PMID: 

Biomol Ther (Seoul). 2019 Nov 1 ;27(6):584-590. PMID: 31646844

Abstract Title: 

Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors.

Abstract: 

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with ICof 1.19, 0.84μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

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PMID: 

BMC Oral Health. 2019 Oct 26 ;19(1):229. Epub 2019 Oct 26. PMID: 31655580

Abstract Title: 

Luteolin supports osteogenic differentiation of human periodontal ligament cells.

Abstract: 

BACKGROUND: Previous research revealed that luteolin could improve the activation of alkaline phosphatase (ALP) and osteocalcin in mouse osteoblasts. We aimed to determine the effect of luteolin on osteogenic differentiation of periodontal ligament cells (PDLCs).METHODS: Cultured human PDLCs (HPDLCs) were treated by luteolin at 0.01, 0.1, 1, 10, 100 μmol/L, Wnt/β-catenin pathway inhibitor (XAV939, 5 μmol/L) alone or in combination with 1 μmol/L luteolin. Immunohistochemical staining was performed to ensure cells source. Cell activity and the ability of osteogenic differentiation in HPDLCs were determined by MTT, ALP and Alizarin RedS staining. Real-time Quantitative PCR Detecting System (qPCR) and Western blot were performed to measure the expressions of osteogenic differentiation-related genes such as bone morphogenetic protein 2 (BMP2), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), Osterix (OSX) and Wnt/β-catenin pathway proteins members cyclin D1 and β-catenin.RESULTS: Luteolin at concentrations of 0.01, 0.1, 1, 10, 100 μmol/L promoted cell viability, ALP activity and increased calcified nodules content in HPDLCs. The expressions of BMP2, OCN, OSX, RUNX2, β-catenin and cyclin D1 were increased by luteolin at concentrations of 0.01, 0.1, 1 μmol/L, noticeably, 1 μmol/L luteolin produced the strongest effects. In addition, XAV939 inhibited the expressions of calcification and osteogenic differentiation-related genes in HPDLCs, and 1 μmol/L luteolin availably decreased the inhibitory effect.CONCLUSION: 1 μmol/L luteolin accelerated osteogenic differentiation of HPDLCs via activating the Wnt/β-catenin pathway, which could be clinically applied to treat periodontal disease.

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PMID: 

J Nutr Biochem. 2019 Aug 15 ;73:108222. Epub 2019 Aug 15. PMID: 31665675

Abstract Title: 

Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice.

Abstract: 

Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing the risk of cardiovascular diseases. However, the dosages of phytochemicals in the cellular and animal studies are too high to reach in humans by relevant foods or dietary supplement intake. The aims of this study were to investigate whether and how combined curcumin and luteolin synergistically inhibit tumor necrosis factor-alpha (TNF-α)-induced monocytes adhesion endothelium, a crucial step of the development of endothelial dysfunction, both in human vascular cells and mouse aortic endothelium. Our results show that combined curcumin (1 μM) and luteolin (0.5 μM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocytes adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. We also found that TNF-α-enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and nuclearfactor (NF)-κB translocation were synergistically reduced by the combined curcumin and luteolin in EA.hy 926 cells while the individual chemical did not have this inhibitory effect. Consistently, 2 weeks dietary intake of combined curcumin (500 mg/kg) and luteolin (500 mg/kg) in C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium ex vivo as well as the TNF-α-increased aortic protein expression of MCP-1 and VCAM-1. Therefore, combined curcumin and luteolin at physiological concentrations synergistically inhibits TNF-α-induced monocytesadhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into the nucleus.

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PMID: 

Inflammation. 2019 Oct 31. Epub 2019 Oct 31. PMID: 31673976

Abstract Title: 

Luteolin Alters Macrophage Polarization to Inhibit Inflammation.

Abstract: 

Luteolin is a natural flavonoid compound derived from vegetables, fruits, and herbs with potent anti-inflammatory activity. Macrophage polarization is important in the development and progression of inflammation. However, whether luteolin can inhibit inflammation by regulating the polarized phenotypes of macrophages remains unknown. The aim of this study was to investigate the effects of luteolin on the inflammatory polarization of macrophages and the underlying mechanisms. RAW264.7 macrophages were induced to M1 polarization by stimulation with lipopolysaccharide plus interferon-γ or to M2 polarization with interleukin 4 (IL-4), simultaneously, accompanied with different concentrations of luteolin. Laser confocal microscopy was used to observe cell morphology; flow cytometry was employed to detect the expression of membrane surface molecule CD86 and CD206; qPCR was performed to examine the mRNA expression of M1 markers (iNOS, IL-1β, IL-6) and M2 markers (Arg1, CD206, CD163, IL-10, and IL-13), respectively; ELISA was used to examine the levels of IL-6, TNF-α, and IL-10; and Western blotting was used to evaluate the p-STAT3 and p-STAT6 protein pathway. The morphologyof activated M1 macrophages changed significantly, developing dendritic characteristics. After luteolin treatment, the expression of M1-type proinflammatory mediators and the surface marker CD86 were decreased evidently, but those of M2-related anti-inflammatory factors and CD206 were increased markedly. Moreover, p-STAT3 was downregulated and p-STAT6 was upregulated in a dose-dependent manner. Conclusion, luteolin can alter the M1/M2 polarization of macrophages, thereby playing an anti-inflammatory role via downregulation of p-STAT3 and upregulation of p-STAT6. Therefore, luteolin may be potentially valuable to inhibit inflammation.

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PMID: 

J Cell Biochem. 2019 Nov 6. Epub 2019 Nov 6. PMID: 31691375

Abstract Title: 

Antioxidant, hepatoprotective, genoprotective, and cytoprotective effects of quercetin in a murine model of arthritis.

Abstract: 

Rheumatoid arthritis is a highly debilitating inflammatory autoimmune disease which is characterized by joint destruction. The present study sought to investigate the effect of quercetin in rats with complete Freund's adjuvant-induced arthritis. Animals were divided into control/saline, control/quercetin (5 mg/kg, 25 mg/kg, and 50 mg/kg) arthritis/saline, and arthritis/quercetin (5 mg/kg, 25 mg/kg, and 50 mg/kg); the treatments were administered for 45 days. Biochemical, oxidative stress, genotoxicity, and cytotoxicity parameters were evaluated. All doses of quercetin reduced the levels ofaspartate aminotransferase, thiobarbituric acid-reactive substances, and reactive oxygen species; however, only treatment with 25 or 50 mg/kg increased catalase activity. Total thiol and reduced glutathione levels were not significantly affected by the induction nor by the treatments. Genotoxicity assessed by DNA damage, and cytotoxicity through picogreen assay, decreased after treatments with quercetin. Our results present evidence of the antioxidant, cytoprotective, genoprotective and hepatoprotective, and effects of quercetin, demonstrating its potential as a candidate for coadjuvant therapy.

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PMID: 

Int Clin Psychopharmacol. 2019 Nov 11. Epub 2019 Nov 11. PMID: 31714321

Abstract Title: 

Effects of Passiflora incarnata Linnaeus on polysomnographic sleep parameters in subjects with insomnia disorder: a double-blind randomized placebo-controlled study.

Abstract: 

The purpose of the present double-blind randomized placebo-controlled clinical study was to investigate the effects of Passionflower on polysomnographic sleep parameters in subjects with insomnia disorder. A total number 110 adult participants (mean age = 40.47± 11.68, Female = 53.6%) met the inclusion criteria of insomnia disorder according to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders). After randomization, patients received either the Passionflower extract or the placebo for 2 weeks. Patients underwent an overnight polysomnography and completed sleep diaries, Insomnia Severity Index, and Pittsburgh Sleep Quality Index. Within group comparisons were analyzed with paired t-tests or Wilcoxon's signed rank tests, and between-group comparisons were analyzed with independent t-tests or Mann-Whitney U Tests, as appropriate. Totalsleep time (TST) was significantly increased in the Passionflower group compared with placebo (Passionflower vs placebo, 23.05 ± 54.26 vs -0.16 ± 53.12; P = 0.049). Sleep efficiency and wake after sleep onset (WASO) significantly improved after 2 weeks in the Passionflower group but there was no difference compared with the placebo group. The current study demonstrated the positive effects of Passionflower on objective sleep parameters including TST on polysomnography in adults with insomnia disorder. Further study is needed to investigate the clinical efficacy of Passionflower on insomnia.

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PMID: 

Curr Diabetes Rev. 2019 Oct 26. Epub 2019 Oct 26. PMID: 31738145

Abstract Title: 

Effectiveness of passion fruit peel flour (passiflora edulis l.) Versus turmeric flour (curcuma longa l.) On glycemic control: systematic review and meta-analysis.

Abstract: 

BACKGROUND: It is undeniable that diabetes may cause several health complications for the population. Many of these complications are associated with poor glycemic control. Because of this, strategies to handle this problem are of great clinical importance and may contribute to reduce the various complications from diabetes.OBJECTIVE: The aim of this study was to compare the effectiveness of the passion fruit peel flour versus turmeric flour on glycemic control.METHOD: This is a systematic review and meta-analysis following the PRISMA protocol. The following inclusion criteria were applied: (1) case-control studies, cohort studies, and clinical trials, due to the improved statistical analysis and, in restrict cases, cross-sectional studies; (2) articles published in any language. The databases used for the search were PubMed, Scopus, Web of Science, Cochrane, and LILACS. A bias analysis and a meta-analyses were undertaken using R Studio (version 3.3.1) using effect-size models.RESULTS: A total of 565 studies were identified from which 11 met the inclusion and exclusion criteria. Through isolated analysis, the effectiveness of turmeric flour on glycemic control was in the order of 0.73 CI (Confidence Interval) (from 0.68 to 0.79) and the effectiveness of passion fruit peel flour was 0.32 CI (0.23 to 0.45). The joint analysis resulted in 0.59 CI (0.52 to 0.68). The assessment of blood glucose was by glycated hemoglobin levels. All values were significant at a p

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PMID: 

Metab Brain Dis. 2019 Nov 14. Epub 2019 Nov 14. PMID: 31728889

Abstract Title: 

Passiflora caerulea L. fruit extract and its metabolites ameliorate epileptic seizure, cognitive deficit and oxidative stress in pilocarpine-induced epileptic mice.

Abstract: 

The anticonvulsant potential of aqueous fruit extract of Passiflora caerulea (PCAE) was evaluated in swiss albino mice induced by pilocarpine. The antioxidant activities of PCAE were determined which showed strong antioxidant activity and the polyphenol compounds such as ginsenoside, naringenin, chrysoeriol 8-c-glucoside, luteolin-6-C-glucoside, apigenin-6,8-di-C-β-D-glucopyranoside were profiled through RP-HPLC and UPLC-ESI-MS/MS. Chronic effects of PCAE on pilocarpine (85 mg/kg; i.p)-induced convulsions were evaluated in Swiss adult male albino mice. PCAE at 100 and 200 mg/kg, (p.o.) and diazepam (5 mg/kg, i.p) were administered once daily for 15 days. In Y-maze test, percentage of correct entry by pilocarpine administered animals were significantly lower when compared to control, whereas PCAE at both doses improved the alteration score significantly. Administration of higher dose (200 mg/kg) of PCAE significantly delayed onset of convulsions and decreased duration of clonic convulsions. Association of ROS production during seizure period was further confirmed by histopathological studies revealing loss of normal neuronal cells in hippocampus region. The data obtained showed anticonvulsant activity and improved cognitive function; reduced the oxidative damage and significantly activated the cholinergic neurotransmission in a dose dependent manner similar to diazepam which is evident in the biochemical parameters and histopathological study, suggesting therapeutic potential for epilepsy and neurodegeneration.

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PMID: 

Antioxidants (Basel). 2019 Nov 15 ;8(11). Epub 2019 Nov 15. PMID: 31731716

Abstract Title: 

Dietary Flavonoids Luteolin and Quercetin Inhibit Migration and Invasion of Squamous Carcinoma through Reduction of Src/Stat3/S100A7 Signaling.

Abstract: 

Flavonoids are well-known antioxidants and have shown the ability to prevent tumor formation and recurrence. Especially in dietary flavonoids, they have provided convenience and consistence of intake for long-term prevention of tumor formation. Previous reports suggested that S100 calcium-binding protein A7 (S100A7) might activate epithelial-mesenchymal transition (EMT) signaling and promote the metastasis of tumor cells; however, the regulatory signaling was unclear. In this study, we found that S100A7 was highly expressed in cancer cells and could be reduced by luteolin (Lu) and quercetin (Qu) through Src/Stat3 signaling. We found that the protein levels of S100A7, phosphorylated Src (p-Src), and p-Stat3 were increased in A431-III cells. Flavonoids Lu and Qu reduce protein levels of p-Src, p-Stat3 and S100A7 in A431-III cells. Treatment of A431-III cells with Src inhibitor SU6656 and Stat3 inhibitor S3I-201 also reduced the protein levels of S100A7. Transactivation activity of 5'-upstream regions ofwas activated by Stat3 but was reduced by treatment with Lu, Qu, SU6656 and S3I-201. The treatment also reduced the migratory and invasive abilities of A431-III cells. In a further analysis of EMT markers, the protein level of E-cad increased and that of Twist decreased after treatment with the inhibitors and flavonoids. Overexpression of S100A7 decreased the protein level of E-cad and increased the Twist level, whereas knockdown of S100A7 had the opposite effects. Treatment with S3I-201, Lu and Qu, compared to the control, were found to decrease metastasis of tumor cells in zebrafish larvae. These results suggest that Lu and Qu may inhibit Src/Stat3/S100A7 signaling to reduce tumorigenesis of cancer cells.

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PMID: 

Int J Mol Sci. 2019 Nov 16 ;20(22). Epub 2019 Nov 16. PMID: 31744123

Abstract Title: 

Quercetin Exposure Suppresses the Inflammatory Pathway in Intestinal Organoids from Winnie Mice.

Abstract: 

Inflammatory bowel diseases (IBDs) are chronic and relapsing immune disorders that result, or possibly originate, from epithelial barrier defects. Intestinal organoids are a new reliable tool to investigate epithelial response in models of chronic inflammation. We produced organoids from the ulcerative colitis murine model Winnie to explore if the chronic inflammatory features observed in the parental intestine were preserved by the organoids. Furthermore, we investigated if quercetin administration to in vitro cultured organoids could suppress LPS-induced inflammation in wild-type organoids (WT-organoids) and spontaneous inflammation in ulcerative colitis organoids (UC-organoids). Our data demonstrate that small intestinal organoids obtained from Winnie mice retain the chronic intestinal inflammatory features characteristic of the parental tissue. Quercetin administration was able to suppress inflammation both in UC-organoids and in LPS-treated WT-organoids. Altogether, our data demonstrate that UC-organoids are a reliable experimental system for investigating chronic intestinal inflammation and pharmacological responses.

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