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May N, Shi J, Clunas H, de Sousa Alves Neri JL, Kelso C, Morgan J, Yu Y, Charlton K, Weston-Green K. Characterisation and quantification of phenolic, anthocyanidin and terpene species in plant foods and plant food-based complementary products with antioxidant and neuroprotective properties. Food Funct 2024; 15:11537-11563. [PMID: 39498635 DOI: 10.1039/d4fo02942a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
Phytochemicals, including phenolic compounds and terpenes, are of interest for the treatment and prevention of conditions with oxidative stress, inflammatory and neurodegenerative pathologies. Certain plant foods have shown beneficial effects for the brain; however, the specific phenolic and terpene species in these foods are unclear. The present study aimed to characterise and quantify the phenolic, anthocyanidin and terpene species in six plant foods (Queen Garnet plum (QGP, Prunus salicina); black pepper (BPF, Piper nigrum); clove (CF, Syzygium aromaticum); elderberry (EF, Sambucus nigra); lemon balm (LBF, Melissa officinalis); and sage (SF, Salvia officinalis)) and six plant food-based complementary products (clove (CC), elderberry (EC), lemon balm (LBC), and sage (SC), plus two blends (Astragalus membranaceus and lemon balm-rich, WC and R8)). The relationships between the concentration of phytochemical species in these samples and their antioxidant capacities (i.e. oxygen and nitrogen free radical scavenging, Cu2+ and Fe2+ chelating capacities, and the ability to prevent H2O2-induced oxidative stress in neuroblast-like SH-SY5Y cells, in vitro) were also examined. WC had the highest concentration of phenolics, followed by QGP, EF, CC and CF. BPF had the highest total terpene concentration followed by CC, CF and SF. Correlations between certain compounds and antioxidant capacity were demonstrated. The results provide insight into the potential functional capabilities of species of phenolics and terpenes. Understanding the phytochemical profile of plant foods and their correlations may be important in understanding their potential therapeutic benefits for brain health.
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Affiliation(s)
- Naomi May
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Jiahua Shi
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Helen Clunas
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Julianna Lys de Sousa Alves Neri
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Celine Kelso
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Chemistry and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Jody Morgan
- School of Chemistry and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Yinghua Yu
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Karen Charlton
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
| | - Katrina Weston-Green
- Molecular Horizons, University of Wollongong, NSW, 2522, Australia.
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, NSW, 2522, Australia
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Policastro PF, Schneider CA, Winkler CW, Leung JM, Peterson KE. Retinoic acid-induced differentiation and oxidative stress inhibitors increase resistance of human neuroblastoma cells to La Crosse virus-induced cell death. J Virol 2024; 98:e0030024. [PMID: 39382324 PMCID: PMC11575257 DOI: 10.1128/jvi.00300-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/13/2024] [Indexed: 10/10/2024] Open
Abstract
La Crosse Virus (LACV) encephalitis patients are at risk for long-term deficits in cognitive function due to neuronal apoptosis following virus infection. However, the specific etiology underlying neuronal damage remains elusive. In this study, we examined how differentiation and mitotic inhibition of neuroblastoma cells influence their susceptibility to LACV infection and cell death. Treatment of SH-SY5Y cells with retinoic acid induced a neuronal cell phenotype which was similarly susceptible to LACV infection as untreated cells but had significantly delayed virus-induced cell death. Protein and RNA transcript analysis showed that retinoic acid-treated cells had decreased oxidative stress responses to LACV infection compared to untreated cells. Modulation of oxidative stress in untreated cells with specific compounds also delayed cell death, without substantially impacting virus production. Thus, the oxidative stress response of neurons to virus infection may be a key component of neuronal susceptibility to virus-induced cell death. IMPORTANCE Encephalitic viruses like La Crosse Virus (LACV) infect and kill neurons. Disease onset and progression is rapid meaning the time frame to treat patients before significant and long-lasting damage occurs is limited. Examining how neurons, the primary cells infected by LACV in the brain, resist virus-induced cell death can provide avenues for determining which pathways to target for effective treatments. In the current study, we studied how changing neuroblastoma growth and metabolism with retinoic acid treatment impacted their susceptibility to LACV-induced cell death. We utilized this information to test compounds for preventing death in these cells.
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Affiliation(s)
- Paul F Policastro
- Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Hamilton, Montana, USA
| | - Christine A Schneider
- Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Hamilton, Montana, USA
- Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Hamilton, Montana, USA
| | - Clayton W Winkler
- Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Hamilton, Montana, USA
| | - Jacqueline M Leung
- Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Hamilton, Montana, USA
| | - Karin E Peterson
- Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Hamilton, Montana, USA
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Choi J, Nguyen QN, Baek JY, Cho DE, Kang KS, Hahm DH, Jang TW, Park JH, Lee AY, Lee S. Beneficial role of Boehmeria nivea in health and phytochemical constituents. J Food Biochem 2022; 46:e14474. [PMID: 36209491 DOI: 10.1111/jfbc.14474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/02/2022] [Accepted: 09/27/2022] [Indexed: 01/14/2023]
Abstract
The leaf and stem extracts of Boehmeria nivea (BN) collected from three different regions in Korea were screened for their antioxidant, neuroprotective, estrogenic, insulin secretion, and α-glucosidase inhibitory activity. We also examined whether BN extracts regulate cancer cell growth, inflammatory-related gene expression, and lipid accumulation in cellular system. Leaf extracts possessed greater antioxidant, anti-proliferative in cancer cells, neuroprotective, estrogenic activity, and inhibitory effect on pro-inflammatory gene expression than stem extracts. Leaf and stem extracts inhibited lipid accumulation in three T3-L1 adipocytes but did not affect glucose-stimulated insulin secretion in INS-1 cells. We isolated and identified the phytochemical constituents in the n-butanol and ethyl acetate fractions of BN leaves by combining silica gel column chromatography with mass spectrometry and 1 H- and 13 C-NMR analysis. The active compounds (caffeic acid, isoquercitrin, p-coumaric acid, and rutin) exhibited ABTS and DPPH radical scavenging activity, which may contribute to the biological activities of BN leaf extract. An analytical method was developed to quantify marker compounds for the discrimination of BN collected from different regions. Our results support the use of this analysis method for accurate identification and quantification of marker compounds in BN for the development of functional foods. PRACTICAL APPLICATIONS: Boehmeria nivea (BN) has been used as a raw material for the textile industry or traditional herbal medicine. The current study established the biological activities and active components of BN. Our results showed that BN leaf and stem extracts exhibit antioxidant, neuroprotective, and estrogenic activity. BN leaf extract also inhibited cancer cell growth, inflammatory mediators and cytokines production, and lipid accumulation in vitro. Moreover, the bioactive compounds, such as caffeic acid, isoquercitrin, p-coumaric acid, and rutin, exert ABTS and DPPH radical scavenging activities. Therefore, BN could potentially be a promising source of bioactive phytochemicals for the development of functional foods or drugs.
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Affiliation(s)
- Jungwon Choi
- Department of Plant Science and Technology, Chung-Ang University, Anseong, Republic of Korea
| | - Quynh Nhu Nguyen
- Department of Preventive Medicine, Gachon University, Seongnam, Republic of Korea
| | - Ji Yun Baek
- Department of Preventive Medicine, Gachon University, Seongnam, Republic of Korea
| | - Da-Eun Cho
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Ki Sung Kang
- Department of Preventive Medicine, Gachon University, Seongnam, Republic of Korea
| | - Dae-Hyun Hahm
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Tae Won Jang
- Department of Pharmaceutical Science, Jungwon University, Goesan, Republic of Korea
| | - Jae Ho Park
- Department of Pharmaceutical Science, Jungwon University, Goesan, Republic of Korea
| | - Ah Young Lee
- Department of Food Science and Nutrition, Gyeongsang National University, Jinju, Republic of Korea
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong, Republic of Korea.,Natural Product Institute of Science and Technology, Anseong, Republic of Korea
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Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin. Int J Mol Sci 2022; 23:ijms232314957. [PMID: 36499286 PMCID: PMC9737263 DOI: 10.3390/ijms232314957] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/02/2022] [Accepted: 11/10/2022] [Indexed: 12/02/2022] Open
Abstract
Herein, I present an updated and contextualized literature review of functional genomic studies of natural phenols in the context of cancer. I suggest multilevel chemopreventive and anticancer mechanisms of action, which are shared by multiple dietary natural phenols. Specifically, I cite evidence that curcumin and resveratrol have multilevel anti-cancer effects through: (1) inducing either p53-dependent or p53-independent apoptosis in cancer cell lines, (2) acting as potent regulators of expression of oncogenic and anti-oncogenic microRNAs, and (3) inducing complex epigenetic changes that can switch off oncogenes/switch on anti-oncogenes. There is no simple reductionist explanation for anti-cancer effects of curcumin and resveratrol. More generally, multilevel models of chemoprevention are suggested for related natural phenols and flavonoids such as genistein, quercetin, or luteolin.
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Gautam D, Kailashiya J, Tiwari A, Chaurasia RN, Annarapu GK, Guchhait P, Dash D. Fibrinogen Mitigates Prion-Mediated Platelet Activation and Neuronal Cell Toxicity. Front Cell Dev Biol 2022; 10:834016. [PMID: 35386203 PMCID: PMC8977893 DOI: 10.3389/fcell.2022.834016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/17/2022] [Indexed: 11/23/2022] Open
Abstract
Prion peptide (PrP) misfolds to infectious scrapie isoform, the β pleat-rich insoluble fibrils responsible for neurodegeneration and fatal conformational diseases in humans. The amino acid sequence 106–126 from prion proteins, PrP(106–126), is highly amyloidogenic and implicated in prion-induced pathologies. Here, we report a novel interaction between PrP(106–126) and the thrombogenic plasma protein fibrinogen that can lead to mitigation of prion-mediated pro-thrombotic responses in human platelets as well as significant decline in neuronal toxicity. Thus, prior exposure to fibrinogen-restrained PrP-induced rise in cytosolic calcium, calpain activation, and shedding of extracellular vesicles in platelets while it, too, averted cytotoxicity of neuronal cells triggered by prion peptide. Interestingly, PrP was found to accelerate fibrin-rich clot formation, which was resistant to plasmin-mediated fibrinolysis, consistent with enhanced thrombus stability provoked by PrP. We propose that PrP-fibrinogen interaction can be clinically exploited further for prevention and management of infectious prion related disorders. Small molecules or peptides mimicking PrP-binding sites on fibrinogen can potentially mitigate PrP-induced cellular toxicity while also preventing the negative impact of PrP on fibrin clot formation and lysis.
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Affiliation(s)
- Deepa Gautam
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
- Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Jyotsna Kailashiya
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Arundhati Tiwari
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Rameshwar Nath Chaurasia
- Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Gowtham K. Annarapu
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Prasenjit Guchhait
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Debabrata Dash
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
- *Correspondence: Debabrata Dash,
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He B, Bai X, Tan Y, Xie W, Feng Y, Yang GY. Glycosyltransferases: Mining, engineering and applications in biosynthesis of glycosylated plant natural products. Synth Syst Biotechnol 2022; 7:602-620. [PMID: 35261926 PMCID: PMC8883072 DOI: 10.1016/j.synbio.2022.01.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/10/2021] [Accepted: 01/02/2022] [Indexed: 12/14/2022] Open
Abstract
UDP-Glycosyltransferases (UGTs) catalyze the transfer of nucleotide-activated sugars to specific acceptors, among which the GT1 family enzymes are well-known for their function in biosynthesis of natural product glycosides. Elucidating GT function represents necessary step in metabolic engineering of aglycone glycosylation to produce drug leads, cosmetics, nutrients and sweeteners. In this review, we systematically summarize the phylogenetic distribution and catalytic diversity of plant GTs. We also discuss recent progress in the identification of novel GT candidates for synthesis of plant natural products (PNPs) using multi-omics technology and deep learning predicted models. We also highlight recent advances in rational design and directed evolution engineering strategies for new or improved GT functions. Finally, we cover recent breakthroughs in the application of GTs for microbial biosynthesis of some representative glycosylated PNPs, including flavonoid glycosides (fisetin 3-O-glycosides, astragalin, scutellarein 7-O-glucoside), terpenoid glycosides (rebaudioside A, ginsenosides) and polyketide glycosides (salidroside, polydatin).
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Affiliation(s)
- Bo He
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xue Bai
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yumeng Tan
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wentao Xie
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan Feng
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Guang-Yu Yang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
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Quercetin mitigates the deoxynivalenol mycotoxin induced apoptosis in SH-SY5Y cells by modulating the oxidative stress mediators. Saudi J Biol Sci 2020; 28:465-477. [PMID: 33424329 PMCID: PMC7783655 DOI: 10.1016/j.sjbs.2020.10.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/15/2022] Open
Abstract
Deoxynivalenol (DON) is Fusarium mycotoxin that is frequently found in many cereal-based foods, and its ingestion has a deleterious impact on human health. In this investigation, we studied the mechanism of DON-induced neurotoxicity and followed by cytoprotective efficacy of quercetin (QUE) in contradiction of DON-induced neurotoxicity through assessing the oxidative stress and apoptotic demise in the human neuronal model, i.e. SH-SY5Y cells. DON diminished the proliferation of cells in the manner of dose and time-dependent as revealed by cell viability investigations, i.e. MTT and lactate dehydrogenase assays. Additional studies, such as intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), DNA damage, cell cycle, and neuronal biomarkers (amino acid decarboxylase, tyrosine hydroxylase, and brain-derived neurotrophic factor) demonstrated that DON induces apoptotic demise in neuronal cells through oxidative stress intermediaries. On another hand, pre-treatment of neuronal cells with 1 mM of quercetin (QUE) showed decent viability upon exposure to 100 µM of DON. In detailed studies demonstrated that QUE (1 mM) pre-treated cells show strong attenuation efficiency against DON-induced ROS generation, LPO, MMP loss, DNA impairment, cell cycle arrest, and down-regulation of neuronal biomarkers. The consequences of the investigation concluded that QUE mitigates the DON-induced stress viz., decreased ROS production and LPO generation, upholding MMP and DNA integrity and regulation of neuronal biomarker gene expression in SH-SY5Y cells.
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8
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Jiang T, Zhang G, Lou Z. Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis. Front Oncol 2020; 10:1788. [PMID: 33014877 PMCID: PMC7506081 DOI: 10.3389/fonc.2020.01788] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 08/11/2020] [Indexed: 12/15/2022] Open
Abstract
Metabolic changes are a major feature of tumors, including various metabolic forms, such as energy, lipid, and amino acid metabolism. Sterol regulatory element binding proteins (SREBPs) are important modules in regulating lipid metabolism and play an essential role in metabolic diseases. In the previous decades, the regulatory range of SREBPs has been markedly expanded. It was found that SREBPs also played a critical role in tumor development. SREBPs are involved in energy supply, lipid supply, immune environment and inflammatory environment shaping in tumor cells, and as a protective umbrella to support the malignant proliferation of tumor cells. Natural medicine and traditional Chinese medicine, as an important part of drug therapy, demonstrates the multifaceted effects of SREBPs regulation. This review summarizes the core processes in the involvement of SREBPs in tumors and provides a comprehensive understanding of the pathways through which natural drugs target the SREBP pathway and regulate tumor progression.
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Affiliation(s)
- Tao Jiang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guangji Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhaohuan Lou
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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Liu J, Ma G, Wang Y, Zhang Y. Moringa oleifera leaf flavonoids protect bovine mammary epithelial cells from hydrogen peroxide-induced oxidative stress in vitro. Reprod Domest Anim 2020; 55:711-719. [PMID: 32144827 DOI: 10.1111/rda.13670] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/01/2020] [Indexed: 11/26/2022]
Abstract
Bovine mammary epithelial cells (BMECs) of high-producing dairy cows are subject to constant oxidative stress as a result of high metabolic rate and physiological adaptation to intensive farming. Moringa (Moringa oleifera) leaf has been proposed to have the antioxidant potential in scavenging free radicals due to the presence of flavonoids. In this study, we investigated the cytoprotective effects of moringa leaf flavonoids in alleviating oxidative stress in BMECs in vitro. Oxidative stress was established by exposing isolated BMECs to H2 O2 for 2 hr. Doses of moringa leaf flavonoids were evaluated by treating BMECs for 12 hr. The optimal concentrations of H2 O2 and moringa leaf flavonoids were 500 μmol/L and 1.0 mg/ml, respectively. The results showed that moringa leaf flavonoids increased the activities of superoxide dismutase, catalase, and glutathione peroxidase; and reduced malondialdehyde activity and intracellular accumulation of reactive oxygen species (ROS) in the H2 O2 -induced oxidative stress system. A Hoechst33258 staining assay revealed that moringa leaf flavonoids decreased the apoptosis rate in BMECs, while leaving membrane integrity and nucleolar morphology unchanged. We concluded that moringa leaf flavonoids have the antioxidant capacity to effectively reduce oxidative stress in BMECs.
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Affiliation(s)
- Ji Liu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, China.,College of Food and Bioengineering, Qiqihar University, Qiqihar, China
| | - Guangming Ma
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Yan Wang
- College of Food and Bioengineering, Qiqihar University, Qiqihar, China
| | - Yonggen Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
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10
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Hua H, Yang T, Huang L, Chen R, Li M, Zou Z, Wang N, Yang D, Liu Y. Protective Effects of Lanosterol Synthase Up-Regulation in UV-B-Induced Oxidative Stress. Front Pharmacol 2019; 10:947. [PMID: 31555133 PMCID: PMC6726740 DOI: 10.3389/fphar.2019.00947] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 07/24/2019] [Indexed: 12/17/2022] Open
Abstract
UV-B radiation may be an important risk factor in cataract etiology. After exposure to UV-B radiation, cells show imbalances in the repair of DNA damage, which induce changes in the levels of certain proteins, including alpha-crystallin, which is the most abundant protein in the lens and crucial for the maintenance of lens transparency. Lanosterol synthase (LSS), an essential rate-limiting enzyme in cholesterol biosynthesis, might play significant roles in oxidative stress and in the maintenance of lens transparency. However, the roles of LSS in UV-B-induced apoptosis are not well understood. Therefore, we irradiated female Sprague-Dawley rats with ultraviolet radiation to establish an animal model for exploring the variations in LSS expression during the early stages of UV-B exposure. In addition, we cultured human lens epithelial (HLE) cells that overexpress LSS and exposed them to UV-B radiation to explore the function of increased LSS expression in UV-B-induced apoptosis. The data demonstrated that UV-B exposure induced oxidative stress and apoptosis in rat lens epithelial cells and that irradiance exposure increased the level of lenticular damage. Additionally, UV-B exposure decreased the alpha-crystallin content and increased the expressions of Bax and cleaved caspase-3 compared with the control levels. After exposure to UV-B, the apoptosis-related index of HLE cells overexpressing LSS was lower than that of the control cells. Furthermore, ROS overproduction might activate the sirtuin 1 (Sirt1) pathway, which induced protein expressions of sterol regulatory element-binding transcription factor 2 (SREBF2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and LSS. However, the specific mechanism of the Sirt1 pathway needed to be further studied. In summary, UV-B exposure induced oxidative injury and resulted in crystallin denaturation and apoptosis in lens epithelial cells, and LSS might play a protective role during the early stages of this process and could be an important target in the cataract prevention.
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Affiliation(s)
- Hui Hua
- School of Public Health, China Medical University, Shenyang, China
| | - Tianyao Yang
- School of Public Health, China Medical University, Shenyang, China
| | - Liting Huang
- School of Public Health, China Medical University, Shenyang, China
| | - Rentong Chen
- School of Public Health, China Medical University, Shenyang, China
| | - Menglin Li
- School of Public Health, China Medical University, Shenyang, China
| | - Zhenzhen Zou
- School of Public Health, China Medical University, Shenyang, China
| | - Nan Wang
- School of Public Health, China Medical University, Shenyang, China
| | - Dan Yang
- School of Public Health, China Medical University, Shenyang, China
| | - Yang Liu
- School of Public Health, China Medical University, Shenyang, China
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Lin M, Zhang J, Chen X. Bioactive flavonoids in Moringa oleifera and their health-promoting properties. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.06.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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12
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Tan C, Meng F, Reece EA, Zhao Z. Modulation of nuclear factor-κB signaling and reduction of neural tube defects by quercetin-3-glucoside in embryos of diabetic mice. Am J Obstet Gynecol 2018; 219:197.e1-197.e8. [PMID: 29733843 DOI: 10.1016/j.ajog.2018.04.045] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/17/2018] [Accepted: 04/26/2018] [Indexed: 01/25/2023]
Abstract
BACKGROUND Diabetes mellitus in early pregnancy increases the risk of birth defects in infants. Maternal hyperglycemia stimulates the expression of nitric oxide synthase 2, which can be regulated by transcription factors of the nuclear factor-κB family. Increases in reactive nitrogen species generate intracellular stress conditions, including nitrosative, oxidative, and endoplasmic reticulum stresses, and trigger programmed cell death (or apoptosis) in the neural folds, resulting in neural tube defects in the embryo. Inhibiting nitric oxide synthase 2 can reduce neural tube defects; however, the underlying mechanisms require further delineation. Targeting nitric oxide synthase 2 and associated nitrosative stress using naturally occurring phytochemicals is a potential approach to preventing birth defects in diabetic pregnancies. OBJECTIVE This study aims to investigate the effect of quercetin-3-glucoside, a naturally occurring polyphenol flavonoid, in reducing maternal diabetes-induced neural tube defects in an animal model, and to delineate the molecular mechanisms underlying quercetin-3-glucoside action in regulating nitric oxide synthase 2 expression. STUDY DESIGN Female mice (C57BL/6) were induced to develop diabetes using streptozotocin before pregnancy. Diabetic pregnant mice were administered quercetin-3-glucoside (100 mg/kg) daily via gavage feeding, introduction of drug to the stomach directly via a feeding needle, during neurulation from embryonic day 6.5-9.5. After treatment at embryonic day 10.5, embryos were collected and examined for the presence of neural tube defects and apoptosis in the neural tube. Expression of nitric oxide synthase 2 and superoxide dismutase 1 (an antioxidative enzyme) was quantified using Western blot assay. Nitrosative, oxidative, and endoplasmic reticulum stress conditions were assessed using specific biomarkers. Expression and posttranslational modification of factors in the nuclear factor-κB system were investigated. RESULTS Treatment with quercetin-3-glucoside (suspended in water) significantly decreased neural tube defect rate and apoptosis in the embryos of diabetic mice, compared with those in the water-treated diabetic group (3.1% vs. 24.7%; P < .001). Quercetin-3-glucoside decreased the expression of nitric oxide synthase 2 and nitrosative stress (P < .05). It also increased the levels of superoxide dismutase 1 (P < .05), further increasing the antioxidative capacity of the cells. Quercetin-3-glucoside treatment also alleviated of endoplasmic reticulum stress in the embryos of diabetic mice (P < .05). Quercetin-3-glucoside reduced the levels of p65 (P < .05), a member of the nuclear factor-κB transcription factor family, but augmented the levels of the inhibitor of κBα (P < .05), which suppresses p65 nuclear translocation. In association with these changes, the levels of inhibitor of κB kinase-α and inhibitor of κBα phosphorylation were elevated (P < .05). CONCLUSION Quercetin-3-glucoside reduces the neural tube defects rate in the embryos of diabetic dams. Quercetin-3-glucoside suppresses nitric oxide synthase 2 and increases superoxide dismutase 1 expression, leading to alleviation of nitrosative, oxidative, and endoplasmic reticulum stress conditions. Quercetin-3-glucoside may regulate the expression of nitric oxide synthase 2 via modulating the nuclear factor-κB transcription regulation system. Quercetin-3-glucoside, a naturally occurring polyphenol that has high bioavailability and low toxicity, is a promising candidate agent to prevent birth defects in diabetic pregnancies.
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Torki M, Schokker D, Duijster-Lensing M, Van Krimpen MM. Effect of nutritional interventions with quercetin, oat hulls, β-glucans, lysozyme and fish oil on performance and health status related parameters of broilers chickens. Br Poult Sci 2018; 59:579-590. [PMID: 29969287 DOI: 10.1080/00071668.2018.1496402] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
1. An experiment was conducted to evaluate the effects of technical feed ingredients between 14 and 28 d of age on performance and health status of broilers (d 14-35) fed diets with a high inclusion rate of rapeseed meal as a nutritional challenge. It was hypothesized that the feed ingredients would improve health status related parameters. 2. A total of 1008 one-day-old male Ross 308 chicks were distributed over 36 floor pens and allocated to one of six iso-caloric (AMEN 13 MJ/kg) growing diets (d 15-28): a control and five test diets supplemented with quercetin (400 mg/kg), oat hulls (50 g/kg), β-glucan (100 mg/kg), lysozyme (40 mg/kg) or fish oil ω-3 fatty acids (40 g/kg), with six replicate pens per treatment. 3. Dietary inclusion of oat hulls and lysozyme resulted in a reduction in broiler performance during the first week after providing the experimental diets. 4. No effect of interventions on the microbiota diversity in the jejunum and ileum was observed. Ileal microbiota composition of birds fed oat hulls differed from the other groups, as shown by a higher abundance of the genus Enterococcus, mainly at the expense of the genus Lactobacillus. 5. In the jejunum, villus height and crypt depth of lysozyme-fed birds at d 28 were decreased compared to the control group. Higher total surface area of villi occupied by goblet cells and total villi surface area in jejunum (d 21 and 28) were observed in chickens fed oat hulls compared to other groups. 6. Genes related to the growth-factor-activity pathway were more highly expressed in birds fed β-glucan compared to the control group, while the genes related to anion-transmembrane-transporter-activity pathway in the quercetin- and oat hull-fed birds were less expressed. The genes differently expressed between dietary interventions did not seem to be directly involved in immune related processes. 7. It was concluded that the tested nutritional interventions in the current experiment only marginally effected health status related parameters.
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Affiliation(s)
- M Torki
- a Department of Animal Nutrition , Wageningen Livestock Research, Wageningen University & Research , The Netherlands.,b Animal Science Department , Razi University , Kermanshah , Iran
| | - D Schokker
- a Department of Animal Nutrition , Wageningen Livestock Research, Wageningen University & Research , The Netherlands
| | | | - M M Van Krimpen
- a Department of Animal Nutrition , Wageningen Livestock Research, Wageningen University & Research , The Netherlands
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Rocha-Parra D, Chirife J, Zamora C, de Pascual-Teresa S. Chemical Characterization of an Encapsulated Red Wine Powder and Its Effects on Neuronal Cells. Molecules 2018; 23:molecules23040842. [PMID: 29642422 PMCID: PMC6017672 DOI: 10.3390/molecules23040842] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 03/23/2018] [Accepted: 03/23/2018] [Indexed: 11/16/2022] Open
Abstract
Red wine polyphenols are known for their implications for human health protection, although they suffer from high instability. For this reason, a red wine powder was prepared by freeze-drying encapsulation in maltodextrin/arabic gum matrix, and its composition was determined by means of high-performance liquid chromatography coupled quadrupole time-of-flight mass spectrometry (HPLC-MS-QTOF). More than thirty polyphenols, including anthocyanins, flavanols, flavonols, phenolic acids and stilbenoids, were identified. Some of the main quantified polyphenols were: malvidin-3-O-glucoside, malvidin 3-O-(6″-acetyl-glucose), petunidin-3-O-glucoside, quercetin-3-O-glucuronide, syringenin-3-O-glucoside, epicatechin, gallic acid and syringic acid. The biological activity of this de-alcoholized and encapsulated red wine on human neuroblastoma SH-SY5Y cells was studied. The results showed that the encapsulated red wine powder has active redox properties, as verified by performing reactive oxygen species (ROS) analysis utilizing a neuronal model. This could help explain its action against the neurotoxicity induced by 6-hydroxydopamine (6-OHDA).
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Affiliation(s)
- Diego Rocha-Parra
- Faculty of Engineering and Agricultural Sciences, Pontifical Catholic University of Argentina, Buenos Aires C1107AAZ, Argentina.
- National Scientific and Technical Research Council (CONICET), Buenos Aires C1425FQB, Argentina.
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), E-28040 Madrid, Spain.
| | - Jorge Chirife
- Faculty of Engineering and Agricultural Sciences, Pontifical Catholic University of Argentina, Buenos Aires C1107AAZ, Argentina.
| | - Clara Zamora
- Faculty of Engineering and Agricultural Sciences, Pontifical Catholic University of Argentina, Buenos Aires C1107AAZ, Argentina.
- National Scientific and Technical Research Council (CONICET), Buenos Aires C1425FQB, Argentina.
| | - Sonia de Pascual-Teresa
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), E-28040 Madrid, Spain.
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Phenolic Compounds and Antioxidant Activity in Grape Juices: A Chemical and Sensory View. BEVERAGES 2018. [DOI: 10.3390/beverages4010022] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway. Chem Biol Interact 2018; 284:32-40. [DOI: 10.1016/j.cbi.2018.02.017] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/15/2018] [Accepted: 02/13/2018] [Indexed: 11/18/2022]
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Cavalcante A, Lins T, Santos J, Barros V, Monte A, Barberino RS, Almeida J, Matos M. Supplemented Morus nigra extract-based medium associated with FSH enables the survival and growth of isolated ovine secondary ovarian follicles. Reprod Domest Anim 2017; 53:423-432. [PMID: 29265671 DOI: 10.1111/rda.13122] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 11/06/2017] [Indexed: 01/15/2023]
Abstract
The effects of Morus nigra ethanolic extract, without or with addition of supplements associated or not with FSH, on in vitro culture of ovine secondary follicles were evaluated. In experiment 1, isolated secondary follicles were cultured for 12 days in α-MEM alone (control) or in different concentrations of M. nigra extract (MN 0.025; 0.05 or 0.1 mg/ml). In experiment 2, culture media were α-MEM supplemented with BSA, insulin, transferrin, selenium, glutamine, hypoxanthine and ascorbic acid (α-MEM+ ) or this medium associated with FSH (α-MEM+ + FSH), or 0.1 mg/ml M. nigra without supplements (MN 0.1) or supplemented (MN 0.1+ ) without or with FSH (MN 0.1+ + FSH). In experiment 1, 0.1 mg/ml M. nigra showed the highest percentages (p < .05) of normal follicles and fully grown oocytes, besides a higher follicular diameter than α-MEM and other M. nigra extract concentrations. Moreover, MN 0.1 showed lower (p < .05) glutathione (GSH) levels and similar (p > .05) mitochondrial activity compared to α-MEM. In experiment 2, MN 0.1+ + FSH showed similar results (p > .05) to α-MEM+ + FSH for all parameters evaluated, except for the daily growth rate, which was higher (p < .05) in MN 0.1+ + FSH. The GSH levels were higher in MEM+ than all treatments. In addition, oocytes from follicles cultured in MN 0.1+ + FSH showed ability to resume meiosis. In conclusion, M. nigra extract (0.1 mg/ml) added by supplements and FSH can be an efficient medium for ovine secondary follicle development.
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Affiliation(s)
- Ayp Cavalcante
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Tlbg Lins
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Jms Santos
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Vrp Barros
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Apo Monte
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - R S Barberino
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Jrgs Almeida
- Center for Studies and Research on Medicinal Plants, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
| | - Mht Matos
- Nucleus of Biotechnology Applied to Ovarian Follicle Development, Federal University of San Francisco Valley, Petrolina, Pernambuco, Brazil
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Raju A, Jaisankar P, Borah A, Mohanakumar KP. 1-Methyl-4-Phenylpyridinium-Induced Death of Differentiated SH-SY5Y Neurons Is Potentiated by Cholesterol. Ann Neurosci 2017; 24:243-251. [PMID: 29849448 DOI: 10.1159/000481551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Background/Aims Hypercholesterolemia is recently considered a risk factor for Parkinson's disease (PD), the most consistent neurodegenerative movement disorder. The study aimed to investigate the effect of exogenous cholesterol on 1-methyl-4-phenylpyridinium (MPP+) parkinsonian neurotoxin-induced cell death, loss of mitochondrial membrane potential, and dopaminergic deficiency in a cellular model of PD. Methods Cholesterol (50 μM) when added in the culture media alone or in combination with MPP+ was studied in SH-SY5Y neuroblastoma cells. There were 4 groups that were studied; SH-SY5Y cells treated with vehicle (control), cells that were treated with 1 mM MPP+ (MPP+), or cholesterol (chol) or both (M + chol). The loss of cell survival was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Dopamine depletion, microtubule-associated protein 2 (MAP-2), and tyrosine hydroxylase (TH)-positive neuronal loss were determined by HPLC-electrochemical detection and TH immunocytochemistry respectively. Mitochondrial membrane potential in cells stained by tetramethylrhodamine methyl ester dye was analysed by flow cytometry. Results Cholesterol treatment potentiated a reduction of neuronal viability with loss of TH-positive neurons in cultures. MPP+-induced depletion of dopamine level in the post-mitotic MAP-2 immunoreactive neurons and loss of mitochondrial membrane potential were also heightened by cholesterol. Conclusion Apparently, changes in neuronal cholesterol content significantly influenced the neurotoxicity and the direct mitochondrial mechanisms involved in MPP+-induced cell death. Our observations demonstrate that high cholesterol incorporated into the differentiated human neuroblastoma cells worsened dopaminergic neuronal survivability through increased depolarization of mitochondrial membrane potential, which is a known mechanism of dopaminergic cell death by MPP+. The present findings support the hypothesis that hypercholesterolemia could be a risk factor for PD.
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Affiliation(s)
- Anu Raju
- Division of Cell Biology and Physiology, Kolkata, India.,Division of Chemistry, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR Campus, CSIR Road, Taramani, Chennai, India
| | - Parasuram Jaisankar
- Division of Chemistry, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR Campus, CSIR Road, Taramani, Chennai, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, India
| | - Kochupurackal Parameswarannayar Mohanakumar
- Division of Cell Biology and Physiology, Kolkata, India.,Division of Chemistry, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.,Inter University Centre for Biomedical Research and Super Speciality Hospital (IUCBR and SSH), Mahatma Gandhi University Campus at Thalappady, Kottayam, India
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Zhu Y, Bi F, Li Y, Yin H, Deng N, Pan H, Li D, Xiao B. α- and β-Naphthoflavone synergistically attenuate H 2O 2-induced neuron SH-SY5Y cell damage. Exp Ther Med 2017; 13:1143-1150. [PMID: 28450955 DOI: 10.3892/etm.2017.4045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 11/11/2016] [Indexed: 01/07/2023] Open
Abstract
Previous studies have demonstrated an association between neurological diseases and oxidative stress (OS). Naphthoflavone is a synthetic derivative of naturally occurring flavonoids that serves an important role in the treatment and prevention of OS-related diseases. The current study was designed to apply α- and β-Naphthoflavone individually and in combination to counteract the detrimental effects of OS on neurons in vitro. Neuronal SH-SY5Y cells were subjected to 20 µM H2O2, followed by exposure to 20 µM α-Naphthoflavone and/or 10 µM β-Naphthoflavone. Results indicated that α- and β-Naphthoflavone effectively antagonized the apoptosis-promoting effect of H2O2 on neuronal SH-SY5Y cells, and that β-Naphthoflavone significantly (P<0.05) reversed H2O2-inhibited cell viability. Notably, co-treatment of α- and β-Naphthoflavone reversed the H2O2-induced apoptosis rate elevation and cell viability reduction. Further analysis demonstrated that H2O2 inhibited the activities of antioxidant enzymes including catalase, superoxide dismutase and glutathione peroxidase, but this was reversed by the co-treatment with α- and β-Naphthoflavone and selectively enhanced by the treatment with α- or β-Naphthoflavone. H2O2-stimulated p38 mitogen-activated protein kinase activation was repressed following treatment with α- and/or β-Naphthoflavone, along with a decreased expression of the apoptosis-related factors and inhibited caspase-3 activation. In conclusion, co-treatment with α- and β-Naphthoflavone minimized H2O2-led neuron damage compared with treatment with α- or β-Naphthoflavone, suggesting a synergetic effect between α- and β-Naphthoflavone. This indicates that utilizing α- and β-Naphthoflavone together in the clinical setting may provide a novel therapeutic for neurological disease.
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Affiliation(s)
- Yong Zhu
- Department of Neurology, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
| | - Fangfang Bi
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yanchun Li
- Department of Neurology, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
| | - Huiming Yin
- Department of Respiration, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
| | - Na Deng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Haiquan Pan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Dongfang Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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An DG, Yang SM, Kim BG, Ahn JH. Biosynthesis of two quercetin O-diglycosides in Escherichia coli. ACTA ACUST UNITED AC 2016; 43:841-9. [DOI: 10.1007/s10295-016-1750-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 02/15/2016] [Indexed: 11/30/2022]
Abstract
Abstract
Various flavonoid glycosides are found in nature, and their biological activities are as variable as their number. In some cases, the sugar moiety attached to the flavonoid modulates its biological activities. Flavonoid glycones are not easily synthesized chemically. Therefore, in this study, we attempted to synthesize quercetin 3-O-glucosyl (1→2) xyloside and quercetin 3-O-glucosyl (1→6) rhamnoside (also called rutin) using two uridine diphosphate-dependent glycosyltransferases (UGTs) in Escherichia coli. To synthesize quercetin 3-O-glucosyl (1→2) xyloside, sequential glycosylation was carried out by regulating the expression time of the two UGTs. AtUGT78D2 was subcloned into a vector controlled by a Tac promoter without a lacI operator, while AtUGT79B1 was subcloned into a vector controlled by a T7 promoter. UDP-xyloside was supplied by concomitantly expressing UDP-glucose dehydrogenase (ugd) and UDP-xyloside synthase (UXS) in the E. coli. Using these strategies, 65.0 mg/L of quercetin 3-O-glucosyl (1→2) xyloside was produced. For the synthesis of rutin, one UGT (BcGT1) was integrated into the E. coli chromosome and the other UGT (Fg2) was expressed in a plasmid along with RHM2 (rhamnose synthase gene 2). After optimization of the initial cell concentration and incubation temperature, 119.8 mg/L of rutin was produced. The strategies used in this study thus show promise for the synthesis of flavonoid diglucosides in E. coli.
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Affiliation(s)
- Dae Gyun An
- grid.258676.8 0000000405328339 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center Konkuk University 05029 Seoul Korea
| | - So Mi Yang
- grid.258676.8 0000000405328339 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center Konkuk University 05029 Seoul Korea
| | - Bong Gyu Kim
- grid.440929.2 0000000417707889 Department of Forest Resources Gyeongnam National University of Science and Technology 33 Dongjin-ro, Jinju-si 660-758 Gyeongsangman-do Republic of Korea
| | - Joong-Hoon Ahn
- grid.258676.8 0000000405328339 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center Konkuk University 05029 Seoul Korea
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Sonkar V, Kulkarni PP, Chaurasia SN, Dash A, Jauhari A, Parmar D, Yadav S, Dash D. Plasma Fibrinogen Is a Natural Deterrent to Amyloid Beta-Induced Platelet Activation. Mol Med 2016; 22:224-232. [PMID: 27262026 DOI: 10.2119/molmed.2016.00003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 05/02/2016] [Indexed: 12/20/2022] Open
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by extensive loss of neurons, and deposition of amyloid beta (Aβ) in the form of extracellular plaques. Aβ is considered to have critical role in synaptic loss and neuronal death underlying cognitive decline. Platelets contribute to 95% of circulating amyloid-precursor protein that releases Aβ into circulation. We have recently demonstrated that, Aβ active fragment containing amino acid sequence 25-35 (Aβ25-35) is highly thrombogenic in nature, and elicits strong aggregation of washed human platelets in RhoA-dependent manner. In the present study we evaluated the influence of fibrinogen on Aβ-induced platelet activation. Intriguingly, Aβ failed to induce aggregation of platelets suspended in plasma but not in buffer. Fibrinogen brought about dose-dependent decline in aggregatory response of washed human platelets elicited by Aβ25-35, which could be reversed by increasing doses of Aβ. Fibrinogen also attenuated Aβ-induced platelet responses like secretion, clot retraction, rise in cytosolic Ca+2 and reactive oxygen species (ROS). Fibrinogen prevented intracellular accumulation of full length amyloid beta peptide (Aβ42) in platelets as well as neuronal cells. We conclude that fibrinogen serves as a physiological check against the adverse effects of Aβ by preventing its interaction with cells.
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Affiliation(s)
- Vijay Sonkar
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Paresh P Kulkarni
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Susheel N Chaurasia
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ayusman Dash
- Indian Institute of Science Education and Research, Kolkata, India
| | - Abhishek Jauhari
- Developmental Toxicology Division, Indian Institute of Toxicological Research, Lucknow, Uttar Pradesh, India
| | - Devendra Parmar
- Developmental Toxicology Division, Indian Institute of Toxicological Research, Lucknow, Uttar Pradesh, India
| | - Sanjay Yadav
- Developmental Toxicology Division, Indian Institute of Toxicological Research, Lucknow, Uttar Pradesh, India
| | - Debabrata Dash
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Orfali GDC, Duarte AC, Bonadio V, Martinez NP, de Araújo MEMB, Priviero FBM, Carvalho PO, Priolli DG. Review of anticancer mechanisms of isoquercitin. World J Clin Oncol 2016; 7:189-199. [PMID: 27081641 PMCID: PMC4826964 DOI: 10.5306/wjco.v7.i2.189] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/19/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
This review was based on a literature search of PubMed and Scielo databases using the keywords “quercetin, rutin, isoquercitrin, isoquercitin (IQ), quercetin-3-glucoside, bioavailability, flavonols and favonoids, and cancer” and combinations of all the words. We collected relevant scientific publications from 1990 to 2015 about the absorption, bioavailability, chemoprevention activity, and treatment effects as well as the underlying anticancer mechanisms of isoquercitin. Flavonoids are a group of polyphenolic compounds widely distributed throughout the plant kingdom. The subclass of flavonols receives special attention owing to their health benefits. The main components of this class are quercetin, rutin, and IQ, which is a flavonoid and although mostly found as a glycoside, is an aglycone (lacks a glycoside side chain). This compound presents similar therapeutic profiles to quercetin but with superior bioavailability, resulting in increased efficacy compared to the aglycone form. IQ has therapeutic applications owing to its wide range of pharmacological effects including antioxidant, antiproliferative, anti-inflammatory, anti-hypertensive, and anti-diabetic. The protective effects of IQ in cancer may be due to actions on lipid peroxidation. In addition, the antitumor effect of IQ and its underlying mechanism are related to interactions with Wnt signaling pathway, mixed-lineage protein kinase 3, mitogen-activated protein kinase, apoptotic pathways, as well proinflammatory protein signaling. This review contributed to clarifying the mechanisms of absorption, metabolism, and actions of IQ and isoquercitrin in cancer.
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McClintick JN, McBride WJ, Bell RL, Ding ZM, Liu Y, Xuei X, Edenberg HJ. Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats. Alcohol Clin Exp Res 2016; 40:955-68. [PMID: 27061086 DOI: 10.1111/acer.13056] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/28/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear, and anxiety. The periaqueductal gray (PAG) is involved in processing pain, fear, and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied. METHODS Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-hour sessions/d during the dark/cycle, 5 days/wk for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 to 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression. RESULTS Ethanol significantly altered the expression of 1,670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were found to be altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes, and 4 glycine receptor genes showed decreased expression in the alcohol-drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium, and 5 calcium ion channels were found to be differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate-limiting enzyme. Genes involved in the production of myelin also had decreased expression. CONCLUSIONS The results demonstrate that binge alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear, and anxiety, which could contribute to excessive drinking to relieve these negative effects.
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Affiliation(s)
- Jeanette N McClintick
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, Indiana
| | - William J McBride
- Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
| | - Richard L Bell
- Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng-Ming Ding
- Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
| | - Yunlong Liu
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Xiaoling Xuei
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Howard J Edenberg
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.,Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, Indiana.,Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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Nichols M, Zhang J, Polster BM, Elustondo PA, Thirumaran A, Pavlov EV, Robertson GS. Synergistic neuroprotection by epicatechin and quercetin: Activation of convergent mitochondrial signaling pathways. Neuroscience 2015; 308:75-94. [PMID: 26363153 DOI: 10.1016/j.neuroscience.2015.09.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 08/25/2015] [Accepted: 09/03/2015] [Indexed: 01/08/2023]
Abstract
In view of evidence that increased consumption of epicatechin (E) and quercetin (Q) may reduce the risk of stroke, we have measured the effects of combining E and Q on mitochondrial function and neuronal survival following oxygen-glucose deprivation (OGD). Relative to mouse cortical neuron cultures pretreated (24h) with either E or Q (0.1-10μM), E+Q synergistically attenuated OGD-induced neuronal cell death. E, Q and E+Q (0.3μM) increased spare respiratory capacity but only E+Q (0.3μM) preserved this crucial parameter of neuronal mitochondrial function after OGD. These improvements were accompanied by corresponding increases in cyclic AMP response element binding protein (CREB) phosphorylation and the expression of CREB-target genes that promote neuronal survival (Bcl-2) and mitochondrial biogenesis (PGC-1α). Consistent with these findings, E+Q (0.1 and 1.0μM) elevated mitochondrial gene expression (MT-ND2 and MT-ATP6) to a greater extent than E or Q after OGD. Q (0.3-3.0μM), but not E (3.0μM), elevated cytosolic calcium (Ca(2+)) spikes and the mitochondrial membrane potential. Conversely, E and E+Q (0.1 and 0.3μM), but not Q (0.1 and 0.3μM), activated protein kinase B (Akt). Nitric oxide synthase (NOS) inhibition with L-N(G)-nitroarginine methyl ester (1.0μM) blocked neuroprotection by E (0.3μM) or Q (1.0μM). Oral administration of E+Q (75mg/kg; once daily for 5days) reduced hypoxic-ischemic brain injury. These findings suggest E and Q activate Akt- and Ca(2+)-mediated signaling pathways that converge on NOS and CREB resulting in synergistic improvements in neuronal mitochondrial performance which confer profound protection against ischemic injury.
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Affiliation(s)
- M Nichols
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Brain Repair Centre, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, 1348 Summer Street, P.O. Box 15000, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - J Zhang
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Brain Repair Centre, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, 1348 Summer Street, P.O. Box 15000, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - B M Polster
- Department of Anesthesiology, Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - P A Elustondo
- Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - A Thirumaran
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Brain Repair Centre, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, 1348 Summer Street, P.O. Box 15000, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - E V Pavlov
- Department of Basic Sciences, College of Dentistry, New York University, 345 East 24th Street, New York, NY 10010, USA.
| | - G S Robertson
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; Department of Psychiatry, 5909 Veterans' Memorial Lane, 8th Floor Abbie J. Lane Memorial Building, QEII Health Sciences Centre, Halifax, Nova Scotia B3H 2E2, Canada.
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Seo YA, Wessling-Resnick M. Ferroportin deficiency impairs manganese metabolism in flatiron mice. FASEB J 2015; 29:2726-33. [PMID: 25782988 DOI: 10.1096/fj.14-262592] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 02/27/2015] [Indexed: 02/07/2023]
Abstract
We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P = 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P = 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P = 0.0204) were reduced in ffe/+ mice compared to +/+ controls. Erythrocyte Mn-superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P = 0.0101), 9 (0.131 vs. 0.089, P = 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P < 0.0001). (54)Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P = 0.0243), while clearance of injected isotope was similar in ffe/+ and +/+ mice. These values were compared to intestinal absorption of (59)Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P = 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis. -
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Affiliation(s)
- Young Ah Seo
- Departments of Genetics and Complex Diseases and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Marianne Wessling-Resnick
- Departments of Genetics and Complex Diseases and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
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Kim BG, Yang SM, Kim SY, Cha MN, Ahn JH. Biosynthesis and production of glycosylated flavonoids in Escherichia coli: current state and perspectives. Appl Microbiol Biotechnol 2015; 99:2979-88. [PMID: 25750049 DOI: 10.1007/s00253-015-6504-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 02/19/2015] [Accepted: 02/22/2015] [Indexed: 11/29/2022]
Abstract
Flavonoids are plant secondary metabolites containing several hydroxyl groups that are targets for modification reactions such as methylation and glycosylation. In plants, flavonoids are present as glycones. Although glucose is the most common sugar attached to flavonoids, arabinose, galactose, glucuronic acid, rhamnose, and xylose are also linked to flavonoids. Depending on the kind and the position of the attached sugar, flavonoid glycones show different biological properties. Flavonoid-O-glycosides are synthesized by uridine diphosphate-dependent glycosyltransferases (UGTs), which use nucleotide sugar as a sugar donor and a diverse compound as a sugar acceptor. Recently, diverse flavonoid-O-glycosides have been synthesized in Escherichia coli by introducing UGTs from plants and bacteria and modifying endogenous pathways. The nucleotide sugar biosynthesis pathway in E. coli has been engineered to provide the proper nucleotide sugar for flavonoid-O-glycoside biosynthesis. In this review, we will discuss recent advances in flavonoid-O-glycoside biosynthesis using engineered E. coli.
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Affiliation(s)
- Bong Gyu Kim
- Department of Forest Resources, Gyeongnam National University of Science and Technology, 33 Dongjin-ro, Jinju-si, Gyeongsangman-do, 660-758, Republic of Korea
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Isoquercitrin: Pharmacology, toxicology, and metabolism. Food Chem Toxicol 2014; 68:267-82. [DOI: 10.1016/j.fct.2014.03.018] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/11/2014] [Accepted: 03/14/2014] [Indexed: 01/10/2023]
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Warford J, Jones QR, Nichols M, Sullivan V, Rupasinghe HV, Robertson GS. The flavonoid-enriched fraction AF4 suppresses neuroinflammation and promotes restorative gene expression in a mouse model of experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 268:71-83. [DOI: 10.1016/j.jneuroim.2014.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/10/2014] [Accepted: 01/14/2014] [Indexed: 11/16/2022]
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29
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Chiou YS, Wu JC, Huang Q, Shahidi F, Wang YJ, Ho CT, Pan MH. Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary polyphenols. J Funct Foods 2014. [DOI: 10.1016/j.jff.2013.08.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Isoquercetin protects cortical neurons from oxygen-glucose deprivation-reperfusion induced injury via suppression of TLR4-NF-кB signal pathway. Neurochem Int 2013; 63:741-9. [PMID: 24099731 DOI: 10.1016/j.neuint.2013.09.018] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Revised: 09/10/2013] [Accepted: 09/22/2013] [Indexed: 12/29/2022]
Abstract
In the present study, oxygen-glucose deprivation followed by reperfusion (OGD/R), an in vitro model of ischemia, was used to evaluate the neuroprotective effect of isoquercetin in primary culture of rat cortical neuronal cells. It was found that isoquercetin administered prior to the insult could prevent OGD/R-induced intracellular calcium concentrations ([Ca(2+)]i) increase, lactate dehydrogenase (LDH) release and cell viability decrease. For the first time, isoquercetin is described as a neuroprotective agent that potentially explains the alleviation and prevention from OGD/R-induced injury in neurons. Mechanistic studies showed that the neuroprotective effect of isoquercetin was carried out by anti-inflammatory signaling pathway of inhibiting protein expression of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB), and mRNA expression of TNF-α and IL-6, accompanied by the anti-apoptotic signaling pathway of deactivation of extracellular-regulated kinase (ERK), Jun kinase (JNK) and p38, and inhibition of activity of caspase-3. Therefore, these studies highlighted the confirmation of isoquercetin, a flavonoid compound, as an anti-inflammation and anti-apoptosis factor which might be used as a therapeutic strategy for the ischemia/reperfusion (I/R) brain injury and related diseases.
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31
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Kim HS, Kim BG, Sung S, Kim M, Mok H, Chong Y, Ahn JH. Engineering flavonoid glycosyltransferases for enhanced catalytic efficiency and extended sugar-donor selectivity. PLANTA 2013; 238:683-93. [PMID: 23801300 DOI: 10.1007/s00425-013-1922-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 06/14/2013] [Indexed: 05/15/2023]
Abstract
Flavonoids are predominantly found as glycosides in plants. The glycosylation of flavonoids is mediated by uridine diphosphate-dependent glycosyltransferases (UGT). UGTs attach various sugars, including arabinose, glucose, galactose, xylose, and glucuronic acid, to flavonoid aglycones. Two UGTs isolated from Arabidopsis thaliana, AtUGT78D2 and AtUGT78D3, showed 89 % amino acid sequence similarity (75 % amino acid sequence identity) and both attached a sugar to the 3-hydroxyl group of flavonols using a UDP-sugar. The two enzymes used UDP-glucose and UDP-arabinose, respectively, and AtUGT78D2 was approximately 90-fold more efficient than AtUGT78D3 when judged by the k(cat)/K(m) value. Domain exchanges between AtUGT78D2 and AtUGT78D3 were carried out to find UGTs with better catalytic efficiency for UDP-arabinose and exhibiting dual sugar selectivity. Among 19 fusion proteins examined, three showed dual sugar selectivity, and one fusion protein had better catalytic efficiency for UDP-arabinose compared with AtUGT78D3. Using molecular modeling, the changes in enzymatic properties in the chimeric proteins were elucidated. To the best of our knowledge, this is the first report on the construction of fusion proteins with expanded sugar-donor range and enhanced catalytic efficiencies for sugar donors.
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Affiliation(s)
- Hye Soo Kim
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Korea
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Low level of hydrogen peroxide induces lipid synthesis in BRL-3A cells through a CAP-independent SREBP-1a activation. Int J Biochem Cell Biol 2013; 45:1419-26. [DOI: 10.1016/j.biocel.2013.04.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 03/26/2013] [Accepted: 04/03/2013] [Indexed: 01/18/2023]
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Lombardi G, Prosperini A, Font G, Ruiz MJ. Effect of polyphenols on enniatins-induced cytotoxic effects in mammalian cells. Toxicol Mech Methods 2013; 22:687-95. [PMID: 22888764 DOI: 10.3109/15376516.2012.717120] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Enniatins (ENs) are fungal secondary metabolites produced by genus Fusarium. The ENs exert antimicrobial and insecticidal effect, and has also been demonstrated cytotoxic effects on several mammalian cell lines. On the other hands, it has been proved that natural polyphenols have antioxidant effect. In this study, cell effects at low levels of exposure of four ENs (A, A(1), B and B(1)) and five polyphenols (quercetin, quercetin-3-β-D-glucoside, rutin, myricetin and t-pterostilbene) present in wine; and the cytoprotective effect of these polyphenols exposed simultaneously with ENs in Chinese Hamster Ovary (CHO-K1) cells, were studied. Cell effects were determined by the MTT test after 24 h of exposure. All ENs showed cytotoxic effect. The IC(50) obtained ranged from 4.5 ± 1.2 to 11.0 ± 2.7 µM. The concentration of polyphenols tested ranged from 5 to 50 µM. Polyphenols did not show cytotoxicity and the cytoprotective effect of polyphenols varies depending on the EN tested. The cytoprotective effect of polyphenols in CHO-K1 cells exposed to ENs was as follow: quercetin, from 24 to 84%; quercetin-3-β-D-glucoside, from 12 to 76%; rutin, from 17 to 83%; myricetin, from 16 to 92% and pterostilbene from 25 to 100%. All polyphenols protected CHO-K1 cells against EN A(1) exposure.
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Affiliation(s)
- G Lombardi
- Dipartmento di Scienze Economico-Estimative e degli Alimenti, Sezione di Chimica Bromatologica, Biochimica, Fisiologia e Nutrizione, Facoltà di Farmacia, Università degli Studi di Perugia, Perugia, Italy
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Mizohata E, Okuda T, Hatanaka S, Nakayama T, Horikawa M, Nakayama T, Ono E, Inoue T. Crystallization and preliminary X-ray crystallographic analysis of UDP-glucuronic acid:flavonol-3-O-glucuronosyltransferase (VvGT5) from the grapevine Vitis vinifera. Acta Crystallogr Sect F Struct Biol Cryst Commun 2013; 69:65-8. [PMID: 23295490 PMCID: PMC3539707 DOI: 10.1107/s1744309112045095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 10/31/2012] [Indexed: 11/10/2022]
Abstract
Grapevine (Vitis vinifera) glycosyltransferase 5 (VvGT5) is a UDP-glucuronic acid:flavonol-3-O-glucuronosyltransferase that catalyses the 3-O-specific glucuronosylation of flavonols using UDP-glucuronic acid as a sugar donor to produce flavonol 3-O-glucosides, which are important bioactive phytochemicals. Recombinant VvGT5 expressed in Escherichia coli cells was purified and crystallized by the sitting-drop vapour-diffusion method. A full set of X-ray diffraction data was collected to 2.2 Å Bragg spacing from a single crystal using a synchrotron-radiation source. The crystal was hexagonal, belonging to space group P6(1)22, with unit-cell parameters a = b = 102.70, c = 535.92 Å. The initial phases were determined by the molecular-replacement method.
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Affiliation(s)
- Eiichi Mizohata
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takuma Okuda
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Seika Hatanaka
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Taisuke Nakayama
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Manabu Horikawa
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Shimamoto, Mishima, Osaka 618-8503, Japan
| | - Toru Nakayama
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Eiichiro Ono
- Institute for Plant Science, Suntory Business Expert Ltd, Shimamoto, Mishima, Osaka 618-8503, Japan
| | - Tsuyoshi Inoue
- Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
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Palazzolo G, Horvath P, Zenobi-Wong M. The flavonoid isoquercitrin promotes neurite elongation by reducing RhoA activity. PLoS One 2012; 7:e49979. [PMID: 23209630 PMCID: PMC3510166 DOI: 10.1371/journal.pone.0049979] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 10/18/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Neurite formation and synaptic patterning are fundamental to the development of a functional nervous system. Flavonoids are natural molecules known for having beneficial effects on brain health through diverse molecular pathways. Cytoskeletal changes occurring during neuritogenesis and synapse formation often involve Rho GTPases. Here we hypothesized that the flavonoid isoquercitrin promotes neuronal differentiation through Rho signalling. METHODOLOGY/PRINCIPAL FINDINGS We performed time lapse imaging of NG108-15 cells during incubation with/without isoquercitrin. Isoquercitrin stimulated extensive neurites enriched in the synaptic vesicle protein synaptotagmin-1. Neurite extension was augmented by the ROCK inhibitor Y-27632 suggesting an inactivation of RhoA/Rho kinase as the mechanism. To test this, we first measured the dose-dependent effect of isoquercitrin on RhoA activity and found a 47% reduction in RhoA activity at concentrations which induced neurites (≥40 µM). Secondly, we tested the ability of isoquercitrin to rescue the neural phenotype in a model of RhoA-induced neurite retraction and found that 40 µM isoquercitrin added to cultures previously treated with the RhoA activator calpeptin produced significantly more neurite length/cell than calpeptin alone. Finally, we tested the hypothesis that isoquercitrin may affect RhoA localization preventing the translocation to the plasma membrane. Unexpectedly, immunolocalization studies showed that RhoA was present in nuclear compartments of control NG108-cells, but underwent translocation to the cytoplasm upon treatment with isoquercitrin. DNA microarrays and reverse transcription - quantitative PCR (RT-qPCR) revealed differences in global gene expression of Rho GTPase family members. These data taken together indicate that isoquercitrin is a potential stimulator of neuronal differentiation, through multiple Rho GTPase mediated mechanisms. CONCLUSIONS/SIGNIFICANCE As several members of the Rho GTPase family are implicated in human neurological disorders/injuries, our results suggest that isoquercitrin could be used in the treatment of these pathological states through its effect on this family of molecular switches.
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Affiliation(s)
- Gemma Palazzolo
- Cartilage Engineering+Regeneration Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Peter Horvath
- Light Microscopy and Screening Centre, ETH Zurich, Zurich, Switzerland
| | - Marcy Zenobi-Wong
- Cartilage Engineering+Regeneration Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
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Quercetin protects neuroblastoma SH-SY5Y cells against oxidative stress by inhibiting expression of Krüppel-like factor 4. Neurosci Lett 2012; 527:115-20. [DOI: 10.1016/j.neulet.2012.08.082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Revised: 07/10/2012] [Accepted: 08/09/2012] [Indexed: 01/12/2023]
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Production of a novel quercetin glycoside through metabolic engineering of Escherichia coli. Appl Environ Microbiol 2012; 78:4256-62. [PMID: 22492444 DOI: 10.1128/aem.00275-12] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Most flavonoids exist as sugar conjugates. Naturally occurring flavonoid sugar conjugates include glucose, galactose, glucuronide, rhamnose, xylose, and arabinose. These flavonoid glycosides have diverse physiological activities, depending on the type of sugar attached. To synthesize an unnatural flavonoid glycoside, Actinobacillus actinomycetemcomitans gene tll (encoding dTDP-6-deoxy-L-lyxo-4-hexulose reductase, which converts the endogenous nucleotide sugar dTDP-4-dehydro-6-deoxy-L-mannose to dTDP-6-deoxytalose) was introduced into Escherichia coli. In addition, nucleotide-sugar dependent glycosyltransferases (UGTs) were screened to find a UGT that could use dTDP-6-deoxytalose. Supplementation of this engineered strain of E. coli with quercetin resulted in the production of quercetin-3-O-(6-deoxytalose). To increase the production of quercetin 3-O-(6-deoxytalose) by increasing the supplement of dTDP-6-deoxytalose in E. coli, we engineered nucleotide biosynthetic genes of E. coli, such as galU (UTP-glucose 1-phosphate uridyltransferase), rffA (dTDP-4-oxo-6-deoxy-d-glucose transaminase), and/or rfbD (dTDP-4-dehydrorahmnose reductase). The engineered E. coli strain produced approximately 98 mg of quercetin 3-O-(6-deoxytalose)/liter, which is 7-fold more than that produced by the wild-type strain, and the by-products, quercetin 3-O-glucose and quercetin 3-O-rhamnose, were also significantly reduced.
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Hatic H, Kane MJ, Saykally JN, Citron BA. Modulation of transcription factor Nrf2 in an in vitro model of traumatic brain injury. J Neurotrauma 2012; 29:1188-96. [PMID: 22201269 DOI: 10.1089/neu.2011.1806] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Traumatic brain injury (TBI) afflicts approximately 1.4 million people in the United States and TBIs have been labeled a major cause of death and disability on a global scale. Regulatory responses in a variety of neuronal loss conditions have supported the protective involvement of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor. Nrf2 regulates antioxidant enzyme genes, and an increase in Nrf2 expression may counteract oxidative damage that results from TBI. Elevated Nrf2 may ultimately act through the upregulation of downstream target genes such as thioredoxin (Trx) and heat-shock protein-70 (HSP70) and this may reduce neuronal loss. We performed multiple mild biaxial stretch injuries to neuroblastoma cells in culture, and examined the effects of the Nrf2 activator, tert-butylhydroquinone (tBHQ). We also compared the stretch injury to oxidative insult. We confirmed that Trx and HSP70 were upregulated by treatment with tBHQ. We observed that tBHQ protected neurons from either insult, and that this was evident by different measures of cell viability and a decrease in annexin V binding. Neuronal health after insult was improved approximately 50% by tBHQ, indicating that neurons exposed to TBI in vitro can be protected.
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Affiliation(s)
- Haris Hatic
- Laboratory of Molecular Biology, Research and Development 151, Bay Pines VA Healthcare System, Bay Pines, Florida 33744-4125, USA
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Ultra-sonication-assisted solvent extraction of quercetin glycosides from 'Idared' apple peels. Molecules 2011; 16:9783-91. [PMID: 22117169 PMCID: PMC6264348 DOI: 10.3390/molecules16129783] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 11/22/2011] [Accepted: 11/22/2011] [Indexed: 11/18/2022] Open
Abstract
Quercetin and quercetin glycosides are physiologically active flavonol molecules that have been attributed numerous health benefits. Recovery of such molecules from plant matrices depends on a variety of factors including polarity of the extraction solvent. Among the solvents of a wide range of dielectric constants, methanol recovered the most quercetin and its glycosides from dehydrated ‘Idared’ apple peels. When ultrasonication was employed to facilitate the extraction, exposure of 15 min of ultrasound wavelengths of dehydrated apple peel powder in 80% to 100% (v/v) methanol in 1:50 (w:v) solid to solvent ratio provided the optimum extraction conditions for quercetin and its glycosides. Acidification of extraction solvent with 0.1% (v/v) or higher concentrations of HCl led to hydrolysis of naturally occurring quercetin glycosides into the aglycone as an extraction artifact.
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Papandreou MA, Tsachaki M, Efthimiopoulos S, Klimis-Zacas D, Margarity M, Lamari FN. Cell-Line Specific Protection by Berry Polyphenols Against Hydrogen Peroxide Challenge and Lack of Effect on Metabolism of Amyloid Precursor Protein. Phytother Res 2011; 26:956-63. [DOI: 10.1002/ptr.3670] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 09/01/2011] [Accepted: 09/02/2011] [Indexed: 01/01/2023]
Affiliation(s)
- Magdalini A. Papandreou
- Laboratory of Human and Animal Physiology, Department of Biology; University of Patras; Greece
| | - Maria Tsachaki
- Division of Animal and Human Physiology, Department of Biology; University of Athens; Greece
| | - Spiros Efthimiopoulos
- Division of Animal and Human Physiology, Department of Biology; University of Athens; Greece
| | - Dorothy Klimis-Zacas
- Department of Food Science and Human Nutrition; University of Maine; Orono ME 04469 USA
| | - Marigoula Margarity
- Laboratory of Human and Animal Physiology, Department of Biology; University of Patras; Greece
| | - Fotini N. Lamari
- Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy; University of Patras; Greece
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Suematsu N, Hosoda M, Fujimori K. Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. Neurosci Lett 2011; 504:223-7. [PMID: 21964380 DOI: 10.1016/j.neulet.2011.09.028] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 09/14/2011] [Accepted: 09/15/2011] [Indexed: 12/29/2022]
Abstract
Hydrogen peroxide (H(2)O(2)) is a major reactive oxygen species that has been implicated in various neurodegenerative diseases. Quercetin, one of the plant flavonoids, has been reported to harbor various physiological properties including antioxidant activity. In this study, we investigated the neuroprotective effects of quercetin against H(2)O(2)-induced apoptosis in human neuronal SH-SY5Y cells. H(2)O(2)-mediated cytotoxicity and lactate dehydrogenase release were suppressed in a quercetin concentration-dependent manner. In addition, quercetin repressed the expression of the pro-apoptotic Bax gene and enhanced that of the anti-apoptotic Bcl-2 gene in SH-SY5Y cells. Moreover, quercetin effectively inhibited the activation of the caspase cascade that leads to DNA fragmentation, a key feature of apoptosis, and subsequent cell death. These results indicate the importance of quercetin in protecting against H(2)O(2)-mediated neuronal cell death. Thus, quercetin might potentially serve as an agent for prevention of neurodegenerative diseases caused by oxidative stress and apoptosis.
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Affiliation(s)
- Namiko Suematsu
- Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
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Ono E, Homma Y, Horikawa M, Kunikane-Doi S, Imai H, Takahashi S, Kawai Y, Ishiguro M, Fukui Y, Nakayama T. Functional differentiation of the glycosyltransferases that contribute to the chemical diversity of bioactive flavonol glycosides in grapevines (Vitis vinifera). THE PLANT CELL 2010; 22:2856-71. [PMID: 20693356 PMCID: PMC2947185 DOI: 10.1105/tpc.110.074625] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
We identified two glycosyltransferases that contribute to the structural diversification of flavonol glycosides in grapevine (Vitis vinifera): glycosyltransferase 5 (Vv GT5) and Vv GT6. Biochemical analyses showed that Vv GT5 is a UDP-glucuronic acid:flavonol-3-O-glucuronosyltransferase (GAT), and Vv GT6 is a bifunctional UDP-glucose/UDP-galactose:flavonol-3-O-glucosyltransferase/galactosyltransferase. The Vv GT5 and Vv GT6 genes have very high sequence similarity (91%) and are located in tandem on chromosome 11, suggesting that one of these genes arose from the other by gene duplication. Both of these enzymes were expressed in accordance with flavonol synthase gene expression and flavonoid distribution patterns in this plant, corroborating their significance in flavonol glycoside biosynthesis. The determinant of the specificity of Vv GT5 for UDP-glucuronic acid was found to be Arg-140, which corresponded to none of the determinants previously identified for other plant GATs in primary structures, providing another example of convergent evolution of plant GAT. We also analyzed the determinants of the sugar donor specificity of Vv GT6. Gln-373 and Pro-19 were found to play important roles in the bifunctional specificity of the enzyme. The results presented here suggest that the sugar donor specificities of these Vv GTs could be determined by a limited number of amino acid substitutions in the primary structures of protein duplicates, illustrating the plasticity of plant glycosyltransferases in acquiring new sugar donor specificities.
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Affiliation(s)
- Eiichiro Ono
- Core Research Group, R&D Planning Division, Suntory Holdings Ltd., Shimamoto, Mishima, Osaka 618-8503, Japan
| | - Yu Homma
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Manabu Horikawa
- Suntory Institute for Bioorganic Research, Shimamoto, Mishima, Osaka 618-8503, Japan
| | - Satoshi Kunikane-Doi
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Haruna Imai
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Seiji Takahashi
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Yosuke Kawai
- College of Life Sciences, Institute of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
| | - Masaji Ishiguro
- Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Akiha, Niigata 956-8603, Japan
| | - Yuko Fukui
- Institute for Health Care Science, Suntory Wellness Ltd., Shimamoto, Mishima, Osaka 618-8503, Japan
| | - Toru Nakayama
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
- Address correspondence to
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Rupasinghe HPV, Ronalds CM, Rathgeber B, Robinson RA. Absorption and tissue distribution of dietary quercetin and quercetin glycosides of apple skin in broiler chickens. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2010; 90:1172-1178. [PMID: 20393998 DOI: 10.1002/jsfa.3944] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
BACKGROUND Apple skins are a rich source of flavonols, in particular quercetin (Q) glycosides. The objective of the present study was to investigate the presence of Q metabolites in plasma, various tissues, and excreta when the commercial broiler chicken's diet was supplemented with Q (0, 50, 150, 300, or 600 mg kg(-1) body weight per day), an apple skin extract (ASE; 50, 150 mg total phenolics kg(-1) body weight per day), or a dried apple skin powder (ASP; 50 mg total phenolics kg(-1) body weight per day). RESULTS When Q was supplemented for 3 days, Q sulfate, Q glucuronide, Q glucoside glucuronide, Q glucoside sulfate, and isorhamnetin glucoside were detected by liquid chromatography-tandem mass spectrometry in the liver and duodenum. Deconjugated Q was also detected in the breast and thigh tissues of ASE- and ASP-supplemented broilers. Regardless of the source or concentration of Q, the antioxidant capacity measured by ferric reducing ability of plasma (FRAP) assay in the plasma and tissues of the broilers did not change significantly. CONCLUSIONS As far as is known, this is the first report to demonstrate that Q and its glycosides can be absorbed and metabolized by broiler chickens.
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Quercetin supplementation and its effect on human monocyte gene expression profiles in vivo. Br J Nutr 2010; 104:336-45. [DOI: 10.1017/s0007114510000711] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Quercetin has been described as having a wide range of beneficial effects in humans, ranging from anti-carcinogenic properties to reducing the risk of CVD. Nevertheless, underlying molecular mechanisms have been mostly investigated in vitro. Here, we tested whether a daily supplementation of quercetin leads to reproducible changes in human monocyte gene expression profiles. In study I, quercetin in varying dosages was given to healthy subjects for 2 weeks. RNA from monocytes isolated at the beginning and end of the study from subjects receiving 150 mg quercetin per d was subjected to transcriptome-wide microarray analysis. In study II, a double-blind cross-over study, twenty subjects exhibiting a ‘cardiovascular risk phenotype’ received 150 mg quercetin or placebo daily for 6 weeks each and served as the verification group. Microarray analysis revealed a number of differentially expressed genes. The most significantly represented functional groups were those of the immune system, nucleic acid metabolism, apoptosis and O-glycan biosynthesis. Twenty-four genes were chosen for technical replication and independent verification by quantitative real-time PCR. When comparing placebo and quercetin treatment, four genes showed significantly different expression changes (C1GALT1, O-glycan biosynthesis; GM2A, glycolipid catabolism; HDGF, cell proliferation; SERPINB9, apoptosis). However, these were minimal in respect to magnitude of fold change. In conclusion, although microarray analysis revealed extensive effects of quercetin on gene expression, the employment of a placebo-controlled study design showed no comparable results for twenty-four verification targets. This emphasises the need for stringent designs in nutritional intervention studies with the aim to identify relevant changes in gene expression.
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Albini A, Indraccolo S, Noonan DM, Pfeffer U. Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs. Clin Exp Metastasis 2010; 27:419-39. [PMID: 20383568 DOI: 10.1007/s10585-010-9312-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Accepted: 02/16/2010] [Indexed: 01/28/2023]
Abstract
Angiogenesis is a highly regulated physiological process that has been studied in considerable detail given its importance in several chronic pathologies. Many endogenous factors and hormones intervene in the regulation of angiogensis and classical as well as targeted drugs have been developed for its control. Angiogenesis inhibition has come off the bench and entered into clinical application for cancer therapy, particularly for metastatic disease. While the clinical benefit is currently in terms of months, preclinical data suggest that novel drugs and drug combinations could lead to substantial improvement. The many targets of endogenous angiogenesis inhibitors reflect the complexity of the process; in contrast, current clinical therapies mainly target the vascular endothelial growth factor system. Cancer chemopreventive compounds can retard tumor insurgence and delay or prevent metastasis and many of these molecules hinder angiogenesis, a mechanism that we termed angioprevention. Angiopreventive drugs appear to prevalently act through the inhibition of the pro-inflammatory and anti-apoptotic player NFkappaB, thus contrasting inflammation dependent angiogenesis. Relatively little is known concerning the effects of these angiogenesis inhibitors on gene expression of endothelial cells, the main target of many of these molecules. Here we provide an exhaustive list of anti-angiogenic molecules, and summarize their effects, where known, on the transcriptome and functional genomics of endothelial cells. The regulation of specific genes can be crucial to preventive or therapeutic intervention. Further, novel targets might help to circumvent resistance to anti-angiogenic therapy. The studies we review are relevant not only to cancer but also to other chronic degenerative diseases involving endothelial cells, such as cardiovascular disorders, diabetes, rheumatoid arthritis and retinopaties, as well as vessel aging.
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Affiliation(s)
- Adriana Albini
- MultiMedica Castellanza (VA) and Oncology Research, IRCCS MultiMedica, 20138 Milan, Italy.
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Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN. Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease. J Neurochem 2010; 111:1275-308. [PMID: 20050287 DOI: 10.1111/j.1471-4159.2009.06408.x] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.
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Affiliation(s)
- Ian J Martins
- Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Australia.
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Ossola B, Kääriäinen TM, Männistö PT. The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 2009; 8:397-409. [PMID: 19538101 DOI: 10.1517/14740330903026944] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This review discusses the most recent data on the potential of quercetin to confer neuroprotection. Unfortunately, most of the in vitro studies have used quercetin aglycone, which is not detectable in the plasma or in the brain after oral intake. Moreover, quercetin metabolites and glycosides seem to be less neuroprotective and penetrate the BBB less efficiently than aglycone. Surprisingly, quercetin has beneficial effects on various in vivo models of neural disorders, particularly in cerebrovascular insults; contrasting data also do exist. This may be due to an increase of BBB permeability, described in many of these animal models, which would facilitate quercetin brain penetration. Although quercetin causes no significant toxicity in several animal studies, the risk for neurotoxicity is not negligible because of its narrow therapeutic dose-range in vitro. Notably, this risk may be even higher in the case of increased quercetin access to the brain, which may occur pathologically or artificially (e.g., by liposomal preparations). Based on the referred literature, we doubt that quercetin possesses any significant efficacy in neurodegenerative disorders. Instead, therapeutic trials should focus more on the quercetin efficacy in cerebrovascular insults rather than neurodegeneration.
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Affiliation(s)
- Bernardino Ossola
- University of Helsinki, Division of Pharmacology & Toxicology PO Box 56, (Viikinkaari 5E), Helsinki FIN-00014, Finland
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Abstract
PURPOSE OF REVIEW Quercetin is discussed since several decades as a multipotent bioflavonoid with great potential for the prevention and treatment of disease. In the current review, we present the most recent findings on quercetin with regard to the pharmacology, the in-vitro and in-vivo effects in different cell systems and animal models, and the clinical effects in humans. RECENT FINDINGS Quercetin bioavailability has been underestimated in the past and can be improved by food matrix components or particular delivery forms. Among the biological effects of particular relevance, the antihypertensive effects of quercetin in humans and the improvement of endothelial function should be emphasized. Together with its antithrombotic and anti-inflammatory effects, the latter mainly mediated through the inhibition of cytokines and nitric oxide, quercetin is a candidate for preventing obesity-related diseases. Most exiting are the findings that quercetin enhances physical power by yet unclear mechanisms. The anti-infectious and immunomodulatory activities of quercetin might be related to this effect. SUMMARY Quercetin is a most promising compound for disease prevention and therapy; however, many of the effects still need confirmation by human intervention trials.
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Affiliation(s)
- Stephan C Bischoff
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
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