Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity
| Autor: | Mohammad A. Kaisar, Jee Hyun Park, Ravi K. Sajja, Luca Cucullo, Thomas J. Abbruscato, Taylor Liles, Shikha Prasad, Heidi Villalba |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry medicine.disease_cause Biochemistry Mice 0302 clinical medicine Smoke Endothelial dysfunction 2DM Type 2 diabetes mellitus lcsh:QH301-705.5 Cells Cultured lcsh:R5-920 TEER Trans-endothelial electrical resistance Brain Glut−1 Glucose transporter TJ Tight junction Cigarette smoke BBB Blood-brain barrier Metformin CSE Cigarette smoke extract HO-1 Heme oxygenase 1 3. Good health medicine.anatomical_structure Neuroprotective Agents Blood-Brain Barrier Blood brain barrier Toxicity medicine.symptom lcsh:Medicine (General) medicine.drug Signal Transduction Research Paper FITC Fluorescein isothiocyanate medicine.medical_specialty SFN Sulforaphane Cell Survival NF-E2-Related Factor 2 CS Cigarette smoke TS Tobacco smoke Inflammation COPD Chronic obstructive pulmonary disease Blood–brain barrier Thrombomodulin Nrf2 03 medical and health sciences Nrf2 Nuclear factor erythroid 2-related factor ICAM-1 Intercellular adhesion molecule-1 Internal medicine Tobacco medicine Animals MF Metformin Tight junctions Glucose transporter ZO-1 Zonulae occludentes-1 business.industry FTC Federal trade control Blood hemostasis Organic Chemistry Endothelial Cells RITC Rhodamine B isothiocyanate medicine.disease NQO-1 NAD(P)H: Quinone reductase I Oxidative Stress 030104 developmental biology Endocrinology lcsh:Biology (General) ISO International organization for standardization ARE Anti-oxidant response element PECAM-1 Platelet endothelial cell adhesion molecule-1 business Reactive Oxygen Species HG Hyperglycemia 030217 neurology & neurosurgery Oxidative stress ROS Reactive oxygen species |
| Zdroj: | Redox Biology, Vol 12, Iss, Pp 58-69 (2017) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Herein we provide evidence of the role played by nuclear factor erythroid 2-related factor (Nrf2) in CS-induced cerebrobvascular/BBB impairments and how these cerebrovascular harmful effects can be circumvented by the use of metformin (MF; a widely prescribed, firstline anti-diabetic drug) treatment. Our data in fact revealed that MF activates counteractive mechanisms primarily associated with the Nrf2 pathway which drastically reduce CS toxicity at the cerebrovascular level. These include the suppression of tight junction (TJ) protein downregulation and loss of BBB integrity induced by CS, reduction of inflammation and oxidative stress, renormalization of the expression levels of the major BBB glucose transporter Glut-1 and that of the anticoagulant factor thrombomodulin. Further, we provide additional insights on the controversial interplay between Nrf2 and AMPK. Graphical abstract fx1 Highlights • Prolonged cigarette smoke exposure causes cerebrovascular impairment and decreases thrombomodulin release. • Metformin prevents cigarette smoke extract-induced BBB endothelial cells dysfunction and loss of BBB integrity. • Metformin prevents cigarette smoke extract-induced cerebrovascular impairment in vivo. • Nrf2 activation by Metformin enhances ZO-1 and Glut-1 protein expression and is independent of AMPK phosphorylation. |
| Databáze: | OpenAIRE |
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