The role of Nrf2 in periodontal disease by regulating lipid peroxidation, inflammation and apoptosis

Nuclear factor E2-related factor 2(Nrf2) is a transcription factor that mainly regulates oxidative stress in the body. It initiates the expression of several downstream antioxidants, anti-inflammatory proteins and detoxification enzymes through the Kelch-like ECH-associating protein 1 (Keap1) -nuclear factor E2-related factor 2(Nrf2) -antioxidant response element (ARE) signaling pathway. Its anti-apoptosis, anti-oxidative stress and anti-inflammatory effects have gradually become the focus of periodontal disease research in recent years. In this paper, the structure and function of Nrf2 pathway and its mechanism of action in the treatment of periodontitis in recent years were analyzed and summarized, so as to further clarify the relationship between Nrf2 pathway and oxidative stress in the occurrence and development of periodontitis, and to provide ideas for the development of new treatment drugs targeting Nrf2 pathway.

[1]  Mikiko Suzuki,et al.  Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu , 2022, Antioxidants.

[2]  Xulei Tang,et al.  The Role of NRF2 in Bone Metabolism – Friend or Foe? , 2022, Frontiers in Endocrinology.

[3]  L. Ge,et al.  The cannabinoid receptor I (CB1) enhanced the osteogenic differentiation of BMSCs by rescue impaired mitochondrial metabolism function under inflammatory condition , 2022, Stem Cell Research & Therapy.

[4]  N. Simin,et al.  Can Polyphenols Inhibit Ferroptosis? , 2022, Antioxidants.

[5]  Shuilin Wu,et al.  Photothermal therapy with regulated Nrf2/NF-κB signaling pathway for treating bacteria-induced periodontitis , 2021, Bioactive materials.

[6]  Dongxu Liu,et al.  Nrf2 Activation Is Involved in Cyclic Mechanical Stress-Stimulated Osteogenic Differentiation in Periodontal Ligament Stem Cells via PI3K/Akt Signaling and HO1-SOD2 Interaction , 2022, Frontiers in Cell and Developmental Biology.

[7]  J. Kristl,et al.  Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases , 2021, Pharmaceutics.

[8]  X. Luan,et al.  hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis , 2021, Frontiers in Immunology.

[9]  Shaobing Zhou,et al.  A Hierarchical‐Structured Mineralized Nanofiber Scaffold with Osteoimmunomodulatory and Osteoinductive Functions for Enhanced Alveolar Bone Regeneration , 2021, Advanced healthcare materials.

[10]  Biao Dong,et al.  Quercetin-Loaded Ceria Nanocomposite Potentiate Dual-Directional Immunoregulation via Macrophage Polarization against Periodontal Inflammation. , 2021, Small.

[11]  S. Guan,et al.  Autophagy Inhibition Plays a Protective Role in Ferroptosis Induced by Alcohol via the p62-Keap1-Nrf2 Pathway. , 2021, Journal of agricultural and food chemistry.

[12]  Hongjuan Ning,et al.  Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis , 2021, Stem cell research & therapy.

[13]  Hong Liu,et al.  Nrf2 activation is involved in osteogenic differentiation of periodontal ligament stem cells under cyclic mechanical stretch. , 2021, Experimental cell research.

[14]  B. Stockwell,et al.  Ferroptosis: mechanisms, biology and role in disease , 2021, Nature Reviews Molecular Cell Biology.

[15]  Xujie Wang,et al.  Exosomes from adipose-derived stem cells alleviate the inflammation and oxidative stress via regulating Nrf2/HO-1 axis in macrophages. , 2021, Free radical biology & medicine.

[16]  Khatereh Khorsandi,et al.  Extracellular vesicles in bone and periodontal regeneration: current and potential therapeutic applications , 2021, Cell & Bioscience.

[17]  Wanhong Chen,et al.  Cullin3 aggravates the inflammatory response of periodontal ligament stem cells via regulation of SHH signaling and Nrf2 , 2021, Bioengineered.

[18]  Zuolin Wang,et al.  Trem2 mediated Syk-dependent ROS amplification is essential for osteoclastogenesis in periodontitis microenvironment , 2020, Redox biology.

[19]  T. Taketomi,et al.  Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss , 2020, Acta biomaterialia.

[20]  E. Park,et al.  Panax ginseng Fruit Has Anti-Inflammatory Effect and Induces Osteogenic Differentiation by Regulating Nrf2/HO-1 Signaling Pathway in In Vitro and In Vivo Models of Periodontitis , 2020, Antioxidants.

[21]  Pei-Ming Chu,et al.  The Promising Role of Antioxidant Phytochemicals in the Prevention and Treatment of Periodontal Disease via the Inhibition of Oxidative Stress Pathways: Updated Insights , 2020, Antioxidants.

[22]  L. Lei,et al.  Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy , 2020, Cell death discovery.

[23]  L. Saso,et al.  An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation , 2020, Molecules.

[24]  Minqi Li,et al.  Eldecalcitol Inhibits LPS-Induced NLRP3 Inflammasome-Dependent Pyroptosis in Human Gingival Fibroblasts by Activating the Nrf2/HO-1 Signaling Pathway , 2020, Drug design, development and therapy.

[25]  Chun-Chieh Huang,et al.  Bone Regeneration is Mediated by Macrophage Extracellular Vesicles. , 2020, Bone.

[26]  Suixin Liu,et al.  The Latest View on the Mechanism of Ferroptosis and Its Research Progress in Spinal Cord Injury , 2020, Oxidative medicine and cellular longevity.

[27]  Duanjing Chen,et al.  Low-intensity Pulsed Ultrasound regulates alveolar bone homeostasis in experimental Periodontitis by diminishing Oxidative Stress , 2020, Theranostics.

[28]  T. Wen,et al.  NRF2, a Transcription Factor for Stress Response and Beyond , 2020, International journal of molecular sciences.

[29]  Bin Zhao,et al.  Curcumin promotes osteogenic differentiation of periodontal ligament stem cells through the PI3K/AKT/Nrf2 signaling pathway , 2020, Iranian journal of basic medical sciences.

[30]  A. A. de Araújo,et al.  Efficacy of antimicrobial photodynamic therapy with chloro-aluminum phthalocyanine on periodontal clinical parameters and salivary GSH and MDA levels in patients with periodontitis. , 2020, Photodiagnosis and photodynamic therapy.

[31]  Lihua Zhou,et al.  Cypermethrin-induced cortical neurons apoptosis via the Nrf2/ARE signaling pathway. , 2020, Pesticide biochemistry and physiology.

[32]  Masayuki Yamamoto,et al.  The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway , 2020, Molecular and Cellular Biology.

[33]  H. Forman,et al.  Beyond repression of Nrf2: An update on Keap1. , 2020, Free radical biology & medicine.

[34]  Leon M Larcher,et al.  Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics , 2020, Theranostics.

[35]  K. Itoh,et al.  Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology , 2020, Biomolecules.

[36]  Wenjing Zhang,et al.  Metformin promotes osteogenic differentiation and protects against oxidative stress-induced damage in periodontal ligament stem cells via activation of the Akt/Nrf2 signaling pathway. , 2019, Experimental cell research.

[37]  A. Rego,et al.  Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases , 2019, Ageing Research Reviews.

[38]  Jiake Xu,et al.  Loureirin B suppresses RANKL-induced osteoclastogenesis and ovariectomized osteoporosis via attenuating NFATc1 and ROS activities , 2019, Theranostics.

[39]  H. Barkema,et al.  Chlorogenic acid promotes the Nrf2/HO-1 anti-oxidative pathway by activating p21Waf1/Cip1 to resist dexamethasone-induced apoptosis in osteoblastic cells. , 2019, Free radical biology & medicine.

[40]  C. Das,et al.  Uncovering the Structural Basis of a New Twist in Protein Ubiquitination. , 2019, Trends in biochemical sciences.

[41]  I. Fraser,et al.  NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration , 2019, Front. Immunol..

[42]  S. Lim,et al.  Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration. , 2019, Acta biomaterialia.

[43]  S. Doré,et al.  Critical Role of Nrf2 in Experimental Ischemic Stroke , 2019, Front. Pharmacol..

[44]  Donna D. Zhang,et al.  NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis , 2019, Redox biology.

[45]  Donna D. Zhang,et al.  Modulating NRF2 in Disease: Timing Is Everything. , 2019, Annual review of pharmacology and toxicology.

[46]  Ji Li,et al.  Paeonol attenuates ligation-induced periodontitis in rats by inhibiting osteoclastogenesis via regulating Nrf2/NF-κB/NFATc1 signaling pathway. , 2019, Biochimie.

[47]  W. Cai,et al.  Enhanced Oxidative Damage and Nrf2 Downregulation Contribute to the Aggravation of Periodontitis by Diabetes Mellitus , 2018, Oxidative medicine and cellular longevity.

[48]  Angela C. Brown,et al.  Aggregatibacter actinomycetemcomitans Leukotoxin Is Delivered to Host Cells in an LFA-1-Indepdendent Manner When Associated with Outer Membrane Vesicles , 2018, Toxins.

[49]  L. Saso,et al.  Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review , 2018, Drug design, development and therapy.

[50]  C. Silva-Islas,et al.  Canonical and non‐canonical mechanisms of Nrf2 activation , 2018, Pharmacological research.

[51]  Masayuki Yamamoto,et al.  The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. , 2018, Physiological reviews.

[52]  Chunyun Li,et al.  Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway. , 2018, Microbial pathogenesis.

[53]  Xuan Shi,et al.  Nrf2 activation protects against intratracheal LPS induced mouse/murine acute respiratory distress syndrome by regulating macrophage polarization. , 2018, Biochemical and biophysical research communications.

[54]  B. Brüne,et al.  Nrf2, the Master Regulator of Anti-Oxidative Responses , 2017, International journal of molecular sciences.

[55]  Srijit Das,et al.  Oxidative Stress in Oral Diseases: Understanding Its Relation with Other Systemic Diseases , 2017, Front. Physiol..

[56]  E. Miao,et al.  Gasdermins: Effectors of Pyroptosis. , 2017, Trends in cell biology.

[57]  A. Murphy,et al.  Metabolic Remodeling, Inflammasome Activation, and Pyroptosis in Macrophages Stimulated by Porphyromonas gingivalis and Its Outer Membrane Vesicles , 2017, Front. Cell. Infect. Microbiol..

[58]  Yulong Niu,et al.  The Role of Reactive Oxygen Species and Autophagy in Periodontitis and Their Potential Linkage , 2017, Front. Physiol..

[59]  M. Glogauer,et al.  The Role of NrF2 in the Regulation of Periodontal Health and Disease , 2017, Journal of dental research.

[60]  Y. Mao,et al.  Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes , 2017, Journal of clinical periodontology.

[61]  M. Conrad,et al.  Ferroptosis Inhibition: Mechanisms and Opportunities. , 2017, Trends in pharmacological sciences.

[62]  Min Zhang,et al.  Nrf2 Inhibits Periodontal Ligament Stem Cell Apoptosis under Excessive Oxidative Stress , 2017, International journal of molecular sciences.

[63]  Wenqing Gao,et al.  Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. , 2017, Trends in biochemical sciences.

[64]  Akhileshwar Namani,et al.  Nrf2 signaling pathway: Pivotal roles in inflammation. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[65]  Yajing Wang,et al.  Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming. , 2017, Antioxidants & redox signaling.

[66]  M. Serdar,et al.  Impact of non-surgical periodontal therapy on saliva and serum levels of markers of oxidative stress , 2017, Clinical Oral Investigations.

[67]  D. Averill-Bates,et al.  Activation of apoptosis signalling pathways by reactive oxygen species. , 2016, Biochimica et biophysica acta.

[68]  M. Glogauer,et al.  Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis. , 2016, The American journal of pathology.

[69]  K. Nakayama,et al.  Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription , 2016, Nature Communications.

[70]  Yu-Ting Wu,et al.  Mitochondria in mesenchymal stem cell biology and cell therapy: From cellular differentiation to mitochondrial transfer. , 2016, Seminars in cell & developmental biology.

[71]  S. Kook,et al.  Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. , 2016, Acta biomaterialia.

[72]  Tso‐Hsiao Chen,et al.  Activation of Nrf2/HO-1signaling pathway involves the anti-inflammatory activity of magnolol in Porphyromonas gingivalis lipopolysaccharide-stimulated mouse RAW 264.7 macrophages. , 2015, International immunopharmacology.

[73]  Takafumi Suzuki,et al.  Molecular basis of the Keap1-Nrf2 system. , 2015, Free radical biology & medicine.

[74]  S. Kook,et al.  Activation of canonical Wnt/β-catenin signaling inhibits H2O2-induced decreases in proliferation and differentiation of human periodontal ligament fibroblasts , 2015, Molecular and Cellular Biochemistry.

[75]  J. Hayes,et al.  Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3. , 2015, Biochemical Society transactions.

[76]  Yu-Mei Chang,et al.  The Protective Effects of Salidroside from Exhaustive Exercise-Induced Heart Injury by Enhancing the PGC-1 α–NRF1/NRF2 Pathway and Mitochondrial Respiratory Function in Rats , 2015, Oxidative medicine and cellular longevity.

[77]  Xi Li,et al.  Elevation of HO-1 Expression Mitigates Intestinal Ischemia-Reperfusion Injury and Restores Tight Junction Function in a Rat Liver Transplantation Model , 2015, Oxidative medicine and cellular longevity.

[78]  T. Sorsa,et al.  Matrix metalloproteinases regulate extracellular levels of SDF-1/CXCL12, IL-6 and VEGF in hydrogen peroxide-stimulated human periodontal ligament fibroblasts. , 2015, Cytokine.

[79]  H. Kanzaki,et al.  Nrf2 Activation Attenuates Both Orthodontic Tooth Movement and Relapse , 2015, Journal of dental research.

[80]  D. Hou,et al.  Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. , 2014, Archives of biochemistry and biophysics.

[81]  Seok-Woo Chang,et al.  Deferoxamine promotes osteoblastic differentiation in human periodontal ligament cells via the nuclear factor erythroid 2-related factor-mediated antioxidant signaling pathway. , 2014, Journal of periodontal research.

[82]  Hong-Hee Kim,et al.  Nrf2 is a novel regulator of bone acquisition. , 2014, Bone.

[83]  S. Reddy,et al.  Reactive oxygen species in inflammation and tissue injury. , 2014, Antioxidants & redox signaling.

[84]  T. Kodama,et al.  The Keap1/Nrf2 Protein Axis Plays a Role in Osteoclast Differentiation by Regulating Intracellular Reactive Oxygen Species Signaling* , 2013, The Journal of Biological Chemistry.

[85]  B. Avcı,et al.  8-hydroxy-deoxyguanosine levels in gingival crevicular fluid and saliva in patients with chronic periodontitis after initial periodontal treatment. , 2013, Journal of periodontology.

[86]  S. Niture,et al.  Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. , 2013, Free radical biology & medicine.

[87]  C. Klaassen,et al.  Genetic Activation of Nrf2 Protects against Fasting-Induced Oxidative Stress in Livers of Mice , 2013, PloS one.

[88]  Hye Eun Lee,et al.  Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. , 2013, Cell metabolism.

[89]  A. Cuadrado,et al.  Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. , 2012, Oncogene.

[90]  D. Graves,et al.  Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes. , 2012, Journal of Clinical Endocrinology and Metabolism.

[91]  A. Jahanian-Najafabadi,et al.  Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity , 2012, Cell Stress and Chaperones.

[92]  S. Niture,et al.  Nrf2 Protein Up-regulates Antiapoptotic Protein Bcl-2 and Prevents Cellular Apoptosis* , 2012, The Journal of Biological Chemistry.

[93]  Young Hun Kim,et al.  Schisandra chinensis α-iso-cubebenol induces heme oxygenase-1 expression through PI3K/Akt and Nrf2 signaling and has anti-inflammatory activity in Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages. , 2011, International immunopharmacology.

[94]  J. Chung,et al.  Effects of nicotine on apoptosis in human gingival fibroblasts. , 2011, Archives of oral biology.

[95]  B. Gao,et al.  Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. , 2011, Molecular aspects of medicine.

[96]  M. Kruszewski,et al.  Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. , 2011, Free radical biology & medicine.

[97]  D. Wei,et al.  Lipid peroxidation levels, total oxidant status and superoxide dismutase in serum, saliva and gingival crevicular fluid in chronic periodontitis patients before and after periodontal therapy. , 2010, Australian dental journal.

[98]  T. Lawrence.  The nuclear factor NF-kappaB pathway in inflammation. , 2009, Cold Spring Harbor perspectives in biology.

[99]  M. Hung,et al.  KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. , 2009, Molecular cell.

[100]  J. Qu,et al.  NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. , 2008, Biochimica et biophysica acta.

[101]  S. Ghosh,et al.  Shared Principles in NF-κB Signaling , 2008, Cell.

[102]  M. Dianzani,et al.  Lipid peroxidation: control of cell proliferation, cell differentiation and cell death. , 2008, Molecular aspects of medicine.

[103]  K. Król,et al.  Total antioxidant status and 8-hydroxy-2′-deoxyguanosine levels in gingival and peripheral blood of periodontitis patients , 2007, Archivum Immunologiae et Therapiae Experimentalis.

[104]  Cenk Fatih Çanakçı,et al.  New evidence of premature oxidative DNA damage: mitochondrial DNA deletion in gingival tissue of patients with periodontitis. , 2006, Journal of periodontology.

[105]  Young-Myeong Kim,et al.  3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. , 2006, Atherosclerosis.

[106]  E. Hinoi,et al.  Nrf2 Negatively Regulates Osteoblast Differentiation via Interfering with Runx2-dependent Transcriptional Activation* , 2006, Journal of Biological Chemistry.

[107]  K. Itoh,et al.  Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model , 2006, Molecular and Cellular Biology.

[108]  N. Ozmeric,et al.  A multifaceted molecule, nitric oxide in oral and periodontal diseases. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[109]  H. Chen,et al.  Lipid peroxidation: a possible role in the induction and progression of chronic periodontitis. , 2005, Journal of periodontal research.

[110]  Y. Çiçek,et al.  Reactive Oxygen Species and Human Inflammatory Periodontal Diseases , 2005, Biochemistry (Moscow).

[111]  Koichi Ito,et al.  A marker of oxidative stress in saliva: association with periodontally-involved teeth of a hopeless prognosis. , 2005, Journal of oral science.

[112]  Mark Hannink,et al.  Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress , 2003, Molecular and Cellular Biology.

[113]  M. Kwak,et al.  Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[114]  Koichi Ito,et al.  Detection of mitochondrial DNA mutations in human gingival tissues. , 2000, Journal of oral science.

[115]  K. Fox,et al.  Timing Is Everything , 2000, Neuron.

[116]  P. Datta,et al.  Heme oxygenase-1 induction attenuates inducible nitric oxide synthase expression and proteinuria in glomerulonephritis. , 1999, Journal of the American Society of Nephrology : JASN.

[117]  J. D. Engel,et al.  Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. , 1999, Genes & development.

[118]  A. Salzman,et al.  Protective effects of mercaptoethylguanidine, a selective inhibitor of inducible nitric oxide synthase, in ligature‐induced periodontitis in the rat , 1998, British journal of pharmacology.

[119]  K. Itoh,et al.  Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site , 1996, Molecular and cellular biology.

[120]  B. Halliwell,et al.  Lipid peroxidation: its mechanism, measurement, and significance. , 1993, The American journal of clinical nutrition.

[121]  M. B. Edlund,et al.  Peptostreptococcus micros has a uniquely high capacity to form hydrogen sulfide from glutathione. , 1993, Oral microbiology and immunology.

[122]  H. Woodward.  Acquisition , 1979, Critical Inquiry.