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      FOXO1 inhibition prevents renal ischemia–reperfusion injury via cAMP‐response element binding protein/PPAR‐γ coactivator‐1α‐mediated mitochondrial biogenesis

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          Abstract

          Growing evidence indicates targeting mitochondrial dynamics and biogenesis could accelerate recovery from renal ischemia–reperfusion (I/R) injury, but the underlying mechanisms remain elusive. Transcription factor forkhead box O1 (FOXO1) is a key regulator of mitochondrial homeostasis and plays a pathological role in the progression of renal disease. A mouse model of renal I/R injury and a hypoxia/reoxygenation (H/R) injury model for human renal tubular epithelial cells were used. I/R injury up‐regulated renal expression of FOXO1 and treatment with FOXO1‐selective inhibitor AS1842856 prior to I/R injury decreased serum urea nitrogen, serum creatinine and the tubular damage score after injury. Post‐I/R injury AS1842856 treatment could also ameliorate renal function and improve the survival rate of mice following injury. AS1842856 administration reduced mitochondrial‐mediated apoptosis, suppressed the overproduction of mitochondrial ROS and accelerated recovery of ATP both in vivo and in vitro. Additionally, FOXO1 inhibition improved mitochondrial biogenesis and suppressed mitophagy. Expression of PPAR‐γ coactivator 1α (PGC‐1α), a master regulator of mitochondrial biogenesis, was down‐regulated in both I/R and H/R injury, which could be abrogated by FOXO1 inhibition. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that FOXO1 inhibited PGC‐1α transcription by competing with cAMP‐response element binding protein (CREB) for its binding to transcriptional coactivators CREBBP/EP300 ( https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2734 / https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2737 ). These findings suggested that FOXO1 was critical to maintain mitochondrial function in renal tubular epithelial cells and FOXO1 may serve as a therapeutic target for pharmacological intervention in renal I/R injury.

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          FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress

          FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone's beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARγ agonist(s) on liver IRI are dependent on FAM3A-ATP-Akt pathway.
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            Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology

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              Author and article information

              Contributors
              Journal
              British Journal of Pharmacology
              Br J Pharmacol
              Wiley
              0007-1188
              1476-5381
              January 17 2020
              January 2020
              December 23 2019
              January 2020
              : 177
              : 2
              : 432-448
              Affiliations
              [1 ]State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical SciencesPeking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University Beijing China
              [2 ]Research Center of Integrative Medicine, School of Basic Medical SciencesGuangzhou University of Chinese Medicine Guangzhou China
              [3 ]Department of Endocrinology and MetabolismPeking University People's Hospital Beijing China
              [4 ]Department of Pathology, School of Basic Medical SciencesPeking University Beijing China
              [5 ]Institute of Clinical PharmacologyGuangzhou University of Chinese Medicine Guangzhou China
              Article
              10.1111/bph.14878
              6989953
              31655022
              148e59b1-a2bc-47cf-a2a1-20a52d59470d
              © 2020

              http://onlinelibrary.wiley.com/termsAndConditions#vor

              http://doi.wiley.com/10.1002/tdm_license_1.1

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