1,8-Cineole alleviates Nrf2-mediated redox imbalance and mitochondrial dysfunction in diabetes mellitus by targeting Sirt1

Phytomedicine. 2024 Dec:135:156099. doi: 10.1016/j.phymed.2024.156099. Epub 2024 Oct 1.

Abstract

Background: Type 2 diabetes mellitus (T2DM) is primarily attributed to impaired insulin secretion caused by β cell dysfunction. 1,8-Cineole is a key bioactive compound in the essential oil extracted from Fructus Alpiniae Zerumbet, which possesses anti-inflammatory and antioxidant properties. Nevertheless, it remains elusive about the protective effect and precise mechanisms of 1,8-Cineole against the β cell deterioration in T2DM.

Purpose: To investigate the effect of 1,8-Cineole on β cell dysfunction in T2DM and the potential mechanism of its action.

Methods: A mouse model of T2DM and a β cell model of high glucose induction were generated to analyze the pharmacological properties of 1,8-Cineole. Proteomic and network pharmacological analyses were conducted to identify the crucial pathways involved in T2DM. Resveratrol [a Sirtuin1 (Sirt1) agonist] and Sirt1 knockdown were used to ascertain the mechanism of 1,8-Cineole in T2DM. The binding affinity of 1,8-Cineole to Sirt1 was assessed with molecular docking, surface plasmon resonance, immunoprecipitation assay, and cellular thermal shift assay.

Results: Firstly, dysregulated crucial pathways in T2DM were screened out, including redox imbalance and mitochondrial dysfunction. Subsequently, 1,8-Cineole was found to activate Sirt1 and nuclear factor E2-related factor 2 (Nrf2) to repress oxidative stress in both T2DM mice and high glucose-induced β cells, thereby relieving mitochondrial dysfunction and apoptosis. Furthermore, 1,8-Cineole specifically targeted Sirt1 and favored the direct interaction between Sirt1 and Nrf2, ultimately restoring β cell function.

Conclusions: Our findings provide the first evidence that 1,8-Cineole directly binds to Sirt1 and enhances its stability, therefore rectifying impaired oxidative homeostasis, and then suppressing mitochondrial dysfunction and apoptosis in T2DM, indicating that 1,8-Cineole may be a potential candidate drug for T2DM treatment.

Keywords: 1,8-Cineole; Diabetes mellitus; Mitochondrion; Nrf2; Oxidative stress; Sirt1.

MeSH terms

  • Alpinia / chemistry
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / metabolism
  • Eucalyptol* / pharmacology
  • Insulin-Secreting Cells* / drug effects
  • Insulin-Secreting Cells* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria* / drug effects
  • Mitochondria* / metabolism
  • Molecular Docking Simulation*
  • NF-E2-Related Factor 2* / metabolism
  • Oxidation-Reduction* / drug effects
  • Oxidative Stress / drug effects
  • Sirtuin 1* / metabolism

Substances

  • Sirtuin 1
  • Eucalyptol
  • NF-E2-Related Factor 2
  • Sirt1 protein, mouse
  • Nfe2l2 protein, mouse