PMID: 

Obstet Gynecol Sci. 2019 Jul ;62(4):242-248. Epub 2019 Jun 19. PMID: 31338341

Abstract Title: 

Effect of quercetin on the anti-tumor activity of cisplatin in EMT6 breast tumor-bearing mice.

Abstract: 

Objective: The purpose of this study was to determine the effect of quercetin on the antitumor activity of cisplatin and its side-effects.Methods: EMT6 cells, a mouse breast cancer cell line, were injected subcutaneously in mice to generate a breast tumor-bearing mouse model. Experimental groups were divided into four groups: control (C), quercetin (Q), cisplatin (CP), and cisplatin+quercetin (CP+Q).Results: The tumor volume of the CP+Q group was significantly lower than that of the CP group. Serum blood urea nitrogen and creatinine levels in the CP+Q group were lower than those in the CP group. Renalγ-glutamyltranspeptidase and alkaline phosphatase activities were significantly higher in the CP+Q group than in the CP group, and the content of renal thiobarbituric acid reactive substance was significantly lower in the CP+Q group than that in the CP group. These results suggested that quercetinand cisplatin synergistically increased cellular toxicity in breast cancer cells and mediated cancer growth inhibition, thereby enhancing the antitumor effect of cisplatin compared to when only cisplatin was administered. Quercetin also reduced renal toxicity, which arose as a potential a side effect of cisplatin.Conclusion: The enhanced antitumor effect of cisplatin and decreased renal toxicity after quercetin treatment suggested the applicability of quercetin as an adjuvant for chemotherapeutic agents.

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PMID: 

Mol Nutr Food Res. 2019 Oct ;63(19):e1801390. Epub 2019 Jul 31. PMID: 31338984

Abstract Title: 

Quercetin-Induced miR-369-3p Suppresses Chronic Inflammatory Response Targeting C/EBP-β.

Abstract: 

SCOPE: Dendritic cells (DCs) are the most potent antigen-presenting cells that play an important role in the crosstalk between the innate and the adaptive immune response. Quercetin exposure is identified as an effective strategy to suppress the inflammatory response induced by LPS.METHODS AND RESULTS: In this study, using a next-generation sequencing analysis, the effect of quercetin on microRNAs (miRNAs) expression in DCs is examined. A signature of 113 miRNAs that are differentially regulated in LPS-stimulated DCs after quercetin exposure is defined. It is demonstrated that the loss of function of miR-369-3p in LPS-stimulated DCs during quercetin exposure led to an increase of CCAAT/enhancer binding proteinβ (C/EBP-β) mRNA and protein and its downstream targets tumor necrosis factor-α (TNF-α) and interleukin 6 (IL6). Conversely, it is shown that the ectopic induction of miR-369-3p without quercetin suppresses the inflammatory response of LPS reducing C/EBP-β, TNF-α, and IL6 production. In vivo,oral administration of quercetin in dextran-sulfate-sodium-induced colitis induces miR-369-3p expression.CONCLUSIONS: These findings indicate that quercetin-induced miR-369-3p regulates the inflammatory cascade in chronic inflammatory response and present promising therapeutic implications.

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PMID: 

Oxid Med Cell Longev. 2019 ;2019:7683051. Epub 2019 Jun 24. PMID: 31341535

Abstract Title: 

Nanoencapsulated Quercetin Improves Cardioprotection during Hypoxia-Reoxygenation Injury through Preservation of Mitochondrial Function.

Abstract: 

The effective delivery of antioxidants to the cells is hindered by their high metabolization rate. In this work, quercetin was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. They were characterized in terms of its physicochemical properties (particle size distribution,-potential, encapsulation efficiency, quercetin release and biological interactions with cardiac cells regarding nanoparticle association, and internalization and protective capability against relevant challenges). A better delivery of quercetin was achieved when encapsulated versus free. When the cells were challenged with antimycin A, it resulted in lower mitochondrial O(4.65- vs. 5.69- fold) and HOrate production (1.15- vs. 1.73- fold). Similarly, under hypoxia-reoxygenation injury, a better maintenance of cell viability was found (77 vs. 65%), as well as a reduction of thiol groups (~70 vs. 40%). Therefore, the delivery of encapsulated quercetin resulted in the preservation of mitochondrial function and ATP synthesis due to its improved oxidative stress suppression. The results point to the potential of this strategy for the treatment of oxidative stress-based cardiac diseases.

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PMID: 

Front Genet. 2019 ;10:951. Epub 2019 Oct 10. PMID: 31649729

Abstract Title: 

Perinatal Bisphenol A Exposure and Reprogramming of Imprinted Gene Expression in the Adult Mouse Brain.

Abstract: 

Genomic imprinting, a phenomenon by which genes are expressed in a monoallelic, parent-of-origin-dependent fashion, is critical for normal brain development. Expression of imprinted genes is regulatedepigenetic mechanisms, including DNA methylation (5-methylcytosine, 5mC), and disruptions in imprinting can lead to disease. Early-life exposure to the endocrine disrupting chemical bisphenol A (BPA) is associated with abnormalities in brain development and behavior, as well as with disruptions in epigenetic patterning, including 5mC and DNA hydroxymethylation (5-hydroxymethylcytosine, 5hmC). Using an established mouse model of perinatal environmental exposure, the objective of this study was to examine the effects of perinatal BPA exposure on epigenetic regulation of imprinted gene expression in adult mice. Two weeks prior to mating, dams were assigned to control chow or chow containing an environmentally relevant dose (50µg/kg) of BPA. Exposure continued until offspring were weaned at post-natal day 21, and animals were followed until 10 months of age. Expression of three imprinted genes-, and, as well as three genes encoding proteins critical for regulation of 5mC and 5hmC-,, and, were evaluated in the right cortex and midbrain using qRT-PCR. Perinatal BPA exposure was associated with a significant increase in adult(p = 0.04) and(p = 0.02) expression in the right cortex, as well as increased expression ofin the midbrain (p = 0.03). Expression ofandwere positively correlated in the midbrain. Analysis of 5mC and 5hmC at thelocus was conducted in parallel samples using standard and oxidative bisulfite conversion followed by pyrosequencing. This analysis revealed enrichment of both 5mC and 5hmC at this locus in both brain regions. No significant changes in 5mC and 5hmC atwere observed with perinatal BPA exposure. Together, these data suggest that perinatal BPA exposure results in altered expression of,, andin the adult mouse brain. Further studies with larger sample sizes are necessary to understand the mechanistic basis for these changes, as well as to determine the implications they have for brain development and function.

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PMID: 

J Mol Recognit. 2019 Oct 21:e2814. Epub 2019 Oct 21. PMID: 31637788

Abstract Title: 

Eriodictyol and naringenin inhibit the formation of AGEs: An in vitro and molecular interaction study.

Abstract: 

Maillard reaction occurs between the carbonyl group of reducing sugars and the free amino groups of protein, which eventually results in the formation and accumulation of advanced glycation end products (AGEs) irreversibly. Excessive production of AGEs is associated with many diseases, such as Alzheimer disease, neuropathy, retinopathy, and nephropathy. In this study, the effects of eriodictyol and naringenin on the inhibition of AGEs were studied with bovine serum albumin (BSA)-methylglyoxal (MGO) model by spectroscopic techniques and molecular docking methods. The fluorescence spectroscopy results suggested that eriodictyol and naringenin could inhibit the formation of AGEs. Circular dichroism (CD) studies indicated that eriodictyol and naringenin could stabilize the structure of BSA and inhibit the formation of AGEs. The molecular docking results demonstrated that eriodictyol formed two hydrogen bonds with Lys 350 and Leu 480 and the main forces were hydrogen bonding and hydrophobic interactions. However, naringenin interacted with Arg 484 of BSA, and the main force was hydrophobic interaction. It can be concluded that eriodictyol and naringenin can inhibit the formation of AGEs and eriodictyol has stronger inhibitory activity of AGEs than that of naringenin, which is probably due to the additional hydroxyl group in the position C-3' of B ring of eriodictyol.

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PMID: 

Autoimmunity. 2019 Oct 26:1-9. Epub 2019 Oct 26. PMID: 31656085

Abstract Title: 

Bisphenol A modified DNA: A possible immunogenic stimulus for anti-DNA autoantibodies in systemic lupus erythematosus.

Abstract: 

Anti-DNA antibodies are now considered as a universal diagnostic feature for the patients with systemic lupus erythematosus (SLE) but the mechanism(s) involved in the generation of these autoantibodies remains to be investigated. Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacturing of polycarbonated plastics. Upon mixing in the diet, it causes several health hazards. This study was undertaken to investigate the contribution of BPA induced DNA damage in SLE patients. Human DNA was modified by BPAand the binding characteristics of SLE circulating immunoglobulin Gs (SLE-IgGs) with BPA damaged DNA (BPA-DNA) were screened and compared with the IgGs from normal healthy humans (NH-IgGs). Immunogenicity of BPA-DNA was determined by immunisation in rabbits. DNA from SLE patients (SLE-DNA) or healthy humans (NH-DNA) were isolated and their binding specificity with rabbit anti-BPA-DNA-IgGs was studied. Treatment of human DNA with BPA caused extensive damaged. Circulating SLE-IgGs showed strong recognition of BPA-DNA. BPA-DNA induced high titre antibodies in rabbits. Rabbit anti-BPA-DNA-IgGs showed strong cross reaction with isolated DNA from SLE patients. In short, we concluded that the structural alterations in DNA by BPA, generate neo-epitopes that may be a factor responsible for the induction of anti-DNA autoantibodies in SLE.

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PMID: 

Eur J Pharmacol. 2019 Oct 13 ;865:172730. Epub 2019 Oct 13. PMID: 31618621

Abstract Title: 

Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways.

Abstract: 

There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CClwas given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCltreatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced bynaringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.

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PMID: 

J Med Food. 2019 Oct 31. Epub 2019 Oct 31. PMID: 31670603

Abstract Title: 

Naringenin Increases Insulin Sensitivity and Metabolic Rate: A Case Study.

Abstract: 

Our studies in primary human adipocytes show that naringenin, a citrus flavonoid, increases oxygen consumption rate and gene expression of uncoupling protein 1 (UCP1), glucose transporter type 4, and carnitine palmitoyltransferase 1(CPT1). We investigated the safety of naringenin, its effects on metabolic rate, and blood glucose and insulin responses in a single female subject with diabetes. The subject ingested 150 mg naringenin from an extract of whole oranges standardized to 28% naringenin three times/day for 8 weeks, and maintained her usual food intake. Body weight, resting metabolic rate, respiratory quotient, and blood chemistry panel including glucose, insulin, and safety markers were measured at baseline and after 8 weeks. Adverse events were evaluated every 2 weeks. We also examined the involvement of peroxisome proliferator-activated receptor(PPAR), peroxisome proliferator-activated receptor(PPAR), protein kinase A (PKA), and protein kinase G (PKG) in the response of human adipocytes to naringenin treatment. Compared to baseline, the body weight decreased by 2.3 kg. The metabolic rate peaked at 3.5% above baseline at 1 h, but there was no change in the respiratory quotient. Compared to baseline, insulin decreased by 18%, but the change in glucose was not clinically significant. Other blood safety markers were within their reference ranges, and there were no adverse events.andmRNA expression was reduced by inhibitors of PPARand PPAR, but there was no effect of PKA or PKG inhibition. We conclude that naringenin supplementation is safe in humans, reduces body weight and insulin resistance, and increases metabolic rate by PPARand PPARactivation. The effects of naringenin on energy expenditure and insulin sensitivity warrant investigation in a randomized controlled clinical trial.

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PMID: 

J Food Biochem. 2019 May ;43(5):e12844. Epub 2019 Mar 21. PMID: 31353530

Abstract Title: 

α-Amylase inhibition of xanthones from Garcinia mangostana pericarps and their possible use for the treatment of diabetes with molecular docking studies.

Abstract: 

Chromatographic separation of the methanol extract of Garcinia mangostana (mangosteen, Guttiferae) dried pericarps led to the isolation and structural characterization of a new xanthone, namely garcimangostin A (5), together with garcixanthone A (1), gartanin (2), normangostin (3), and garcinone C (4). Their structural characterization was achieved using various NMR spectroscopic tools as well as HRMS. Theirα-amylase inhibitory (AAI) potential was assessed. It is noteworthy that 5 had the most potent inhibitory effect with % inhibition 94.1 compared to acarbose (96.7%). Moreover, the molecular modeling studies were estimated. The observed scoring results correlated to those results of the AAI assay. Interestingly, 5 was completely fitting with acarbose structure and a superimposition of acarbose complexed structure with 5 in the enzyme binding site was observed. The AAI activity of 5 could be attributed to the xanthone moiety insertion in the active site of the enzyme via H-bonds network and pi-pi interactions. PRACTICAL APPLICATIONS: Garcinia mangostana is a widely consumed fruit for its unique pleasant aroma and sweet taste. Also, it contains valuable nutritious compounds that are advantageous for human body. It is used as various traditional medicines for treating several ailments suchas skin infection, hyperkeratosis, eczema, wounds, psoriasis, amebic dysentery, cholera, diarrhea, and suppuration. The findings of this work can demonstrate the significant AAI potential of G. mangostana xanthones. Therefore, mangosteen as a functional food could help in lowering the postprandial glucose absorption and identifying lead compounds from α-amylase inhibition for the treatment and/or prevention of diabetes and obesity.

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PMID: 

Int J Environ Res Public Health. 2019 Oct 28 ;16(21). Epub 2019 Oct 28. PMID: 31661889

Abstract Title: 

Combined Exposure to Fructose and Bisphenol A Exacerbates Abnormal Lipid Metabolism in Liver of Developmental Male Rats.

Abstract: 

The aim of this study was to investigate whether combined exposure to fructose and bisphenol A (BPA) has a synergistic effect on abnormal lipid metabolism in the liver of developmental male rats and its possible mechanism. Fifty weaned male Wistar rats were divided into five groups: the control, 13% fructose, 20% fructose, 1µg/mL BPA, and 13% fructose + 1 µg/mL BPA (combined exposure). Rats were exposed to fructose and/or BPA through drinking water for eight weeks. Genes or proteins regulating lipid metabolism include sterol regulatory element binding protein 1 (SREBP1), adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), zinc α 2 glycoprotein (ZAG) and estrogen receptor α (ERα), and the expression of proteins regulating inflammatory response, such as TLR4 and NF-κB, were determined. Serum total cholesterol (T-CHO), triglyceride (TG), low, high density lipoprotein cholesterol (LDL-C, HDL-C), blood glucose, insulin, IL-17 and TNF-α levels were also measured. Liver tissue morphology was observed by H&E staining. The results showed that the levels of gene and protein catalyzing lipogenesis were increased (SREBP1, ACC1 and FAS), while those catalyzing lipolysis were decreased (ATGL, HSL and ZAG), accompanied by dyslipidemia, insulin resistance and hepatic fat accumulation, and there were higher expression of TLR4 and NF-κB protein and lower expression of ERα protein in liver, and increased serum IL-17 and TNF-α levels in fructose and/or BPA exposed rats compared with controls. Moreover, the above indicators were more serious in combined exposure group than in single exposure group. Therefore, abnormal lipid metabolism in the liver of developmental rats could be exacerbated by combined exposed to fructose and BPA.

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