Anthocyanins isolated from Hibiscus syriacus L. attenuate lipopolysaccharide-induced inflammation and endotoxic shock by inhibiting the TLR4/MD2-mediated NF-κB signaling pathway

Karunarathne, Wisurumuni Arachchilage Hasitha Maduranga; Lee, Kyoung Tae; Choi, Yung Hyun; Jin, Cheng‐Yun; Kim, Gi‐Young

doi:10.1016/j.phymed.2020.153237

Cited by 43 publications

(38 citation statements)

References 45 publications

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“…Previous studies have demonstrated that the induction of the NF-κB signaling pathway by LPS significantly increases the maturation of IL-1β by promoting the formation of the NLRP3 inflammasome [ 36 ]. Therefore, inhibition of the TLR4/MD2 complex is considered to be a promising therapeutic strategy for ameliorating NLRP3-mediated inflammatory disorders [ 26 , 37 ]. A study demonstrated that an intravenous injection of fisetin alleviated acute lung injury in LPS-treated mice by inhibiting the expression of TLR4 and NF-κB [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Zebrafish larvae (3 days post-fertilization) were pretreated with fisetin (0–400 µM) for 2 h prior to treatment with 5 µg/mL LPS for 2 h and subsequent stimulation with 2 mM ATP for 24 h. Each group of larvae ( n = 20) was cultured at 28.5 °C and observed for the mortality. The heart rate of the larvae was manually counted using stereomicroscopy (Olympus, Tokyo, Japan) for two minutes and used as an indicator for the cardiac toxicity evaluations [ 26 ]. The heart rate was represented as beats/min.…”

Section: Methodsmentioning

confidence: 99%

“…Macrophage in zebrafish larvae was detected using neutral red staining 24 h after LPS/ATP treatment. Briefly, zebrafish larvae were treated in 2.5 μg/mL neutral read solution (Sigma-Aldrich) containing 0.003% PTU at 28.5 °C for 6–8 h [ 26 ]. After staining, macrophages in the brain area were observed using stereomicroscopy.…”

Section: Methodsmentioning

confidence: 99%

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Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

et al. 2021

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Fisetin has numerous therapeutic properties, such as anti-inflammatory, antioxidative, and anticancer effects. However, the mechanism by which fisetin inhibits NLRP3 inflammasome remains unclear. In this study, we observed that fisetin bound to TLR4 and occluded the hydrophobic pocket of MD2, which in turn inhibited the binding of LPS to the TLR4/MD2 complex. This prevented the initiation of scaffold formation by the inhibition of MyD88/IRAK4 and subsequently downregulated the NF-κB signaling pathway. The result also demonstrated that fisetin downregulated the activation of the NLRP3 inflammasome induced by LPS and ATP (LPS/ATP) and the subsequent maturation of IL-1β. Fisetin also activated mitophagy and prevented the accumulation of damaged mitochondria and the excessive production of mitochondrial reactive oxygen species. The transient knockdown of p62 reversed the inhibitory activity of fisetin on the LPS/ATP-induced formation of the NLRP3 inflammasome. This indicated that fisetin induces p62-mediated mitophagy for eliminating damaged mitochondria. Recently, the existence of inflammasomes in non-mammalian species including zebrafish have been identified. Treatment of an LPS/ATP-stimulated zebrafish model with fisetin aided the recovery of the impaired heart rate, decreased the recruitment of macrophage to the brain, and gradually downregulated the expression of inflammasome-related genes. These results indicated that fisetin inhibited the TLR4/MD2-mediated activation of NLRP3 inflammasome by eliminating damaged mitochondria in a p62-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

et al. 2021

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“…81,82 Several studies reported that apigenin treatment significantly suppressed IL12 signaling activation in lipopolysaccharide treated macrophages, dendritic cells, and periodontal ligament cells. 83,84 Apigenin treatment also increased the production of IL10 in Ts1Cje embryonic brain above baseline. In adult Ts1Cje brains, the anti-inflammatory actions of apigenin were less pronounced than in the embryonic forebrain and were only restricted to the overproduction of the potent anti-inflammatory cytokine IL10 without affecting the expression of IFNG, NFkB, and IL1A signaling.…”

Section: Effects Of Apigenin Treatment On Human Amniocytesmentioning

confidence: 83%

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Guedj

Siegel

Pennings

et al. 2020

The American Journal of Human Genetics

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Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFkB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.

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“…In order to investigate the anti-inflammatory effect of this compound, an immunohistochemical assay was conducted to evaluate the binding capability to TLR4/MD2 and nuclear translocation of NF-κB p65. Molecular docking data showed that apigetrin powerfully bound to MD2 and TLR4 via hydrogen bonding and could be used as immunomodulator for the effective treatment of LPS-mediated inflammatory diseases [ 189 ]. The in vitro modulation of the complement system was determined on 87 by the assay based on the hemolysis of erythrocytes membrane generated after complement activation, both for the classical way and for the alternative one.…”

Section: Biological Activitymentioning

confidence: 99%

Stevia Genus: Phytochemistry and Biological Activities Update

et al. 2021

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The Stevia genus (Asteraceae) comprises around 230 species, distributed from the southern United States to the South American Andean region. Stevia rebaudiana, a Paraguayan herb that produces an intensely sweet diterpene glycoside called stevioside, is the most relevant member of this genus. Apart from S. rebaudiana, many other species belonging to the Stevia genus are considered medicinal and have been popularly used to treat different ailments. The members from this genus produce sesquiterpene lactones, diterpenes, longipinanes, and flavonoids as the main types of phytochemicals. Many pharmacological activities have been described for Stevia extracts and isolated compounds, antioxidant, antiparasitic, antiviral, anti-inflammatory, and antiproliferative activities being the most frequently mentioned. This review aims to present an update of the Stevia genus covering ethnobotanical aspects and traditional uses, phytochemistry, and biological activities of the extracts and isolated compounds.

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Anthocyanins isolated from Hibiscus syriacus L. attenuate lipopolysaccharide-induced inflammation and endotoxic shock by inhibiting the TLR4/MD2-mediated NF-κB signaling pathway

Cited by 43 publications

References 45 publications

Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Stevia Genus: Phytochemistry and Biological Activities Update

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