Citrate reduced oxidative damage in stem cells by regulating cellular redox signaling pathways and represent a potential treatment for oxidative stress-induced diseases

Xiaopei Wu,Honglian Dai,Langlang Liu,Chao Xu,Yixia Yin,Jiling Yi,Monika Dorota Bielec,Yingchao Han,Shipu Li

doi:10.1016/j.redox.2018.11.015

Xiaopei Wu, Honglian Dai + Show 7 more

Open Access

https://doi.org/10.1016/j.redox.2018.11.015

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Abstract

Chemical substances containing citrate such as calcium citrate, citrate esters and citric acid exhibit anti-oxidant and anti-inflammatory properties in different cells and tissues. However, data on the anti-oxidant and anti-inflammatory properties and mechanisms of action of citrate are insufficient. In this study, we systematically evaluated the anti-oxidant capacity of citrate using chemical, cellular and animal assays. Citrate showed a stable molecular structure and did not directly react with oxides. Citrate exerted protective and anti-apoptotic effects on BMSCs and also showed significant inhibitory effects on the oxidative stress and inflammatory reactions in the rat air pouch model. By using proteomics, we found that PPARγ contributed to the upregulation of various free radical scavenging proteins and the downregulation of diverse components of the inflammatory responses. Citrate-regulated global PPARγ expression was evidenced by the significant increase expression of PPARγ in PC12 cell line. Our results provide novel insights into the role of citrate in regulating cellular redox signaling and the function of PPARγ signaling in this process and also provide basic molecular cell biology information to improve the applications of biomaterials or stem cells as treatments for oxidative stress-induced degenerative diseases and inflammatory diseases.

Highlights

Oxidative stress has been implicated in cardiovascular disease [1], pulmonary diseases [2], diabetes [3], neurodegenerative diseases [4], cancer [5], and inflammatory diseases [6]
Anti-FAM120B anti-body produced in rabbit, anti-PAFAH1B3 anti-body produced in rabbit, and antiCOX7B anti-body produced in rabbit were purchased from Abcam
Ferrous ions chelated by citrate will not be able to participate in the ferrozine reaction, resulting in lower absorbance

Summary

Introduction

Oxidative stress has been implicated in cardiovascular disease [1], pulmonary diseases [2], diabetes [3], neurodegenerative diseases [4], cancer [5], and inflammatory diseases [6]. Numerous studies examining conjugation of small molecule anti-oxidants such as superoxide dismutase mimetics (mSOD), vitamin E, gallic acid, catechin, ascorbic acid and glutathione to ultra-high molecular weight poly (ethylene) (UHMPE), poly (acrylic acid), gelatin, poly (methyl methacrylate) and poly (ethylene glycol) have been reported [12,13,14,15,16]. This approach has resulted in the suppression of oxidative stress to some extent, the delivery of a low dose and unstable molecular structure of anti-oxidants in these materials have limited their long-term clinical use [17]. Small molecules which have diffusion coefficients an order of magnitude greater than large proteins are better suited for localized drug delivery

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