PMID: 

Cells. 2019 Sep 15 ;8(9). Epub 2019 Sep 15. PMID: 31540162

Abstract Title: 

Fisetin, a 3,7,3',4'-Tetrahydroxyflavone Inhibits the PI3K/Akt/mTOR and MAPK Pathways and Ameliorates Psoriasis Pathology in 2D and 3D Organotypic Human Inflammatory Skin Models.

Abstract: 

Psoriasis is a chronic immune-mediated skin disease that involves the interaction of immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation, and angiogenesis. Because the available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can repair the molecular defects associated with psoriasis and could possibly be developed for its management. Fisetin (3,7,3',4'-tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables, has demonstrated proapoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological, and tissue engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC), and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose- and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α stimulated NHEKs also significantly inhibited the activation of p38 and JNK, but had enhanced effect on ERK1/2 (MAPK). In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFN-γ and IL-17A by 12–tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in vivo human psoriatic skin lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify the prodifferentiative, antiproliferative, and anti-inflammatory effects of fisetin, via modulation of the PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin models of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.

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PMID: 

Food Chem Toxicol. 2019 Sep 17 ;134:110824. Epub 2019 Sep 17. PMID: 31539617

Abstract Title: 

Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway.

Abstract: 

Fisetin, a natural flavonoid found in plants, fruits and vegetables, exerts anti-cancer, anti-oxidant, anti-inflammatory and anti-mitotic effects. The current study instigates the protective effect of fisetin against lead-induced synaptic dysfunction, neuroinflammation and neurodegeneration in mice, and explores its underlying mechanisms. The results indicated fisetin can significantly ameliorated behavioral impairments in Pb-treated mice. Fisetin inhibited Pb-induced the apoptotic neurodegeneration, as indicated by the decreased levels of Bax and cleaved caspase-3. Fisetin suppressed activations of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), NF-κB and subsequently inactivate pro-inflammatory factor including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). It can also decrease the accumulation of p-tau and amyloid-beta (Aβ) and increased the expression of the Aβ remover neprilysin (NEP) in brains of mice. Fisetin also reversed Pb-induced synaptic dysfunction by increasing the levels of synaptosomal associated protein-25 (SNAP-25), postsynaptic density-95 (PSD-95), cyclic-AMP-response element-binding protein (CREB) phosphorylation and calcium/calmodulin kinase II (CaMKII) phosphorylation. Fisetin promoted Pb-induced autophagy in the brains of mice. Moreover, fisetin can increase levels of the denosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and SIRT1. Fisetin may be developed as a potential nutritional target for the prevention of Pb-induced neurotoxicity.

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PMID: 

J Clin Med. 2019 Jun 14 ;8(6). Epub 2019 Jun 14. PMID: 31207963

Abstract Title: 

Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment.

Abstract: 

Phytomedicine based natural flavonoids have potent antioxidant, anti-inflammatory, and neuroprotective activities against neurodegenerative diseases. The aim of the present study is to investigate the potent neuroprotective and antioxidant potential effects of fisetin (natural flavonoid) against central nervous system (CNS)-insult, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS), neuroinflammation, neurodegeneration, and synaptic/memory deficits in adult mice. The mice were injected intraperitoneally (i.p.) with LPS (250μg/kg/day for 1 week) and a fisetin dosage regimen (20 mg/kg/day i.p. for 2 weeks, 1 week pre-treated to LPS and 1 week co-treated with LPS). Behavioral tests, and biochemical and immunofluorescence assays were applied. Our results revealed that fisetin markedly abrogated the LPS-induced elevated ROS/oxidative stress and activated phosphorylated c-JUN N-terminal Kinase (p-JNK) in the adult mouse hippocampus. Fisetin significantly alleviated LPS-induced activated gliosis. Moreover, fisetin treatment inhibited LPS-induced activation of the inflammatory Toll-like Receptors (TLR4)/cluster of differentiation 14 (CD14)/phospho-nuclear factor kappa (NF-κB) signaling and attenuated other inflammatory mediators (tumor necrosis factor-α (TNF-α), interleukin-1 β (IL1-β), and cyclooxygenase (COX-2). Furthermore, immunoblotting and immunohistochemical results revealed that fisetin significantlyreversed LPS-induced apoptotic neurodegeneration. Fisetin improved the hippocampal-dependent synaptic and memory functions in LPS-treated adult mice. In summary, our results strongly recommend that fisetin, a natural potent antioxidant, and neuroprotective phytomedicine, represents a promising, valuable, and therapeutic candidate for the prevention and treatment of neurodegenerative diseases.

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PMID: 

Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619871359. PMID: 31434498

Abstract Title: 

Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial.

Abstract: 

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.

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PMID: 

Evid Based Complement Alternat Med. 2015 ;2015:649568. Epub 2015 Jun 25. PMID: 26199636

Abstract Title: 

Liquiritigenin Protects Rats from Carbon Tetrachloride Induced Hepatic Injury through PGC-1α Pathway.

Abstract: 

The lack of effective treatment for liver cirrhosis and hepatocellular carcinomas imposes serious challenges to the healthcare system. Here, we investigated the efficacy and mechanism of liquiritigenin involved in preventing or retarding the progression of liver diseases in a rat model with chronic carbon tetrachloride (CCl4) exposure. Sprague Dawley rats were given CCl4 and lliquiritigenin alone or simultaneously for 8 weeks before liver was harvested to check histological changes by Hematoxylin and Eosin (H&E) staining, apoptosis by TUNEL assay, ROS by dihydroethidium staining, antioxidant enzyme activities and malondialdehyde using specific kits, and gene expression by quantitative real-time PCR and western blot. Chronic CCl4 exposure caused profound changes in liver histology with extensive hepatocyte death (necrosis and apoptosis), fat accumulation, and infiltration of inflammatory cells, accompanied by depressed activities of antioxidant enzymes, increased oxidative stress, elevated expression of inflammation and fibrotic genes, and downregulation of PGC-1α, ND1, and Bcl-x in rat liver. All these changes were abolished or alleviated by lliquiritigenin. The results demonstrated that liquiritigenin is effective in protecting liver from injury or treating chronic liver diseases. The modulation of PGC-1α and its downstream genes might play a critical role in relieving CCl4-induced hepatic pathogenesis by liquiritigenin.

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PMID: 

Psychiatry Res. 2016 Jun 30 ;240:131-136. Epub 2016 Apr 14. PMID: 27107388

Abstract Title: 

Protective effect of liquiritigenin on depressive-like behavior in mice after lipopolysaccharide administration.

Abstract: 

Liquiritigenin (Liq), the main active ingredient of traditional Chinese medicine licorice, possesses anti-inflammatory and neuroprotective properties. The current investigation was designed to explore whether liquiritigenin could relieve lipopolysaccharide (LPS)-induced depression-like behavior in mice and the underlying mechanism. Liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) were pretreated intragastrically once daily for 7 consecutive days. LPS (0.5mg/kg) was injected subcutaneously to establish the depression model 30min after pretreatment on day 7. Interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in serum and hippocampus were detected by enzyme-linked immunosorbent assay (ELISA). Behavioral assessment was conduct 24h post LPS injection. The expressions of p65NF-κB, IκBα, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in hippocampus were determined by western blot. The obtained results showed that liquiritigenin effectively reduced the levels of pro-inflammatory cytokines and the expressions of p-p65NF-κB and p-IκBα. Furthermore, liquiritigenin preconditioning could down-regulate the immobility time in tail suspension test (TST), forcedswimming test (FST) and up-regulate BDNF and TrkB contents in hippocampus. Thus, it is assumed that the antidepressant activity of liquiritigenin might be attributed to its anti-inflammatory property and BDNF/TrkB signaling pathway.

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PMID: 

Biomed Pharmacother. 2017 Feb ;86:694-704. Epub 2016 Dec 28. PMID: 28039849

Abstract Title: 

Liquiritigenin attenuates cardiac injury induced by high fructose-feeding through fibrosis and inflammation suppression.

Abstract: 

Diabetes combined with cardiomyopathy is considered as an essential complication, showing diastolic persistently and causing cardiac injury, which is linked to fibrosis progression and inflammation response. Fibrosis and inflammation response are two markers for cardiomyopathy. Liquiritigenin is a flavanone, isolated from Radix glycyrrhiza, which exhibits various biological properties, including anti-cancer and anti-inflammatory activities. Here, in our study, the protective effects and anti-inflammatory activity of liquiritigenin were explored in mice and cardiac muscle cells treated by fructose to reveal the possible mechanism by which liquiritigenin attenuates cardiac injury. The mice were separated into five groups. The diabetic model of mouse was established with 30% high fructose feeding. Liquiritigenin dramatically reduced the lipid accumulation induced by high fructose diet. Compared to mice only treated with high fructose, mice in the presence of liquiritigenin after fructose feeding developed less cardiac fibrosis with lower levels of alpha smooth muscle-actin (α-SMA), Collagen type I, Collagen type II, TGF-β1 and Procol1a1. Additionally, liquiritigenin markedly down-regulated inflammatory cytokines secretion and phosphorylated NF-κB via inhibiting IKKα/IκBα signaling pathway. Our results indicate that liquiritigenin has a protective role in high fructose feeding-triggered cardiac injury through fibrosis and inflammation response suppression by inactivating NF-κB signaling pathway. Thus, liquiritigenin may be a potential candidate for diabetes-associated cardiac injury.

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PMID: 

Behav Brain Res. 2016 07 15 ;308:177-86. Epub 2016 Apr 22. PMID: 27113683

Abstract Title: 

Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

Abstract: 

Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) contentwas reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin(5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

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PMID: 

Biomed Pharmacother. 2016 Dec ;84:1930-1936. Epub 2016 Nov 15. PMID: 27863839

Abstract Title: 

Antihyperuricemic effect of liquiritigenin in potassium oxonate-induced hyperuricemic rats.

Abstract: 

The aim is to investigate the anti-hyperuricemic and renal protective effects of liquiritigenin in potassium oxonate-induced hyperuricemic rats. Hyperuricemia in rats was induced were induced with potassium oxonate (250mg/kg) intragastrically for 7 days, and liquiritigenin (20, 40mg/kg) and allopurinol (5mg/kg) were daily administrated to the rats orally 1h after the potassium oxonate exposure. Liquiritigenin significantly reversed the elevated productions of uric acid in serum and urine and pro-inflammation cytokines in serum and kidney, which shown that liquiritigenin has renal protective effects. Histological study shows that liquiritigenin inhibited severe necrosis and inflammatory cell infiltration in potassium oxonate-treated rats. Furthermore, liquiritigenin mediated the activities of aquaporins 4 (AQP4), and regulated the activation of NF-κB p65 and the degradation of IκBα. Finally, significant increases of nod-like receptor protein 3 (NLRP3) inflammasome, apoptosis-associated speck-like protein adaptor (ASC) adaptor and cleaved caspased-1 were restored by liquiritigenin. Therefore, liquiritigenin might improve renal inflammationby suppressing renal AQP4/NF-κB/IκBα and NLRP3 inflammasome activation in hyperuricemic rats.

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PMID: 

Nutr Res. 2019 Jul 30 ;69:30-41. Epub 2019 Jul 30. PMID: 31470289

Abstract Title: 

Brazilian propolis extract reduces intestinal barrier defects and inflammation in a colitic mouse model.

Abstract: 

Brazilian propolis is rich in cinnamic acid derivatives and reportedly reduces intestinal inflammation in rodents; however, the underlying mechanisms remain unclear. We hypothesized that the regulation of tight junction (TJ) barrier, Th17 cell differentiation, and/or, macrophage activation by cinnamic acid derivatives were involved in the propolis-mediated anti-inflammatory effect. Mice were orally administered 2% dextran sodium sulfate (DSS) in combination with either the feeding control or a diet containing 0.3% ethanol extract of Brazilian propolis for 9 days. DSS administration induced acute colitis in mice, whereas the propolis extract mitigated DSS-induced weight loss; colon shortening; increased plasma levels of lipopolysaccharide-binding protein; reduced expression of TJ proteins, such as zonula occludens, junctional adhesion molecule-A, occludin, and claudins; and increased expression of inflammatory cytokines, such as tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL-17a. Cinnamic acid derivatives, such as artepillin C and caffeic acid phenethyl ester, present in the propolis extract suppressed the IL-17 production from cultured murine splenocytes through decreased retinoic acid-related orphan receptor gT expression. Baccharin, drupanin, and culifolin, which are also present in Brazilian propolis, reduced the TNF-α and/or IL-6 production by suppressing inflammatory signaling in murine RAW 264.7 macrophages. Taken together, the regulation of Th17 differentiation and macrophage activation by cinnamic acid derivatives, at leastin part, contribute to the anti-inflammatory effect mediated by Brazilian propolis.

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