Unripe Carica papaya Protects Methylglyoxal-Invoked Endothelial Cell Inflammation and Apoptosis via the Suppression of Oxidative Stress and Akt/MAPK/NF-κB Signals.

Wattanased Jarisarapurin,Suvara K. Wattanapitayakul,Khwandow Kunchana,Linda Chularojmontri

doi:10.3390/antiox10081158

Wattanased Jarisarapurin, Suvara K. Wattanapitayakul + Show 2 more

Open Access

https://doi.org/10.3390/antiox10081158

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Journal: Antioxidants	Publication Date: Jul 21, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Srinakharinwirot University, Thammasat University

Abstract

Methylglyoxal (MGO), a highly reactive dicarbonyl compound, causes endothelial oxidative stress and vascular complications in diabetes. Excessive MGO-induced ROS production triggers eNOS uncoupling, inflammatory responses, and cell death signaling cascades. Our previous study reported that unripe Carica papaya (UCP) had antioxidant activities that prevented H2O2-induced endothelial cell death. Therefore, this study investigated the preventive effect of UCP on MGO-induced endothelial cell damage, inflammation, and apoptosis. The human endothelial cell line (EA.hy926) was pretreated with UCP for 24 h, followed by MGO-induced dicarbonyl stress. Treated cells were evaluated for intracellular ROS/O2•− formation, cell viability, apoptosis, NO releases, and cell signaling through eNOS, iNOS, COX-2, NF-κB, Akt, MAPK (JNK and p38), and AMPK/SIRT1 autophagy pathways. UCP reduced oxidative stress and diminished phosphorylation of Akt, stress-activated MAPK, leading to the decreases in NF-kB-activated iNOS and COX-2 expression. However, UCP had no impact on the autophagy pathway (AMPK and SIRT1). Although UCP pretreatment decreased eNOS phosphorylation, the amount of NO production was not altered. The signaling of eNOS and NO production were decreased after MGO incubation, but these effects were unaffected by UCP pretreatment. In summary, UCP protected endothelial cells against carbonyl stress by the mechanisms related to ROS/O2•− scavenging activities, suppression of inflammatory signaling, and inhibition of JNK/p38/apoptosis pathway. Thus, UCP shows considerable promise for developing novel functional food and nutraceutical products to reduce risks of endothelial inflammation and vascular complications in diabetes.

Highlights

Glycolytic overload has contributed to the development and comorbidity of numerous metabolic syndromes and chronic disorders, including diabetic complications, cardiovascular disease, and cancer [1]
Endothelial cells preincubated with unripe Carica papaya (UCP) (1, 10, 100, and 1000 μg/mL) for 24 h had no toxic effect on EA hy926 cells (Figure 1b)
Among the five toxic concentrations, MGO at 800 μM was selected for further experiments in this study as it moderately induced cell death to the degree that the cytoprotection by UCP could be clearly observed

Summary

Introduction

Glycolytic overload has contributed to the development and comorbidity of numerous metabolic syndromes and chronic disorders, including diabetic complications, cardiovascular disease, and cancer [1]. Methylglyoxal (MGO) is a by-product generated during the glycolysis pathway, as well as being present in the natural resources such as honey, coffee, wine, whisky, and bread [2]. MGO causes dicarbonyl stress and inflammation by altering the protein and DNA structure, resulting in the formation of irreversible advanced glycation end products (AGEs) [3]. MGO and MGO-derived AGEs induce mitochondrial dysfunction, endoplasmic reticulum (ER) stress, activation of NADPH oxidase, leading to the overproduction of reactive oxygen species (ROS) [4]. Oxidative stress stimulates the mitogen-activated protein kinase (MAPK) pathway to send the downstream signals to ERK, p38, and JNK, causing nuclear factor kappa B (NF-κB) translocation.

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