Antioxidants & redox signaling
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Coronavirus 2019 (COVID-19) is a pandemic associated with a high risk of mortality. Human serum albumin (HSA) is an acute phase reactant with antioxidant property; however, its behavior and impact on survival in COVID-19 patients have never been studied so far. ⋯ At the Cox regression analysis, albumin (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.23-0.63, p < 0.001) and age (HR: 1.03, 95% CI: 1.01-1.06, p = 0.001) were independently associated with mortality, irrespective of adjustment for gender, ICU admission, heart failure, COPD, and hs-CRP levels. Our observation leads to the hypothesis that HSA analysis may be used to identify patients at higher risk of death in COVID-19 patients.
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Antioxid. Redox Signal. · Jul 2020
Nix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation.
Aims: Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies. ⋯ In addition, Nix-/- mice were found to exhibit increased mitochondrial mass, likely due to the inability to clear damaged or dysfunctional mitochondria. Innovation: These results demonstrate the importance of mitophagy within the intestinal epithelium during IBD pathogenesis. Conclusion: NIX-mediated mitophagy is required to maintain intestinal homeostasis during inflammation, highlighting the impact of mitochondrial damage on IBD progression.
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Antioxid. Redox Signal. · Nov 2019
ReviewGenomic and Genetic Approaches to Deciphering Acute Respiratory Distress Syndrome Risk and Mortality.
Significance: Acute respiratory distress syndrome (ARDS) is a severe, highly heterogeneous critical illness with staggering mortality that is influenced by environmental factors, such as mechanical ventilation, and genetic factors. Significant unmet needs in ARDS are addressing the paucity of validated predictive biomarkers for ARDS risk and susceptibility that hamper the conduct of successful clinical trials in ARDS and the complete absence of novel disease-modifying therapeutic strategies. Recent Advances: The current ARDS definition relies on clinical characteristics that fail to capture the diversity of disease pathology, severity, and mortality risk. ⋯ We further attempted to address the well-known health disparities that exist in susceptibility to and mortality from ARDS. Critical Issues: Bioinformatic analyses identified 201 ARDS candidate genes with pathway analysis indicating a strong predominance in key evolutionarily conserved inflammatory pathways, including reactive oxygen species, innate immunity-related inflammation, and endothelial vascular signaling pathways. Future Directions: Future studies employing a system biology approach that combines clinical characteristics, genomics, transcriptomics, and proteomics may allow for a better definition of biologically relevant pathways and genotype-phenotype connections and result in improved strategies for the sub-phenotyping of diverse ARDS patients via molecular signatures. These efforts should facilitate the potential for successful clinical trials in ARDS and yield a better fundamental understanding of ARDS pathobiology.
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Antioxid. Redox Signal. · May 2019
Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis.
Pulmonary fibrosis (PF) is characterized by myofibroblast activation through oxidative stress. However, the precise regulation of myofibroblast transdifferentiation remains largely uncharacterized. ⋯ In this study, we found that tanshinone IIA (Tan-IIA), an active component in the root of Salvia miltiorrhiza Bunge, can suppress reactive oxygen species (ROS)-mediated activation of myofibroblast and reduce extracellular matrix deposition in bleomycin (BLM)-challenged mice through the regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). Additionally, Tan-IIA restored redox homeostasis by upregulating Nrf2 with NADPH oxidase 4 suppression and effectively prevented myofibroblast activation by blocking ROS-mediated protein kinase C delta (PKCδ)/Smad3 signaling. Nrf2 knockdown in the fibroblasts and the lungs of BLM-treated mice reduced the inhibitory effects of Tan-IIA, indicating the essential role of Nrf2 in the Tan-IIA activity. Tan-IIA impaired the binding of kelch-like ECH-associated protein 1 (Keap1) to Nrf2 by promoting the degradation of Keap1 and thereby increasing Nrf2 induction by protecting Nrf2 stability against ubiquitination and proteasomal degradation. Importantly, we also found that the glutamate anaplerotic pathway was involved in energy generation and biosynthesis in activated myofibroblasts and their proliferation. Tan-IIA shunted glutaminolysis into glutathione (GSH) production by activating Nrf2, resulting in the reduction of glutamate availability for tricarboxylic acid cycle. Ultimately, myofibroblast activation was prevented by impairing cell proliferation. Innovation and Conclusion: In addition to the regulation of redox homeostasis, our work showed that Tan-IIA activated Nrf2/GSH signaling pathway to limit glutaminolysis in myofibroblast proliferation, which provided further insight into the critical function of Nrf2 in PF.
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Antioxid. Redox Signal. · Apr 2019
Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury.
Aims: Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen species (ROS) transmitted by gap junction (GJ) composed of connexin32 (Cx32) contributed to AKI. However, the precise underlying pathophysiologic mechanisms were largely unknown. ⋯ More importantly, Cx32 inhibition not only decreased ROS generation and distribution in human or rat kidney tubular epithelial cells but also inhibited its downstream NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathway activation. Innovation and Conclusion: This is the first identification of the underlying mechanisms of IR-induced renal injury integrally which demonstrates the critical role played by Cx32 in IR-induced AKI. Moreover, GJ composed of Cx32 manipulates ROS generation and distribution between neighboring cells, and alters activation of NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathways. Both inhibiting Cx32 function and scavenging ROS effectively reduce mitochondrial apoptosis and subsequently attenuate AKI, providing effective strategies for kidney protection.