7‐methoxyflavanone alleviates neuroinflammation in lipopolysaccharide‐stimulated microglial cells by inhibiting TLR4/MyD88/MAPK signalling and activating the Nrf2/NQO‐1 pathway

Published on Mar 1, 2020in Journal of Pharmacy and Pharmacology2.571
· DOI :10.1111/JPHP.13219
Zhao Qu1
Estimated H-index: 1
(Guangzhou University of Chinese Medicine),
Yan Chen1
Estimated H-index: 1
(Guangzhou University of Chinese Medicine)
+ 2 AuthorsYing-Jie Hu6
Estimated H-index: 6
(Guangzhou University of Chinese Medicine)
OBJECTIVES: Neuroprotective potential of 7-methoxyflavanone (7MF) and its underlying mechanism was investigated. METHODS: Inhibitory effects of 7MF on microglial activation and neuroinflammation were evaluated by employment of lipopolysaccharide (LPS)-induced BV2 microglial cells. Changes in expression of genes and proteins of interest were investigated by RT-qPCR analysis and Western blot analysis. Inhibitory effects of 7MF on microglial overactivation were verified in LPS-treated C57BL/6J mice using ionized calcium-binding adaptor molecule-1 (Iba1) in the brain and interleukin-6 (IL-6) in serum as indicators. KEY FINDINGS: In BV2 cells, pretreatment with 7MF antagonized LPS-induced production of inflammatory factors IL-6, tumour necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Mechanistic studies revealed reduced expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88), phosphorylated forms of c-Jun N-terminal kinase (p-JNK) and extracellular signal-regulated kinases 1/2 (p-ERK) but increased nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and cellular expression of NAD(P)H quinone dehydrogenase-1 (NQO-1) by 7MF. In LPS-treated mice, pretreatment with 7MF reduced the brain level of Iba1 and serum level of IL-6. CONCLUSIONS: 7-methoxyflavanone inhibited LPS-stimulated TLR4/MyD88/MAPK signalling and activated Nrf2-mediated transcription of antioxidant protein NQO-1, showing antineuroinflammatory effect, so it is a potential neuroprotective agent.
📖 Papers frequently viewed together
30 Citations
24 Citations
10 Citations
#1Shofiul Azam (Konkuk University)H-Index: 7
#2Md. Jakaria (Konkuk University)H-Index: 9
Last. Dong-Kug Choi (Konkuk University)H-Index: 41
view all 6 authors...
Neuronal dysfunction initiates several intracellular signalling cascades to release different proinflammatory cytokines and chemokines, as well as various reactive oxygen species. In addition to neurons, microglia and astrocytes are also affected by this signalling cascade. This release can either be helpful, neutral or detrimental for cell survival. Toll-like receptors (TLRs) activate and signal their downstream pathway to activate NF-κB and pro-IL-1β, both of which are responsible for neuroinf...
56 CitationsSource
#1Albena T. Dinkova-Kostova (Dund.: University of Dundee)H-Index: 64
#2Rumen V. Kostov (Dund.: University of Dundee)H-Index: 9
Last. Aleksey G. Kazantsev (Harvard University)H-Index: 32
view all 3 authors...
The transcription factor Nrf2 (nuclear factor‐erythroid 2 p45‐related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclero...
91 CitationsSource
Oxytropis falcata has long been used to treat inflammation, sores, and bleeding in Tibet. However, the burn remedy and underlying molecular mechanisms are not well understood. This study is aimed at assessing the effect of Oxytropis falcate gel (OFG) on deep second-degree burn rats and exploring its mechanism. Wistar rats with second-degree burn were treated with OFG and silver sulfadiazine. Immunohistochemical detections for EGF and VEGF were performed, and ELISA detections for EGF, VEGF, p38, ...
3 CitationsSource
#1Ana I. Rojo (CSIC: Spanish National Research Council)H-Index: 34
#2Marta Pajares (CSIC: Spanish National Research Council)H-Index: 10
Last. Antonio Cuadrado (CSIC: Spanish National Research Council)H-Index: 57
view all 11 authors...
Abstract Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains re...
75 CitationsSource
#1Mahban Rahimifard (Tehran University of Medical Sciences)H-Index: 15
#2Faheem Maqbool (Tehran University of Medical Sciences)H-Index: 16
Last. Seyed Fazel Nabavi (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 49
view all 8 authors...
A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to norm...
137 CitationsSource
#1Marco Colonna (WashU: Washington University in St. Louis)H-Index: 127
#2Oleg Butovsky (Brigham and Women's Hospital)H-Index: 39
Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger th...
472 CitationsSource
Abstract Traditionally the brain has been viewed as being an immune-privileged organ. However, endogenous stimuli such as the presence of misfolded or aggregated proteins, as well as systemic inflammatory events may lead to the activation of microglial cells, the brain's innate immune system, and, subsequently, to neuroinflammation. Alzheimer's disease, the leading cause of dementia, is characterized by amyloid beta deposition and tau hyperphosphorylation. Neuroinflammation in Alzheimer's diseas...
47 CitationsSource
#1Yong Sung Choi (Yonsei University)H-Index: 4
#2Dong Myung Kim (Yonsei University)H-Index: 1
Last. Jin Hyun Jeong (Yonsei University)H-Index: 4
view all 7 authors...
The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the ability to pass through the blood-brain barrier (BBB). They showed in vitro antioxidant effects against hydrogen peroxide, and did not result in severe cytotoxicity. Moreov...
6 CitationsSource
#1Diego Gomez-Nicola (University of Southampton)H-Index: 24
#2V. Hugh Perry (University of Southampton)H-Index: 55
The study of the dynamics and functions of microglia in the healthy and diseased brain is a matter of intense scientific activity. The application of new techniques and new experimental approaches has allowed the identification of novel microglial functions and the redefinition of classic ones. In this review, we propose the study of microglial functions, rather than their molecular profiles, to better understand and define the roles of these cells in the brain. We review current knowledge on th...
167 CitationsSource
#1Céline Vaure (Sanofi Pasteur)H-Index: 1
#2Yuanqing Liu (Sanofi Pasteur)H-Index: 2
Toll-like receptors (TLRs) belong to the pattern recognition receptor (PRR) family, a key component of the innate immune system. TLRs detect invading pathogens and initiate an immediate immune response to them, followed by a long-lasting adaptive immune response. Activation of TLRs leads to the synthesis of pro-inflammatory cytokines and chemokines and the expression of co-stimulatory molecules. TLR4 specifically recognizes bacterial lipopolysaccharide (LPS), along with several other components ...
312 CitationsSource
Cited By2
#1Ronald N. KostoffH-Index: 38
#2Michael B. BriggsH-Index: 10
Last. Darla R. Shores (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 3
view all 3 authors...
Inflammatory bowel disease (IBD) incidence has been increasing steadily, most dramatically in the Western developed countries. Treatment often includes lifelong immunosuppressive therapy and surgery. There is a critical need to reduce the burden of IBD and to discover medical therapies with better efficacy and fewer potential side-effects. Repurposing of treatments originally studied in other diseases with similar pathogenesis is less costly and time intensive than de novo drug discovery. This s...
3 CitationsSource