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Tuesday, June 27th, 2017
Table of Contents

1 Introduction
5 PMID
 [F] Diseases Research  / PubMed Research Articles  /
In vitro studies on nobiletin isolated from citrus plants and the bioactive metabolites, inhibitory action against gelatinase enzymatic activity and the molecular mechanisms in human retinal Müller cell line.

PubMed

 

Resource

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017 Jun 17; 93()

Authors

Miyata Y1; Nagase T2; Katsura Y3; Takahashi H4; Natsugari H5; Oshitari T6; Kosano H7;

Author Information
  • 1Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
  • 2The fifth Department of Internal Medicine, Tokyo Medical University, 3-20-1 Ami, Ibaraki 300-0332, Japan.
  • 3The fifth Department of Internal Medicine, Tokyo Medical University, 3-20-1 Ami, Ibaraki 300-0332, Japan.
  • 4Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. Electronic address: h-kosano@pharm.teikyo-u.ac.jp.
  • 5Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
  • 6Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
  • 7Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

Abstract

Diabetic retinopathy (DR) is the most common cause of vision loss in patients with diabetes mellitus. Despite the presence of effective therapy, DR is still a significant health burden. A recent research suggests that matrix metalloproteinases (MMPs) could be promising targets, which exert multiple actions on early- and late-stage pathogenesis of DR. Among the MMP family, gelatinases (MMP-2 and MMP-9) act as potent proinflammatory, proangiogenic, and pro-apoptotic factors. Therefore, the pharmacological inhibitory effect of gelatinases on retinal MMP-producing cells may be useful in the treatment or prevention of DR. Nobiletin isolated from citrus plants is a multi-functional polymethoxylated flavone, which exerts biological effects including inhibitory action against MMP activity in several cancer cells. In the present study, we demonstrated that nobiletin isolated from citrus plants attenuated MMP-9 enzymatic activity through the suppression of transcription for MMP-9 gene expression and augmentation of TIMP-1 production in retinal Müller cells. Nobiletin regulated MMP-9 gene expression and TIMP-1 by inhibiting the PI3K/Akt signaling pathway. In addition, we observed the augmentation of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin, which is a major metabolite of nobiletin. We believe that the enhancement of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin is through the dual inhibition on Erk1/2 and Akt phosphorylation. The structure-activity relationship analysis revealed that, for the enhancement of inhibitory action against MMP-9 enzymatic activity, demethylation at position 4' in B-ring was a key structural modification in Müller cells, which are an important source of MMPs found in vitreous fluid and retinal tissues in retinal proliferative diseases. These results suggested that nobiletin, derived from a natural source, may serve as a novel MMP inhibitor with minimal side effects, and lead compound for the design of more efficacious drugs.

Copyright © 2017. Published by Elsevier Masson SAS.

PMID

28623785

Others

Publication Type: Journal Article


This article is licensed under the the National Library of Medicine License. It uses material from the PubMed National Library of Medicine Data.


Last Modified:   2016-03-27


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