Browsing by Subject "Lipid Peroxidation"

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    Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.
    (J Immunol, 2011-03-15) Michalek, Ryan D; Gerriets, Valerie A; Jacobs, Sarah R; Macintyre, Andrew N; MacIver, Nancie J; Mason, Emily F; Sullivan, Sarah A; Nichols, Amanda G; Rathmell, Jeffrey C
    Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.
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    Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair.
    (eLife, 2021-07-19) Ide, Shintaro; Kobayashi, Yoshihiko; Ide, Kana; Strausser, Sarah A; Abe, Koki; Herbek, Savannah; O'Brien, Lori L; Crowley, Steven D; Barisoni, Laura; Tata, Aleksandra; Tata, Purushothama Rao; Souma, Tomokazu
    Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.
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    Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential.
    (Redox biology, 2016-12) Du, Kuo; Ramachandran, Anup; Jaeschke, Hartmut
    Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.