Abstract
Continuous free radical assault upsets cellular homeostasis and dysregulates associated signaling pathways to promote stress-induced cell death. In spite of the continuous development and implementation of effective therapeutic strategies, limitations in treatments for stress-induced toxicities remain. The purpose of the present study was to determine the potential therapeutic efficacy of bacterial fucose polysaccharides against hydrogen peroxide (H2O2)-induced stress in human lung fibroblast (WI38) cells and to understand the associated molecular mechanisms. In two different fermentation processes, Bacillus megaterium RB-05 biosynthesized two non-identical fucose polysaccharides; of these, the polysaccharide having a high-fucose content (∼42%) conferred the maximum free radical scavenging efficiency in vitro. Structural characterizations of the purified polysaccharides were performed using HPLC, GC-MS, and 1H/13C/2D-COSY NMR. H2O2 (300 µM) insult to WI38 cells showed anti-proliferative effects by inducing intracellular reactive oxygen species (ROS) and by disrupting mitochondrial membrane permeability, followed by apoptosis. The polysaccharide (250 µg/mL) attenuated the cell death process by directly scavenging intracellular ROS rather than activating endogenous antioxidant enzymes. This process encompasses inhibition of caspase-9/3/7, a decrease in the ratio of Bax/Bcl2, relocalization of translocated Bax and cytochrome c, upregulation of anti-apoptotic members of the Bcl2 family and a decrease in the phosphorylation of MAPKs (mitogen activated protein kinases). Furthermore, cellular homeostasis was re-established via stabilization of MAPK-mediated Nrf2/Keap1 signaling and transcription of downstream cytoprotective genes. This molecular study uniquely introduces a fucose-rich bacterial polysaccharide as a potential inhibitor of H2O2-induced stress and toxicities.
Highlights
Reactive oxygen species (ROS), which are derivatives of cellular metabolic reactions, modulate the fundamental physiological functions of aerobic life
The apparent average molecular weight of the jute culture (JC)-derived Extracellular polysaccharide (EPS) was 1.286105 Da, whereas an apparent molecular weight of 1.76105 Da was observed for the EPS synthesized in glucose mineral salts medium (GMSM)
The carbohydrate and protein contents of the EPS produced in GMSM were 95.763.5 and 2.560.4 wt.%, respectively, whereas the corresponding values for the JC-derived EPS were 93.963.1 and 3.560.8 wt.%, respectively
Summary
Reactive oxygen species (ROS), which are derivatives of cellular metabolic reactions, modulate the fundamental physiological functions of aerobic life. Oxidative stress is a specific cellular stress in which the physiological ratio between oxidants and reductants stands in favor of the oxidant, creating species such as free oxygen radicals. There is increasing evidence indicating that ROS and other oxygen-derived free radicals may contribute to a variety of pathological effects and induce diseases, including aging, cancer, neurodegenerative disorders, atherosclerosis, lung damage, diabetes and rheumatoid arthritis [1,2]. Cellular oxidative damage is challenged by both synthetic and natural antioxidants. Literature review reveals that many polysaccharides of plant and microbial origin stimulate a range of biological effects [8,9], including free radical scavenging and antioxidant activity [10]
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