Flavonoid Apigenin Inhibits Lipopolysaccharide-Induced Inflammatory Response through Multiple Mechanisms in Macrophages

Zhang, Xiaoxuan; Wang, Guangji; Gurley, Emily C.; Zhou, Huiping

doi:10.1371/journal.pone.0107072

Cited by 195 publications

(157 citation statements)

References 61 publications

(68 reference statements)

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“…In endothelial cells, apigenin provides a protective effect against LPS-induced inflammation by decreasing caspase-3 activation and modulating mitochondrial function (11). Apigenin exerts anti-inflammatory activity via multiple mechanisms (12), including the induction of apoptosis and the regulation of MAPK signaling pathways in mouse macrophage ANA-1 cells (13). Other mechanisms include the inhibition of inflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Apigenin protects against bleomycin-induced lung fibrosis in rats

Chen

Zhao

2015

Experimental and Therapeutic Medicine

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Abstract. Apigenin is a non-toxic and non-mutagenic flavone that exists abundantly in numerous herbs and vegetables. Apigenin exerts anti-proliferative and anti-inflammatory properties. The aim of the present study was to investigate the effects of apigenin on bleomycin-induced lung fibrosis in rats. A single intratracheal instillation of bleomycin (5 mg/kg) was administered and rats were sacrificed on 7 and 28 days post bleomycin instillation. The instillation of bleomycin resulted in decreased body weight and an increase in the lung index. In addition, bleomycin administration increased the hydroxyproline content, myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β levels and decreased the superoxide dismutase (SOD) activity in the rat lung tissues. Excessive collagen deposits were detected in the lung tissues in bleomycin-treated rats compared with normal control rats. Notably, the oral administration of apigenin (10, 15 and 20 mg/kg/day) appeared to prevent the fibrotic process. The treatment suppressed the increases in hydroxyproline content, MPO activity, TNF-α and TGF-β levels and attenuated the reduction of SOD activity that were induced by bleomycin. Furthermore, excessive collagen deposition was inhibited by the apigenin treatment. Collectively, these results suggest that apigenin may function as a potent anti-inflammatory and anti-fibrotic agent against bleomycin-induced lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

Apigenin protects against bleomycin-induced lung fibrosis in rats

Chen

Zhao

2015

Experimental and Therapeutic Medicine

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“…[22][23][24] In this study, we attempted to clarify whether some flavonoids have the ability to suppress CoCl 2 -elicited decreases in EC-SOD. Among the 7 flavonoids examined in the present study (Fig.…”

Section: Effects Of Flavonoids On Cocl 2 -Elicited Decreases In Ec-sodmentioning

confidence: 99%

“…[22][23][24] We previously reported that luteolin significantly suppressed phorbol ester (TPA)-induced human monocytic differentiation into macrophages, and these events were closely associated with the inhibition of intracellular ROS signaling. 25) Accordingly, some flavonoids may be seed compounds that maintain redox homeostasis.…”

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confidence: 99%

CoCl<sub>2</sub> Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

Hattori

Kamiya

Hara

et al. 2016

Biological & Pharmaceutical Bulletin

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Extracellular-superoxide dismutase (EC-SOD), one of the SOD isozymes, is negatively regulated under hypoxic conditions, and decreases in its expression may exacerbate vascular diseases. Moreover, epigenetics, such as DNA methylation and histone modifications, are known to play a critical role in the progression of cancer, type 2 diabetes, and atherosclerosis. We previously investigated the involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) in decreases in EC-SOD expression in hypoxic COS7 cells; however, the role of epigenetics in this process currently remains unknown. In the present study, we demonstrated that the hypoxia mimetic cobalt chloride (CoCl 2 ) decreased histone acetylation levels, and a pretreatment with 4-phenyl butyric acid (PBA), an inhibitor of histone deacetylase, significantly suppressed CoCl 2 -elicited histone deacetylation and decreases in EC-SOD. We found that CoCl 2 -elicited decreases in EC-SOD were accompanied by reductions in histone H3 acetylation levels within its promoter region. Furthermore, luteolin, a well-known flavonoid, significantly suppressed the CoCl 2 -elicited accumulation of ROS, p38-MAPK activation, and histone deacetylation. Collectively, the results of the present study showed for the first time that CoCl 2 decreases the expression of EC-SOD through its deacetylation and luteolin may be one of the seed compounds that maintain redox homeostasis, even under hypoxic conditions.

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“…TNF-α was inhibited in the ARMs (1:2) treated group. It is reported that apigenin was less potent in regulating TNF-α expression and secretion than IL-1β and IL-6 in the range from 6.25 to 25 µM [27]. Concentrations of apigenin in AMs and ARMs (1:0.5), (1:1), and (1:2) were 3.8 µM, 6.5 µM, 9.0 µM and 12.1 µM, respectively.…”

Section: Discussionmentioning

confidence: 97%

Resveratrol as a bioenhancer to improve anti-inflammatory activities of apigenin

2016

Planta Med

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Abstract:The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a K i value of 7.782 µM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.

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Flavonoid Apigenin Inhibits Lipopolysaccharide-Induced Inflammatory Response through Multiple Mechanisms in Macrophages

Cited by 195 publications

References 61 publications

Apigenin protects against bleomycin-induced lung fibrosis in rats

Apigenin protects against bleomycin-induced lung fibrosis in rats

CoCl<sub>2</sub> Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

Resveratrol as a bioenhancer to improve anti-inflammatory activities of apigenin

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