Bilobalide attenuates hypoxia induced oxidative stress, inflammation, and mitochondrial dysfunctions in 3T3-L1 adipocytes via its antioxidant potential

Abstract

Excessive expansion of white adipose tissue leads to hypoxia which is considered as a key factor responsible for adipose tissue dysfunction in obesity. Hypoxia induces inflammation, insulin resistance, and other obesity related complications. So the hypoxia-signalling pathway is expected to provide a new target for the treatment of obesity-associated complications. Inhibition or downregulation of the HIF-1 pathway could be an effective target for the treatment of obesity related hypoxia. In the present study, we evaluated the effect of hypoxia on functions of 3T3-L1 adipocytes emphasising on oxidative stress, antioxidant status, inflammation and mitochondrial functions. We have also evaluated the protective role of bilobalide, a bioactive from Gingko biloba, on hypoxia induced alterations. The results revealed that hypoxia significantly altered all the vital parameters of adipocyte biology like HIF-1α expression (103.47% ↑), lactate and glycerol release (184.34% and 69.1% ↑, respectively), reactive oxygen species (ROS) production (432.53% ↑), lipid and protein oxidation (376.6% and 566.6% ↑, respectively), reduction in antioxidant enzymes (superoxide dismutase and catalase) status, secretion of inflammatory markers (TNF-α, IL-6, IL-1β and IFN-γ) and mitochondrial functions (mitochondrial mass, membrane potential, permeability transition pore integrity, superoxide generation). Bilobalide significantly protected adipocytes from adverse effects of hypoxia in a dose-dependent manner by attenuating oxidative stress, inflammation and protecting mitochondria. Acriflavine (HIF-1 inhibitor) was used as positive control. On the basis of this study, a detailed investigation is needed to delineate the mechanism of action of bilobalide to develop it as therapeutic target for obesity.

Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity

“…Bilobalide has four five-membered rings (three lactones and a carbocycle) and a tert-butyl group. Many terpene lactones are reported to have anti-inflammatory [6,7], endothelial protective [8,9], cardioprotective [10], antiplatelet [11], and antioxidant properties in cell-based and animal-based studies [12,13]. Ginkgolides A, B, and C are also platelet-activating factor (PAF) receptor antagonists [14,15].…”

Enhancing amplification of late‐outgrowth endothelial cells by bilobalide

“…Certainly, ONOO − and H 2 O 2 may partly convert into OH • . Bilobalide has antioxidant potential through promoting antioxidase expression in a variety of cell types . We failed to get a special reagent for indication of intracellular ONOO − but HPF, a fluorescence probe reactive to OH • and ONOO − .…”

“…32 Multiple stimuli such as growth factors and fluid shear stress activate eNOS by Ser-1177 phosphorylation 33 Bilobalide has antioxidant potential through promoting antioxidase expression in a variety of cell types. 18,19,24,25 We failed to get a special reagent for indication of intracellular ONOO À but HPF, a fluorescence probe reactive to OH • and ONOO À . Our present data showed that bilobalide pre-treatment limited the increase of OH • / ONOO À , O 2 À • and H 2 O 2 in proliferating OECs, implying bilobalide F I G U R E 8 Effect of bilobalide on hydroxyl radical/peroxynitrite, superoxide anion and hydrogen peroxide in proliferating lateoutgrowth endothelial cells (OECs).…”

What Is the Role of Inflammatory Mediators on Energy Metabolism?

“…These changes lead to cells deterioration, resulting in insulin resistance or in a greater lipid accumulation in adipocytes, due to the increased nicotinamide adenine dinucleotide phosphate-reduced (NADPH) supply, predisposing to obesity by changes in energy metabolism [4,20] . Hypoxia, from adiposity excess significantly alter the adipocytes vital parameters, such as: the increase in ROS (432.53%), lipids and proteins oxidation (376.6% and 566.6%, respectively), the antioxidant enzymes and inflammatory mediators release reduction [21] . Thus, the adiposity excess and oxidative stress observed in obesity trigger an inflammatory cascade by phosphorylation of signal transduction and activation of transcription (STAT) pathways -Jun N-terminal kinase proteins (JNK); Nuclear Factor kappa Beta (NF-KB) [22] .…”