Isoschaftoside Inhibits Lipopolysaccharide-Induced Inflammation in Microglia through Regulation of HIF-1α-Mediated Metabolic Reprogramming

Abstract

Isoschaftoside is a C-glycosyl flavonoid extracted from the root exudates of Desmodium uncinatum and Abrus cantoniensis. Previous studies suggested that C-glycosyl flavonoid has neuroprotective effects with the property of reducing oxidative stress and inflammatory markers. Microglia are key cellular mediators of neuroinflammation in the central nervous system. The aim of this study was to investigate the effect of isoschaftoside on lipopolysaccharide-induced activation of BV-2 microglial cells. The BV-2 cells were exposed to 10 ng/ml lipopolysaccharide and isoschaftoside (0–1000 μM). Isoschaftoside effectively inhibited lipopolysaccharide-induced nitric oxide production and proinflammatory cytokines including iNOS, TNF-α, IL-1β, and COX2 expression. Isoschaftoside also significantly reduced lipopolysaccharide-induced HIF-1α, HK2, and PFKFB3 protein expression. Induction of HIF-1α accumulation by CoCl2 was inhibited by isoschaftoside, while the HIF-1α specific inhibitor Kc7f2 mitigated the metabolic reprogramming and anti-inflammatory effect of isoschaftoside. Furthermore, isoschaftoside attenuated lipopolysaccharide-induced phosphorylation of ERK1/2 and mTOR. These results suggest that isoschaftoside can suppress inflammatory responses in lipopolysaccharide-activated microglia, and the mechanism was partly due to inhibition of the HIF-1α-mediated metabolic reprogramming pathway.

Comparison of Nutritional Diversity in Five Fresh Legumes Using Flavonoids Metabolomics and Postharvest Botrytis cinerea Defense Analysis of Peas Mediated by Sakuranetin

“…Kaempferitrin has effects that inhibit cell proliferation, promote cell apoptosis, and ameliorate inflammation . Isoschaftoside has neuroprotective effects by reducing oxidative stress and inflammatory markers . In kidney bean, quercetin5-O-glucuronide and quercetin-3-O-sambubioside were more abundant than in other legumes and cynaroside and astragalin were specifically contained.…”

“…36 Isoschaftoside has neuroprotective effects by reducing oxidative stress and inflammatory markers. 37 In kidney bean, quercetin5-O-glucuronide and quercetin-3-O-sambubioside were more abundant than in other legumes and cynaroside and astragalin were specifically contained. Cynaroside possesses antibacterial, antifungal, antileishmanial, hepatoprotective, antidiabetic, and anticancer properties.…”

Ethnobotanical Uses and Pharmacological Activities of Moroccan Ephedra Species

“…Among the many beneficial flavonoids, one can underline the anti-inflamma-tory action of isoschaftoside found in E. alata, for example [95]. This compound is a potent antioxidant and an anti-inflammatory agent with an anti-steatosis activity useful to combat metabolic liver disease [165,166]. Other flavonol glycosides, such as isorhamnetin-3-O-rutinoside, contribute similarly to the antioxidant and anti-inflammatory effects [16].…”

HIF‐1α inhibition in macrophages preserves acute liver failure by reducing IL‐1β production

“…21 Notably, HIF-1α accumulates in all proinflammatory activated immune cells, including macrophages, under normoxic conditions and is involved in regulating the transcription of inflammatory genes such as Il-1β. [22][23][24] HIF-1α inhibition markedly reduces Il-1β gene expression, and myeloidspecific HIF-1α deletion protects against inflammationinduced acute and chronic liver injury. 25,26 A small number of studies have indicated a protective role of HIF-1α inhibitors against inflammation-induced acute liver failure, 25,27 but this effect has not yet been well elucidated.…”

“…Under normoxic and homeostatic conditions, HIF‐1α protein is prolyl‐hydroxylated by prolyl hydroxylases (PHDs) and subsequently polyubiquitinated by von Hippel–Lindau tumor suppressor protein (VHL), marking it for proteasomal degradation 21 . Notably, HIF‐1α accumulates in all proinflammatory activated immune cells, including macrophages, under normoxic conditions and is involved in regulating the transcription of inflammatory genes such as Il‐1β 22–24 . HIF‐1α inhibition markedly reduces Il‐1β gene expression, and myeloid‐specific HIF‐1α deletion protects against inflammation‐induced acute and chronic liver injury 25,26 .…”