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  • Therefore to better understand the functional properties of


    Therefore, to better understand the functional properties of Peruvian infusion tea plants and provide evidence for the development of functional food supplements containing the Peruvian infusion tea plant, the aldose reductase inhibition together with the antioxidant activities of 24 selected Peruvian infusion tea plants were evaluated. Phoradendron sp. (LNP-P83), which is a member of the plant family Loranthaceae widely distributed in South America, showed the highest AR inhibition and considerable antioxidant effects. To identify the components responsible for the bioactivities of LNP-P83 and provide evidence for further study, an AR ultrafiltration-high performance liquid chromatography (HPLC) assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH)-HPLC assay were developed to guide the isolation of ARIs and antioxidants of LNP-P83. Moreover, the effects of LNP-P83 and its bioactive compounds, which possess AR inhibition activity, on nitric oxide (NO) generation in RAW 264.7 cells were also investigated.
    Materials and methods
    Result and discussion
    Conclusion In the present study, the antioxidant and AR inhibitory activities of 24 Peruvian infusion tea plants were investigated, and LNP-P83, which showed the highest AR inhibitory and considerable antioxidant effects would be a good ingredient for the development of functional foods. Furthermore, chlorogenic acid, 3,5-di-O-caffeoylquinic acid, apigenin, and 1,3,5-tri-O-caffeoylquinic jak stat pathway were identified as the antioxidants of LNP-P83 by the DPPH-HPLC assay. Chlorogenic acid, 3,5-di-O-caffeoylquinic acid, and 1,3,5-tri-O-caffeoylquinic acid were identified as the AR inhibitory components of LNP-P83 by the ultrafiltration-HPLC assay. Finally, LNP-P83 and its ARIs showed good anti-inflammatory effects on RAW 264.7 cells without cellular toxicity. These results suggested that LNP-P83 may be a potent functional food ingredient acting as an antioxidant, ARI and anti-inflammatory agent.
    Conflict of interest
    Acknowledgments The authors would like to thank Soo Kyeong Lee for her contribution towards the experiments in this study. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01059199).
    Aldose reductase (ALR2 or AKR1B1) belongs to the aldo–keto reductase (AKR) enzyme superfamily, and is the first enzyme in the polyol pathway, which reduces glucose into sorbitol in the presence of NADPH as a reductant., Because this enzyme is implicated in the onset of diabetic complications, ALR2 inhibitors (ARIs) have been thought to be effective in preventing diabetic complications, and thus various inhibitors, such as epalrestat, sorbinil (), and others, have so far been developed., However, most of these have failed clinical trials because of unfavorable side effects, low efficacy, or toxicity. Currently, only epalrestat (Kinedak®) has been launched in the Japanese market as a chemotherapeutic agent for treating diabetic peripheral neuropathy. However, during the six years after its launch, 17 cases of unexpected severe liver dysfunction, for which a causal relationship to the drug cannot be ruled out, have been reported., Thus, the development of new ALR2 inhibitors is still strongly desired. The whole active site of ALR2 consists of three distinct pockets. The most important one is the catalytic site, or an “anion binding pocket”, which is made up of Tyr48, His110, and Trp111 side chains and commonly found in enzymes belonging to the AKR superfamily. Adjacent to this, there is a pocket composed of the residues Cys298, Leu300, Cys303, and Trp111. These residues are not conserved in other AKRs, and therefore this pocket is often designated as “the specificity pocket.” The third one is a hydrophobic pocket formed by the residues Trp20, Phe122, and Trp219. Aldehyde reductase (ALR1 or AKR1A1), another member of the AKR superfamily, has 65% sequence homology with ALR2, as well as structural homology., This enzyme is often found in the kidneys and detoxifies or metabolizes toxic aldehydes; it is not associated with the onset of diabetic complications in spite of its similarity to ALR2. Therefore, it is important for ARIs to specifically interact with amino acid residues characteristic of ALR2, because the selectivity towards ALR2 and not ALR1 plays a role in suppressing the side effects., With respect to this, it is known that Leu300 in the specificity pocket of ALR2 is replaced by Pro in ALR1, while the anion binding pocket of ALR1 is composed of the same amino acid residues as those of ALR2. Thus, the specific interaction with Leu300 as well as that with the aromatic residues composing the specificity pocket in ALR2 is considered essential for inhibitors to accomplish the enzyme-selective inhibition. In this context, we take notice of pterin-7-carboxamides, reported as ricin toxin A-chain (RTA) inhibitors, because the pterin ring in these compounds is capable of interacting with an aromatic residue through an aromatic-aromatic interaction as well as hydrogen bonding with the protein backbone and amino acid residues adjacent to the aromatic residue. These features of the pterin ring motivated us to utilize this unit as a key structure interacting with both an aromatic residue and Leu300 in the specificity pocket of ALR2. In addition, peptide-conjugated pterin carboxamides were proven to be readily accessible, indicating that the carboxylate functional group, which is required to attain high ALR2 inhibitory activity, can be readily introduced. However, no attempt to develop ARIs based on pterin-7-carboxamides has been made so far. Furthermore, pterin rings are found in some biologically profitable compounds, such as biopterin and folic acid (), suggesting that newly designed ARIs synthesized from pterin are potential low-toxicity agents. Thus, in this study, several amino-acid-conjugated pterin-7-carboxamides have been synthesized and evaluated for their in vitro inhibitory activity against recombinant human ALR2 (h-ALR2) for the first time.