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Tipcome K, Watanapa WB, Ruamyod K. Hesperetin Relaxes Depolarizing Contraction in Human Umbilical Vein by Inhibiting L-Type Ca 2+ Channel. Chin J Integr Med 2025; 31:412-421. [PMID: 38236522 DOI: 10.1007/s11655-024-3713-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2023] [Indexed: 01/19/2024]
Abstract
OBJECTIVE To study hesperetin-induced vasorelaxation after depolarizing contraction in human umbilical veins (HUVs) to elucidate the role of L-type Ca2+ channel (LTCC) and related signaling pathway. METHODS Isometric tension recording was performed in HUV rings pre-contracted with K+. Hesperetin relaxing mechanism was investigated using a LTCC opener (BayK8644) and blockers of cyclic nucleotides and phosphodiesterases (PDEs). Whole-cell patch-clamping in A7r5 cells, a rat vascular smooth muscle cell line, was performed to study the effect of hesperetin on LTCC current. RESULTS After depolarizing precontraction, hesperetin induced HUV relaxation concentration-dependently and endothelium-independently; 1 mmol/L hesperetin reduced denuded HUV ring tension by 68.7% ± 4.3% compared to matching vehicle, osmolality, and time controls (P<0.0001). Importantly, hesperetin competitively inhibited BayK8644-induced contraction, shifting the half maximal effective concentration of BayK8644 response from 1.08 nmol/L [95% confidence interval (CI) 0.49-2.40] in vehicle control to 11.30 nmol/L (95% CI 5.45-23.41) in hesperetin (P=0.0001). Moreover, hesperetin elicited further vasorelaxation in denuded HUV rings pretreated with inhibitors of soluble guanylyl cyclase, adenylyl cyclase, PDE3, PDE4, and PDE5 (P<0.01), while rings pretreated with PDE1 inhibitors could not be relaxed by hesperetin (P>0.05). However, simultaneously applying inhibitors of soluble guanylyl cyclase and adenylyl cyclase could not inhibit hesperetin's effect (P>0.05). In whole-cell patch-clamping, hesperetin rapidly decreased LTCC current in A7r5 cells to 66.7% ± 5.8% (P=0.0104). CONCLUSIONS Hesperetin diminishes depolarizing contraction of human vascular smooth muscle through inhibition of LTCC, and not cyclic nucleotides nor PDEs. Our evidence supports direct LTCC interaction and provides additional basis for the use of hesperetin and its precursor hesperidin as vasodilators and may lead to future vasodilator drug development as a treatment alternative for cardiovascular diseases.
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Affiliation(s)
- Kritsana Tipcome
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wattana B Watanapa
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Katesirin Ruamyod
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Heidari Z, Farahmandpour F, Bazyar H, Pashayee-Khamene F. Effects of Hesperidin Supplementation on Cardiometabolic Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Nutr Rev 2025; 83:e1014-e1033. [PMID: 39038797 DOI: 10.1093/nutrit/nuae084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024] Open
Abstract
CONTEXT Hesperidin is a naturally occurring bioactive compound that may influence cardiometabolic markers, but the existing evidence is inconclusive. OBJECTIVE This study aims to further investigate the effects of hesperidin supplementation on cardiometabolic markers in adults. DATA SOURCES A comprehensive search was conducted up to August 2023, utilizing relevant key words in databases such as PubMed, Scopus, Embase, and the Cochrane Central Register of Controlled Trials, focusing on randomized controlled trials (RCTs). DATA EXTRACTION RCTs that examined the impact of hesperidin on fasting blood sugar (FBS), insulin, quantitative insulin-sensitivity check index (QUICKI), homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic blood pressure (SBP), diastolic blood pressure (DBP), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) were selected independently by 2 authors. The GRADE assessment was used to ascertain the certainty of the evidence. Results were pooled using a random-effects model as weighted mean differences and 95% CIs. DATA ANALYSIS The results of this study demonstrate that hesperidin supplementation had a significant impact on reducing FBS, TG, TC, LDL-C, SBP, and TNF-α. However, there was no significant effect observed on insulin, HOMA-IR, QUICKI, HDL-C, DBP, and hs-CRP. The study's subgroup analyses also revealed that interventions lasting more than 12 weeks were effective in reducing FBS, TG, TC, and LDL-C. Moreover, hesperidin dosage exceeding 500 mg/day showed significance in reducing FBS, TC, and LDL-C levels. CONCLUSION In conclusion, this research suggests that hesperidin can be consumed as an effective dietary approach to enhance cardiometabolic markers. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42022325775.
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Affiliation(s)
- Zeinab Heidari
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 6135715794, Iran
| | - Fatemeh Farahmandpour
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 6135715794, Iran
| | - Hadi Bazyar
- Department of Public Health, Sirjan School of Medical Sciences, Sirjan, 7816916338, Iran
- Student Research Committee, Sirjan School of Medical Sciences, Sirjan, 7816916338, Iran
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Beaver LM, Jamieson PE, Wong CP, Hosseinikia M, Stevens JF, Ho E. Promotion of Healthy Aging Through the Nexus of Gut Microbiota and Dietary Phytochemicals. Adv Nutr 2025; 16:100376. [PMID: 39832641 PMCID: PMC11847308 DOI: 10.1016/j.advnut.2025.100376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 01/22/2025] Open
Abstract
Aging is associated with the decline of tissue and cellular functions, which can promote the development of age-related diseases like cancer, cardiovascular disease, neurodegeneration, and disorders of the musculoskeletal and immune systems. Healthspan is the length of time an individual is in good health and free from chronic diseases and disabilities associated with aging. Two modifiable factors that can influence healthspan, promote healthy aging, and prevent the development of age-related diseases, are diet and microbiota in the gastrointestinal tract (gut microbiota). This review will discuss how dietary phytochemicals and gut microbiota can work in concert to promote a healthy gut and healthy aging. First, an overview is provided of how the gut microbiota influences healthy aging through its impact on gut barrier integrity, immune function, mitochondria function, and oxidative stress. Next, the mechanisms by which phytochemicals effect gut health, inflammation, and nurture a diverse and healthy microbial composition are discussed. Lastly, we discuss how the gut microbiota can directly influence health by producing bioactive metabolites from phytochemicals in food like urolithin A, equol, hesperetin, and sulforaphane. These and other phytochemical-derived microbial metabolites that may promote healthspan are discussed. Importantly, an individual's capacity to produce health-promoting microbial metabolites from cruciferous vegetables, berries, nuts, citrus, and soy products will be dependent on the specific bacteria present in the individual's gut.
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Affiliation(s)
- Laura M Beaver
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; School of Nutrition and Public Health, Oregon State University, Corvallis, OR, United States
| | - Paige E Jamieson
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; School of Nutrition and Public Health, Oregon State University, Corvallis, OR, United States
| | - Carmen P Wong
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; School of Nutrition and Public Health, Oregon State University, Corvallis, OR, United States
| | - Mahak Hosseinikia
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; School of Nutrition and Public Health, Oregon State University, Corvallis, OR, United States
| | - Jan F Stevens
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon, United States
| | - Emily Ho
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States; School of Nutrition and Public Health, Oregon State University, Corvallis, OR, United States.
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OKADA D, KANAI K, OTAKA Y, MATSUMOTO T, IZUMOTO A, UCHIYAMA Y, NAGAI N, YAMASHITA Y, ICHIKAWA Y, SUGIUCHI M, TAJIMA K. Anti-inflammatory effects of water-dispersible hesperetin on endotoxin-induced uveitis in rats involving the nuclear factor κB and Wnt/β-catenin signaling pathways. J Vet Med Sci 2025; 87:223-231. [PMID: 39814392 PMCID: PMC11830440 DOI: 10.1292/jvms.24-0453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/25/2024] [Indexed: 01/18/2025] Open
Abstract
This study investigated the anti-inflammatory effects of water-dispersible hesperetin (WD-Hpt) in an endotoxin-induced uveitis (EIU) rat model. The rats were orally administered 10, 25, or 50 mg/kg WD-Hpt immediately after lipopolysaccharide (LPS) injection at the concentration of 200 μg. Clinical scores, cellular inflammation, the aqueous humor (ApH) protein concentration, as well as the levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) in AqH, and histopathological grades were assessed. Immunohistostaining and mRNA analyses measured expressions of TNF-α, COX-2, iNOS, activated nuclear factor (NF)-κB p65, I kappa B (IκB)-α degradation, phosphorylated (p)-IκB kinase (IKK) α/β, β-catenin, and glycogen synthase kinase (GSK)-3β. Compared to LPS treated group (LPS txg), WD-Hpt treatment groups (WD-Hpt txg) resulted in the following results: 1) clinical scores improved [LPS txg; 3.90 ± 0.20, WD-Hpt txg; 2.40 ± 0.37 (P<0.05)], 2) the number of inflammatory cells in AqH decreased [LPS txg; 8.65 ± 1.41 × 105 cells/mL, WD-Hpt txg; 3.83 ± 1.20 × 105 cells/mL (P<0.05)], 3) AqH protein concentration reduced [LPS txg; 36.65 ± 2.71 mg/mL, WD-Hpt txg; 28.73 ± 2.36 mg/mL (P<0.05)], and 4) decreased levels of TNF-α [LPS txg; 69.55 ± 7.38 pg/mL, WD-Hpt txg; 35.18 ± 9.22 pg/mL (P<0.001)], iNOS [LPS txg; 153.37 ± 12.72 μM, WD-Hpt txg; 110.79 ± 13.27 μM (P<0.05)], and COX-2 [LPS txg; 1,080.56 ± 196.06 pg/mL, WD-Hpt txg; 477.80 ± 66.61 pg/mL (P<0.01)] in AqH were observed, and histopathological grades improved [LPS txg; 2.80 ± 0.40, WD-Hpt txg; 1.50 ± 0.50 (P<0.05)]. Immunostaining and mRNA analysis revealed that 50 mg/kg WD-Hpt effectively suppressed iNOS, COX-2, NF-κB p65, IκB-α degradation, p-IKKα/β, β-catenin, and GSK-3β expression. These findings suggested that WD-Hpt exerts anti-inflammatory effects by targeting the NF-κB and Wnt/β-catenin pathways.
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Affiliation(s)
- Daiki OKADA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Kazutaka KANAI
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Yuya OTAKA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Tsubasa MATSUMOTO
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Akane IZUMOTO
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Yumiko UCHIYAMA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Noriaki NAGAI
- Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Yohei YAMASHITA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Yoichiro ICHIKAWA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Misaki SUGIUCHI
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Kazuki TAJIMA
- Department of Small Animal Internal Medicine II, School of
Veterinary Medicine, Kitasato University, Aomori, Japan
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Song B, Hao M, Zhang S, Niu W, Li Y, Chen Q, Li S, Tong C. Comprehensive review of Hesperetin: Advancements in pharmacokinetics, pharmacological effects, and novel formulations. Fitoterapia 2024; 179:106206. [PMID: 39255908 DOI: 10.1016/j.fitote.2024.106206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/01/2024] [Accepted: 09/06/2024] [Indexed: 09/12/2024]
Abstract
Hesperetin is a flavonoid compound naturally occurring in the peel of Citrus fruits from the Rutaceae family. Previous studies have demonstrated that hesperetin exhibits various pharmacological effects, such as anti-inflammatory, anti-tumor, antioxidative, anti-aging, and neuroprotective properties. In recent years, with the increasing prevalence of diseases and the rising awareness of traditional Chinese medicine, hesperetin has garnered growing attention for its wide-ranging pharmacological effects. To substantiate its health benefits and elucidate potential mechanisms, knowledge of pharmacokinetics is crucial. However, the limited solubility of hesperetin restricts its bioavailability, thereby diminishing its efficacy as a beneficial health agent. To enhance the bioavailability of hesperetin, various novel formulations have been developed, including nanoparticles, liposomes, and cyclodextrin inclusion complexes. This article reviews recent advances in the pharmacokinetics of hesperetin and methods to improve its bioavailability, as well as its pharmacological effects and mechanisms, aiming to provide a theoretical basis for clinical applications.
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Affiliation(s)
- Bocui Song
- Heilongjiang Provincial Key Laboratory of Environmental Microbiology and Recycling of Argo-Waste in Cold Region, College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China.
| | - Meihan Hao
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China
| | - Shuang Zhang
- Administration Committee of Jilin Yongji Economic Development Zone, Jilin, Jilin, China
| | - Wenqi Niu
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China
| | - Yuqi Li
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China
| | - Qian Chen
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China
| | - Shuang Li
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China
| | - Chunyu Tong
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, China.
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Cuijpers I, Dohmen CGM, Bouwman FG, Troost FJ, Sthijns MMJPE. Hesperetin but not ellagic acid increases myosin heavy chain expression and cell fusion in C2C12 myoblasts in the presence of oxidative stress. Front Nutr 2024; 11:1377071. [PMID: 39285862 PMCID: PMC11402829 DOI: 10.3389/fnut.2024.1377071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 07/24/2024] [Indexed: 09/19/2024] Open
Abstract
Introduction Skeletal muscle regeneration is impaired in elderly. An oxidative stress-induced decrease in differentiation capacity of muscle satellite cells is a key factor in this process. The aim of this study is to investigate whether orange polyphenol hesperetin and pomegranate polyphenol ellagic acid enhance myoblast differentiation in the presence and absence of oxidative stress, and to explore underlying mechanisms. Methods C2C12 myoblasts were proliferated for 24 h and differentiated for 120 h while exposed to hesperetin (5, 20, 50 μM), ellagic acid (0.05, 0.1 μM) or a combination (20 μM hesperetin, 0.05 μM ellagic acid) with and without oxidative stress-inducing compound menadione (9 μM) during 24 h of proliferation and during the first 5 h of differentiation. The number of proliferating cells was assessed using fluorescent labeling of incorporated 5-ethynyl-2'-deoxyuridine. Myosin heavy chain expression was assessed by fluorescence microscopy and cell fusion index was calculated. Furthermore, protein expression of phosphorylated p38 and myomixer were assessed using Western blot. Results None of the compounds induced effects on cell proliferation. Without menadione, 50 μM hesperetin increased fusion index by 12.6% compared to control (p < 0.01), while ellagic acid did not affect measured parameters of differentiation. Menadione treatment did not change myosin heavy chain expression and fusion index. In combination with menadione, 20 μM hesperetin increased myosin heavy chain expression by 35% (p < 0.01) and fusion index by 7% (p = 0.04) compared to menadione. Furthermore, the combination of menadione with hesperetin and ellagic acid increased myosin heavy chain expression by 35% compared to menadione (p = 0.02). Hesperetin and ellagic acid did not change p38 phosphorylation and myomixer expression compared to control, while treatment with menadione increased p38 phosphorylation (p < 0.01) after 5 h and decreased myomixer expression (p = 0.04) after 72 h of differentiation. Conclusion and discussion Hesperetin increased myosin heavy chain expression in the presence of oxidative stress induced by menadione, and increased cell fusion both in the presence and absence of menadione. Ellagic acid did not affect the measured parameters of myoblast differentiation. Therefore, hesperetin should be considered as nutritional prevention or treatment strategy to maintain muscle function in age-related diseases such as sarcopenia. Future research should focus on underlying mechanisms and translation of these results to clinical practice.
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Affiliation(s)
- Iris Cuijpers
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, Netherlands
| | - Colin G M Dohmen
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, Netherlands
| | - Freek G Bouwman
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Freddy J Troost
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, Netherlands
| | - Mireille M J P E Sthijns
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, Netherlands
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Tew WY, Tan CS, Yan CS, Loh HW, Wang X, Wen X, Wei X, Yam MF. Mechanistic study on vasodilatory and antihypertensive effects of hesperetin: ex vivo and in vivo approaches. Hypertens Res 2024; 47:2416-2434. [PMID: 38914702 DOI: 10.1038/s41440-024-01652-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 02/06/2024] [Accepted: 03/01/2024] [Indexed: 06/26/2024]
Abstract
Hesperetin is one of the prominent flavonoids found in citrus fruit. Several research studies have reported that hesperetin can promote vasodilation in vascular tissue by increasing the level of nitric oxide and cyclic nucleotides. However, these may not be the only pathway for hesperetin to exert its vasodilatory effect. In addition to vasodilation, hesperetin has been found to carry an antihypertensive effect through intraperitoneal injection, although no study has comprehensively investigated the antihypertensive effect of hesperetin through oral administration. Therefore, this study aimed to determine the possible mechanism pathways involved in hesperetin-induced vasodilation and investigated its antihypertensive effects on hypertensive rats' model via oral administration. The ex vivo experimental findings showed that the NO/sGC/cGMP signalling pathway was involved in hesperetin-mediated vasodilation. Moreover, hesperetin activated the AC/cAMP/PKA pathway through PGI2 and activated the β2-adrenergic receptor. Hesperetin can act as a voltage-gated potassium channel (KV) and ATP-sensitive potassium channel (KATP) opener. The intracellular calcium in vascular smooth muscle was reduced by hesperetin through blocking the voltage-operated calcium channels (VOCC) and inositol triphosphate receptor (IP3R). In the in vivo assessment, hesperetin shows a significant decrease in Spontaneously Hypertensive rats' blood pressure following 21 days of oral treatment. The sub-chronic toxicity assessment demonstrated that hesperetin exhibited no deleterious effects on the body weights, clinical biochemistry and haematological profile of Sprague-Dawley rats. This study implies that hesperetin holds promise as a potential medication for hypertension treatment, devoid of undesirable side effects.
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Affiliation(s)
- Wan Yin Tew
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Shangjie, Minhou, Fuzhou, 350122, Fujian, China
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia
| | - Chu Shan Tan
- Material Characterization and Inorganic Spectroscopy, Perkin Elmer Sdn. Bhd., #2.01. Level 2, Wisma Academy, Lot 4A, Jalan 19/1, 46300, Petaling Jaya, Selangor, Malaysia
| | - Chong Seng Yan
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia
| | - Hui Wei Loh
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia
| | - Xuye Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia
| | - Xu Wen
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Shangjie, Minhou, Fuzhou, 350122, Fujian, China
| | - Xu Wei
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Shangjie, Minhou, Fuzhou, 350122, Fujian, China.
| | - Mun Fei Yam
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Shangjie, Minhou, Fuzhou, 350122, Fujian, China.
- Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Pulau Pinang, Malaysia.
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Raj A, Thomas RK, Vidya L, Neelima S, Aparna VM, Sudarsanakumar C. A Minor Groove Binder with Significant Cytotoxicity on Human Lung Cancer Cells: The Potential of Hesperetin Functionalised Silver Nanoparticles. J Fluoresc 2024; 34:2179-2196. [PMID: 37721707 DOI: 10.1007/s10895-023-03409-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023]
Abstract
Natural drug functionalised silver (Ag) nanoparticles (NPs) have gained significant interest in pharmacology related applications due to their therapeutic efficiency. We have synthesised silver nanoparticle using hesperetin as a reducing and capping agent. This work aims to discuss the relevance of the hesperetin functionalised silver nanoparticles (H-AgNPs) in the field of nano-medicine. The article primarily investigates the anticancer activity of H-AgNPs and then their interactions with calf thymus DNA (ctDNA) through spectroscopic and thermodynamic techniques. The green synthesised H-AgNPs are stable, spherical in shape and size of 10 ± 3 nm average diameter. The complex formation of H-AgNPs with ctDNA was established by UV-Visible absorption, fluorescent dye displacement assay, isothermal calorimetry and viscosity measurements. The binding constants obtained from these experiments were consistently in the order of 104 Mol-1. The melting temperature analysis and FTIR measurements confirmed that the structural alterations of ctDNA by the presence of H-AgNPs are minimal. All the thermodynamic variables and the endothermic binding nature were acquired from ITC experiments. All these experimental outcomes reveal the formation of H-AgNPs-ctDNA complex, and the results consistently verify the minor groove binding mode of H-AgNPs. The binding constant and limit of detection of 1.8 μM found from the interaction studies imply the DNA detection efficiency of H-AgNPs. The cytotoxicity of H-AgNPs against A549 and L929 cell lines were determined by in vitro MTT cell viability assay and lactate dehydrogenase (LDH) assay. The cell viability and LDH enzyme release are confirmed that the H-AgNPs has high anticancer activity. Moreover, the calculated LD50 value for H-AgNPs against lung cancer cells is 118.49 µl/ml, which is a low value comparing with the value for fibroblast cells (269.35 µl/ml). In short, the results of in vitro cytotoxicity assays revealed that the synthesised nanoparticles can be considered in applications related to cancer treatments. Also, we have found that, H-AgNPs is a minor groove binder, and having high DNA detection efficiency.
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Affiliation(s)
- Aparna Raj
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India
| | - Riju K Thomas
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India
- Bharata Mata College, Thrikkakara, Ernakulam, Kerala, 682032, India
| | - L Vidya
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India
| | - S Neelima
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India
| | - V M Aparna
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India
| | - C Sudarsanakumar
- School of Pure & Applied Physics, Mahatma Gandhi University, P.D Hills (P.O), Kottayam, Kerala, 686 560, India.
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Jalili F, Moradi S, Talebi S, Mehrabani S, Ghoreishy SM, Wong A, Jalalvand AR, Kermani MAH, Jalili C, Jalili F. The effects of citrus flavonoids supplementation on endothelial function: A systematic review and dose-response meta-analysis of randomized clinical trials. Phytother Res 2024; 38:2847-2859. [PMID: 38561995 DOI: 10.1002/ptr.8190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 01/25/2024] [Accepted: 03/03/2024] [Indexed: 04/04/2024]
Abstract
The present systematic review and dose-response meta-analysis was conducted to synthesize existing data from randomized clinical trials (RCTs) concerning the impact of citrus flavonoids supplementation (CFS) on endothelial function. Relevant RCTs were identified through comprehensive searches of the PubMed, ISI Web of Science, and Scopus databases up to May 30, 2023. Weighted mean differences and their corresponding 95% confidence intervals (CI) were pooled utilizing a random-effects model. A total of eight eligible RCTs, comprising 596 participants, were included in the analysis. The pooled data demonstrated a statistically significant augmentation in flow-mediated vasodilation (FMD) (2.75%; 95% CI: 1.29, 4.20; I2 = 87.3%; p < 0.001) associated with CFS compared to the placebo group. Furthermore, the linear dose-response analysis indicated that each increment of 200 mg/d in CFS led to an increase of 1.09% in FMD (95% CI: 0.70, 1.48; I2 = 94.5%; p < 0.001). The findings from the nonlinear dose-response analysis also revealed a linear relationship between CFS and FMD (Pnon-linearity = 0.903, Pdose-response <0.001). Our findings suggest that CFS enhances endothelial function. However, more extensive RTCs encompassing longer intervention durations and different populations are warranted to establish more precise conclusions.
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Affiliation(s)
- Farnaz Jalili
- University of Adelaide Faculty of Medicine, Adelide, Australia
| | - Sajjad Moradi
- Department of Nutrition and Food Sciences, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Sepide Talebi
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Sanaz Mehrabani
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Mojtaba Ghoreishy
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
- Student Research Committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Alexei Wong
- Department of Health and Human Performance, Marymount University, School of Health Sciences, Arlington, Virginia, USA
| | - Ali R Jalalvand
- Research Center of Oils and Fats, Research Institute for Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Ali Hojjati Kermani
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Cyrus Jalili
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Faramarz Jalili
- School of Health Administration, Dalhousie University, Halifax, Canada
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10
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Mukai R, Okuyama H, Uchimura M, Sakao K, Matsuhiro M, Ikeda-Imafuku M, Ishima Y, Nishikawa M, Ikushiro S, Tai A. The binding selectivity of quercetin and its structure-related polyphenols to human serum albumin using a fluorescent dye cocktail for multiplex drug-site mapping. Bioorg Chem 2024; 145:107184. [PMID: 38364549 DOI: 10.1016/j.bioorg.2024.107184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/25/2024] [Accepted: 02/04/2024] [Indexed: 02/18/2024]
Abstract
Human serum albumin (HSA) is a serum protein that carries flavonoids in blood circulation. In this report, the binding selectivity and strength of interactions to HSA-binding sites (sites I or II) by flavonoids were evaluated using competition experiments and the specific fluorescent dyes, dansylamide and BD140. Most tested flavonoids bound site I preferentially, with the binding strength dependent on the mother structure in the order flavonol > flavone > flavanone > flavan 3-ols. Glycosylation or glucuronidation reduced the binding of quercetin to site I of HSA, whereas sulfation increased binding. Quercetin 7-sulfate showed the strongest binding and molecular docking simulations supported this observation. Prenylation at any position or glucuronidation and sulfation at the C-4' or C-7 position of quercetin facilitated stronger binding to site II. The binding affinity of flavonoids toward site I correlated with the partition coefficient value (logP), whereas no corresponding correlation was observed for site II.
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Affiliation(s)
- Rie Mukai
- Department of Food Science, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1, Minamijosan-jima, Tokushima 770-8513, Japan.
| | - Hitomi Okuyama
- Department of Food Science, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1, Minamijosan-jima, Tokushima 770-8513, Japan
| | - Miku Uchimura
- Department of Food Science and Technology, Graduate School of Agriculture, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan.
| | - Kozue Sakao
- Department of Food Science and Technology, Graduate School of Agriculture, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan.
| | - Miyu Matsuhiro
- Department of Food Science, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1, Minamijosan-jima, Tokushima 770-8513, Japan.
| | - Mayumi Ikeda-Imafuku
- Department of Physical Pharmaceutics, School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichiban-cho, Wakayama 640-8156, Japan.
| | - Yu Ishima
- Laboratory of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
| | - Miyu Nishikawa
- Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
| | - Shinichi Ikushiro
- Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
| | - Akihiro Tai
- Department of Food Science, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1, Minamijosan-jima, Tokushima 770-8513, Japan.
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11
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Dai W, Li B, Xiong Y, Dai L, Tian Y, Zhang L, Wang Q, Qian G. Non-Volatile Component and Antioxidant Activity: A Comparative Analysis between Litsea cubeba Branches and Leaves. Molecules 2024; 29:788. [PMID: 38398540 PMCID: PMC10892920 DOI: 10.3390/molecules29040788] [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: 12/04/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Litsea cubeba, which is found widely distributed across the Asian region, functions as both an economic tree and a medicinal plant with a rich historical background. Previous investigations into its chemical composition and biological activity have predominantly centered on volatile components, leaving the study of non-volatile components relatively unexplored. In this study, we employed UPLC-HRMS technology to analyze the non-volatile components of L. cubeba branches and leaves, which successfully resulted in identifying 72 constituents. Comparative analysis between branches and leaves unveiled alkaloids, organic acids, and flavonoids as the major components. However, noteworthy differences in the distribution of these components between branches and leaves were observed, with only eight shared constituents, indicating substantial chemical variations in different parts of L. cubeba. Particularly, 24 compounds were identified for the first time from this plant. The assessment of antioxidant activity using four methods (ABTS, DPPH, FRAP, and CUPRAC) demonstrated remarkable antioxidant capabilities in both branches and leaves, with slightly higher efficacy observed in branches. This suggests that L. cubeba may act as a potential natural antioxidant with applications in health and therapeutic interventions. In conclusion, the chemical composition and antioxidant activity of L. cubeba provides a scientific foundation for its development and utilization in medicine and health products, offering promising avenues for the rational exploitation of L. cubeba resources in the future.
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Affiliation(s)
- Wei Dai
- Teaching and Experimental Center, Guangdong Pharmaceutical University, Guangzhou 510006, China; (W.D.)
| | - Boyi Li
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China (Y.X.)
| | - Yanli Xiong
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China (Y.X.)
| | - Liping Dai
- Teaching and Experimental Center, Guangdong Pharmaceutical University, Guangzhou 510006, China; (W.D.)
| | - Yuan Tian
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
| | - Liangqian Zhang
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
| | - Qi Wang
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
| | - Guoqiang Qian
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China (Y.X.)
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12
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Kapoor MP, Moriwaki M, Abe A, Morishima S, Ozeki M, Sato N. Hesperetin-7- O-glucoside/β-cyclodextrin Inclusion Complex Induces Acute Vasodilator Effect to Inhibit the Cold Sensation Response during Localized Cold-Stimulate Stress in Healthy Human Subjects: A Randomized, Double-Blind, Crossover, and Placebo-Controlled Study. Nutrients 2023; 15:3702. [PMID: 37686734 PMCID: PMC10489958 DOI: 10.3390/nu15173702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/17/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023] Open
Abstract
Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.
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Affiliation(s)
- Mahendra P. Kapoor
- Nutrition Division, Taiyo Kagaku Co., Ltd., 1-3 Takaramachi, Yokkaichi 510-0844, Mie, Japan
| | - Masamitsu Moriwaki
- Nutrition Division, Taiyo Kagaku Co., Ltd., 1-3 Takaramachi, Yokkaichi 510-0844, Mie, Japan
| | - Aya Abe
- Nutrition Division, Taiyo Kagaku Co., Ltd., 1-3 Takaramachi, Yokkaichi 510-0844, Mie, Japan
| | - So Morishima
- Nutrition Division, Taiyo Kagaku Co., Ltd., 1-3 Takaramachi, Yokkaichi 510-0844, Mie, Japan
| | - Makoto Ozeki
- Nutrition Division, Taiyo Kagaku Co., Ltd., 1-3 Takaramachi, Yokkaichi 510-0844, Mie, Japan
| | - Norio Sato
- Taiyo Kagaku Co., Ltd., 800 Yamada-Cho, Yokkaichi 510-1111, Mie, Japan
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13
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Martínez-Noguera FJ, Alcaraz PE, Carlos-Vivas J, Marín-Pagán C. 8 weeks of 2 S-hesperidin prevents a decrease in pO 2 at submaximal intensity in amateur cyclists in off-season: randomized controlled trial. Food Funct 2023; 14:2750-2767. [PMID: 36857626 DOI: 10.1039/d2fo03007a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Although chronic supplementation with 2S-hesperidin has been shown to improve performance, to date, the possible mechanisms underlying this effect have not been explored. Therefore, the aim of this study was to assess whether changes in gasometry may be associated with improved performance after the intake of 2S-hesperidin (500 mg d-1, 8 weeks). Forty amateur cyclists (n = 20 2S-hesperidin, n = 20 placebo) performed a rectangular test, during which capillary blood samples were taken at the baseline, FatMax1, ventilatory threshold 1 and 2 (VT1 and VT2), power maximum (PMAX), FatMax2 and excess post-exercise O2 consumption (EPOC) to measure gasometry parameters. Significantly increased CO2 and tCO2 was found at FatMax1, VT1, FatMax2 and EPOC (p = <0.05) after 8 weeks of 2S-hesperidin ingestion. Conversely, the placebo group had a significant decrease in pO2 at VT2 (p = 0.04) during the rectangular test, with no changes in the 2S-hesperidin group. Therefore, chronic supplementation with 2S-hesperidin prevents decreases in pO2 at submaximal intensities in amateur cyclists in an off-season period.
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Affiliation(s)
- Francisco Javier Martínez-Noguera
- Research Center for High Performance Sport, Catholic University of Murcia, Campus de los Jerónimos N° 135, UCAM, 30107, Murcia, Spain.
| | - Pedro E Alcaraz
- Research Center for High Performance Sport, Catholic University of Murcia, Campus de los Jerónimos N° 135, UCAM, 30107, Murcia, Spain.
| | - Jorge Carlos-Vivas
- Health, Economy, Motricity and Education Research Group (HEME), Faculty of Sport Sciences, University of Extremadura, Avda. de Elvas, s/n., 06006, Badajoz, Spain.
| | - Cristian Marín-Pagán
- Research Center for High Performance Sport, Catholic University of Murcia, Campus de los Jerónimos N° 135, UCAM, 30107, Murcia, Spain.
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14
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Moriwaki M, Kito K, Nakagawa R, Tominaga E, Kapoor MP, Matsumiya Y, Fukuhara T, Yamagata H, Katsumata T, Minegawa K. Mutagenic, Acute, and Subchronic Toxicity Studies of the Hesperetin-7-Glucoside-β-Cyclodextrin Inclusion Complex. Int J Toxicol 2022; 42:50-62. [PMID: 36280476 PMCID: PMC9841476 DOI: 10.1177/10915818221134022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Hesperetin glucosides such as hesperidin and hesperetin-7-glucoside are abundantly present in citrus fruits and have various pharmacological properties. However, the potential toxicity of hesperetin glucosides remains unclear. An initial assessment of the safety of hesperetin-7-glucoside-β-cyclodextrin inclusion complex (HPTGCD) as a functional food ingredient was undertaken to assess toxicity and mutagenic potential. A bacterial reverse mutation assay (Ames test) using Salmonella typhimurium (strains TA98, TA1535, TA100, and TA1537) and Escherichia coli (strain WP2 uvrA) with HPTGCD (up to 5000 µg/plate) in the absence and presence of metabolic activation was negative. In a single oral (gavage) toxicity study in male and female rats, HPTGCD at dose up to 2000 mg/kg did not produce mortality nor clinical signs of toxicity or change in body weight. In a subchronic oral (dietary admix) toxicity study in rats receiving 0, 1.5, 3, and 5% HPTGCD for 13 weeks, no adverse effects were noted and the no-observed-adverse-effect level (NOAEL) was 5% in the diet (equivalent to 3267.7 mg/kg/day for males and to 3652.4 mg/kg/day for females). These results provide initial evidence of the safety of HPTGCD.
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Affiliation(s)
- Masamitsu Moriwaki
- Taiyo Kagaku Co. Ltd., Nutrition
Division, Mie, Japan,Masamitsu Moriwaki, Taiyo Kagaku Co. Ltd.,
Nutrition Division, 1-3 Takaramachi, Yokkaichi, Mie 510-0844, Japan.
| | - Kento Kito
- Taiyo Kagaku Co. Ltd., Nutrition
Division, Mie, Japan
| | - Ryo Nakagawa
- Taiyo Kagaku Co. Ltd., Nutrition
Division, Mie, Japan
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15
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Sheridan R, Spelman K. Polyphenolic promiscuity, inflammation-coupled selectivity: Whether PAINs filters mask an antiviral asset. Front Pharmacol 2022; 13:909945. [PMID: 36339544 PMCID: PMC9634583 DOI: 10.3389/fphar.2022.909945] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 10/03/2022] [Indexed: 11/26/2023] Open
Abstract
The Covid-19 pandemic has elicited much laboratory and clinical research attention on vaccines, mAbs, and certain small-molecule antivirals against SARS-CoV-2 infection. By contrast, there has been comparatively little attention on plant-derived compounds, especially those that are understood to be safely ingested at common doses and are frequently consumed in the diet in herbs, spices, fruits and vegetables. Examining plant secondary metabolites, we review recent elucidations into the pharmacological activity of flavonoids and other polyphenolic compounds and also survey their putative frequent-hitter behavior. Polyphenols, like many drugs, are glucuronidated post-ingestion. In an inflammatory milieu such as infection, a reversion back to the active aglycone by the release of β-glucuronidase from neutrophils and macrophages allows cellular entry of the aglycone. In the context of viral infection, virions and intracellular virus particles may be exposed to promiscuous binding by the polyphenol aglycones resulting in viral inhibition. As the mechanism's scope would apply to the diverse range of virus species that elicit inflammation in infected hosts, we highlight pre-clinical studies of polyphenol aglycones, such as luteolin, isoginkgetin, quercetin, quercetagetin, baicalein, curcumin, fisetin and hesperetin that reduce virion replication spanning multiple distinct virus genera. It is hoped that greater awareness of the potential spatial selectivity of polyphenolic activation to sites of pathogenic infection will spur renewed research and clinical attention for natural products antiviral assaying and trialing over a wide array of infectious viral diseases.
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Affiliation(s)
| | - Kevin Spelman
- Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States
- Health Education and Research, Driggs, ID, United States
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16
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Imperatrice M, Cuijpers I, Troost FJ, Sthijns MMJPE. Hesperidin Functions as an Ergogenic Aid by Increasing Endothelial Function and Decreasing Exercise-Induced Oxidative Stress and Inflammation, Thereby Contributing to Improved Exercise Performance. Nutrients 2022; 14:nu14142955. [PMID: 35889917 PMCID: PMC9316530 DOI: 10.3390/nu14142955] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 02/06/2023] Open
Abstract
The regulation of blood flow to peripheral muscles is crucial for proper skeletal muscle functioning and exercise performance. During exercise, increased mitochondrial oxidative phosphorylation leads to increased electron leakage and consequently induces an increase in ROS formation, contributing to DNA, lipid, and protein damage. Moreover, exercise may increase blood- and intramuscular inflammatory factors leading to a deterioration in endurance performance. The aim of this review is to investigate the potential mechanisms through which the polyphenol hesperidin could lead to enhanced exercise performance, namely improved endothelial function, reduced exercise-induced oxidative stress, and inflammation. We selected in vivo RCTs, animal studies, and in vitro studies in which hesperidin, its aglycone form hesperetin, hesperetin-metabolites, or orange juice are supplemented at any dosage and where the parameters related to endothelial function, oxidative stress, and/or inflammation have been measured. The results collected in this review show that hesperidin improves endothelial function (via increased NO availability), inhibits ROS production, decreases production and plasma levels of pro-inflammatory markers, and improves anaerobic exercise outcomes (e.g., power, speed, energy). For elite and recreational athletes, hesperidin could be used as an ergogenic aid to enhance muscle recovery between training sessions, optimize oxygen and nutrient supplies to the muscles, and improve anaerobic performance.
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Affiliation(s)
- Maria Imperatrice
- BioActor BV, Gaetano Martinolaan 50, 6229 GS Maastricht, The Netherlands
- Correspondence: (M.I.); (I.C.)
| | - Iris Cuijpers
- Food Innovation and Health, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands; (F.J.T.); (M.M.J.P.E.S.)
- Correspondence: (M.I.); (I.C.)
| | - Freddy J. Troost
- Food Innovation and Health, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands; (F.J.T.); (M.M.J.P.E.S.)
| | - Mireille M. J. P. E. Sthijns
- Food Innovation and Health, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands; (F.J.T.); (M.M.J.P.E.S.)
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17
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Guo X, Cao X, Fang X, Guo A, Li E. Involvement of phase II enzymes and efflux transporters in the metabolism and absorption of naringin, hesperidin and their aglycones in rats. Int J Food Sci Nutr 2022; 73:480-490. [PMID: 34974785 DOI: 10.1080/09637486.2021.2012562] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/18/2021] [Accepted: 11/26/2021] [Indexed: 10/19/2022]
Abstract
This study examined the effects of phase II metabolism and efflux transportation on the bioavailability of naringin, hesperidin, and their aglycones (naringenin and hesperetin) in rats. Results indicated naringin and hesperidin have a lower oral bioavailability than their aglycones. Of all the phase II enzymes tested, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A2, UGT1A3, UGT1A7 and SULT sulfotransferase (SULT) 1B1 were of minor importance regarding the phase II metabolism of naringenin and hesperetin in the small intestine. Naringin, hesperidin, and their aglycones were all extensively metabolised in the liver. Naringin and hesperidin were more extensively transported by efflux transporters compared to their aglycones. Significant correlations between phase II enzymes and efflux transporters were detected. In conclusion, more extensive metabolism of naringin and hesperidin than their aglycones in the small intestine, and the interplay of phase II enzymes and efflux transporters in the small intestine explain the lower relative oral bioavailability of naringin and hesperidin than their aglycones.
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Affiliation(s)
- Xiao Guo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xuedan Cao
- Zhejiang Citrus Research Institute, Zhejiang Academy of Agricultural Sciences, Taizhou, China
| | - Xiugui Fang
- Zhejiang Citrus Research Institute, Zhejiang Academy of Agricultural Sciences, Taizhou, China
| | - Ailing Guo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Erhu Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
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18
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Abou Baker DH. An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: A comprehensive review based on up to date knowledge. Toxicol Rep 2022; 9:445-469. [PMID: 35340621 PMCID: PMC8943219 DOI: 10.1016/j.toxrep.2022.03.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 12/11/2022] Open
Abstract
Flavonoids -a class of low molecular weight secondary metabolites- are ubiquitous and cornucopia throughout the plant kingdom. Structurally, the main structure consists of C6-C3-C6 rings with different substitution patterns so that many sub-classes are obtained, for example: flavonols, flavonolignans, flavonoid glycosides, flavans, anthocyanidins, aurones, anthocyanidins, flavones, neoflavonoids, chalcones, isoflavones, flavones and flavanones. Flavonoids are evaluated to have drug like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others. However, information on the relationship between their structure and biological activity is scarce. Therefore, the present review tries to summarize all the therapeutic activities of flavonoids, their mechanisms of action and the structure activity relationship.
Latest updated ethnopharmacological review of the therapeutic effects of flavonoids. Flavonoids are attracting attention because of their therapeutic properties. Flavonoids are valuable candidates for drug development against many dangerous diseases. This overview summarizes the most important therapeutic effect and mechanism of action of flavonoids. General knowledge about the structure activity relationship of flavonoids is summarized. Substitution of chemical groups in the structure of flavonoids can significantly change their biological and chemical properties. The chemical properties of the basic flavonoid structure should be considered in a drug-based structural program.
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19
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Lu Q, Kishi H, Zhang Y, Morita T, Kobayashi S. Hesperetin Inhibits Sphingosylphosphorylcholine-Induced Vascular Smooth Muscle Contraction by Regulating the Fyn/Rho-Kinase Pathway. J Cardiovasc Pharmacol 2022; 79:456-466. [PMID: 34983908 PMCID: PMC8983948 DOI: 10.1097/fjc.0000000000001210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/17/2021] [Indexed: 11/27/2022]
Abstract
ABSTRACT Cardiovascular diseases are the leading cause of mortality and disability worldwide. We have previously found that sphingosylphosphorylcholine (SPC) is the key molecule leading to vasospasm. We have also identified the SPC/Src family protein tyrosine kinase Fyn/Rho-kinase (ROK) pathway as a novel signaling pathway for Ca2+ sensitization of vascular smooth muscle (VSM) contraction. This study aimed to investigate whether hesperetin can inhibit the SPC-induced contraction with little effect on 40 mM K+-induced Ca2+-dependent contraction and to elucidate the underlying mechanisms. Hesperetin significantly inhibited the SPC-induced contraction of porcine coronary artery smooth muscle strips with little effect on 40 mM K+-induced contraction. Hesperetin blocked the SPC-induced translocation of Fyn and ROK from the cytosol to the membrane in human coronary artery smooth muscle cells (HCASMCs). SPC decreased the phosphorylation level of Fyn at Y531 in both VSMs and HCASMCs and increased the phosphorylation levels of Fyn at Y420, myosin phosphatase target subunit 1 at T853, and myosin light chain (MLC) at S19 in both VSMs and HCASMCs, which were significantly suppressed by hesperetin. Our results indicate that hesperetin inhibits the SPC-induced contraction at least in part by suppressing the Fyn/ROK pathway, suggesting that hesperetin can be a novel drug to prevent and treat vasospasm.
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Affiliation(s)
- Qian Lu
- Department of Molecular and Cellular Physiology, Yamaguchi University Graduate School of Medicine, Ube, Japan ; and
| | - Hiroko Kishi
- Department of Molecular and Cellular Physiology, Yamaguchi University Graduate School of Medicine, Ube, Japan ; and
| | - Ying Zhang
- Department of Molecular and Cellular Physiology, Yamaguchi University Graduate School of Medicine, Ube, Japan ; and
| | - Tomoka Morita
- Department of Molecular and Cellular Physiology, Yamaguchi University Graduate School of Medicine, Ube, Japan ; and
| | - Sei Kobayashi
- Department of Advanced Preventive Medicine, School of Medicine, Yamaguchi University, Ube, Japan
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20
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Valls RM, Pedret A, Calderón-Pérez L, Llauradó E, Pla-Pagà L, Companys J, Moragas A, Martín-Luján F, Ortega Y, Giralt M, Rubió L, Canela N, Puiggrós F, Caimari A, Del Bas JM, Arola L, Solà R. Hesperidin in orange juice improves human endothelial function in subjects with elevated blood pressure and stage 1 hypertension: A randomized, controlled trial (Citrus study). J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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21
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Zhang M, Zhu S, Yang W, Huang Q, Ho CT. The biological fate and bioefficacy of citrus flavonoids: bioavailability, biotransformation, and delivery systems. Food Funct 2021; 12:3307-3323. [PMID: 33735339 DOI: 10.1039/d0fo03403g] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Citrus fruits are among the most popularly consumed fruits worldwide, including oranges, grapefruits, pomelos and lemons. Citrus flavonoids such as hesperidin, naringin and nobiletin have shown an array of health benefits in cell, animal and clinical studies, including antioxidative, anti-inflammatory, neuroprotective, anticancer, and anti-obesity activities. Citrus flavonoids have limited bioavailability after oral administration, leaving the major part unabsorbed and persisted in the colon. Recent studies have highlighted the important role of the gut microbiota and in vivo biotransformation on the bioactivity of citrus flavonoids. This article discusses the biological fate of citrus flavonoids from the viewpoint of their absorption, distribution, metabolism and excretion in vivo. Many delivery systems have been designed to enhance the oral bioavailability of citrus flavonoids, such as emulsions, self-emulsifying systems, nanoparticles and solid dispersions. The ultimate goal of these delivery systems is to enhance the bioefficacy of citrus flavonoids. Several studies have found that the increased bioavailability leads to enhanced bioefficacy of citrus flavonoids in specific animal models. Regarding the complex dynamics of citrus flavonoids and gut microbiota, the bioavailability-bioactivity relationship is an interesting but under-discussed area. Comprehensively understanding the biological fate and bioefficacy of citrus flavonoids would be helpful to develop functional foods with better health benefits.
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Affiliation(s)
- Man Zhang
- Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick 08901, New Jersey, USA.
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22
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Ávila-Gálvez MÁ, Giménez-Bastida JA, González-Sarrías A, Espín JC. New Insights into the Metabolism of the Flavanones Eriocitrin and Hesperidin: A Comparative Human Pharmacokinetic Study. Antioxidants (Basel) 2021; 10:435. [PMID: 33799874 PMCID: PMC8000041 DOI: 10.3390/antiox10030435] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/06/2021] [Accepted: 03/09/2021] [Indexed: 12/17/2022] Open
Abstract
The intake of hesperidin-rich sources, mostly found in orange juice, can decrease cardiometabolic risk, potentially linked to the gut microbial phase-II hesperetin derivatives. However, the low hesperidin solubility hampers its bioavailability and microbial metabolism, yielding a high inter-individual variability (high vs. low-producers) that prevents consistent health-related evidence. Contrarily, the human metabolism of (lemon) eriocitrin is hardly known. We hypothesize that the higher solubility of (lemon) eriocitrin vs. (orange) hesperidin might yield more bioavailable metabolites than hesperidin. A randomized-crossover human pharmacokinetic study (n = 16) compared the bioavailability and metabolism of flavanones from lemon and orange extracts and postprandial changes in oxidative, inflammatory, and metabolic markers after a high-fat-high-sugars meal. A total of 17 phase-II flavanone-derived metabolites were identified. No significant biomarker changes were observed. Plasma and urinary concentrations of all metabolites, including hesperetin metabolites, were higher after lemon extract intake. Total plasma metabolites showed significantly mean lower Tmax (6.0 ± 0.4 vs. 8.0 ± 0.5 h) and higher Cmax and AUC values after lemon extract intake. We provide new insights on hesperetin-eriodictyol interconversion and naringenin formation from hesperidin in humans. Our results suggest that regular consumption of a soluble and eco-friendly eriocitrin-rich lemon extract could provide a circulating concentration metabolites threshold to exert health benefits, even in the so-called low-producers.
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Affiliation(s)
| | | | | | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, Campus de Espinardo, CEBAS-CSIC, P.O. Box 164, 30100 Murcia, Spain; (M.Á.Á.-G.); (J.A.G.-B.); (A.G.-S.)
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23
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Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management? Antioxidants (Basel) 2020; 9:antiox9100973. [PMID: 33050575 PMCID: PMC7600646 DOI: 10.3390/antiox9100973] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/04/2020] [Accepted: 10/07/2020] [Indexed: 12/25/2022] Open
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cell signaling mechanism in maintaining redox homeostasis in humans. The role of dietary flavonoids in activating Nrf2/ARE in relation to cancer chemoprevention or cancer promotion is not well established. Here we summarize the dual effects of flavonoids in cancer chemoprevention and cancer promotion with respect to the regulation of the Nrf2/ARE pathway, while underlying the possible cellular mechanisms. Luteolin, apigenin, quercetin, myricetin, rutin, naringenin, epicatechin, and genistein activate the Nrf2/ARE pathway in both normal and cancer cells. The hormetic effect of flavonoids has been observed due to their antioxidant or prooxidant activity, depending on the concentrations. Reported in vitro and in vivo investigations suggest that the activation of the Nrf2/ARE pathway by either endogenous or exogenous stimuli under normal physiological conditions contributes to redox homeostasis, which may provide a mechanism for cancer chemoprevention. However, some flavonoids, such as luteolin, apigenin, myricetin, quercetin, naringenin, epicatechin, genistein, and daidzein, at low concentrations (1.5 to 20 µM) facilitate cancer cell growth and proliferation in vitro. Paradoxically, some flavonoids, including luteolin, apigenin, and chrysin, inhibit the Nrf2/ARE pathway in vitro. Therefore, even though flavonoids play a major role in cancer chemoprevention, due to their possible inducement of cancer cell growth, the effects of dietary flavonoids on cancer pathophysiology in patients or appropriate experimental animal models should be investigated systematically.
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24
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Nobiletin, sinensetin, and tangeretin are the main perpetrators in clementines provoking food-drug interactions in vitro. Food Chem 2020; 319:126578. [DOI: 10.1016/j.foodchem.2020.126578] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/18/2020] [Accepted: 03/08/2020] [Indexed: 12/30/2022]
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25
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Shakour ZTA, Fayek NM, Farag MA. How do biocatalysis and biotransformation affect Citrus dietary flavonoids chemistry and bioactivity? A review. Crit Rev Biotechnol 2020; 40:689-714. [DOI: 10.1080/07388551.2020.1753648] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Zeinab T. Abdel Shakour
- Laboratory of Phytochemistry, National Organization for Drug Control and Research, Cairo, Egypt
| | - Nesrin M. Fayek
- Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Mohamed A. Farag
- Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, Egypt
- Chemistry Department, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt
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26
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Liu Y, Zhang L, Dong L, Song Q, Guo P, Wang Y, Chen Z, Zhang M. Hesperetin improves diabetic coronary arterial vasomotor responsiveness by upregulating myocyte voltage‑gated K+ channels. Exp Ther Med 2020; 20:486-494. [PMID: 32509018 PMCID: PMC7271715 DOI: 10.3892/etm.2020.8670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 03/03/2020] [Indexed: 12/04/2022] Open
Abstract
Hesperetin (HSP) is a naturally occurring flavonoid. The present study aimed to investigate the potential vasomotor effects and mechanisms of HSP action on rat coronary arteries (RCAs) injured by diabetes or high glucose concentrations. HSP (100 mg/kg/day) was intragastrically administered to the rats for 8 weeks, which were rendered diabetic with a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). The vascular tone of RCAs was recorded using a wire myograph. The voltage-dependent K+ (Kv) currents were examined using patch clamping. The expression of Kv channels (Kv1.2 and Kv1.5) was examined by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR). Diabetes induced contractile hypersensitivity and vasodilator hyposensitivity in RCAs, both of which were attenuated by the chronic administration of HSP. Patch clamp data revealed that chronic HSP treatment reduced diabetes-induced suppression of Kv currents in the myocytes. Western blot and RT-qPCR analyses revealed that chronic HSP administration increased the expression of Kv1.2, but not Kv1.5, in the RCAs of diabetic rats compared with those from non-diabetic rats. In vitro analysis showed that co-incubation with HSP ameliorated high-glucose-induced suppression of Kv currents and Kv 1.2 protein expression in the myocytes. Taken together, the present study demonstrated that HSP alleviated RCA vasomotor dysfunction as a result of diabetes in rats by upregulating the expression of myocyte Kv channels.
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Affiliation(s)
- Yu Liu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Lei Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Lina Dong
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Qiying Song
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Pengmei Guo
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yan Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Zhaoyang Chen
- Shanxi Key Laboratory of Experimental Animal Science and Animal Model of Human Disease, Laboratory Animal Center of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Mingsheng Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
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27
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Khan H, Ullah H, Tundis R, Belwal T, Devkota HP, Daglia M, Cetin Z, Saygili EI, Campos MDG, Capanoglu E, Du M, Dar P, Xiao J. Dietary Flavonoids in the Management of Huntington’s Disease: Mechanism and Clinical Perspective. EFOOD 2020; 1:38-52. [DOI: 10.2991/efood.k.200203.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive loss of neurons, which leads to behavioral systems and mental decline. HD is linked to repeat expansions of cytosine, adenine, and guanine in the Huntingtin (HTT) gene that give rise to mutation, leading to the formation of the HTT protein product. Oxidative stress also provokes the initiation and progression of HD as it leads to protein misfolding that results in the formation of inclusion which clumps together and alters neurotransmission. Despite the advancement in the field of pharmaceutical sciences, current therapeutic approaches suppress only the severity of symptoms and no therapy exists that can cure HD from its root cause. Flavonoids are the most abundant polyphenols widely present in daily dietary sources. Dietary flavonoids have a wide range of pharmacological bioactivities and many therapeutic applications. Dietary flavonoids including hesperidin, naringin, quercetin, rutin, fisetin, myricetin, luteolin, and epigallocatechin 3‐O‐gallate can prevent and manage HD through exerting antioxidant and anti‐inflammatory activities, altering intracellular pathways, genetic alterations, and metal ion chelation. This review highlights flavonoids as therapeutic options for HD and will open new dimensions for flavonoids as safe and effective therapeutic agents in diminishing HD.
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Affiliation(s)
- Haroon Khan
- Department of Pharmacy Abdul Wali Khan University Mardan 23200 Pakistan
| | - Hammad Ullah
- Department of Pharmacy Abdul Wali Khan University Mardan 23200 Pakistan
| | - Rosa Tundis
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria Via P. Bucci 87036 Rende CS Italy
| | - Tarun Belwal
- G.B. Pant National Institute of Himalayan Environment and Sustainable Development Kosi‐Katarmal Almora Uttarakhand India
| | - Hari Prasad Devkota
- School of Pharmacy Kumamoto University 5‐1 Oe‐honmachi, Chuo ku Kumamoto 862‐0973 Japan
| | - Maria Daglia
- Department of Drug Science University of Pavia Pavia Italy
| | - Zafer Cetin
- Department of Medical Biology and Genetic SANKO University School of Medicine Gaziantep Turkey
| | - Eyup Ilker Saygili
- Department of Medical Biochemistry SANKO University School of Medicine Gaziantep Turkey
| | - Maria da Graça Campos
- Observatory of Herb‐Drug Interactions/Faculty of Pharmacy University of Coimbra Heath Sciences Campus, Azinhaga de Santa Comba Coimbra Portugal
- Coimbra Chemistry Centre (CQC, FCT Unit 313) (FCTUC) University of Coimbra Rua Larga Coimbra Portugal
| | - Esra Capanoglu
- Food Engineering Department Faculty of Chemical and Metallurgical Engineering Istanbul Technical University, Maslak 34469 Istanbul Turkey
| | - Ming Du
- School of Food Science and Technology National Engineering Research Center of Seafood Dalian Polytechnic University Dalian 116034 China
| | - Parsa Dar
- Institute of Chinese Medical Sciences State Key Laboratory of Quality Control in Chinese Medicine University of Macau Avenida da Universidade Taipa Macau
| | - Jianbo Xiao
- Institute of Chinese Medical Sciences State Key Laboratory of Quality Control in Chinese Medicine University of Macau Avenida da Universidade Taipa Macau
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28
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Xiong K, Zhou L, Wang J, Ma A, Fang D, Xiong L, Sun Q. Construction of food-grade pH-sensitive nanoparticles for delivering functional food ingredients. Trends Food Sci Technol 2020. [DOI: 10.1016/j.tifs.2019.12.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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29
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Ruviaro AR, Barbosa PDPM, Alexandre EC, Justo AFO, Antunes E, Macedo GA. Aglycone-rich extracts from citrus by-products induced endothelium-independent relaxation in isolated arteries. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2020. [DOI: 10.1016/j.bcab.2019.101481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Yari Z, Movahedian M, Imani H, Alavian SM, Hedayati M, Hekmatdoost A. The effect of hesperidin supplementation on metabolic profiles in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial. Eur J Nutr 2019; 59:2569-2577. [PMID: 31844967 DOI: 10.1007/s00394-019-02105-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 09/30/2019] [Indexed: 01/28/2023]
Abstract
PURPOSE Hesperidin as an antioxidant flavonoid exerts anti-adipogenic, anti-inflammatory, anti-oxidant and anti-hypercholesterolemic effects. Besides, the increasing prevalence of metabolic syndrome (MetS) and its allied complications, on the one hand, and the willingness of individuals to use natural products for curing their diseases, on the other hand, led to the design of this study to evaluate the efficacy of hesperidin in normalizing the metabolic abnormalities in patients with MetS. METHODS In this clinical trial with a parallel-group design, 49 patients with MetS received either 500-mg hesperidin or placebo, twice daily, for 12 weeks. Number of participants with treated MetS was considered as a primary end point. Anthropometric parameters, dietary intake, physical activity, lipid profile, glucose homeostasis parameter, tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP) were assessed at the beginning and at the end of the study. This trial is registered at clinicaltrials.gov as NCT03734874. RESULTS Compared with the placebo group, hesperidin decreased fasting glucose level (- 6.07 vs. - 13.32 mg/dL, P = 0.043), triglyceride (- 8.83 vs. - 49.09 mg/dL, P = 0.049), systolic blood pressure (- 0.58 vs. - 2.68 mmHg, P = 0.048) and TNF-α (- 1.29 vs. - 4.44 pg/mL, P = 0.009). Based on the within-group analysis, hesperidin led to significant decrease in serum levels of glucose, insulin, triglyceride, total cholesterol, low density lipoprotein cholesterol, TNF-α and hs-CRP, while in control group only glucose and insulin significantly decreased. CONCLUSIONS The results indicate that hesperidin supplementation can improve metabolic abnormalities and inflammatory status in patients with MetS.
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Affiliation(s)
- Zahra Yari
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Movahedian
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology, Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Imani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | | | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology, Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Maaliki D, Shaito AA, Pintus G, El-Yazbi A, Eid AH. Flavonoids in hypertension: a brief review of the underlying mechanisms. Curr Opin Pharmacol 2019; 45:57-65. [DOI: 10.1016/j.coph.2019.04.014] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 02/12/2019] [Accepted: 04/16/2019] [Indexed: 12/21/2022]
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32
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Sheokand S, Navik U, Bansal AK. Nanocrystalline solid dispersions (NSD) of hesperetin (HRN) for prevention of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in Sprague-Dawley (SD) rats. Eur J Pharm Sci 2019; 128:240-249. [DOI: 10.1016/j.ejps.2018.12.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/01/2018] [Accepted: 12/09/2018] [Indexed: 11/16/2022]
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33
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Knez Hrnčič M, Španinger E, Košir IJ, Knez Ž, Bren U. Hop Compounds: Extraction Techniques, Chemical Analyses, Antioxidative, Antimicrobial, and Anticarcinogenic Effects. Nutrients 2019; 11:E257. [PMID: 30678345 PMCID: PMC6412513 DOI: 10.3390/nu11020257] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/10/2019] [Accepted: 01/18/2019] [Indexed: 12/11/2022] Open
Abstract
Hop plants comprise a variety of natural compounds greatly differing in their structure and properties. A wide range of methods have been developed for their isolation and chemical analysis, as well as for determining their antioxidative, antimicrobial, and antigenotoxic potentials. This contribution provides an overview of extraction and fractionation techniques of the most important hop compounds known for their health-promoting features. Although hops remain the principal ingredient for providing the taste, stability, and antimicrobial protection of beer, they have found applications in the pharmaceutical and other food industries as well. This review focuses on numerous health-promoting effects of hops raging from antioxidative, sedative, and anti-inflammatory potentials, over anticarcinogenic features to estrogenic activity. Therefore, hops should be exploited for the prevention and even healing of several prevalent diseases like cardiovascular disorders and various cancer types. New ideas for future studies on hops are finally presented: computational investigations of chemical reactivities of hop compounds, nanoencapsulation, and synergistic effects leading to a higher bioavailability of biologically active substances as well as the application of waste hop biomass from breweries for the production of high-added-value products in accordance with the biorefinery concept.
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Affiliation(s)
- Maša Knez Hrnčič
- Laboratory of Separation Processes and Product Design, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
| | - Eva Španinger
- Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
| | - Iztok Jože Košir
- Slovenian Institute of Hop Research and Brewing, Cesta Žalskega Tabora 2, SI-3310 Žalec, Slovenia.
| | - Željko Knez
- Laboratory of Separation Processes and Product Design, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
| | - Urban Bren
- Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
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Kang S, Lim Y, Kim YJ, Jung ES, Suh DH, Lee CH, Park E, Hong J, Velliquette RA, Kwon O, Kim JY. Multivitamin and Mineral Supplementation Containing Phytonutrients Scavenges Reactive Oxygen Species in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Trial. Nutrients 2019; 11:E101. [PMID: 30621298 PMCID: PMC6356358 DOI: 10.3390/nu11010101] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/26/2018] [Accepted: 12/29/2018] [Indexed: 02/06/2023] Open
Abstract
Phytonutrients and vitamin and mineral supplementation have been reported to provide increased antioxidant capacity in humans; however, there is still controversy. In the current clinical trial, we examined the antioxidant and DNA protection capacity of a plant-based, multi-vitamin/mineral, and phytonutrient (PMP) supplementation in healthy adults who were habitually low in the consumption of fruits and vegetables. This study was an eight-week, double-blind, randomized, parallel-arm, and placebo-controlled trial. PMP supplementation for eight weeks reduced reactive oxygen species (ROS) and prevented DNA damage without altering endogenous antioxidant system. Plasma vitamins and phytonutrients were significantly correlated with ROS scavenging and DNA damage. In addition, gene expression analysis in PBMC showed subtle changes in superoxide metabolic processes. In this study, we showed that supplementation with a PMP significantly improved ROS scavenging activity and prevented DNA damage. However, additional research is still needed to further identify mechanisms of actions and the role of circulating phytonutrient metabolites.
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Affiliation(s)
- Seunghee Kang
- Department of Nutritional Science and Food Management, Ewha Womans Universiy, Seoul 03760, Korea.
| | - Yeni Lim
- Department of Nutritional Science and Food Management, Ewha Womans Universiy, Seoul 03760, Korea.
| | - You Jin Kim
- Department of Nutritional Science and Food Management, Ewha Womans Universiy, Seoul 03760, Korea.
| | - Eun Sung Jung
- Department of Systems Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Dong Ho Suh
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Eunmi Park
- Department of Food and Nutrition, Hannam University, Daejeon 34430, Korea.
| | - Jina Hong
- Access Business Group International, LLC, 5600 Beach Blvd., Buena Park, CA 90621, USA.
| | - Rodney A Velliquette
- Access Business Group International, LLC, 5600 Beach Blvd., Buena Park, CA 90621, USA.
| | - Oran Kwon
- Department of Nutritional Science and Food Management, Ewha Womans Universiy, Seoul 03760, Korea.
| | - Ji Yeon Kim
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Korea.
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35
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Jargin SV. Scientific Papers and Patents on Substances with Unproven Effects. Part 2. RECENT PATENTS ON DRUG DELIVERY & FORMULATION 2019; 13:160-173. [PMID: 31424374 PMCID: PMC7011683 DOI: 10.2174/1872211313666190819124752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/19/2019] [Accepted: 08/01/2019] [Indexed: 12/03/2022]
Abstract
Several examples are discussed in this review, where substances without proven effects were proposed for practical use within the scope of evidence-based medicines. The following is discussed here: generalizations of the hormesis concept and its use in support of homeopathy; phytoestrogens and soy products potentially having feminizing effects; glycosaminoglycans for the treatment of osteoarthritis and possibilities of their replacement by diet modifications; flavonoids recommended for the treatment of chronic venous insufficiency and varicose veins; acetylcysteine as a mucolytic agent and its questionable efficiency especially by an oral intake; stem cells and cell therapies. In conclusion, placebo therapies can be beneficial and ethically justifiable but it is not a sufficient reason to publish biased information. Importantly, placebo must be devoid of adverse effects, otherwise, it is named pseudo-placebo. Therapeutic methods with unproven effects should be tested in high-quality research shielded from the funding bias. Some issues discussed in this review are not entirely clear, and the arguments provided here can initiate a constructive discussion.
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Affiliation(s)
- Sergei V. Jargin
- Peoples’ Friendship University of Russia, Clementovski per 6-82, Moscow115184, Russia
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36
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Sugasawa N, Katagi A, Kurobe H, Nakayama T, Nishio C, Takumi H, Higashiguchi F, Aihara KI, Shimabukuro M, Sata M, Kitagawa T. Inhibition of Atherosclerotic Plaque Development by Oral Administration of α-Glucosyl Hesperidin and Water-Dispersible Hesperetin in Apolipoprotein E Knockout Mice. J Am Coll Nutr 2018; 38:15-22. [PMID: 30321103 DOI: 10.1080/07315724.2018.1468831] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Hesperidin, an abundant flavonoid in citrus fruit, and its aglycone, hesperetin, have been reported to possess various physiological activities, including antioxidant, anti-inflammatory, hypolipidemic, and antihypertensive activities. In this study, we investigated whether α-glucosyl hesperidin and water-dispersible hesperetin have protective effects on atherosclerotic progression in apolipoprotein E knockout (Apo-E KO) mice. METHODS Ten-week-old male Apo-E KO mice were randomly assigned a regular high-fat diet, a high-fat diet with 0.5% α-glucosyl hesperidin, or a high-fat diet with 0.1% water-dispersible hesperetin for 12 weeks. Measurement of plasma total cholesterol levels, histological staining of aortic root, and immunohistochemistry for macrophages were performed to evaluate atherosclerotic plaque formation. Vascular reactivity of mouse aortic rings was also measured. RESULTS Both α-glucosyl hesperidin and water-dispersible hesperetin reduced plasma total cholesterol level. They also reduced plaque formation area, adipose deposition, and macrophage infiltration into atherosclerotic lesion. Vascular-endothelium-dependent relaxation in response to acetylcholine was improved in both experimental diet groups compared to the high-fat diet group. CONCLUSIONS Our study suggests that both α-glucosyl hesperidin and water-dispersible hesperetin exert protective effects on atherosclerotic progression in Apo-E KO mice because they exhibit hypolipidemic activity, reduce inflammation through macrophages, and prevent endothelial dysfunction.
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Affiliation(s)
- Noriko Sugasawa
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Ayako Katagi
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Hirotsugu Kurobe
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Taisuke Nakayama
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Chika Nishio
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | | | | | - Ken-Ichi Aihara
- c Department of Community Medicine for Diabetes and Metabolic Disorders , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Michio Shimabukuro
- d Department of Cardio-Diabetes Medicine , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Masataka Sata
- e Department of Cardiovascular Medicine , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
| | - Tetsuya Kitagawa
- a Department of Cardiovascular Surgery , Tokushima University Graduate School/Institute of Biomedical Sciences , Tokushima , Japan
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The acute effects of citrus flavanones on the metabolism of glycogen and monosaccharides in the isolated perfused rat liver. Toxicol Lett 2018; 291:158-172. [PMID: 29626522 DOI: 10.1016/j.toxlet.2018.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 03/06/2018] [Accepted: 04/02/2018] [Indexed: 10/17/2022]
Abstract
Citrus flavanones are often linked to their antihyperglycemic properties. This effect may be in part due to the inhibition of hepatic gluconeogenesis through different mechanisms. One of the possible mechanisms appears to be impairment of oxidative phosphorylation, which may also interfere with glycogen metabolism. Based on these facts, the purpose of the present study was to investigate the effects of three citrus flavanones on glycogenolysis in the isolated perfused rat liver. Hesperidin, hesperetin, and naringenin stimulated glycogenolysis and glycolysis from glycogen with concomitant changes in oxygen uptake. At higher concentrations (300 μM), hesperetin and naringenin clearly altered fructose and glucose metabolism, whereas hesperidin exerted little to no effects. In subcellular fractions hesperetin and naringenin inhibited the activity of glucose 6-phosphatase and glucokinase and the mitochondrial respiration linked to ADP phosphorylation. Hesperetin and naringenin also inhibited the transport of glucose into the cell. At a concentration of 300 μM, the glucose influx rate inhibition was 83% and 43% for hesperetin and naringenin, respectively. Hesperidin was the less active among the assayed citrus flavanones, indicating that the rutinoside moiety noticeably decrease the activity of these compounds. The effects on glycogenolysis and fructolysis were mainly consequence of an impairment on mitochondrial energy metabolism. The increased glucose release, due to the higher glycogenolysis, together with glucose transport inhibition is the opposite of what is expected for antihyperglycemic agents.
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Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial. Phytother Res 2018; 32:1073-1079. [DOI: 10.1002/ptr.6046] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 12/14/2017] [Accepted: 01/10/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Fatemeh Homayouni
- Department of Nutrition, Faculty of Paramedical Sciences, Nutrition and Metabolic Diseases Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz 61357-15794 Iran
| | - Fatemeh Haidari
- Department of Nutrition, Faculty of Paramedical Sciences, Nutrition and Metabolic Diseases Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz 61357-15794 Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences; Shahid Beheshti University of Medical Sciences; Tehran 19839-63113 Iran
| | - Mehrnoosh Zakerkish
- Department of Endocrinology and Metabolism, Diabetes Research Center; Ahvaz Jundishapur University of Medical Sciences; Ahvaz Iran
| | - Kambiz Ahmadi
- Department of Statistics and Epidemiology, Faculty of Public Health; Ahvaz Jundishapur University of Medical Sciences; Ahvaz Iran
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Non-extractable polyphenols produce gut microbiota metabolites that persist in circulation and show anti-inflammatory and free radical-scavenging effects. Trends Food Sci Technol 2017. [DOI: 10.1016/j.tifs.2017.07.010] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Nakajima VM, Moala T, Caria CREP, Moura CS, Amaya-Farfan J, Gambero A, Macedo GA, Macedo JA. Biotransformed citrus extract as a source of anti-inflammatory polyphenols: Effects in macrophages and adipocytes. Food Res Int 2017; 97:37-44. [PMID: 28578062 DOI: 10.1016/j.foodres.2017.03.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/14/2017] [Accepted: 03/19/2017] [Indexed: 02/06/2023]
Abstract
Chronic non-communicable diseases such as obesity are preceded by increased macrophage infiltration in adipose tissue and greater secretion of pro-inflammatory cytokines. We evaluated the anti-inflammatory potential of Biotransformed extract, and two control extracts: In Natura and Autoclaved. The assays were performed using a cellular model with RAW264.7, 3T3-L1 cells, and RAW264.7 and 3T3-L1 co-culture. The innovation of the study was the use of Biotransformed extract, a unique phenolic extract of a bioprocessed citrus residue. LPS stimulated RAW264.7 cells treated with the Biotransformed extract exhibited lower secretion of TNF-α and NO and lower protein expression of NFκB. In RAW264.7 and 3T3-L1 co-culture, treatment with 1.0mg/mL of the Biotransformed extract reduced secretion of TNF-α (30.7%) and IL-6 (43.4%). Still, the Biotransformed extract caused higher increase in adiponectin in relation to control extracts. When the co-culture received a LPS stimulus, the Autoclaved extract at 1.0mg/mL reduced IL-6 and TNF-α concentrations, and raised adiponectin. However, it was noteworthy that the Biotransformed extract was also able to significantly reduce IL-6 concentration while the Natural extract was not. The Biotransformed citrus extract evaluated in this study showed anti-inflammatory activity in macrophages and in co-culture, indicating that bioprocess of citrus residue can contribute to new product development with anti-inflammatory potential.
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Affiliation(s)
- Vânia Mayumi Nakajima
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil.
| | - Tais Moala
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil
| | - Cintia Rabelo E Paiva Caria
- Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Bragança Paulista, SP, Brazil
| | - Carolina Soares Moura
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil
| | - Jaime Amaya-Farfan
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil
| | - Alessandra Gambero
- Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Bragança Paulista, SP, Brazil
| | - Gabriela Alves Macedo
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil
| | - Juliana Alves Macedo
- Department of Food and Nutrition, Faculty of Food Engineering, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 80, Cidade Universitária Zeferino Vaz, CP 6121, CEP 13083-862 Campinas, SP, Brazil
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Boonpawa R, Spenkelink A, Punt A, Rietjens IMCM. Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans. Mol Nutr Food Res 2017; 61. [PMID: 28218440 DOI: 10.1002/mnfr.201600894] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/31/2017] [Accepted: 02/13/2017] [Indexed: 01/01/2023]
Abstract
SCOPE To develop a physiologically based kinetic (PBK) model that describes the absorption, distribution, metabolism, and excretion of hesperidin in humans, enabling the translation of in vitro concentration-response curves to in vivo dose-response curves. METHODS AND RESULTS The PBK model for hesperidin in humans was developed based on in vitro metabolic parameters. Hesperidin was predicted to mainly occur in the systemic circulation as different monoglucuronides. The plasma concentrations of hesperidin aglycone (hesperetin) was predicted to be <0.02 mg/L at an oral dose of 50 mg/kg bw. The developed PBK model allowed conversion of in vitro concentration-response curves for different effects to in vivo dose-response curves. The BMD05 (benchmark dose for 5% response) values for protein kinase A inhibition ranged between 135 and 529 mg/kg bw hesperidin, and for inhibition of endothelial cell migration and prostaglandin E2 and nitric oxide production ranged between 2.19 and 44 mg/kg bw hesperidin. These values are in line with reported human data showing in vivo effects by hesperidin and show that these effects may occur at Western dietary and supplementary intake of hesperidin. CONCLUSIONS The developed PBK model adequately predicts absorption, distribution, metabolism, and excretion of hesperidin in humans and allows to evaluate the human in vivo situation without the need for human intervention studies.
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Affiliation(s)
- Rungnapa Boonpawa
- Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands
| | - Albertus Spenkelink
- Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands
| | - Ans Punt
- Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands
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42
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Fusi F, Spiga O, Trezza A, Sgaragli G, Saponara S. The surge of flavonoids as novel, fine regulators of cardiovascular Ca v channels. Eur J Pharmacol 2016; 796:158-174. [PMID: 28012974 DOI: 10.1016/j.ejphar.2016.12.033] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/15/2016] [Accepted: 12/20/2016] [Indexed: 01/28/2023]
Abstract
Ion channels underlie a wide variety of physiological processes that involve rapid changes in cell dynamics, such as cardiac and vascular smooth muscle contraction. Overexpression or dysfunction of these membrane proteins are the basis of many cardiovascular diseases that represent the leading cause of morbidity and mortality for human beings. In the last few years, flavonoids, widely distributed in the plant kingdom, have attracted the interest of many laboratories as an emerging class of fine ion, in particular Cav, channels modulators. Pieces of in vitro evidence for direct as well as indirect effects exerted by various flavonoids on ion channel currents are now accumulating in the scientific literature. This activity may be responsible, at least in part, for the beneficial and protective effects of dietary flavonoids toward cardiovascular diseases highlighted in several epidemiological studies. Here we examine numerous studies aimed at analysing this feature of flavonoids, focusing on the mechanisms that promote their sometimes controversial activities at cardiovascular Cav channels. New methodological approaches, such as molecular modelling and docking to Cav1.2 channel α1c subunit, used to elucidate flavonoids intrinsic mechanism of action, are introduced. Moreover, flavonoid-membrane interaction, bioavailability, and antioxidant activity are taken into account and discussed.
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Affiliation(s)
- Fabio Fusi
- Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy.
| | - Ottavia Spiga
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy
| | - Alfonso Trezza
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy
| | - Giampietro Sgaragli
- Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy
| | - Simona Saponara
- Dipartimento di Scienze della Vita, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy
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Rendeiro C, Dong H, Saunders C, Harkness L, Blaze M, Hou Y, Belanger RL, Altieri V, Nunez MA, Jackson KG, Corona G, Lovegrove JA, Spencer JPE. Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: a randomised, controlled, double-masked, cross-over intervention study. Br J Nutr 2016; 116:1999-2010. [PMID: 28065188 DOI: 10.1017/s0007114516004219] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Specific flavonoid-rich foods/beverages are reported to exert positive effects on vascular function; however, data relating to effects in the postprandial state are limited. The present study investigated the postprandial, time-dependent (0-7 h) impact of citrus flavanone intake on vascular function. An acute, randomised, controlled, double-masked, cross-over intervention study was conducted by including middle-aged healthy men (30-65 years, n 28) to assess the impact of flavanone intake (orange juice: 128·9 mg; flavanone-rich orange juice: 272·1 mg; homogenised whole orange: 452·8 mg; isoenergetic control: 0 mg flavanones) on postprandial (double meal delivering a total of 81 g of fat) endothelial function. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery at 0, 2, 5 and 7 h. Plasma levels of naringenin/hesperetin metabolites (sulphates and glucuronides) and nitric oxide species were also measured. All flavanone interventions were effective at attenuating transient impairments in FMD induced by the double meal (7 h post intake; P<0·05), but no dose-response effects were observed. The effects on FMD coincided with the peak of naringenin/hesperetin metabolites in circulation (7 h) and sustained levels of plasma nitrite. In summary, citrus flavanones are effective at counteracting the negative impact of a sequential double meal on human vascular function, potentially through the actions of flavanone metabolites on nitric oxide.
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Affiliation(s)
- Catarina Rendeiro
- 1Department of Food and Nutritional Sciences,School of Chemistry, Food and Pharmacy,University of Reading,PO Box 226,Reading RG2 6AP,UK
| | - Honglin Dong
- 1Department of Food and Nutritional Sciences,School of Chemistry, Food and Pharmacy,University of Reading,PO Box 226,Reading RG2 6AP,UK
| | | | - Laura Harkness
- 3Global R+D Nutrition,PepsiCo Inc.,Valhalla, NY 10595,USA
| | - Melvin Blaze
- 4PepsiCo R+D Biological & Discovery Analytics,PepsiCo Inc.,New Haven, CT 06511,USA
| | - Yanpeng Hou
- 4PepsiCo R+D Biological & Discovery Analytics,PepsiCo Inc.,New Haven, CT 06511,USA
| | | | | | | | | | - Giulia Corona
- 1Department of Food and Nutritional Sciences,School of Chemistry, Food and Pharmacy,University of Reading,PO Box 226,Reading RG2 6AP,UK
| | - Julie A Lovegrove
- 1Department of Food and Nutritional Sciences,School of Chemistry, Food and Pharmacy,University of Reading,PO Box 226,Reading RG2 6AP,UK
| | - Jeremy P E Spencer
- 1Department of Food and Nutritional Sciences,School of Chemistry, Food and Pharmacy,University of Reading,PO Box 226,Reading RG2 6AP,UK
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44
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Antispasmodic effect of selected Citrus flavonoids on rat isolated jejunum specimens. Eur J Pharmacol 2016; 791:640-646. [DOI: 10.1016/j.ejphar.2016.10.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/28/2016] [Accepted: 10/05/2016] [Indexed: 11/23/2022]
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45
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Inhibitory effects of hesperetin on Kv1.5 potassium channels stably expressed in HEK 293 cells and ultra-rapid delayed rectifier K + current in human atrial myocytes. Eur J Pharmacol 2016; 789:98-108. [DOI: 10.1016/j.ejphar.2016.07.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 06/29/2016] [Accepted: 07/07/2016] [Indexed: 12/16/2022]
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46
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Zhao M, Wang S, Li F, Dong D, Wu B. Arylsulfatase B Mediates the Sulfonation-Transport Interplay in Human Embryonic Kidney 293 Cells Overexpressing Sulfotransferase 1A3. Drug Metab Dispos 2016; 44:1441-9. [PMID: 27325375 DOI: 10.1124/dmd.116.070938] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 06/17/2016] [Indexed: 02/13/2025] Open
Abstract
Elucidating the intricate relationships between metabolic and transport pathways contributes to improved predictions of in vivo drug disposition and drug-drug interactions. Here we reported that inhibited excretion of conjugative metabolites [i.e., hesperetin 3'-O-sulfate (H3'S) and hesperetin 7-O-sulfate (H7S)] by MK-571 led to reduced metabolism of hesperetin (a maximal 78% reduction) in human embryonic kidney 293 cells overexpressing sulfotransferase 1A3 (named SULT293 cells). The strong dependence of cellular sulfonation on the efflux transport of generated sulfated metabolites revealed an interplay of sulfonation metabolism with efflux transport (or sulfonation-transport interplay). Polymerase chain reaction (PCR) and Western blot analyses demonstrated that SULT293 cells expressed multiple sulfatases such as arylsulfatase A (ARSA), ARSB, and ARSC. Of these three desulfonation enzymes, only ARSB showed significant activities toward hesperetin sulfates. The intrinsic clearance values for the hydrolysis of H3'S and H7S were estimated at 0.6 and 0.5 μl/h/mg, respectively. Furthermore, knockdown of ARSB attenuated the regulatory effect of efflux transporter on cellular sulfonation, whereas overexpression of ABSB enhanced the transporter effect. Taken together, the results indicated that ARSB mediated the sulfonation-transport interplay in SULT293 cells.
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Affiliation(s)
- Mengjing Zhao
- Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (M.Z., S.W., B.W.); and Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine, Guangzhou, China (F.L., D.D.)
| | - Shuai Wang
- Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (M.Z., S.W., B.W.); and Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine, Guangzhou, China (F.L., D.D.)
| | - Feng Li
- Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (M.Z., S.W., B.W.); and Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine, Guangzhou, China (F.L., D.D.)
| | - Dong Dong
- Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (M.Z., S.W., B.W.); and Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine, Guangzhou, China (F.L., D.D.)
| | - Baojian Wu
- Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (M.Z., S.W., B.W.); and Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine, Guangzhou, China (F.L., D.D.)
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47
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Xue M, Weickert MO, Qureshi S, Kandala NB, Anwar A, Waldron M, Shafie A, Messenger D, Fowler M, Jenkins G, Rabbani N, Thornalley PJ. Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation. Diabetes 2016; 65:2282-94. [PMID: 27207552 DOI: 10.2337/db16-0153] [Citation(s) in RCA: 163] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/27/2016] [Indexed: 11/13/2022]
Abstract
Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m(2)), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (-37%, P < 0.05) and total body methylglyoxal-protein glycation (-14%, P < 0.01). It decreased fasting and postprandial plasma glucose (-5%, P < 0.01, and -8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min(-1) ⋅ m(-2), P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (-10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.
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Affiliation(s)
- Mingzhan Xue
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K
| | - Martin O Weickert
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire National Health Service Trust, Coventry, U.K
| | - Sheharyar Qureshi
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire National Health Service Trust, Coventry, U.K
| | - Ngianga-Bakwin Kandala
- Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K
| | - Attia Anwar
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K
| | - Molly Waldron
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K
| | - Alaa Shafie
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K
| | | | - Mark Fowler
- Unilever Research & Development Colworth, Bedford, U.K
| | - Gail Jenkins
- Unilever Research & Development Colworth, Bedford, U.K
| | - Naila Rabbani
- Warwick Systems Biology Centre, University of Warwick, Coventry, U.K
| | - Paul J Thornalley
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwick Systems Biology Centre, University of Warwick, Coventry, U.K.
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Masuda H, Mori N, Hirobe Y, Tanaka R, Chino D, Watanabe T, Fukuwatari T. Different Contribution of Non-volatile and Volatile Components in Winter Savory (<i>Satureja montana</i> L.) to Changes in Human Body Temperature. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2016. [DOI: 10.3136/fstr.22.817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
| | - Noriyuki Mori
- School of Human Cultures, The University of Shiga Prefecture
| | - Yuka Hirobe
- School of Human Cultures, The University of Shiga Prefecture
| | - Risako Tanaka
- School of Human Cultures, The University of Shiga Prefecture
| | - Daisuke Chino
- Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University
| | - Tatsuo Watanabe
- School of Food and Nutritional Sciences, University of Shizuoka
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Arya A, Khandelwal K, Ahmad H, Laxman TS, Sharma K, Mittapelly N, Agrawal S, Bhatta RS, Dwivedi AK. Co-delivery of hesperetin enhanced bicalutamide induced apoptosis by exploiting mitochondrial membrane potential via polymeric nanoparticles in a PC-3 cell line. RSC Adv 2016. [DOI: 10.1039/c5ra23067e] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In this research, we reported the co-delivery of anti-androgen drug Bicalutamide with Hesperetin in chitosan coated polycaprolactone nanoparticles to increase their therapeutic efficacy against an androgen independent prostate cancer cell lines.
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Affiliation(s)
- Abhishek Arya
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
- Academy of Scientific & Innovative Research
| | - Kiran Khandelwal
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
- Jawaharlal Nehru University
| | - Hafsa Ahmad
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
| | - Tulsankar Sachin Laxman
- Academy of Scientific & Innovative Research
- Chennai-600113
- India
- Pharmacokinetics and Metabolism
- CSIR-Central Drug Research Institute
| | - Komal Sharma
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
- Academy of Scientific & Innovative Research
| | - Naresh Mittapelly
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
- Academy of Scientific & Innovative Research
| | - Satish Agrawal
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
- Academy of Scientific & Innovative Research
| | - Rabi S. Bhatta
- Pharmacokinetics and Metabolism
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
| | - Anil K. Dwivedi
- Pharmaceutics Division
- CSIR-Central Drug Research Institute
- Lucknow-226031
- India
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Giménez-Bastida JA, González-Sarrías A, Vallejo F, Espín JC, Tomás-Barberán FA. Hesperetin and its sulfate and glucuronide metabolites inhibit TNF-α induced human aortic endothelial cell migration and decrease plasminogen activator inhibitor-1 (PAI-1) levels. Food Funct 2016; 7:118-26. [DOI: 10.1039/c5fo00771b] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Hesperetin and its derived metabolites, at physiologically relevant concentrations, significantly attenuated TNF-α-induced cell migration.
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Affiliation(s)
| | - Antonio González-Sarrías
- Research Group on Quality
- Safety and Bioactivity of Plant Foods
- Dept. Food Science and Technology
- CEBAS-CSIC
- Murcia
| | - Fernando Vallejo
- Research Group on Quality
- Safety and Bioactivity of Plant Foods
- Dept. Food Science and Technology
- CEBAS-CSIC
- Murcia
| | - Juan Carlos Espín
- Research Group on Quality
- Safety and Bioactivity of Plant Foods
- Dept. Food Science and Technology
- CEBAS-CSIC
- Murcia
| | - Francisco A. Tomás-Barberán
- Research Group on Quality
- Safety and Bioactivity of Plant Foods
- Dept. Food Science and Technology
- CEBAS-CSIC
- Murcia
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