PMID: 

Chem Biol Interact. 2019 Sep 1 ;310:108728. Epub 2019 Jun 27. PMID: 31254498

Abstract Title: 

Promotion of mitochondrial protection by naringenin in methylglyoxal-treated SH-SY5Y cells: Involvement of the Nrf2/GSH axis.

Abstract: 

Disruption of the mitochondrial function has been associated with redox impairment and triggering of cell death in nucleated human cells, as observed in several diseases. The administration of chemicals that would prevent mitochondrial dysfunction is an attractive strategy in cases of neurodegeneration, cardiovascular diseases, and metabolic disorders. Methylglyoxal (MG) is a dicarbonyl compound that exhibits an important role as a mitochondrial toxicant in neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease) and diabetes mellitus. On the other hand, naringenin (NGN; CHO) is a natural antioxidant that also presents anti-inflammatory effects in mammalian cells. In this context, we have evaluated whether and how NGN would be able to prevent the mitochondria-related bioenergetics and redox dysfunctions induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were pretreated (for 2 h) with NGN (at 10-80 μM) and then challenged with MG at 500 μM for 24 h. NGN significantly attenuated the effects of MG on the mitochondrial function and redox environment in this experimental model. Moreover, NGN prevented the MG-triggered mitochondria-related cell death in SH-SY5Y cells. Nonetheless, the inhibition of the synthesis of glutathione (GSH, a major non-enzymatic antioxidant) suppressed the promotion of mitochondrial protection by NGN in MG-treated cells. We also found that the synthesis of GSH was induced by NGN through a mechanism associated with the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Therefore, NGN caused mitochondrial protection by an Nrf2/GSH-dependent manner in SH-SY5Y cells exposed to MG.

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PMID: 

Diabetes Obes Metab. 2019 Aug 29. Epub 2019 Aug 29. PMID: 31468636

Abstract Title: 

Safety and Pharmacokinetics of Naringenin: A Randomized, Controlled, Single Ascending Dose, Clinical Trial.

Abstract: 

AIMS: This study evaluated the safety and pharmacokinetics of naringenin in healthy adults, consuming a whole orange (Citrus Sinensis) extract.METHODS: In a single ascending dose randomized crossover trial, 18 adults ingested 150mg (NAR150), 300mg (NAR300), 600mg (NAR600), and 900mg (NAR900) doses of naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least one week. Blood safety markers were evaluated pre-dose and 24 hours post-dose. Adverse events were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150, and NAR600. Four and 24-hour serum measurements were obtained after placebo, NAR300, and NAR900 ingestion. Data were analyzed using a mixed effects linear model.RESULTS: There were no relevant adverse events or changes in blood safety markers following ingestion of all naringenin doses. The pharmacokinetic parameters were: Maximal concentration: 15.76±7.88μM (NAR150) and 48.45±7.88μM (NAR600); Time to peak: 3.17±0.74h (NAR150) and 2.41±0.74h (NAR600); Area under the 24-hour concentration-time curve: 67.61±24.36μM×h (NAR150) and 199.06±24.36μM×h (NAR600); and Apparent oral clearance: 10.21±2.34L/h (NAR150) and 13.70±2.34L/h (NAR 600). Naringenin half-life was 3.0h (NAR150) and 2.65h (NAR600). After NAR300 ingestion, serum concentrations were 10.67±5.74μM (4h) and 0.35±0.30μM (24h). After NAR900 ingestion, serum concentrations were 43.11±5.26μM (4h) and 0.24±0.30μM (24h).CONCLUSIONS: Ingestion of 150 to 900mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8μM) is effective in primary human adipocytes, ingestion of 300mg naringenin twice/day will likely elicit a physiologic effect. This article is protected by copyright. All rights reserved.

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PMID: 

Drug Discov Ther. 2019 ;13(4):212-221. PMID: 31534073

Abstract Title: 

Effects of naringenin on vascular changes in prolonged hyperglycaemia in fructose-STZ diabetic rat model.

Abstract: 

Chronic uncontrolled hyperglycaemia leads to increased oxidative stress and lipid peroxidation resulting in vascular complications and accelerates the progression of diabetic atherosclerosis. Though varieties of modern drugs used in the treatment of diabetes, the complications of diabetes are increasing. Naringenin (NG), has been reported to have potent antioxidant and anti-atherosclerotic properties. However, the effects of NG as vasculoprotective agent in prolonged hyperglycaemia are not well documented. Thus, this study was aimed to determine the effect of NG against vascular changes after prolonged hyperglycaemia in a diabetic rat model. Thirty adult male Sprague-Dawley rats were induced with fructose and streptozotocin to develop the diabetic rat model. After 4 weeks, the rats were randomly divided into 5 groups each group consisting of 6 animals: control, control treated with NG, non-treated diabetes mellitus (DM), DM treated with NG and metformin-treated DM. The treatment with NG (50 mg/kg) and metformin were continued for 5 weeks. The results showed that consumption of NG at 4 weeks post diabetic did not improved blood sugar, blood pressure and serum lipid profile. However, NG did significantly improve oxidative stress parameters in the aortic tissue like malondialdehyde (MDA). Analysis through light microscopy and transmission electron microscope (TEM) reverted the histological changes caused by prolonged hyperglycaemia. The findings thus demonstrated that introduction of NG after prolonged exposure to hyperglycaemia improved the vascular deterioration in diabetic group by decreasing oxidative stress evident by the reduced in the lipid peroxidation activity. Thus, this study showed the potential use of NG as adjunct in managing the diabetic condition during late presentation.

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PMID: 

Toxicol In Vitro. 2019 Sep 5 ;61:104642. Epub 2019 Sep 5. PMID: 31493543

Abstract Title: 

Evaluation of inhibitory effects of flavonoids on breast cancer resistance protein (BCRP): From library screening to biological evaluation to structure-activity relationship.

Abstract: 

Flavonoids are a group of polyphenols ubiquitously present in vegetables, fruits and herbal products, despite various known pharmacological activities, few researches have been done about the interaction of flavonoids with breast cancer resistance protein (BCRP). The present study was designed to investigate the inhibitory effects of 99 flavonoids on BCRP in vitro and in vivo and to clarify structure-activity relationships of flavonoids with BCRP. Eleven flavonoids, including amentoflavone, apigenin, biochanin A, chrysin, diosimin, genkwanin, hypericin, kaempferol, kaempferide, licochalcone A and naringenin, exhibited significant inhibition (>50%) on BCRP in BCRP-MDCKII cells, which reduced the BCRP-mediated efflux of doxorubicin and temozolomide, accordingly increased their cytotoxicity. In addition, co-administration of mitoxantrone with the 11 flavonoids increased the AUCof mitoxantrone in different extents in rats. Among them, chrysin increased the AUCmost significantly, by 81.97%. Molecular docking analysis elucidated the inhibition of flavonoids on BCRP might be associated with Pi-Pi stacked interactions and/or potential Pi-Alkyl interactions, but not conventional hydrogen bonds. The pharmacophore model indicated the aromatic ring B, hydrophobic groups and hydrogen bond acceptors may play critical role in the potency of flavonoids inhibition on BCRP. Thus, our findings would provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.

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PMID: 

Am J Cancer Res. 2019 ;9(8):1517-1535. Epub 2019 Aug 1. PMID: 31497340

Abstract Title: 

Chemopreventive and anticancer activity of flavonoids and its possibility for clinical use by combining with conventional chemotherapeutic agents.

Abstract: 

Cancer is a diverse class of diseases characterized by uncontrolled cell growth with the potential to invade and spread to other parts of the body, and continues to be one of the leading causes of death worldwide. Conventional cancer treatment modalities include antitumor drugs, surgical resection, locally targeted therapies such as radiation therapy. Along with improved understanding of the molecular pathogenesis of various cancers, generation and the use of smart targeted anti-cancer drugs have been challenged. The need for novel therapeutic strategies remains paramount given the sustained development of drug resistance, tumor recurrence, and metastasis. Development of new strategies aimed at improving chemotherapy sensitivity and minimizing the adverse side effects is thus essential for obtaining satisfied therapeutic outcomes for patients and enhancing their quality of life. Emerging evidence has reported that many cancer patients use either herbs employed in complementary therapies or dietary agents that influence cellular signaling worldwide. Numerous components of edible plants, collectively termed phytochemicals that have beneficial effects for health, are being reported increasingly in the scientific literature. Of those, flavonoids have attracted much attention by virtue of its wide variety of biological functions including antioxidant, anti-inflammatory, and anticancer activity. In this review, we highlight the molecular mechanisms underlying its multiple pharmacological effects, especially focusing on cancer chemoprevention. We further discuss possible strategies to develop anticancer therapy by combining flavonoids nutraceuticals and conventional chemotherapeutic agents. We also highlight numerous pharmacokinetic challenges such as bioavailability, drug-drug interactions, which are still fundamental questions concerning its future clinical application.

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PMID: 

Molecules. 2019 Sep 13 ;24(18). Epub 2019 Sep 13. PMID: 31540221

Abstract Title: 

Apple Peel Flavonoid Fraction 4 Suppresses Breast Cancer Cell Growth by Cytostatic and Cytotoxic Mechanisms.

Abstract: 

Many dietary flavonoids possess anti-cancer activities. Here, the effect of apple peel flavonoid fraction 4 (AF4) on the growth of triple-negative (MDA-MB-231, MDA-MB-468), estrogen receptor-positive (MCF-7), and HER2-positive (SKBR3) breast cancer cells was determined and compared with the effect of AF4 on normal mammary epithelial cells and dermal fibroblasts. AF4 inhibited breast cancer cell growth in monolayer cultures, as well as the growth of MCF-7 spheroids, without substantially affecting the viability of non-malignant cells. A sub-cytotoxic concentration of AF4 suppressed the proliferation of MDA-MB-231 cells by inhibiting passage through the G/Gphase of the cell cycle. AF4-treated MDA-MB-231 cells also exhibited reduced in vitro migration and invasion, and decreased Akt (protein kinase B) signaling. Higher concentrations of AF4 were selectively cytotoxic for MDA-MB-231 cells. AF4 cytotoxicity was associated with the intracellular accumulation of reactive oxygen species. Importantly, intratumoral administration of AF4 suppressed the growth of MDA-MB-231 xenografts in non-obese diabetic severe combined immunodeficient (NOD-SCID) female mice. The selective cytotoxicity of AF4 for breast cancer cells, combined with the capacity of sub-cytotoxic AF4 to inhibit breast cancer cell proliferation, migration, and invasion suggests that flavonoid-rich AF4 (and its constituents) has potential as a natural therapeutic agent for breast cancer treatment.

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PMID: 

Phytother Res. 2019 Aug ;33(8):2102-2117. Epub 2019 Jun 17. PMID: 31209984

Abstract Title: 

Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke-induced airway inflammation.

Abstract: 

The total flavonoids from sea buckthorn (TFSB) exhibit a potent anti-inflammatory activity; however, the effect of TFSB on respiratory inflammatory disease is not fully known. The present study evaluated the potential of TFSB to prevent airway inflammation and the underlying mechanism. The results showed that TFSB remarkably inhibited lipopolysaccharide/cigarette smoke extract (LPS/CSE)-induced expression of IL-1β, IL-6, CXCL1, and MUC5AC at both mRNA and protein levels in HBE16 bronchial epithelial cells. TFSB also decreased the production of PGEthrough inhibition the expression of COX2 in LPS/CSE-stimulated HBE16 cells. Furthermore, bronchoalveolar fluid and histological analyses revealed that LPS/cigarette smoke exposure-induced elevated cell numbers of neutrophils and macrophages in bronchoalveolar fluid, inflammatory cell infiltration, and airway remodeling were remarkably attenuated by TFSB in mice. Immunohistochemical results also confirmed that TFSB decreased the expression of IL-1β, IL-6, COX2, CXCL1, and MUC5AC in LPS/CS-exposed mice. Mechanistically, TFSB blocked LPS/CSE-induced activation of ERK, Akt, and PKCα. Molecular docking further confirmed that the main components in TFSB including quercetin and isorhamnetin showed potent binding affinities to MAPK1 and PIK3CG, two upstream kinases of ERK and Akt, respectively. In summary, TFSB exerts a potent protective effect against LPS/CS-induced airway inflammation through inhibition of ERK, PI3K/Akt, and PKCα pathways, suggesting that TFSB may be a novel therapeutic agent for respiratory diseases.

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PMID: 

Fitoterapia. 2019 Sep ;137:104248. Epub 2019 Jun 25. PMID: 31247218

Abstract Title: 

Flavonoid glycosides from seeds of Hippophae rhamnoides subsp. Sinensis withα-glucosidase inhibition activity.

Abstract: 

Hippophae rhamnoides subsp. Sinensis is a famous traditional medicinal plant in Tibet and Mongolia of China. Three novel flavonoid glycosides and ten known analogues were obtained from the seeds of H. rhamnoides. The structures of new compounds were elucidated by spectroscopics, chemical methods as well as literature data. In vitro assay, compounds 5-9, kaempferol and 70% ethanolic elution fraction showed prominentα-glucosidase inhibitory activities with ICvalues ranging from 8.30 to 112.11 μM, better than that of the positive control, acarbose, whose ICvalue was 1727.07 μM.

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PMID: 

Food Funct. 2019 Sep 1 ;10(9):5669-5681. Epub 2019 Aug 21. PMID: 31433440

Abstract Title: 

Sea buckthorn seed oil reduces blood cholesterol and modulates gut microbiota.

Abstract: 

Sea buckthorn seed oil (SBSO) has been used as a functional food in the prevention of heart diseases. The present study investigates the effects of SBSO on blood cholesterol and the gut microbiota in hypercholesterolemia hamsters. Four groups of hamsters (n = 8 each) were given one of four diets, namely a non-cholesterol control diet (NCD), a high-cholesterol control diet (HCD) containing 0.1% cholesterol, and an HCD diet with sea buckthorn seed oil replacing 50% lard (SL) or replacing 100% lard (SH). Feeding SL and SH diets could reduce blood total cholesterol by 20-22%. This was accompanied by the down-regulation of the gene expression of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporter8 (ABCG8). SBSO supplementation also increased the production of intestinal short-chain fatty acids and fecal outputs of neutral sterols. Metagenomic analysis demonstrated that feeding SL and SH diets could favorably modulate the relative abundance of Bacteroidales_S24-7_group, Ruminococcaceae, and Eubacteriaceae. It was therefore concluded that SBSO was effective in reducing blood cholesterol in hypercholesterolemic hamsters via increasing intestinal cholesterol excretion and promoting the growth of SCFA-producing bacteria.

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PMID: 

Ann Anat. 2019 Jul ;224:133-141. Epub 2019 May 18. PMID: 31108189

Abstract Title: 

Effect of aspartame on the placenta of adult albino rat. A histological and immunohistochemical study.

Abstract: 

Aspartame is an artificial sweetener usually consumed by hundreds of millions of persons all over the world. Its metabolites can be toxic to many organs and there are only a few studies on the use of aspartame during gestation. The present study was designed to fully evaluate the effect of aspartame on the histological structure of the placenta in the adult albino rat. Twenty pregnant female rats were equally divided into group I that served as control, and group II that received aspartame at a dose 14 mg/kg by gavage on the 9th, 10th and 11th day of pregnancy. Placental specimens were processed for histological and immunohistochemical staining against vascular endothelial growth factor (VEGF). Aspartame induced a significant decrease in the mean placental weight and the mean thickness of bothlabyrinth and basal zones. Damage in the placenta was detected in the form of rupture of the interhemal membrane, lysis of glycogen trophoblast cells, spongiotrophoblast cells with vacuolated cytoplasm and darkly stained nuclei. A significant increase in vascular endothelial growth factor expressionin both labyrinth and basal zones was detected. Ultrastructural examination showed fetal capillaries with condensed nuclei of endothelial cells, cytotrophoblasts with condensed fragmented nuclei and vacuolated cytoplasm, and syncytiotrophoblasts with irregular condensed fragmented nuclei. It couldbe concluded that aspartame has deeply impacted the normal structure and presumably the function of the placenta, therefore, restrictions are to be imposed on the consumption of aspartame especially during pregnancy.

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