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Keywords {🔍}

skp, cells, pubmed, article, cell, ferroptosis, lung, google, scholar, fig, cas, slca, protein, ubiquitination, sepsis, mice, expression, mle, epithelial, injury, central, lipid, sepsisinduced, measured, data, balf, rcm, zhang, ubiquitin, lungs, pathway, chen, treatment, western, group, ali, death, staining, wang, cystine, added, blotting, analysis, acute, cancer, liu, inflammatory, levels, clp, medium,

Topics {✒️}

pgmlv-cmv-mcs-3 × flag-pgk-puro ras/raf/mek/erk pathway inhibiting nf-kappab-mediated inflammation pancaspase inhibitor v-vad-fmk ampk-skp2-suv39h1-mediated demethylation k48/k63-branched ubiquitin chains k29/k48-branched ubiquitin chains aggravated sepsis-induced ali sepsis-induced ali aggravated article download pdf k48/k63-branched chains [68] treating sepsis-induced ali mek-erk kinase pathway mek/erk kinase pathway sepsis-induced ali remain sepsis-induced myocardial dysfunction β-actin forward 5′-aaggtgacagcagtcggtt-3′ quantitative real-time pcr life-threatening disease related sepsis-induced ali remains ameliorating sepsis-induced ali specific pathogen-free facility skp2-3flag-pgk-puro hrp-conjugated secondary antibody pre-clinical sepsis studies k48-linked nondegradative mechanism lipopolysaccharide-induced cardiac dysfunction inflammatory cytokine-induced ferroptosis exacerbating sepsis-induced ali n-terminal protein gsdmd single-cell transcriptomics analysis canonical ferroptosis axis primary blood-clearing organ mitogen-activated protein kinase k27-linked noncanonic ubiquitination full size image acute lung injury predominant poly-ub forms cell-surface transmembrane protein cdh1-mediated skp2 degradation k48/k63/wildtype-ub branched ubiquitin chains edta-free pancreatic enzymes erk-dependent downregulation lung wet/dry ratio ubiquitin-mediated protein degradation lung gssg/gsh ratio kaplan–meier survival analysis acute kidney injury anti-tnf-alpha therapy

Questions {❓}

• Eisener-Dorman AF, Lawrence DA, Bolivar VJ (2009) Cautionary insights on knockout mouse studies: the gene or not the gene?
• Macias-Rodriguez RU, Inzaugarat ME, Ruiz-Margain A, Nelson LJ, Trautwein C, Cubero FJ (2020) Reclassifying hepatic cell death during liver damage: ferroptosis—a novel form of non-apoptotic cell death?
• Zhu L (2010) Skp2 knockout reduces cell proliferation and mouse body size: and prevents cancer?

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         headline:Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2
         description:Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.
         datePublished:2024-07-30T00:00:00Z
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      headline:Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2
      description:Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.
      datePublished:2024-07-30T00:00:00Z
      dateModified:2024-07-30T00:00:00Z
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      pageEnd:22
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         Sepsis
         Skp2
         Ferroptosis
         Cytokine storm
         SLC3A2
         Cell Biology
         Biomedicine
         general
         Life Sciences
         Biochemistry
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            address:
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            address:
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      name:Ke Nan
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            name:Zhongshan Hospital, Fudan University
            address:
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               type:PostalAddress
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            name:Shanghai Key Laboratory of Perioperative Stress and Protection
            address:
               name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
               type:PostalAddress
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      name:Hao Zhang
      affiliation:
            name:Zhongshan Hospital, Fudan University
            address:
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               type:PostalAddress
            type:Organization
            name:Shanghai Key Laboratory of Perioperative Stress and Protection
            address:
               name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
               type:PostalAddress
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      name:Jun Wang
      affiliation:
            name:Fudan University
            address:
               name:Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China
               type:PostalAddress
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      name:Wankun Chen
      affiliation:
            name:Zhongshan Hospital, Fudan University
            address:
               name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
               type:PostalAddress
            type:Organization
            name:Shanghai Key Laboratory of Perioperative Stress and Protection
            address:
               name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
               type:PostalAddress
            type:Organization
            name:QingPu Branch of Zhongshan Hospital Affiliated to Fudan University
            address:
               name:Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Changhong Miao
      url:http://orcid.org/0009-0004-6273-5384
      affiliation:
            name:Zhongshan Hospital, Fudan University
            address:
               name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
               type:PostalAddress
            type:Organization
            name:Shanghai Key Laboratory of Perioperative Stress and Protection
            address:
               name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
      name:Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
      name:Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
      name:Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China

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