converted to fructose (Fig. 1). The polyol pathway lesion in these two tissues seems to be different. Osmotic consists of two enzymes. The first enzyme, aldose reductase stress, from the accumulation of sorbitol, is a more important (AR), reduces glucose to sorbitol with the aid of its co-factor [18] NADPH, and the second enzyme, sorbitol dehydrogenase factor for the development of diabetic cataracts . Thus, it (SDH), with its co-factor NAD+, converts sorbitol to fructose can be seen that the activation of aldose reductase enzyme in [12]. The AR enzyme is also responsible for the reduction of the polyol pathway can lead to the alteration of various glucose to sorbitol, and causes the reduction of various alde- metabolic factors, particularly the generation of reactive hydes. This pathway is interestingly one of the most active oxygen species which cause oxidative stress and which can parameters through which the mechanism of diabetic reti- be regarded as the initial and the main factor that aggravated nopathy and cataractogenesis can be explained. The forma- diabetic induced cataract complications. Thus the treatment tion of sorbitol from glucose, the accumulation of fructose, with AR inhibitors (ARI) was shown to be effective in pre-

Fig. 1 The polyol pathway

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 venting the development of various diabetic complications, 3.5 Belamcanda chinensis (Iridaceae) including cataract formation, neuropathy, and nephropathy [19]. Twelve phenolic compounds, including tectorigenin, iri- genin and their glucosides, were isolated from the rhizomes 3 Pharmacologically-tested aldose reductase of Belamcanda chinensis (L.) Redouté. All of the compounds inhibitors, isolated from plant sources were found to have significant inhibitory activity against the AR enzyme. Moreover, tectoridin and tectorigenin were ex- Significant research efforts have been going on all over hibited the highest inhibitory potency with IC s of 1.08 and the world on the investigation of naturally-occurring bio- 50 1.12 μmol·L−1, respectively. Treatment with tectoridin and markers responsible for inhibiting the enzyme aldose reduc- tectorigenin at 100 mg·kg−1, p.o. for 10 d in streptozoto- tase. In an attempt to develop potent, safe, and new ARI cin-induced diabetic rats showed significant inhibition of agents from natural sources, many plant materials and iso- sorbitol accumulation in the lens, sciatic nerves and red blood lated phytoconstituents have been tested for ARI activity in [24] cells . both in vivo and in vitro models. Here, the phytoconstitu- 3.6 Berberine ents of the plants which were listed were pharmacologically Aldose reductase inhibitory potential of berberine, the tested against the AR enzyme are listed. main constituent of Coptidis rhizoma and Cortex phelloden- 3.1 Anacardium occidentale (Anacardiaceae) dri in streptozotocin-induced diabetic rats was investigated. Thirteen phenolic derivatives from Anacardium occi- Berberine was found to have sigificant inhibitory activity dentale L. (Anacardiaceae) were reported to have inhibitory against the AR enzyme [25-26]. activity against bovine lens AR enzyme. Among the phyto- 3.7 Caesalpinia brevifolia (Caesalpiniaceae) constituents, 6-pentadecatrienylsalicylic showed maximum Two gallotannins, including 1, 3, 4, 6-tetragalloylglucose, inhibition followed by 5-pentadecenyl and 5-pentadecadieny- isolated from Caesalpinia brevifolia Baill., were tested for lresorcinol [20]. In another study, AR inhibitory activity of inhibitory activity against the AR enzyme. From the results it sixteen compounds including 4-anacardic acids, 4-cardols, was found that both the compounds have potent inhibitory 4-cardanols, and 4-methyl cardols, isolated from the metha- activity against human placenta AR enzyme [20]. nolic extract of Anacardium occidentale were investigated. 3.8 Caesalpinia ferrea (Caesalpiniaceae) Among the phytoconstituents cardanols was found to have Two compound ellagic acid and 2-(2, 3, 6-trihydroxy-4- potent inhibitoty activity against the AR enzyme [21]. carboxyphenyl) ellagic acid, isolated from dry fruits of Caes- 3.2 Neolamarckia cadamba (formerly Anthocephalus alpinia ferrea Mart. were tested for AR inhibitory activity. chinensis) (Rubiaceae) Both the compounds have significant inhibitory activity The flavonoid glycoside (myricetin 3-O-(4"-acetyl)- against the AR enzyme, whereas the nature of the inhibition [27] alpha-fucoside), isolated from the air-dried bark of Neola- was found to be non-competitive . marckia cadamba (Roxb.) Bosser and its aglycone were 3.9 Caesalphinia sappan (Caesalpiniaceae) tested for inhibitory activity against AR enzyme. Both com- The plant pigment brazilin, isolated from Caesalphinia sappan L. was tested for inhibitory activity against the bovine pounds were found to have potent inhibitoty activity against lens AR enzyme. From the result it was found that brazilin the AR enzyme [22]. has significant inhibitory potential against the bovine lens AR 3.3 Artemisia dracunculus (Asteraceae) enzyme [20]. Four compounds, 4, 5-di-O-caffeoylquinic acid, davidi- 3.10 Camptosorus sibiricus (Aspleniaceae) genin, 6-demethoxycapillarisin and 2', 4'-dihydroxy-4- Nine flavonoids and 8 phenolic acids were isolated from methoxydihydrochalcone were isolated from Artemisia Camptosorus sibiricus Rupr. through assay-guided fractiona- dracunculus L. (Asteraceae). All of the compounds were tion. All of the compounds were tested for inhibitory activity found to have significant inhibitory activity ranging from against the AR enzyme and were found to have AR inhibitory [23] 58% to 77% against the AR enzyme . potential [28]. 3.4 Artemisia montana (Asteraceae) 3.11 Cassia tora (Caesalpinaceae) Fifteen compounds, including four chlorogenic acids (3, Nine anthraquinones, aurantio-obtusin, chrysoobtusin, 5-di-O-caffeoylquinic acid, chlorogenic acid, neochlorogenic obtusin, chrysoobtusin-2-O-β-D-glucoside, physcion, emodin, acid, cryptochlorogenic acid), six flavonoids (apigenin, luteo- chrysophanol, obtusifolin, and obtusifolin-2-O-β-D-gluco- lin, quercetin, isoquercitrin, hyperoside, luteolin 7-rutinoside), side were isolated from an ethylacetate soluble extract of the and five coumarins (umbelliferone, scoparone, scopoletin, seeds of Cassia tora L.. Among all of the phytoconstituents esculetin, and scopolin) were isolated from the ethyl acetate aurantio-obtusin, chryso-obtusin-2-O-β-D-glucoside, and and n-butanol fractions of Artemisia montana Schlect. ex. emodin were found to have significant inhibitory activity −1 Ledeb. Among the phytoconstituents, 3, 5-di-O-caffe- with IC50s of 13.6, 8.8, and 15.9 µmol·L , respectively oylquinic acid and chlorogenic acid were found to have po- against the rat lens AR enzyme [29]. −1 tent inhibitory activity with IC50s from 0.19 to 5.37 µmol·L 3.12 Chrysanthemum boreale (Asteraceae) against the rat lens AR enzyme [1]. Four flavonoids, acacetin, apigenin, luteolin, and linarin

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 were isolated from Chrysanthemum boreale Makino. Among Cuminum cyminum L. (Apiaceae) seed oil, was found to have −1 the phytoconstituents, luteolin was found to have the most significant inhibitory activity with an IC50 of 0. 85 μg·mL −1 potent AR inhibitory potential with an IC50 of 0.5 μmol·L against the rat lens AR enzyme. However, cuminaldehyde against the AR enzyme [30]. had 1.6 times lesser inhibitory activity compared to the stan- 3.13 Chrysanthemum indicum (Asteraceae) dard quercitin [36]. Flavone and flavone glycosides together with 3 new eu- 3.19 Curcuma longa (Zingiberaceae) desmane-type sesquiterpenes, kikkanols A-C were isolated Curcuminoids, isolated from Curcuma longa L. (Zingib- from the bioassay-guided separation of the flowers of Chry- eraceae) and some curcumin analogs, such as 2, 6-bis (3, santhemum indicum L.. All of the isolated phytoconstituents 4-dihydroxybenzylidene) cyclohexanone, 2, 5-bis (3, 4-di- were found to have significant inhibitory activity against the hydroxybenzylidene) cyclo-pentanone, 1, 5-bis (3, 4-dihy- AR enzyme [31]. In another study, chlorogenic acid together droxyphenyl)-1, 4-pentadiene-3-one, and 3, 5-bis (3, 4-di- with some flavone and flavone glycosides and two sesquiter- hydroxybenzylidene)-4-piperidone were found to have sig- penes, clovanediol and caryolane 1, 9-β-diol were isolated nificant inhibitory activity with IC50s of 2.9, 2.6, 3.4 and 4.9 from C. indicum. All these compounds showed significant µmol·L−1, respectively against the AR enzyme [37]. [20] inhibitory potential against rat lens AR enzyme . 3.20 Dendranthema indicum (Asteraceae) 3.14 Coptis chinensis (Ranunculaceae) Two flavanone glycosides, (2S)- and (2R)-eriodictyol 7- Six quaternary protoberberine-type alkaloids, berberine, O-β-D-glucopyranosiduronic acids, and a phenylbutanoid palmatine, jateorrhizine, epiberberine, coptisine, groenlan- glycoside, (2S, 3S)-1-phenyl-2, 3-butanediol 3-O-β-D-gluco- dicine, and one quaternary aporphine-type alkaloid, magno- pyranoside, were isolated from the flowers of Dendranthema florine, were isolated from the n-butanol fraction of Coptis indicum Des Moul.. Both isolated compounds were found to chinensis Franch.. Among the phytoconstituents, epiberberine, have significant inhibitory activity against the rat lens AR coptisine, and groenlandicine were found to have moderate enzyme [4]. inhibitory activity with IC50s of 100.1, 118.4, and 140.1 3.21 Duchesnea chrysantha (Rosaceae) −1 µmol·L against the rat lens AR, and 168.1, 187.3, 154.2 Ellagic acid, 3, 3'-di-O-methylellagic acid, 3, 3',4-tri-O- −1 µmol·L , respectively against the human recombinant AR methylellagic acid, isovitexin, kaempferol 3-O-β-D-glu- [32] respectively . curonide methyl ester, quercetin 3-O-α-L-arabinopyranosyl- 3.15 Coptis japonica (Ranunculaceae) (1-6)-β-D-galactopyranoside, ursolic acid, pomolic acid, Five isoquinoline alkaloids, berberine chloride, berberine tormentic acid, euscaphic acid, euscaphic acid 28-O-β-D- sulfate, berberine iodide, palmatine sulfate, and palmatine glucopyranoside, and maslinic acid were isolated from the chloride were isolated from the root of Coptis japonica Ma- ethyl acetate and n-butanol soluble fraction of Duchesnea kino. All of the alkaloids were found to have significant in- chrysantha (Zoll. & Moritzi) Miq.. Among the phytoconstitu- hibitory activity with IC s of 13.98, 13.45, 32.84, 51.78 and 50 ents, ellagic acid, 3, 3'-di-O-methylellagic acid, 3, 3', 4-tri-O- 68.0 nmol·L−1, respectively against the AR enzyme [33]. methylellagic acid, isovitexin, kaempferol 3-O- β-D-glucur- 3.16 Cornus officinalis (Cornaceae) onide methyl ester and quercetin 3-O-α-L-arabino pyranosyl- Six galloyl glucoses, 1, 2, 3-tri-O-galloyl-β-D-glucose, 1, (1-6)-β-D-galactopyranoside were found to have moderate 2, 6-tri-O-galloyl-β-D-glucose, 1, 2, 3, 6-tetra-O-galloyl-β- inhibitory activity against the rat lens AR enzyme [38]. D-glucose, 1, 2, 4, 6-tetra-O-galloyl-β-D-glucose, 1, 2, 3, 4, 3.22 Eleutherococcus senticosus (Araliaceae) 6-penta-O-galloyl-β-D-glucose, and tellimagrandin II, and Hyperin, isolated from Eleutherococcus senticosus two phenolic acids, gallic acid 4-O-β-D-glucoside and gallic Maxim., was tested against the AR enzyme. From the result, acid 4-O-β-D-(6'-O-galloyl)-glucoside were isolated from the it was found that hyperin has significant inhibitory activity ethyl acetate soluble fraction of the seeds of Cornus offici- −1 [39] nalis Seibold & Zucc.. Among all the phytoconstituents, the with an IC50 of 2.63 µmol·L . tetra-O-galloyl glucoses 1, 2, 3, 6-tetra-O-galloyl-β-D-glu- 3.23 Engelhardtia chrysolepis (Juglandaceae) cose and 1, 2, 4, 6-tetra-O-galloyl-β-D-glucose were found to Dihydroflavonol, taxifolin and its glycoside, astilbin, were isolated from Engelhardtia chrysolepis Hance. All of have potent inhibitory activity with IC50s of 0.70 and 0.76 mmol·L−1, respectively against the rat lens AR enzyme [34]. the isolated phytoconstituents were found to have significant 3.17 Corydalis turtschaninovii (Papaveraceae) inhibitory potential against the rat lens AR and human re- [40] Seven alkaloids, isolated from Corydalis turtschaninovii combinant AR enzyme . Besser tubers, were tested against the AR enzyme. Among all 3.24 Enicostemma hyssopifolium (Gentianaceae) the phytoconstituents, the quarternary alkaloid dehydro- One new C-glycoside flavonoid, isolated from Enicos- corydaline was found to have significant inhibitory potential temma hyssopifolium (Willd.) I. Verd. was tested against the against the AR enzyme [35]. AR enzyme. From the result, it was found that the C-gly- 3.18 Cuminum cyminum (Apiaceae) coside flavonoid has potent inhibitory activity with an IC50 of Cuminaldehyde, the biologically active constituent of 0.71 μg·mL−1against AR enzyme [41].

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3.25 Erigeron annuus (Asteraceae) acid, and protocatechualdehyde were isolated from the ethyl Seven phenolic compounds, caffeic acid, 4-hydroxy- acetate fraction of Ganoderma applanatum. Among all the benzoic acid, 4-methoxybenzoic acid, protocatechuic acid, phytoconstituents, protocatechualdehyde was found to have eugenol O-β-D-glucopyranoside, 3, 6-di-O-feruloylsucrose, the most potent inhibitory activity with an IC50 of 0.7 and 3, 5-di-O-caffeoylquinic acid methyl ester were isolated μg·mL−1 against rat lens AR enzyme [48]. In another study, from the ethyl acetate soluble portion of the flowers of Erig- eight compounds such as 2-methoxyfatty acids, 5-dihydro- eron annuus Pers.. Among the isolated phytoconstituents, 3, ergosterol, ergosterol peroxide 3β, 7β, 20, 23ε-tetrahy- 5-di-O-caffeoylquinic acid methyl ester was found to have droxy-11, 15-dioxolanosta-8-en-26-oic aci, 7β, 20, 23ε-tri- potent inhibitory activity against the rat lens AR enzyme [42]. hydroxy-3, 11, 15-trioxolanosta-8-en-26-oic acid, cerevisterol, A novel 2, 3-dioxygenated flavanone, erigeroflavanone as 7β, 23ε-dihydroxy-3, 11, 15-trioxolanosta-8, 20E-dien-26-oic well as eight known flavonoids and two known γ-pyranone acid, and 7β-hydroxy-3, 11, 15, 23-tetraoxolanosta-8, 20E derivatives were isolated from an ethyl acetate-soluble ex- (22)-dien-26-oic acid methyl ester were isolated from the tract of the flowers of Erigeron annuus. All of the isolated fruiting bodies of Ganoderma applanatum. Among all the phytoconstituents were found to have significant inhibitory phytoconstituents, ergosterol peroxide was found to exhibit [43] −1 activity against the rat lens AR enzyme . In another study, maximum inhibitory activity with an IC50 of 15.4 μg·mL sixteen compounds, including three caffeoylquinic acids and against rat lens AR enzyme [49]. four flavonoids, were isolated from the ethyl acetate-soluble 3.30 Ganoderma lucidum (Ganodermataceae) extract of the stems and leaves of E. annuus. Among the iso- One new compound, ganoderic acid Df (lanostane-type lated phytoconstituents, 3, 5-di-O-caffeoyl-epi-quinic acid triterpenoid), isolated from the fruiting body of Ganoderma was found to have the maximum inhibitory potential with an lucidum (Curtis) P. Karst., was tested for AR inhibitory activ- −1 [44] IC50 of 0.44 mol·L against the rat lens AR enzyme . ity. From the result, it was concluded that the compound

3.26 Euodia rutaecarpa (Rutaceae) has significant inhibitory potential with an IC50 of 22.8 Rhetsinine, isolated from hot water extract from the µmol·L−1 against the rat lens AR enzyme [50]. Euodia rutaecarpa Hook. f. & Thomson was tested against 3.31 Glaucium aleppicum (Papaveraceae) the AR enzyme. From the result it was found that rhetsinine Two alkaloids protopine and allocryptopine, isolated has significant inhibitory potential with an IC50 of 24.1 from Glaucium aleppicum, were tested for AR inhibitory µmol·L−1 against the AR enzyme [8]. activity. From the result it was found that, protopine showed

3.27 Flavonoids more activity than allocryptopine against AR enzyme (IC50 of Thirty flavonoids, including flavonols such as quercetin, 38.5 and 27.9 µmol·L−1, respectively) [51]. reyneutrin, quercitrin, isoquercitrin, and avicularin were 3.32 Glycyrrhiza uralensis (Fabaceae) tested against the AR enzyme. Among the phytoconstituents, Prenylated flavonoids (semilicoisoflavone B, 7-O-me- lonicerin, amentoflavone quercitrin, reyneutrin, and sophora- thylluteone, dehydroglyasperin C, dehydroglyasperin D, and flavanone B were found to have strong inhibitory activity isoangustone A), flavonoids (liquiritigenin, isoliquiritigenin, against the rat lens AR enzyme [45]. In another study, the ef- and licochalcone A), and triterpenoids (glycyrrhizin and gly- fects of quercetin and naringin on the AR enzyme were in- cyrrhetinic acid) were isolated from the root of Glycyrrhiza vestigated in streptozotocin-induced diabetic and healthy rats. uralensis. Among all the phytoconstituents, semilicoisofla- The AR enzyme level was reduced up to 73 and 69% in dia- vone B was found to have most potent inhibitory activity −1 betic rats fed by quercetin and naringin, and 63 and 59% in with an IC50 of 1.8 µmol·L against the rat lens AR and 10.6 normal healthy rats respectively compared to the untreated µmol·L−1 against the human recombinant AR enzyme [52]. group [46]. In another study, flavonoids such as quercitrin, 3.33 Glycyrrhizae radix (Legumlnosae) guaijaverin, and desmanthin-1 were found to have significant Six compounds were isolated from the roots of Glycyr- inhibitory activity with IC50s of 0.15, 0.18 and 0.082 rhizae radix. Among all the phytoconstituents, iso-liquiriti- µmol·L−1, respectively against the AR enzyme. Among these genin was found to have most potent inhibitory activity phytoconstituents, desmanthin-1 showed the most potent against the AR enzyme. Further it also suppressed sorbitol activity, equivalent to epalrestat (0.072 μmol·L−1) [4]. accumulation in the tissues of diabetic rats [53]. 3.28 Arctium lappa (Asteraceae) 3.34 Houttuynia cordata (Saururaceae) The total lignan fraction, isolated from Fructus arctii Five compounds, cepharadione B, protocatechuic acid, (fruits of Arctium lappa L.), was found to have potent inhibi- quercetin, afzelin, and quercitrin, were isolated from the ethyl tory activity against the AR enzyme suggesting its preventive acetate soluble extract of Houttuynia cordata Thunb.. Among potential on diabetic complications upon long term admini- the phytoconstituents, afzelin and quercitrin were found to [47] stration . have significant inhibitory activity with IC50s of 0.81 and 3.29 Ganoderma applanatum (Ganodermataceae) 0.16 µmol·L−1, respectively against the rat lens AR enzyme [54]. D-Mannitol, 2-methoxyfatty acids, cerebrosides, dauco- 3.35 Ipomoea batatas (Convolvulaceae) sterol, 2, 5-dihydroxyacetophenone, 2, 5-dihydroxybenzoic A chlorogenic acid derivative, 3, 5-dicaffeoylquinic acid,

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 isolated from the roots of Ipomoea batatas (L.) Poir., was 3.42 Myrcia multiflora (Myrtaceae) tested for AR inhibitory activity. From the result, it was found Flavanone glucosides (myrciacitrins I and II), and ace- that it had significant inhibitory potential against the rat lens tophenone glucosides (myrciaphenones A and B) were iso- AR enzyme [20]. lated, together with several flavonol glycosides (myricitrin, 3.36 Knoxia valerianoides (Rubiaceae) mearnsitrin, quercitrin, desmanthin-1 and guaijaverin) from Eight compounds, lucidin, lucidin-ω-methyl ether, the ethyl acetate soluble portion of Myrcia multiflora DC.. rubiadin, damnacantho, 1, 3, 6-trihydroxy-2-methoxymethyl- Among these phytoconstituents, myrciacitrin I and myrcia- anthraquinone, 3, 6-dihydroxy-2-hydroxymethyl-9, 10-an- phenone B were found to have significant inhibitory activity thraquinone, 1, 3, 6-trihydroxy-2-hydroxymethyl-9, 10-an- against the AR enzyme [61]. Further, three new flavonoids, thraquinone 3-O-β-primeveroside, and vanillic acid were myrciacitrins III, IV, and V, and two previously known fla- isolated from the ethyl acetate and n-butanol soluble fractions vonoids, myrciacitrins I and II, were isolated from the leaves of the roots of Knoxia valerianoides Thorel ex Pit.. Among of Myrcia multiflora. All of these five compounds showed the the phytoconstituents, lucidin, 1, 3, 6-trihydroxy-2-methoxy- rat lens aldose reductase inhibitory activity, but in the case of methylanthraquinone, 3, 6-dihydroxy-2-hydroxymethyl-9, myrciacitrin IV it was found to be maximum with IC50 of 10-anthraquinone, and 1, 3, 6-trihydroxy-2-hydroxymethyl-9, 0.79 μmol·L−1 [33]. In another study, three known flavonoid 10-anthraquinone 3-O-β-primeveroside, were found to have glycosides, quercitrin, guaijaverin, and desmanthin-1, iso- strong inhibitory activity with IC50s of 3.35, 3.04, 6.39, and lated from methanolic extracts of Myrcia multiflora leaves, 2.05 µmol·L−1, respectively against the rat AR enzyme [55]. showed potent inhibitory activity against rat lens aldose re- −1 3.37 Maesa lanceolata (Myrsinaceae) ductase with IC50s of 0.15, 0.18 and 0.082 μmol·L , respec- Maesanin and flaviolin, isolated from the fresh fruits of tivily [33]. In another study, myrciaphenone B was isolated the East African plant Maesa lanceolata Forssk., were tested with some flavone glucosides and flavonol glycosides from for AR inhibitory potential. Both of them showed significant Myrcia multiflora and were tested for AR inhibitory activity. inhibitory activity against the rat lens AR enzyme [20]. From the results, it was found that all of these compounds 3.38 Magnolia fargesii (Magnoliaceae) were found to have significant inhibitory activity against rat Five compounds, scopoletin, northalifoline, stigmast-4- lens AR [20]. en-3-one, tiliroside, and oplopanone were isolated from the 3.43 Myrciaria dubia (Myrtaceae) flower buds of Magnolia fargesii. Among the phytocon- Ellagic acid and its two derivatives, 4-O-methylellagic stituents, scopoletin and tiliroside were found to have potent acid and 4-(α-rhamnopyranosyl) ellagic acid were isolated −1 inhibitory activity with IC50s of 22.5 and 14.9 µmol·L from Myrciaria dubia (Kunth) McVaugh. Among these phy- against the AR enzyme [56]. toconstituents, 4-(α-rhamnopyranosyl) ellagic acid was found

3.39 Manilkara indica (Sapotaceae) to have significant inhibitory activity with an IC50 of 0.041 Isoaffinetin (5, 7, 3', 4', 5'-pentahydroxyflavone-6-C- nmol·L−1 against rat lens AR [62]. glucoside), isolated from Manilkara indica, was tested for 3.44 Nelumbo nucifera (Nelumbonaceae) AR inhibitory activity. From the result, it was found that it Thirteen flavonoids, kaempferol and seven of its gly- co- had significant inhibitory potential against the rat lens AR sides, myricetin 3', 5'-dimethylether 3-O-β-D-glucopy- enzyme [57]. ranoside, quercetin 3-O-β-D-glucopyranoside, two isorham- 3.40 Matteuccia orientalis (Onocleaceae) netin glycosides and four non-flavonoid compounds: adenine, Two new C-methyl flavanone derivatives, matteuorien- myo-inositol, arbutin and β-sitosterol glucopyranoside were ate A and B, isolated from the rhizome of Matteuccia orien- isolated from Nelumbo nucifera Gaertn.. Among the phyto- talis (Hook.) Trevis., were found to have strong inhibitory constituents, kaempferol 3-O-α-L-rhamnopyranosyl-(1-6)-β- activity against rat lens AR enzyme [58]. In another study, five D-glucopyranoside and isorhamnetin 3-O-α-L-rhamnopy - new compounds, matteuorien, matteuorienin and mat- ranosyl-(1-6)-β-D-glucopyranoside were found to have teuorienates A-C, along with 5 known compounds, were iso- maximum inhibitory potential with IC50s of 5.6 and 9.0 lated from the methanol extract of Matteuccia orientalis rhi- µmol·L−1 against the rat lens AR enzyme [63]. zomes. Among the phytoconstituents, matteuorienates A-C 3.45 Nuphar japonica (Nymphaeaceae) were found to have strong inhibition activity against the AR A new compound, 1, 2, 3, 4, 6-pentagalloylglucose, iso- enzyme [59]. lated from Nuphar japonica DC., was tested for AR inhibi- 3.41 Monochasma savatieri (Scrophulariaceae) tory activity. From the result, it was found that it had potent Five iridoid glucosides, along with two phenolic gly- inhibitory activity against human placenta AR enzyme [20]. cosides acteoside and dehydroacteoside, were isolated from 3.46 Oryza sativa (Poaceae) Monochasma savatierii Franch. ex. Maxim.. Among all the Two anthocyanins, cyanidin-3-O-β-glucoside and peoni- phytoconstituents, acteoside was found to have highest in- din-3-O-β-glucoside and ferulic acid, isolated from Oryza −1 hibitory activity with an IC50 of 0.98 μmol·L against the AR sativa L., were tested for AR inhibitory activity. From the enzyme [60]. result, it was found that they had significant AR inhibitory

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 activity in the following decreasing order: cyanidin-3-glu- 3.53 Platycodon grandiflorums (Campanulaceae) coside > quercetin > ferulic acid > peonidin- 3-glucoside > Fifteen compounds, apigenin, apigenin-7-O-β-D-glu- tocopherol against the AR enzyme [7]. copyranoside, apigenin-7-O-(6"-O-acetyl)-β-D-glucopyrano- 3.47 Ouratea spectabilis (Ochnaceae) side, luteolin, luteolin-7-O-β-D-glucopyranoside, luteolin-7- Two biflavonoids, 6, 6"-bigenkwanin and 7, 7"-dimetho- O-(6"-O-acetyl)-β-D-glucopyranoside, isorhamne tin-3-one- xyagathisflavone were isolated from the ethyl acetate extract ohesperidoside, 4-O-caffeoylquinic acid, chlorogenic acid of Ouratea spectabilis Engl. leaves. Among all of the phyto- methyl ester, 4-O-β-D-glucopyranosylcaffeic acid, lobetyolin, constituents, 6, 6"-bigenkwanin was found to have potent cordifolioidyne C, isomultiflorenyl acetate, β-sitosterol glu- −1 inhibitory activity with an IC50 of 11.9 µmol·L compared coside, and α-spinosterol, were isolated from an ethyl acetate with 7, 7"-dimethoxyagathisflavone and quercetin (IC50s of soluble fraction of the flowers of Platycodon grandiflorum 27.7 and 31.4 µmol·L−1, respectively) against the bovine lens A.DC.. Among the phytoconstituents, luteolin was found to [64] AR enzyme . have strongest inhibitory activity with an IC50 of 0.087 3.48 Paeonia suffruticosa (Paeoniaceae) μmol·L−1, followed by luteolin-7-O-β-D-glucopyranoside and −1 8-O-Benzoylpaeonidanin and 5-hydroxy-3S-hydroxy- 4-O-caffeoylquinic acid with IC50s of 0.94 and 1.03 μmol·L , methyl-6-methyl-2, 3-dihydrobenzofuran, 4-O-butylpaeoniflo- respectively against the AR enzyme [68]. rin, monoterpene glycosides, monoterpenes, acetophenones, 3.54 Polygonum hydropiper (Polygonaceae) and two triterpenes were isolated from the methanol extract A sulfated flavonoids, isorhamnetin 3, 7-disulfate, iso- of Paeonia suffruticosa Andrews. Among these phytocon- lated from leaves of Polygonum hydropiper L., was tested for stituents, triterpenes, 4-O-butylpaeoniflorin and monoterpene AR inhibitory activity. From the result, it was found that it glycosides was found to have potent inhibitory activity with had potent inhibitory activity against the rat lens AR enzyme, −1 [9] IC50s of 11.4, 36.2, and 44.6 µmol·L against the rat lens AR whereas the nature of the inhibition was non-competitive . enzyme [3]. 3.55 Potentilla candicans (Rosaceae) 3.49 Paulownia coreana (Paulowniaceae) One new compound, 3, 3', 4-tri-O-methylellagic acid 4'- Nine compounds, caffeic acid, naringenin, apigenin, sulfate potassium salt, isolated from Potentilla candicans luteolin, kaempferol, verbascoside, isoverbascoside, isocam- Kunth, was tested for AR inhibitory activity. From the result, pneoside II, and cistanoside F, were isolated from the ethyl it was found that it had potent inhibitory activity with an IC50 acetate and n-butanol fractions of Paulownia coreana Uyeki. of 0.08 μmol·L−1 against the AR enzyme [69]. Among these phytoconstituents, verbascoside and isocamp- 3.56 Potentilla discolor (Rosaceae) neoside II were found to have significant inhibitory activity Four glycosides, rosamultin, tetracentronside B, 4-O- −1 [65] (IC50s of 2.67 and 5.59 µmol·L ) against the AR enzyme . methylellagic acid 3-O-α-L-rhamnopyranoside, and vanillic 3.50 Phellinus linteus (Hymenochaetaceae) acid 4-O-β-D-glucopyranoside, were isolated from the roots Ten compound, hispidin, phelligridimer A davalliala extract of Potentilla discolor Bunge. Among all the phyto- ctone, methyldavallialactone, hypholomine B, interfungins A, constituents, 4-O-methylellagic acid 3-O-α-L-rhamno- and inoscavin A, together with protocatechuic acid, proto- pyranoside was found to have significant inhibitory activity −1 [70] catechualdehyde, caffeic acid, and ellagic acid were isolated (IC50 8.03 µmol·L ) against the rat lens AR enzyme . from Phellinus linteus (Berk. & M. A. Curtis) Teng.. Among 3.57 Prunus mume (Rosaceae) the phytoconstituents, davallialactone, hypholomine B, and Two new flavonol oligoglycosides, 2"-O-acetylrutin and ellagic acid were found to have significant inhibitory activity 2"-O-acetyl-3'-O-methylrutin, and two new polyacylated −1 with IC50s of 0.33, 0.82, and 0.63 µmol·L , respectively sucroses, prunoses I and II, were isolated together with 11 against the rat lens AR enzyme, and 0.56, 1.28, and 1.37 known constituents from the fresh flowers of Prunus mume µmol·L−1, respectively against the human recombinant AR Seibold & Zucc.. Among all the phytoconstituents, flavonol enzyme respectively [66]. glycosides and prunose I were found to have significant in- 3.51 Phyllanthus niruri (Euphorbiaceae) hibitiory power against the AR enzyme [71]. Three active components, ellagic acid, brevifolin car- 3.58 Pueraria lobata (Leguminosae) boxylic acid, and ethyl brevifolin carboxylate were isolated Puerariafuran, isolated from Pueraria lobata (Willd.) from Phyllanthus niruri L.. Among these phytoconstituents, Ohwi, was tested for AR inhibitory activity. From the result, ellagic acid was found to have significant inhibitory activity it was found that it had potent inhibitory activity with an IC50 against AR enzyme [67]. of 22.34 µmol·L−1 against the rat lens AR enzyme [72]. 3.52 Phyllostachys nigra (Poaceae) 3.59 Rhus verniciflua (Anacardiaceae) Eight compounds, isolated from the leaves of Phyl- Nine compounds were isolated through bioactivity lostachys nigra (Lodd. ex. Lindl.) Munro, were tested for AR guided fractionation from Rhus verniciflua Stokes. Among inhibitory activity. Among all the phytoconstituents, luteolin the isolates, butein and sulfuretin, isolated from ethyl acetate 6-C-(6"-O-trans-caffeoylglucoside) was found to have sig- fraction were found to have potent AR inhibitory activity [5] −1 nificant inhibitory activity against the AR enzyme . with IC50s of 0.5 and 124.7 µmol·L , respectively against the

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 human recombinant AR enzyme [73]. n-butanol extract of the overground parts of Sideritis brevi- 3.60 Salacia chinensis (Celastraceae) bracteata P. H. Davis. Among these phytoconstituents, Six constituents, 3β, 22β-dihydroxyolean-12-en-29-oic hypolaetin was found to have the most significany inhibitory acid, tingenone, tingenine B, regeol A, triptocalline A, and activity against the rat lens AR [80]. mangiferin, isolated from Salacia chinensis L., were tested 3.67 Sinocrassula indica (Crassulaceae) for AR inhibitory activity. From the result, it was found that Six new flavonol glycosides, sinocrassosides B4, B5, C1, all these compounds were found to have significant inhibitory D1, D2, and D3, were isolated from Sinocrassula indica A. activity against the rat lens AR enzyme [74]. Berger. All of these phytoconstituents were found to have 3.61 Salacia oblonga (Hippocrateaceae) significant inhibitory potential against the AR enzyme [81]. Terpenoids isolated from Salacia oblonga Wall., include- 3.68 Sophora flavescens (Leguminosae) ing the new kotalagenin 16-acetate, were found to have sig- Prenylated flavonoids were isolated from Sophora fla- nificant inhibitory potential against the AR enzyme [75]. Three vescens Aiton. Among the phytoconstituents, two prenylated triterpenoids, kotalagenin 16-acetate, maytenfolic acid, 3β, chalcones, desmethylanhydroicaritin and 8-lavandulylkaemp- 22α-dihydroxyolean-12-en-29-oic acid, and two diterpenoids, ferol, along with five prenylated flavanones-kurarinol, kura- 19-hydroxyferruginol and lambertic acid were isolated from rinone, (2S)-2'-methoxykurarinone, (2S)-3β, 7, 4'-trihydroxy- the roots of S oblonga. All of these compounds showed in- 5-methoxy-8-(γ, γ-dimethylally)-flavanone, and kushenol E hibitory activity on rat lens enzyme, whereas 3β, 22α-di- were found to have potent inhibitory activity with IC50s of hydroxyolean-12-en-29-oic acid was found to have maximum 0.95, 3.80, 2.13, 2.99, 3.77, 3.63 and 7.74 µmol·L−1, respec- inhibitory potential against AR enzyme [20]. tively against the rat lens AR enzyme. Moreover, prenylated 3.62 Salicornia herbacea (Chenopodiaceae) flavonols, such as desmethylanhydroicaritin, 8-lavandulyl- One new compound isorhamnetin-3-O-β-D-glucoside, kaempferol and kushenol C, as well as the prenylated chal- isolated from ethyl acetate fraction of Salicornia herbacea L., cone, kuraridin, and a prenylated flavanone, (2S)-7, 4'- dihy- was found to have potent inhibitory activity with an IC50 of droxy-5-methoxy-8-(γ, γ-dimethy lally)-flavanone were also −1 1.4 µmol·L against the AR enzyme. Further, isorhamnetin- found to have significant inhibitory activities with IC50s of 3-O-β-D-glucoside administered orally at 25 mg·kg−1 in 0.45, 0.79, 0.85, 0.27 and 0.37 µmol·L−1, respectively against streptozotocin (STZ)-induced diabetic rats, caused significant the human recombinant AR enzyme [82]. inhibition of sorbitol accumulation in the lenses, red blood 3.69 Symphyocladia latiuscula (Rhodomelaceae) cells (RBC), and sciatic nerves [76]. Five new bromophenols, 2, 2', 3, 6, 6'-pentabromo-3', 4, 3.63 Salvia castanea (Lamiaceae) 4', 5-tetrahydroxydibenzyl ether, bis (2, 3, 6-tribromo-4, 5- Twelve tanshinones, isolated from Salvia castanea Diels, dihydroxyphenyl) methane, 2, 2', 3, 5', 6-pentabromo 3', 4, 4', were tested for AR inhibitory activity. From the result, it was 5-tetrahydroxy diphenylmethane, 2, 3, 6-tribromo-4, 5-di- found that they had significant inhibitory activity against the hydroxymethylbenzene and 2, 3, 6-tribromo-4, 5-dihydroxy- AR enzyme [77]. benzaldehyde isolated from the red alga Symphyocladia lati- 3.64 Salvia miltiorrhiza (Lamiaceae) uscula. All of the phytoconstituents were found to have sig- Two new abietane-type diterpenoids, danshenols A and B, nificant inhibitory activity against the AR enzyme [83]. were isolated, together with dihydrotanshinone I, crypto- 3.70 Viola hondoensis (Violaceae) tanshinone, tanshinone I, tanshinone IIA, (−)-danshexinkun A One isoflavonoid glycoside, isolated from the ethyl ace- and sugiol from Salvia miltiorrhiza Bunge. Among all the tate soluble fraction of Viola hondoensis W. Becker & Bois- phytoconstituents, cryptotanshinone, tanshinone I and sugiol seau, was tested for AR inhibitory actvity. From the result, it were found to have reduced AR inhibitory activity compared shown that it had potent inhibitory activity with an IC50 of −1 [78] −1 [84] to danshenol A (IC50 0.1 µmol·L ) against the AR enzyme . 0.34 μg·m·L against the rat lens AR enzyme . In another study, salvianolic acid A, lithospermic acid B, 3.71 Wikstroemia chamaejasme (Thymelaeaceae) salvianolic acid K, salviaflaside and rosmarinic acid isolated Six biflavonoids, chamaejasmin, 7-methoxyneochamae- from the root of Salvia miltiorrhiza were reported to have jasmin, 7-methoxychamaejasmin, chamaejasmenin B, cha- significant inhibitory potential against the AR enzyme [20]. maechromone, and wikstrol were isolated from Wikstroemia 3.65 Saussurea medusa (Asteraceae) chamaejasme (L.) Domke. Among these phytoconstituents, New flavonoids, lignans, and quinic acid derivatives chamaejasmin, 7-methoxyneochamaejasmin, 7-methoxycha- were isolated together with the new ionone glycosides, saus- maejasmin, and chamaejasmenin B were found to have sig- sureosides A and B, from Saussurea medusa Maxim.. All the nificant inhibitory activity compared to biflavonoids of phytoconstituents were found to have significant inhibitory chamaechromone, and wikstrol A against the AR enzyme [85]. effect against the AR enzyme [79]. 3.72 Zingiber officinale (Zingiberaceae) 3.66 Sideritis brevibracteata (Lamiaceae) Five active compounds were isolated from Zingiber offi- Hypolaetin, soscutellarein, 3-hydroxy-4-O-methylisos- cinale Roscoe. Among the phytoconstituents, 2-(4-hydroxy- cutellarein, verbascoside, acteoside were isolated from the 3-methoxyphenyl) ethanol and 2-(4-hydroxy-3-methoxy-

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 phenyl) ethanoic acid were found to have significat inhibitory foundation due to the fact that medicinal plants have a wide −1 activity with IC50 of (19.2 ± 1.9) µmol·L against the rat lens margin of safety, efficacy, and quality with lesser side effects. AR and (18.5 ± 1.1) µmol·L−1, against the human recom- They can be used directly or in extracted forms for the treat- binant AR enzyme respectively [86]. ment of various complications due to the presence of many phytochemicals. In this review, mention has been made of the 4 Discussion pharmacologically tested phytochemicals, isolated from Diabetes mellitus is recognized as a leading cause of various plants sources, as AR inhibitors against the AR en- blindness and is associated with an increased risk for painful zyme, for which uses are claimeds in the traditional system of neuropathy, heart diseases and kidney failure. Many theories, medicine to treat different types of complication. Plant phy- including accelerated protein glycation, altered signaling, tochemicals, including polyphenols which are currently re- excessive oxidative stress, and stimulation of glucose me- garded as natural antioxidants, are important for human tabolism by the polyol pathway, have been proposed to ex- health, against various types of enzymes which reduce blood plain the causes of the complication. It has been clearly glucose level in diabetics and are capable of reducing oxida- demonstrated that polyol pathway plays an important role in tive stress by scavenging reactive oxygen species and pre- [88-89] the diabetes-induced oxidative stress. The attenuation of oxi- venting cell damage, and are thus of great significance . dative stress therefore leads to the possible generation of In another report, it was found that flavonoids and polyphe- various reactive oxygen species that produce a variety of nols, as well as sugar derivatives, are effective in inhibiting health defects. Aldose reductase is the main enzymes, which, α-glucosidase and the AR enzyme [90]. Few natural products, when activated, can cause the accumulation of sorbitol and such as roots of Salacia oblonga and Salviae multiorrhizae, generate unwanted radicals. Therefore, designing and Glycirrhiza uralensis and Radix astragali, rich in bio- screening specific inhibitors for AR is becoming a therapeutic flavonoids have been reported to reduce the AR activity [91]. strategy which has been proposed to delay or prevent diabetic Quercetin is currently the most commonly used oral agents complications. Even though many compounds have been exbiting good penetrations, through cellular membranes synthesized and tested for theie ARI potential, only a few and considered for the treatment of diabetic complications. In drugs have reached clinical trials. Other available drugs also another study, it was concluded that flavonols and flavanones have some side effects, like carboxylic acid inhibitors having the 7-hydroxy and/or catechol moiety on the B ring (zopolrestat, ponalrestat, tolerestat) which have shown poor exhibit the strongest inhibitory activity against AR. Inhibitory tissue penetration and are not very potent in vivo, spiroimide activity of quercitirin (a glycoside of quercetin) was reported (spirohydantoin) inhibitors penetrate tissues more efficiently, and also compared with cinnamaldehyde from Cinnamomum but many have caused skin reactions and liver toxicity [87]. and showed higher activity [46]. Similarly, flavanone and fla- Hence selecting a possible alternative way from natural vonol glucosides isolated from a plant popularly known as source for the inhibition of AR enzymes may be a superior ‘plant insulin’, have been reported to possess AR inhibitory

Table 1 Aldose reductase inhibitory activity of pharmacologically evaluated plant

S. No. Sources Enzyme sources Plant name References Spinacea oleracea, Cuminum cyminum, Foeniculum vulgare, Ocimum sanc- Commonly Rat lens and tum, Piper nigrum, Trigonella foenumgraceum, Citrus lemon, Momordica consumed recombinant charantia, Citrus sinensis aurantium, Murraya koenigii, Cinamomum zeylen- 1 traditional [87] human aldose cium, Trachyspermum ammi, Psidium guajava, Marmelos bael, Brassica plant/diet reductase enzyme nigra, Malus pumila, Zingiber officinalis, Allium sepa, Allium sativum, Cori- source ander sativum, Vitis vinifera. Acanthopanax sessiliflorus, Actinidia arguta, Adenophora triphylla, Adriana acerifolia, Allium macrostemon, A. victorialis, Alopecurus aequalis, Anthris- cus sylvestris, Aralia cordata, Aruncus dioicus var. kamtschaticus, Aster gle- hni, A. tataricus, A. tataricus, Berberis amurensis var. latifolia, Capsella bursa-pastoris, Cardamine leucantha, Cedrela sinensis, Cercidiphyllum ja- Korean folk Rat lens AR ponicum, Chelidonium majus var. asiaticum, Chrysanthemum boreale, C. 2 [93] plants enzyme indicum, C. indicum, C. pallasianum, C. zawadskii var. latilobum, Cirsium nipponicum, Citrus unshui, Clerodendron trichotomum, C. trichotomum, Cryptotaenia japonica, Dracocephalum argunense, Dystaenia takesimana, Elaeagnus, macrophylla, E. umbellata, E. umbellata, Equisetum arvense, Erigeron annuus, Euonymus alatus, Ficus lyrata, Fragaria ananassa, Gyp- sophila oldhamiana Allium cepa, Mangifera indica, Vaccinium myrtillus, V. myrtillus, Nepeta Herbs Bovine eye cataria, Clidemia octona, Calycogonium squamulosum, Psidium guajava, extracts 3 lenses lens Eugenia borinquenses, Syzygium malaccense, Eucalyptus deglupta, Desmo- [94] and natural AR enzyme dium adscendens, Coccoloba swartzii, Manilkara bidentata, Daucus carota, products Zingiber officinale, Curcuma longa S. bowleyana, S. deserta, S. miltiorrhiza, S. miltiorhiza var. miltiorrhiza f. Salvia 4 AR enzyme alba, S. paramiltiorhiza, S. paramiltiorhiza f. purpureo-rubra, S. przewalskii, [95] species S. przewalskii var. mandarinorum, S. sinica f. purpurea, S. trijuga.

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D. K. Patel, et al. /Chinese Journal of Natural Medicines 2012, 10(5): 388−400 activity [92]. able side effects fewer drugs are available for the treatment of According to the World Health Organization (WHO) re- diabetic complication such as cataract formation. Some in- ports that about 80% of the world’s population in emerging digenous plants were reported to have potent ARI activities countries in 2001 used herbal medicines for their health and their anticataract potentials were evaluated against ga- need [93]. Lots of studies have been done to identify natural lactose-induced biochemical changes in rat lens organ culture. and synthetic compounds that inhibit AR and reduce oxida- Ocimum sanctum was the most effective ARI in vitro with −1 tive stress, and the flavonoids are among the most potent AR IC50 value of 20 µg·mL , Aralia extract is another example, inhibitors known. Moreover, of these, quercetin and querce- and quercetin has been reported to have a corresponding IC50 trin are believed to have strong inhibitory potential against of 1.1 mol·L−1 [94]. Various classes of flavonoid are reported the AR enzyme, though their anticataractous activities in to have good inhibitory potential against the AR enzymes and animal studies remain controversial. Due to the undersir- were mentioned in the Table 2 [96].

Table 2 Rat lens aldose reductase inhibitory activity of various flavonoids

S. No Class of compound Phytoconstituents Reference flavone, 7-hydroxyflavone, chrysin, tectochrysin, 4′, 7-dihydroxyflavone, 3′, 4′-dihydroxyflavone, 3′, 4′, 7-trihydroxyflavone, apigenin, apigenin 7-O-Glc, acacetin 7-O-Rut, luteolin, diosmetin, pilloin, luteolin 7-O-Glc, luteolin 7-O-GlcA, diosmetin 1 Flavonoids 7-O-Glc, 3-hydroxyflavone, izalpinin, kaempferol, kaempferol 3-O-GlcA, quercetin, rham- [96] netin, tamarixetin, ombuine, ayanin, isoquercitrin, hyperin, quercitrin, guaijaverin, quercitrin 3, 7-di-O-Glc, rutin, rhamnetin 3-O-Rut, ombuine 3-O-Rut, fisetin, myricetin, mearnsetin, myricitrin, mearncitrin, desmanthin-1 Flavanones and flavanone, liquiritigenin, liquiritin, eriodictyol, (2S)-eriodictyol 7-O-GlcA, (2R)-eriodictyol 2 [96] flavanonol 7-O-GlcA, fustin.

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