Screening of natural epigenetic modifiers for managing glycemic memory and diabetic nephropathy

Abstract

Short hyperglycaemic episodes trigger metabolic memory (MM) in which managing hyperglycaemia alone is not enough to tackle the progression of Diabetic nephropathy on the epigenetic axis. We used a structural similarity search approach to identify phytochemicals similar to natural epigenetic modifiers and docked with SIRT1 protein and did ADME studies. We found that UMB was 84.3% similar to esculetin. Upon docking, we found that UMB had a binding energy of −9.2 kcal/mol while the standard ligand had −11.8 kcal/mol. ADME showed UMB to be a good lead. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed it to be a good antioxidant with IC₅₀ of 107 µg/mL and MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that it does not promote cell death. Oxidative biomarkers in vitro showed UMB was able to ameliorate glycemic memory induced by high glucose. Western blot revealed decreased histone acetylation under hyperglycaemic conditions and upon treatment with UMB along with DR, its levels increased. This led us to check our hypothesis of whether concomitant diet reversal (DR) together with UMB can alleviate high-fat diet-induced metabolic memory and diabetic nephropathy (DN) in SD rats. UMB was able to decrease blood glucose, lipid, renal, and liver profile concluding UMB was able to ameliorate DN and MM by increasing the histone acetylation level.

Keywords:

• Hyperglycaemia
• metabolic memory
• histone acetylation
• oxidative biomarkers
• diet reversal
• diabetic nephropathy

Acknowledgements

We would like to thank Lovely Professional University for providing us with space and resources to carry out work.

Authors’ contributions

Kriti Kushwaha did all the experiments and wrote the manuscript, Sourbh Suren Garg helped with animal studies, Debojyoti Mandal helped with in vitro studies, Navneet Khurana supervised the animal study and Jeena Gupta was responsible for the conceptualisation of the project, edited and approved the final draft of the paper.

Disclosure statement

Authors declare no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.