Pharmacological inhibition of SIRT-2 by AK-7 modulates redox status and apoptosis via regulating Nrf2 in an experimental model of chronic obstructive pulmonary disease: an invivo and insilico study

Abstract

Chronic obstructive pulmonary disease (COPD) is defined by inflammation and emphysema. Sirtuins (SIRT) are NAD⁺-dependent histone deacetylases that regulate oxidative stress and inflammation. The present work investigates the modulatory role of SIRT-2 in experimental COPD model. Insilico comparative assessment of SIRT-2 inhibitors (AK-7 and AGK-2) by ADMET and molecular docking revealed AK-7 as suitable candidate for invivo application. COPD in mice was established by cigarette smoke (CS) exposure for 2 months. AK-7 (100 µg/kg and 200 µg/kg body weight) was administered intranasally one hour before CS exposure. The present investigation demonstrates that CS exposure increases total cell count, and free radical production (total reactive oxygen species, total oxidant status, myeloperoxidase, and nitric oxide), which were decreased by AK-7. It also altered antioxidant enzymatic activity (total antioxidant status, catalase, superoxide dismutase, glutathione peroxidase, glutathione-s-transferase, glutathione reductase, and reduced glutathione), hence preserving the redox balance. AK-7 significantly decreases apoptosis, protein carbonylation, lipid peroxidation, TNF-α and IFN-ﻻ levels represent COPD generation in mice and were dramatically decreased by AK-7. Histopathological studies shows that CS exposure damages alveoli and produces peribronchiolar inflammation; both of these events were reduced by AK-7. The antioxidative potency of AK-7 was confirmed by observing Nrf2 and Keap1 proteins. Keap-dependent Nrf2 regulation was observed, with cytosolic Nrf2 and Keap1 expression elevated in COPD and reduced in the AK-7 group while nuclear Nrf2 was reduced in COPD and increased in the AK-7 group. The present study concludes that inhibition of SIRT-2 minimizes COPD severity and mediates therapeutic effects in the lungs.

Keywords:

• Sirtuin
• inflammation
• insilico
• oxidative stress
• COPD

Acknowledgements

The authors would like to sincerely thank Dr. Rahul Kumar Singh, Molecular Endocrinology and Toxicology lab (MET lab), Department of Zoology for using chemiluminescence. The authors are also thankful to Central Discovery Centre, Banaras Hindu University for allowing them to use Flow cytometry.

Ethics approval and consent to participate

All animal procedures were performed by protocols approved by Institutional Animal Ethical Committee (IAEC), Banaras Hindu University, Varanasi, India as per the IAEC approval reference No. BHU/DoZ/IAEC/2021-2022/017 dated 15/02/2022.

Authors’ contribution

Vandana Yadav, Vinita Pandey and Atul Srivastava contributed to the conception and design of the study, organized the database and performed the statistical analysis. Subhashini drafted the manuscript. All the authors have read, revised and approved the manuscript for submission.

Disclosure statement

No potential conflict of interest was reported by the author(s). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability statement

All the data generated or analyzed during the study are included in the article and can be produced whenever required.

Additional information

Funding

The present study was financially supported by the Department of Science and Technology, New Delhi (P-07/694), Faculty Incentive grant, IoE (R/Dev/D/IoE/Incentive/2022-23/47654) Banaras Hindu University and Council of Scientific & Industrial Research(CSIR)- File No: 09/013(0907)/2019-EMR-1, India in the form of Senior Research fellowship.