Formononetin protects against inflammation associated with cerebral ischemia-reperfusion injury in rats by targeting the JAK2/STAT3 signaling pathway

Yu, Li; Zhang, Yangyang; Chen, Qianqian; He, Yu; Zhou, Huifen; Wan, Haitong; Yang, Jiehong

doi:10.1016/j.biopha.2022.112836

Cited by 71 publications

(31 citation statements)

References 26 publications

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“…Accumulated evidence showed that the JAK2-STAT3 signaling pathway was involved in the occurrence of various neuroinflammation diseases. − The activated STAT3 initiated the transcription and expression of genes encoding proinflammatory-related elements, forming a vicious circle of the inflammatory response chain, constantly spreading and amplifying the role of proinflammatory factors, thus resulting in pathological damage . Meanwhile, some studies demonstrated that the inactivation of the JAK2-STAT3 pathway ameliorated the polarization toward the M1 phenotype and inhibited the proinflammatory reaction, which was in line with our in vivo and in vitro results showing that SCL reversed the higher IL-6, IL-1β, and TNF-α mRNA levels and protein expression and the hypersecretion of NO via inactivating the JAK2-STAT3 pathway. , In addition, IL-4 and IL-13 stimulated the activation of STAT6. The activation of STAT6 in microglia was also confirmed to exert neuroprotective effects via promoting the polarization of microglia toward the M2 phenotype. ,, These studies were consistent with our results that SCL upregulated the levels of p-STAT6/STAT6 and IL-4, IL-10, CD206, TGF-β, and Ym1/2 mRNA.…”

Section: Discussionsupporting

confidence: 85%

“…43 Meanwhile, some studies demonstrated that the inactivation of the JAK2-STAT3 pathway ameliorated the polarization toward the M1 phenotype and inhibited the proinflammatory reaction, which was in line with our in vivo and in vitro results showing that SCL reversed the higher IL-6, IL-1β, and TNF-α mRNA levels and protein expression and the hypersecretion of NO via inactivating the JAK2-STAT3 pathway. 34,44 In addition, IL-4 and IL-13 stimulated the activation of STAT6. The activation of STAT6 in microglia was also confirmed to exert neuroprotective effects via promoting the polarization of microglia toward the M2 phenotype.…”

Section: ■ Discussionmentioning

confidence: 99%

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Schisandra chinensis Lignans Exert Antidepressant Effects by Promoting BV2 Microglia Polarization toward the M2 Phenotype through the Activation of the Cannabinoid Receptor Type-2–Signal Transducer and Activator of Transcription 6 Pathway

Wang

Zhang

Yang

et al. 2022

J. Agric. Food Chem.

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Based on the current results, they showed that Schisandra chinensis lignans (SCL) ameliorated depressive-like behaviors in chronic unpredictable mild stress (CUMS) mice, alleviated neuroinflammation, and improved neuronal injury. This study aimed to explore whether SCL exerted antidepressant effects through inhibiting neuroinflammation, in turn improving neuronal injury. In vitro studies revealed that SCL blocked lipopolysaccharide-increased BV2 microglial M1 but promoted the M2 phenotype. The BV2−N2a interaction model suggested that increasing the M2 phenotype of BV2 played neuroprotective effects. The current studies demonstrated that SCL up-regulated the expression of CUMS-and LPS-decreased cannabinoid receptor type-2 (CB2R) mRNA. In vitro studies showed that the transfection of BV2 with siCrn2 blocked the SCL-increased M2 phenotype via the inactivating signal transducer and activator of transcription 6 (STAT6) pathway, further decreasing the viability of N2a cells. Finally, the possible pharmacodynamic compounds, γ-schisandrin and schisantherin A, were indicated by AutoDuck analysis. Overall, our study showed that SCL promoted microglia polarization toward the M2 phenotype, in turn exerting neuroprotective effects by activating CB2R-STAT6 signaling further to play antidepressant roles.

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Section: Discussionsupporting

confidence: 85%

Section: ■ Discussionmentioning

confidence: 99%

Schisandra chinensis Lignans Exert Antidepressant Effects by Promoting BV2 Microglia Polarization toward the M2 Phenotype through the Activation of the Cannabinoid Receptor Type-2–Signal Transducer and Activator of Transcription 6 Pathway

Wang

Zhang

Yang

et al. 2022

J. Agric. Food Chem.

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“… Liang et al (2014) also demonstrated that formononetin protected rats from the cerebral ischemia through inhibiting the function of pro-apoptosis pathway and promoting the function of anti-apoptosis molecules ( Liang et al, 2014 ). Yu et al (2022) found that formononetin significantly alleviated the neurological deficit and the pathological state of brain tissues in MCAO rats by attenuating inflammatory pathways and reducing the production of pro-inflammatory cytokines ( Yu et al, 2022 ). The above studies suggest that formononetin is a natural compound with the potential to protect brain against ischemic injury.…”

Section: Neuroprotective Effects Of Formononetinmentioning

confidence: 99%

Focusing on Formononetin: Recent Perspectives for its Neuroprotective Potentials

2022

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Nervous system is the most complex system of the human body, hence, the neurological diseases often lack effective treatment strategies. Natural products have the potential to yield unique molecules and produce integrative and synergic effects compared to standard therapy. Mounting evidence has shown that isoflavonoids contained in traditional medicinal plant or dietary supplementation may play a crucial role in the prevention and treatment of neurological diseases due to their pronounced biological activities correlating to nervous system. Formononetin, a non-steroidal isoflavonoid, is a bioactive constituent of numerous medicinal plants such as red clover (Trifolium pratense) and Astragalus membranaceus. Emerging evidence has shown that formononetin possesses considerable anti-inflammatory, antioxidant and anti-cancer effects. This review intends to analyze the neuropharmacological potential of formononetin on the therapy of nervous system disorders. The neuroprotective properties of formononetin are observed in multiple neurological disorders including Alzheimer’s disease, dementia, cerebral ischemia, traumatic brain injury, anxiety, and depression. The beneficial effects of formononetin are achieved partially through attenuating neuroinflammation and oxidative stress via the related signaling pathway. Despite its evident effects in numerous preclinical studies, the definite role of formononetin on humans is still less known. More well-designed clinical trials are required to further confirm the neuroprotective efficacy and safety profile of formononetin before its application in clinic.

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“…Formononetin further increased the phosphorylation of Akt, ERK, and Trk A and B, as well as the expression of nerve growth factor (NGF), BDNF, β tubulin-III, and GAP-43 [ 130 , 131 ]. In another transient MCAO experiment (occlusion for 60 min), formononetin (30 mg/kg) alleviated the cerebral infarction and the neurological deficit, as well as reduced the mRNA levels of IL-6 and IL-1β in rat brain tissue, the protein levels of NLRP3, ASC, cleaved caspase-1, and cleaved IL-1β, and the phosphorylation of Janus kinase 2 (JAK2) and STAT3 in the MCAO rat brain tissue [ 132 ]. Hence, the benefit mechanism of formononetin against cerebral IR might be related to the reduction in neuroinflammation via the JAK/STAT/inflammasome pathway, the decrease in neuronal apoptosis via the Bcl-2-regulated anti-apoptotic pathway and increase the neuronal differentiation and synaptic plasticity via the BDNF/Trk and PI3K/AKT/ERK pathways.…”

Section: The Protective Mechanism Of Formononetin and Ononin Against ...mentioning

confidence: 99%

Therapeutic Potential and Mechanisms of Novel Simple O-Substituted Isoflavones against Cerebral Ischemia Reperfusion

Yang

Lien

Tsai

et al. 2022

IJMS

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Isoflavones have been widely studied and have attracted extensive attention in fields ranging from chemotaxonomy and plant physiology to human nutrition and medicine. Isoflavones are often divided into three subgroups: simple O-substituted derivatives, prenylated derivatives, and glycosides. Simple O-substituted isoflavones and their glycosides, such as daidzein (daidzin), genistein (genistin), glycitein (glycitin), biochanin A (astroside), and formononetin (ononin), are the most common ingredients in legumes and are considered as phytoestrogens for daily dietary hormone replacement therapy due to their structural similarity to 17-β-estradiol. On the basis of the known estrogen-like potency, these above isoflavones possess multiple pharmacological activities such as antioxidant, anti-inflammatory, anticancer, anti-angiogenetic, hepatoprotective, antidiabetic, antilipidemic, anti-osteoporotic, and neuroprotective activities. However, there are very few review studies on the protective effects of these novel isoflavones and their related compounds in cerebral ischemia reperfusion. This review primarily focuses on the biosynthesis, metabolism, and neuroprotective mechanism of these aforementioned novel isoflavones in cerebral ischemia reperfusion. From these published works in in vitro and in vivo studies, simple O-substituted isoflavones could serve as promising therapeutic compounds for the prevention and treatment of cerebral ischemia reperfusion via their estrogenic receptor properties and neuron-modulatory, antioxidant, anti-inflammatory, and anti-apoptotic effects. The detailed mechanism of the protective effects of simple O-substituted isoflavones against cerebral ischemia reperfusion might be related to the PI3K/AKT/ERK/mTOR or GSK-3β pathway, eNOS/Keap1/Nrf-2/HO-1 pathway, TLRs/TIRAP/MyD88/NFκ-B pathway, and Bcl-2-regulated anti-apoptotic pathway. However, clinical trials are needed to verify their potential on cerebral ischemia reperfusion because past studies were conducted with rodents and prophylactic administration.

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Formononetin protects against inflammation associated with cerebral ischemia-reperfusion injury in rats by targeting the JAK2/STAT3 signaling pathway

Cited by 71 publications

References 26 publications

Schisandra chinensis Lignans Exert Antidepressant Effects by Promoting BV2 Microglia Polarization toward the M2 Phenotype through the Activation of the Cannabinoid Receptor Type-2–Signal Transducer and Activator of Transcription 6 Pathway

Schisandra chinensis Lignans Exert Antidepressant Effects by Promoting BV2 Microglia Polarization toward the M2 Phenotype through the Activation of the Cannabinoid Receptor Type-2–Signal Transducer and Activator of Transcription 6 Pathway

Focusing on Formononetin: Recent Perspectives for its Neuroprotective Potentials

Therapeutic Potential and Mechanisms of Novel Simple O-Substituted Isoflavones against Cerebral Ischemia Reperfusion

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