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Revisiting the bioavailability of flavan-3-ols in humans: A systematic review and comprehensive data analysis. Mol Aspects Med 2023; 89:101146. [PMID: 36207170 DOI: 10.1016/j.mam.2022.101146] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/08/2022] [Accepted: 09/24/2022] [Indexed: 11/07/2022]
Abstract
This systematic review summarizes findings from human studies investigating the different routes of absorption, metabolism, distribution and excretion (ADME) of dietary flavan-3-ols and their circulating metabolites in healthy subjects. Literature searches were performed in PubMed, Scopus and the Web of Science. Human intervention studies using single and/or multiple intake of flavan-3-ols from food, extracts, and pure compounds were included. Forty-nine human intervention studies met inclusion criteria. Up to 180 metabolites were quantified from blood and urine samples following intake of flavan-3-ols, mainly as phase 2 conjugates of microbial catabolites (n = 97), with phenyl-γ-valerolactones being the most representative ones (n = 34). Phase 2 conjugates of monomers and phenyl-γ-valerolactones, the main compounds in both plasma and urine, reached two peak plasma concentrations (Cmax) of 260 and 88 nmol/L at 1.8 and 5.3 h (Tmax) after flavan-3-ol intake. They contributed to the bioavailability of flavan-3-ols for over 20%. Mean bioavailability for flavan-3-ols was moderate (31 ± 23%, n bioavailability values = 20), and it seems to be scarcely affected by the amount of ingested compounds. While intra- and inter-source differences in flavan-3-ol bioavailability emerged, mean flavan-3-ol bioavailability was 82% (n = 1) and 63% (n = 2) after (-)-epicatechin and nut (hazelnuts, almonds) intake, respectively, followed by 25% after consumption of tea (n = 7), cocoa (n = 5), apples (n = 3) and grape (n = 2). This highlights the need to better clarify the metabolic yield with which monomer flavan-3-ols and proanthocyanidins are metabolized in humans. This work clarified in a comprehensive way for the first time the ADME of a (poly)phenol family, highlighting the pool of circulating compounds that might be determinants of the putative beneficial effects linked to flavan-3-ol intake. Lastly, methodological inputs for implementing well-designed human and experimental model studies were provided.
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Antileishmanial Activity of Lignans, Neolignans, and Other Plant Phenols. PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS 2021; 115:115-176. [PMID: 33797642 DOI: 10.1007/978-3-030-64853-4_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Secondary metabolites (SM) from organisms have served medicinal chemists over the past two centuries as an almost inexhaustible pool of new drugs, drug-like skeletons, and chemical probes that have been used in the "hunt" for new biologically active molecules with a "beneficial effect on human mind and body." Several secondary metabolites, or their derivatives, have been found to be the answer in the quest to search for new approaches to treat or even eradicate many types of diseases that oppress humanity. A special place among SM is occupied by lignans and neolignans. These phenolic compounds are generated biosynthetically via radical coupling of two phenylpropanoid monomers, and are known for their multitarget activity and low toxicity. The disadvantage of the relatively low specificity of phenylpropanoid-based SM turns into an advantage when structural modifications of these skeletons are made. Indeed, phenylpropanoid-based SM previously have proven to offer great potential as a starting point in drug development. Compounds such as Warfarin® (a coumarin-based anticoagulant) as well as etoposide and teniposide (podophyllotoxin-based anticancer drugs) are just a few examples. At the beginning of the third decade of the twenty-first century, the call for the treatment of more than a dozen rare or previously "neglected" diseases remains for various reasons unanswered. Leishmaniasis, a neglected disease that desperately needs new ways of treatment, is just one of these. This disease is caused by more than 20 leishmanial parasites that are pathogenic to humans and are spread by as many as 800 sandfly species across subtropical areas of the world. With continuing climate changes, the presence of Leishmania parasites and therefore leishmaniasis, the disease caused by these parasites, is spreading from previous locations to new areas. Thus, leishmaniasis is affecting each year a larger proportion of the world's population. The choice of appropriate leishmaniasis treatment depends on the severity of the disease and its form of manifestation. The success of current drug therapy is often limited, due in most cases to requiring long hospitalization periods (weeks to months) and the toxicity (side effects) of administered drugs, in addition to the increasing resistance of the parasites to treatment. It is thus important to develop new drugs and treatments that are less toxic, can overcome drug resistance, and require shorter periods of treatment. These aspects are especially important for the populations of developing countries. It was reported that several phenylpropanoid-based secondary metabolites manifest interesting antileishmanial activities and are used by various indigenous people to treat leishmaniasis. In this chapter, the authors shed some light on the various biological activities of phenylpropanoid natural products, with the main focus being on their possible applications in the context of antileishmanial treatment.
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H. Shariare M, Afnan K, Iqbal F, A. Altamimi M, Ahamad SR, S. Aldughaim M, K. Alanazi F, Kazi M. Development and Optimization of Epigallocatechin-3-Gallate (EGCG) Nano Phytosome Using Design of Experiment (DoE) and Their In Vivo Anti-Inflammatory Studies. Molecules 2020; 25:molecules25225453. [PMID: 33233756 PMCID: PMC7699940 DOI: 10.3390/molecules25225453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/14/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Inflammation is responsible for the development of many diseases that make up a significant cause of death. The purpose of the study was to develop a novel nanophytosomal preparation of epigallocatechin-3-gallate (EGCG) and egg phospholipid complex that has a lower particle size with higher drug loading capability, physical stability and anti-inflammatory activities. The impact of different factors and material characteristics on the average particle size was studied along with the drug loading of phytosome using design of experiment (DoE). The in vivo anti-inflammatory study was evaluated using a rat model to investigate the performance of EGCG nanophytosome. UHPLC results showed that 500 µg of EGCG were present in 1 mL of green tea extract. SEM data exhibited that phytosome (phospholipid-drug complex) was in the nanosize range, which was further evident from TEM data. Malvern Zetasizer data showed that the average particle size of the EGCG nanophytosome was in the range of 100–250 nm. High drug loading (up to 90%) was achieved with optimum addition rate, stirring temperature and phospholipid concentration. Stability study data suggest that no significant changes were observed in average particle size and drug loading of nanophytome. The in vivo anti-inflammatory study indicated a significant anti-inflammatory activity of green tea extract, pure EGCG and its phytosomal preparations (p ≤ 0.001) against acute paw edema.
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Affiliation(s)
- Mohammad H. Shariare
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (K.A.); (F.I.)
| | - Kazi Afnan
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (K.A.); (F.I.)
| | - Faria Iqbal
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (K.A.); (F.I.)
| | - Mohammad A. Altamimi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.A.); (F.K.A.)
| | - Syed Rizwan Ahamad
- Central Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Mohammed S. Aldughaim
- Research Center, King Fahad Medical City, P.O. Box. 59046, Riyadh 11525, Saudi Arabia;
| | - Fars K. Alanazi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.A.); (F.K.A.)
| | - Mohsin Kazi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.A.); (F.K.A.)
- Correspondence: ; Tel.: +966-(0)-114677372; Fax: +966-(0)-114676295
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Mouhid L, Corzo-Martínez M, Torres C, Vázquez L, Reglero G, Fornari T, Ramírez de Molina A. Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems. JOURNAL OF ONCOLOGY 2017; 2017:7351976. [PMID: 28555156 PMCID: PMC5438845 DOI: 10.1155/2017/7351976] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/06/2017] [Indexed: 02/07/2023]
Abstract
Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.
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Affiliation(s)
- Lamia Mouhid
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
| | - Marta Corzo-Martínez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Carlos Torres
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Luis Vázquez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Guillermo Reglero
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Tiziana Fornari
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
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Gilardini L, Pasqualinotto L, Di Pierro F, Risso P, Invitti C. Effects of Greenselect Phytosome® on weight maintenance after weight loss in obese women: a randomized placebo-controlled study. Altern Ther Health Med 2016; 16:233. [PMID: 27450231 PMCID: PMC4957378 DOI: 10.1186/s12906-016-1214-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 07/14/2016] [Indexed: 11/23/2022]
Abstract
Background Most subjects regain weight after weight loss due to compensatory adaptations finalized to maintain stable body energy stores. Green tea (GT) preparations, which help maintain energy expenditure while dieting could be a useful strategy to facilitate weight maintenance. The usefulness of GT preparations in weight maintenance has been poorly studied so far with conflicting results. This study evaluated if a supplement of GSP and piperine helps obese women to maintain the weight loss obtained with a 3-month lifestyle intervention. Methods In a randomized placebo-controlled study, we examined whether a highly bioavailable GT extract may counteract weight regain after weight loss. Forty obese women (age 50.1 ± 10.1 years, Body Mass Index (BMI) 36.3 ± 2.7 kg/m2) underwent a 3-month lifestyle intervention. At the end of the intervention, the women were randomized in two groups for the weight-maintenance phase: 20 of them were prescribed twice a day, for 3 months, with a formula containing 150 mg/dose of Greenselect Phytosome® and 15 mg/dose of pure piperine (GSP group), and 20 were given placebo (P group). Anthropometric measures and body composition were measured before (V-3) and after lifestyle intervention (V0), 1 (V1), 2 (V2), and 3 (V3) months after prescribing supplements and 3 months following the discontinuation of supplements (V6). Results Lifestyle intervention induced a significant weight reduction in both groups with similar weight change (−6.2 ± 2.6 in GSP group vs. −4.8 ± 3.1 % in P group). In the GSP group, V1 in comparison to V0, had further reduction in weight and fat mass, which remained stable at V2 and V3 and increased at V6. In the P group, weight and fat mass increased from V2 onwards. Weight changes in GSP group and P group from V0 to V3 were −1.0 kg (95 % CI −2.5 to +0.5) and + 0.3 kg (95 % CI −0.9 to +1.6), respectively. The proportion of women with weight loss ≥ 5 % was greater in the GSP group than in the P group (75 % vs. 45 % at V1, and 60 % vs. 30 % at V6, p < 0.05 for both groups). Conclusions Greenselect Phytosome® devoid of caffeine may have a clinical potential for the maintenance of weight after intentional weight loss. Trial registration Clinicaltrials.gov NCT02542449 (September 2015) Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1214-x) contains supplementary material, which is available to authorized users.
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Gu LT, Yang J, Su SZ, Liu WW, Shi ZG, Wang QR. Green Tea Polyphenols Protects Cochlear Hair Cells from Ototoxicity by Inhibiting Notch Signalling. Neurochem Res 2015; 40:1211-9. [PMID: 25896296 DOI: 10.1007/s11064-015-1584-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 04/06/2015] [Accepted: 04/15/2015] [Indexed: 02/07/2023]
Abstract
Notch signalling pathway plays an essential role in the development of cochlea, which inhibits the proliferation of hair cells. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea, which presents strong antioxidant activation and has been applied for anti-cancer and anti-inflammatory. In this study, we treated the cochlear explant cultures with EGCG and found that EGCG can protect cochlear hair cells from ototoxic drug gentamicin. We demonstrated that EGCG could down-regulate the expression of Notch signalling pathway target genes, such as Hes1, Hes5, Hey1 and Hey5. However, the Notch pathway ligands such as Delta1, Jag1 and Jag2 were not affected by EGCG. To further illustrate the mechanism of recover cochlear hair cells, we demonstrated that EGCG inhibited the activity of γ-secrectase to suppress Notch signalling pathway and promoted the proliferation and regeneration of hair cells in the damaged cochlea. Our results suggest for the first time the role of EGCG as an inhibitor of the Notch signalling pathway, and support its potential value in hearing-impaired recovery in clinical therapy.
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Affiliation(s)
- Lin-Tao Gu
- Department of Otolaryngology-Head and Neck Surgery, Qianfo Shan Hospital Affiliated to Shandong University, Jinan, 250014, People's Republic of China
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González J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: New insights. World J Cardiol 2014; 6:353-366. [PMID: 24976907 PMCID: PMC4072825 DOI: 10.4330/wjc.v6.i6.353] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 03/01/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated, a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents, such as superoxide anion, and antioxidant molecules, and leads to a decrease in nitric oxide bioavailability, which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides, such as angiotensin II, endothelin-1 and urotensin II, act through their receptors to stimulate the production of reactive oxygen species, by activating enzymes like NADPH oxidase and xanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents, including vitamin C and E, N-Acetylcysteine, polyphenols and selenium, among others. These substances have different therapeutic targets, but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.
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Bilia AR, Isacchi B, Righeschi C, Guccione C, Bergonzi MC. Flavonoids Loaded in Nanocarriers: An Opportunity to Increase Oral Bioavailability and Bioefficacy. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/fns.2014.513132] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Greenselect phytosome for borderline metabolic syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:869061. [PMID: 24348726 PMCID: PMC3848081 DOI: 10.1155/2013/869061] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 09/26/2013] [Accepted: 09/27/2013] [Indexed: 02/07/2023]
Abstract
The beneficial effects of Greenselect Phytosome, a proprietary lecithin formulation of a caffeine-free green tea catechin extract, were evaluated in a controlled registry study on 50 asymptomatic subjects borderline for metabolic syndrome factors and with increased plasma oxidative stress. After 24 weeks of intervention, improvement in weight, blood lipid profile, and blood pressure positioned 68% of subjects in the treatment arm out of the metabolic syndrome profile, while 80% of the subjects in the control group still remained in their initial borderline disease signature. Compared to the control (lifestyle and dietary changes alone), Greenselect Phytosome was especially effective for weight/waist changes. These results highlight the relevance of addressing multiple factors involved in the development of metabolic syndrome with a pleiotropic agent capable of improving the beneficial effects of lifestyle and dietary changes and foster the attainment of a globally improved health profile.
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Xia HJ, Zhang ZH, Jin X, Hu Q, Chen XY, Jia XB. A novel drug-phospholipid complex enriched with micelles: preparation and evaluation in vitro and in vivo. Int J Nanomedicine 2013. [PMID: 23431115 DOI: 10.2147/ijn.s39526.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Mixed micelles are widely used to increase solubility and bioavailability of poorly soluble drugs. One promising antitumor drug candidate is 20(S)-protopanaxadiol (PPD), although its clinical application is limited by low water solubility and poor bioavailability after oral administration. In this study, we developed mixed micelles consisting of PPD-phospholipid complexes and Labrasol(®) and evaluated their potential for oral PPD absorption. Micelles were prepared using a solvent-evaporation method, and their physicochemical properties, including particle size, zeta potential, morphology, crystal type, drug loading, drug entrapment efficiency, and solubility, were characterized. Furthermore, in vitro release was investigated using the dialysis method, and transport and bioavailability of the mixed micelles were investigated through a Caco-2 cell monolayer and in vivo absorption studies performed in rats. Compared with the solubility of free PPD (3 μg/mL), the solubility of PPD in the prepared mixed micelles was 192.41 ± 1.13 μg/mL in water at room temperature. The in vitro release profiles showed a significant difference between the more rapid release of free PPD and the slower and more sustained release of the mixed micelles. At the end of a 4-hour transport study using Caco-2 cells, the apical-to-basolateral apparent permeability coefficients (P(app)) increased from (1.12 ± 0.21) × 10(6) cm/s to (1.78 ± 0.16) × 10(6) cm/s, while the basolateral-to-apical P(app) decreased from (2.42 ± 0.16) × 10(6) cm/s to (2.12 ± 0.32) × 10(6). In this pharmacokinetic study, compared with the bioavailability of free PPD (area under the curve [AUC](0-∞)), the bioavailability of PPD from the micelles (AUC(0-∞)) increased by approximately 216.36%. These results suggest that novel mixed micelles can significantly increase solubility, enhance absorption, and improve bioavailability. Thus, these prepared micelles might be potential carriers for oral PPD delivery in antitumor therapies.
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Affiliation(s)
- Hai-jian Xia
- Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, China
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Xia HJ, Zhang ZH, Jin X, Hu Q, Chen XY, Jia XB. A novel drug-phospholipid complex enriched with micelles: preparation and evaluation in vitro and in vivo. Int J Nanomedicine 2013; 8:545-54. [PMID: 23431115 PMCID: PMC3575161 DOI: 10.2147/ijn.s39526] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Indexed: 12/26/2022] Open
Abstract
Mixed micelles are widely used to increase solubility and bioavailability of poorly soluble drugs. One promising antitumor drug candidate is 20(S)-protopanaxadiol (PPD), although its clinical application is limited by low water solubility and poor bioavailability after oral administration. In this study, we developed mixed micelles consisting of PPD–phospholipid complexes and Labrasol® and evaluated their potential for oral PPD absorption. Micelles were prepared using a solvent-evaporation method, and their physicochemical properties, including particle size, zeta potential, morphology, crystal type, drug loading, drug entrapment efficiency, and solubility, were characterized. Furthermore, in vitro release was investigated using the dialysis method, and transport and bioavailability of the mixed micelles were investigated through a Caco-2 cell monolayer and in vivo absorption studies performed in rats. Compared with the solubility of free PPD (3 μg/mL), the solubility of PPD in the prepared mixed micelles was 192.41 ± 1.13 μg/mL in water at room temperature. The in vitro release profiles showed a significant difference between the more rapid release of free PPD and the slower and more sustained release of the mixed micelles. At the end of a 4-hour transport study using Caco-2 cells, the apical-to-basolateral apparent permeability coefficients (Papp) increased from (1.12 ± 0.21) × 106 cm/s to (1.78 ± 0.16) × 106 cm/s, while the basolateral-to-apical Papp decreased from (2.42 ± 0.16) × 106 cm/s to (2.12 ± 0.32) × 106. In this pharmacokinetic study, compared with the bioavailability of free PPD (area under the curve [AUC]0–∞), the bioavailability of PPD from the micelles (AUC0–∞) increased by approximately 216.36%. These results suggest that novel mixed micelles can significantly increase solubility, enhance absorption, and improve bioavailability. Thus, these prepared micelles might be potential carriers for oral PPD delivery in antitumor therapies.
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Affiliation(s)
- Hai-jian Xia
- Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, China
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Abstract
Green tea is made from unfermented dried leaves from Camellia sinensis and has been consumed by humans for thousands of years. For nearly as long, it has been used as a folk remedy for a wide array of diseases. More recently, a large number of in-vitro and in-vivo scientific studies have supported this ancient contention that the polyphenols from green tea can provide a number of health benefits. Since these compounds are clearly safe for human consumption and ubiquitous in the food supply, they are highly attractive as lead compounds for drug discovery programs. However, as drugs, they are far from optimum. They are relatively unstable, poorly absorbed, and readily undergo a number of metabolic transformations by intestinal microbiota and human enzymes. Further, since these compounds target a wide array of biological systems, in-vivo testing is rather difficult since effects on alternative pathways need to be carefully eliminated. The purpose of this review is to discuss some of the challenges and benefits of pursuing this family of compounds for drug discovery.
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Affiliation(s)
- Thomas J Smith
- Donald Danforth Plant Science Center, 975 North Warson Road, Saint Louis, MO 63132 USA, Tel: (314)-587-1451
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Li L, Chen CYO, Aldini G, Johnson EJ, Rasmussen H, Yoshida Y, Niki E, Blumberg JB, Russell RM, Yeum KJ. Supplementation with lutein or lutein plus green tea extracts does not change oxidative stress in adequately nourished older adults. J Nutr Biochem 2009; 21:544-9. [PMID: 19447020 DOI: 10.1016/j.jnutbio.2009.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 02/23/2009] [Accepted: 03/02/2009] [Indexed: 02/07/2023]
Abstract
Epigallocatechin gallate, a major component of green tea polyphenols, protects against the oxidation of fat-soluble antioxidants including lutein. The current study determined the effect of a relatively high but a dietary achievable dose of lutein or lutein plus green tea extract on antioxidant status. Healthy subjects (50-70 years) were randomly assigned to one of two groups (n=20 in each group): (1) a lutein (12 mg/day) supplemented group or (2) a lutein (12 mg/day) plus green tea extract (200 mg/day) supplemented group. After 2 weeks of run-in period consuming less than two servings of lightly colored fruits and vegetables in their diet, each group was treated for 112 days while on their customary regular diets. Plasma carotenoids including lutein, tocopherols, flavanols and ascorbic acid were analyzed by HPLC-UVD and HPLC-electrochemical detector systems; total antioxidant capacity by fluorometry; lipid peroxidation by malondialdehyde using a HPLC system with a fluorescent detector and by total hydroxyoctadecadienoic acids using a GC/MS. Plasma lutein, total carotenoids and ascorbic acid concentrations of subjects in either the lutein group or the lutein plus green tea extract group were significantly increased (P<.05) at 4 weeks and throughout the 16-week study period. However, no significant changes from baseline in any biomarker of overall antioxidant activity or lipid peroxidation of the subjects were seen in either group. Our results indicate that an increase of antioxidant concentrations within a range that could readily be achieved in a healthful diet does not affect in vivo antioxidant status in normal healthy subjects when sufficient amounts of antioxidants already exist.
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Affiliation(s)
- Lei Li
- The Jean Mayer USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
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Zecher M, Guichard C, Velásquez MJ, Figueroa G, Rodrigo R. Implications of oxidative stress in the pathophysiology of obstructive uropathy. ACTA ACUST UNITED AC 2008; 37:19-26. [PMID: 19082822 DOI: 10.1007/s00240-008-0163-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Accepted: 11/25/2008] [Indexed: 02/07/2023]
Abstract
Although the functional and clinical alterations occurring in patients with obstructive uropathy are not well understood, it has been suggested that oxidative stress could contribute in the mechanism responsible for the impairment of sodium and water balance. This study aimed to test the hypothesis that red wine administration causes an amelioration of both the renal damage and impairment of renal Na(+), K(+)-ATPase activity occurring after ureteral obstruction in the rat. Twenty-four male Wistar adult rats weighting 200-250 g were used. Half of them received a 10-week treatment with wine as the sole fluid source, while the other group received water. Both groups were subjected to 24-h unilateral ureteral obstruction (UUO). Kidney tissue was collected following the relief of the ligature to perform the biochemical assessments. Urine and blood samples were taken at baseline and after the relief. Results show that the treatment with red wine significantly enhances the activity of antioxidant enzymes, and thus reduces renal lipid peroxidation secondary to UUO, which correlated negatively with Na(+), K(+)-ATPase activity. Based on this and other previous data, it could be suggested that red wine administration may prevent renal damage secondary to UUO by inducing enhanced antioxidant potential.
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Affiliation(s)
- Martin Zecher
- Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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15
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Arendt BM, Ellinger S, Kekic K, Geus L, Fimmers R, Spengler U, Müller WU, Goerlich R. Single and repeated moderate consumption of native or dealcoholized red wine show different effects on antioxidant parameters in blood and DNA strand breaks in peripheral leukocytes in healthy volunteers: a randomized controlled trial (ISRCTN68505294). Nutr J 2005; 4:33. [PMID: 16287499 PMCID: PMC1315342 DOI: 10.1186/1475-2891-4-33] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2005] [Accepted: 11/14/2005] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Red wine (RW) is rich in antioxidant polyphenols that might protect from oxidative stress related diseases, such as cardiovascular disease and cancer. Antioxidant effects after single ingestion of RW or dealcoholized RW (DRW) have been observed in several studies, but results after regular consumption are contradictory. Thus, we examined if single or repeated consumption of moderate amounts of RW or DRW exert antioxidant activity in vivo. METHODS Total phenolic content and concentration of other antioxidants in plasma/serum, total antioxidant capacity (TEAC) in plasma as well as DNA strand breaks in peripheral leukocytes were measured in healthy non-smokers A) before, 90 and 360 min after ingestion of one glass of RW, DRW or water; B) before and after consumption of one glass of RW or DRW daily for 6 weeks. DNA strand breaks (SB) were determined by single cell gel electrophoresis (Comet Assay) in untreated cells and after induction of oxidative stress ex vivo with H2O2 (300 microM, 20 min). RESULTS Both RW and DRW transiently increased total phenolic content in plasma after single consumption, but only RW lead to a sustained increase if consumed regularly. Plasma antioxidant capacity was not affected by single or regular consumption of RW or DRW. Effects of RW and DRW on DNA SB were conflicting. DNA strand breaks in untreated cells increased after a single dose of RW and DRW, whereas H2O2 induced SB were reduced after DRW. In contrast, regular RW consumption reduced SB in untreated cells but did not affect H2O2 induced SB. CONCLUSION The results suggest that consumption of both RW and DRW leads to an accumulation of phenolic compounds in plasma without increasing plasma antioxidant capacity. Red wine and DRW seem to affect the occurrence of DNA strand breaks, but this cannot be referred to antioxidant effects.
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Affiliation(s)
- Bianca M Arendt
- Department of Hemostasis and Transfusion Medicine, School of Medicine, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Sabine Ellinger
- Department of Hemostasis and Transfusion Medicine, School of Medicine, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Klaudia Kekic
- Department of Hemostasis and Transfusion Medicine, School of Medicine, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Leonie Geus
- Department of Hemostasis and Transfusion Medicine, School of Medicine, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Rolf Fimmers
- Institute for Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
| | - Ulrich Spengler
- Department of General Internal Medicine, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
| | | | - Roland Goerlich
- Institute for Molecular Biotechnology, RWTH Aachen, Worringerweg 1, 52074 Aachen, Germany
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16
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Buffoli B, Pechánová O, Kojšová S, Andriantsitohaina R, Giugno L, Bianchi R, Rezzani R. Provinol prevents CsA-induced nephrotoxicity by reducing reactive oxygen species, iNOS, and NF-kB expression. J Histochem Cytochem 2005; 53:1459-68. [PMID: 15956028 PMCID: PMC3957541 DOI: 10.1369/jhc.5a6623.2005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cyclosporine A (CsA) use is associated with several side effects, the most important of which is nephrotoxicity that includes, as we previously showed, tubular injury and interstitial fibrosis. Recently, many researchers have been interested in minimizing these effects by pharmacological interventions. To do this, we tested whether the administration of a red wine polyphenol, Provinol (PV), prevents the development of CsA-induced nephrotoxicity. Rats were treated for 21 days and divided into four groups: control; group treated with PV (40 mg/kg/day by oral administration in tap water); group treated with CsA (15 mg/kg/day by subcutaneous injection); group treated with CsA plus PV. CsA produced a significant increase of systolic blood pressure; it did not affect urinary output, but caused a significant decrease in creatinine clearance. These side effects were associated with an increase in conjugated dienes, which are lipid peroxidation products, inducible NO-synthase (iNOS), and nuclear factor (NF)-kB, which are involved in antioxidant damage. However, PV prevented these negative effects through a protective mechanism that involved reduction of both oxidative stress and increased iNOS and NF-kB expression induced by CsA. These results provide a pharmacological basis for the beneficial effects of plant-derived polyphenols against CsA-induced renal damage associated with CsA.
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Affiliation(s)
- Barbara Buffoli
- Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (BB, LG, RB, RR)
| | - Olga Pechánová
- Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic (OP, SK)
| | - Stanislava Kojšová
- Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic (OP, SK)
| | - Ramaroson Andriantsitohaina
- Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg, Illkirch, France (RA)
| | - Lorena Giugno
- Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (BB, LG, RB, RR)
| | - Rossella Bianchi
- Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (BB, LG, RB, RR)
| | - Rita Rezzani
- Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (BB, LG, RB, RR)
- Correspondence to: Prof. Rita Rezzani, Department of Biomedical Sciences and Biotechnology, Division of Human Anatomy, University of Brescia, Viale Europa, 11, 25123, Brescia, Italy. E-mail:
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17
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Benito S, Buxaderas S, Mitjavila MT. Flavonoid metabolites and susceptibility of rat lipoproteins to oxidation. Am J Physiol Heart Circ Physiol 2004; 287:H2819-24. [PMID: 15308478 DOI: 10.1152/ajpheart.00471.2004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Flavonoids are ingested with vegetables and beverages and exert a beneficial effect on cardiovascular disease. Studies in animals in vitro and in humans ex vivo on the resistance of lipoproteins to oxidation are not consistent and the mechanisms by which flavonoids protect against atherosclerosis are a matter of debate. In the present study, we investigated the effects of administering diets containing 0.3% (wt/wt) quercetin, 0.3% (wt/wt) catechin, or 35% (vol/wt) dealcoholated red wine (DRW) for 10 days in healthy rats on markers of oxidative damage in lipoproteins and in plasma. The antioxidant levels in low-density lipoproteins (LDL) or the lag phase, oxidation rate, and maximum level of conjugated dienes during ex vivo LDL oxidation did not differ between control and treated rats. Plasma levels of α-tocopherol and retinol were similar in all groups. The total antioxidant status of the plasma from rats fed either quercetin or DRW diet was higher than in control rats. Only glucuronide and sulfate compounds of quercetin were detected in plasma from rats fed the quercetin-rich diet, and no flavonoids or their metabolites were detected in plasma or LDL from rats fed the catechin- or the DRW-rich diet. No significant differences in malondialdehyde or in conjugated dienes in plasma were observed. These results indicate that although metabolites from quercetin are present in plasma, they are not detected in lipoproteins and do not modify the level of other antioxidants. In conclusion, in the absence of any pathology or of oxidative stress the intake of quercetin, catechin, or DRW did not protect lipoproteins from oxidation ex vivo.
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Affiliation(s)
- Sonia Benito
- Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain
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18
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Guleria RS, Jain A, Tiwari V, Misra MK. Protective effect of green tea extract against the erythrocytic oxidative stress injury during mycobacterium tuberculosis infection in mice. Mol Cell Biochem 2002; 236:173-81. [PMID: 12190117 DOI: 10.1023/a:1016119718321] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The present study has been undertaken to monitor the extent of oxidative stress in mice infected with M tuberculosis and the role of crude green tea extract in repairing the oxidative damage. The mice were divided into three groups of 9 each; normal, infected-untreated and infected-treated. The infected group of animals exhibited significant enhancement of erythrocytic catalase and glutathione peroxidase activities along with elevated levels of erythrocytic total thiols and plasma lipid peroxidation as compared to normal animals. The infected group also exhibited significantly decreased activity of superoxide dismutase and levels of glutathione in erythrocytes. Upon oral administration of green tea extract for seven days the oxidative stress parameters were reverted back to near normal levels as evidenced by a fall in catalase, glutathione peroxidase, total thiol and extent of lipid peroxidation with concomitant increase in the levels of SOD and reduced glutathione in infected animals. The findings thus, portray that there is a high oxidative stress during early stages of tuberculosis and antioxidants such as green tea extract, can play a vital role by reducing stress through adjuvant therapy.
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Affiliation(s)
- R S Guleria
- Department of Microbiology, K. G's. Medical College, Lucknow, UP, India
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