Exploring sesquiterpene lactone as a dual therapeutic agent for diabetes and oxidative stress: insights into PI3K/AKT modulation

Abstract

Diabetic mellitus (DM) is characterized by hyperglycaemia and defective macromolecular metabolism, arising from insulin resistance or lack of insulin production. The present study investigates the potential of artemisinin, a sesquiterpene lactone isolated from Artemisia annua, to exert anti-diabetic and antioxidant effects through modulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Our computational analyses demonstrated a high binding affinity of artemisinin with proteins belonging to the PI3K/AKT signalling cascade. α-Amylase and α-glucosidase studies revealed a notable increase in inhibition percentages with artemisinin treatment across concentrations ranging from 10 to 160 µM. A similar significant (p < 0.05) dose-dependent inhibition of free radicals was observed for the in vitro anti-oxidant assays. Further, toxicological profiling of artemisinin in the in vivo zebrafish embryo-larvae model from 4 to 96 h post-fertilization (hpf) did not exhibit any harmful repercussions. In addition, gene expression investigations confirmed artemisinin's potential mechanism in modulating hyperglycaemia and oxidative stress through the regulation of the PI3K/AKT pathway. Overall, our investigation suggests that artemisinin can be used as a therapeutic intervention for diabetes and oxidative stress, opening up opportunities for future investigation in clinical settings.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-024-04050-2.

Keywords: Anti-diabetic; Anti-oxidant; Artemisinin; Oxidative stress; Toxicity; Zebrafish larvae.

Fig. 1

Visualization of the three-dimensional (3D) and two-dimensional (2D) interactions between artemisinin and pivotal proteins involved in the PI3K/AKT signalling pathway: A IR, B AKT, C GSK3-β, D PDK1, and E PI3K. The interactions were analysed using Discovery Studio Visualizer, illustrating the binding modes and potential molecular mechanisms underlying artemisinin’s modulation of the PI3K/AKT pathway

Fig. 2

Visualization of the three-dimensional (3D) and two-dimensional (2D) interactions between artemisinin and pivotal proteins involved in the PI3K/AKT signalling pathway: A SOD, B CAT, C GPx, D GR, E GS, and F GST. The interactions were analysed using Discovery Studio Visualizer, illustrating the binding modes and potential molecular mechanisms underlying artemisinin’s modulation of the PI3K/AKT pathway

Fig. 3

Bioavailability radar plot generated using SwissADME to predict the pharmacokinetic parameters and drug-likeness properties of artemisinin. The radar plot provides a comprehensive visual representation of key molecular descriptors such as lipophilicity, water solubility, molecular weight, and pharmacokinetic parameters, aiding in the assessment of artemisinin’s potential as a drug candidate

Fig. 4

The figure illustrates the dose-dependent inhibition activity of artemisinin at concentrations ranging from 10 to 160 µM on A α-amylase and B α-glucosidase enzymes, alongside comparative data with acarbose. Significant differences (p < 0.05) are denoted by asterisks (*). These findings highlight artemisinin’s potential as an inhibitor of key enzymes involved in carbohydrate metabolism, suggesting its therapeutic relevance in managing hyperglycaemia

Fig. 5

It depicts the antioxidant activity of artemisinin at concentrations ranging from 10 to 160 µM against various reactive oxygen species: A DPPH (2,2-diphenyl-1-picrylhydrazyl), B ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), C H₂O₂, and (D) superoxide radicals, in comparison with trolox as a reference antioxidant. Significant differences (p < 0.05) are indicated by asterisks (*), underscoring artemisinin’s potential as a potent antioxidant compound across different assays

Fig. 6

The assessment of nitric oxide (NO) scavenging potential of artemisinin at concentrations ranging from 10 to 160 µM, alongside comparison with Trolox as a standard antioxidant. Significant differences (p < 0.05) are denoted by asterisks (*). These results highlight artemisinin’s ability to scavenge NO, suggesting its potential therapeutic application in managing oxidative stress-related conditions

Fig. 7

The figure displays the outcomes of the assessment on zebrafish larvae, including A survival rate over a period from 4 to 96 h post-fertilization (hpf), B hatching rate at 48 hpf, and C heart rate at 72 hpf. Significant differences (p < 0.05) are indicated by asterisks (*), emphasizing the effects of artemisinin exposure on these developmental and physiological parameters

Fig. 8

In vivo developmental analysis of zebrafish embryos exposed to artemisinin included A embryos at 24 h post-fertilization (hpf, Gastula stage) with a scale of 25 µm, B embryos at 48 hpf (organogenesis stage) with a scale of 25 µm, and C larvae at 72 hpf stage with a scale of 100 µm. The control and treatment groups (10–40 µM) showed no lethal malformations, whereas the 80 µM and 160 µM treatment groups exhibited lethal malformations such as bent tail (BT), yolk sac edema (YSE), and bent spine (BS)

Fig. 9

Behavioural tracking of zebrafish larvae treated with A Control, B Vehicle control, C 10 µM, D 20 µM, E 40 µM, F 80 µM, and G 160 µM of artemisinin, illustrating their movement patterns. H Distance travelled by larvae. Significant differences (p < 0.05) are denoted by asterisks (*). This analysis provides insights into the effects of artemisinin on the behaviour of larvae under oxidative stress conditions

Fig. 10

The figure presents the assessment of artemisinin's impact on antidiabetic and antioxidant gene expression in zebrafish larvae induced with oxidative stress at 96 hpf. Significant differences (p < 0.05) are denoted by asterisks (*), highlighting the potential regulatory effects of artemisinin on genes involved in glucose metabolism and oxidative stress response pathways

Fig. 11

The figure illustrates the hypothesized mechanism by which artemisinin regulates the PI3K/AKT signalling pathway to mitigate insulin sensitivity and oxidative stress. Artemisinin’s interactions with key proteins in the pathway are depicted, highlighting its potential therapeutic role in managing metabolic disorders characterized by insulin resistance and oxidative damage