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      Solutol ®HS15+pluronicF127 and Solutol ®HS15+pluronicL61 mixed micelle systems for oral delivery of genistein

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          Purpose: We aimed to prepare two oral drug delivery systems consisting of polyoxyl 15 hydroxystearate (HS15) with pluronicF127 (F127) and HS15 with pluronicL61 (L61) to overcome the challenges of genistein’s poor oral bioavailability. This provides a good strategy for enhancing the potential value of genistein.

          Methods: We designed two binary mixed micelle systems employing the organic solvent evaporation method using surfactants (HS15, L61, and F127). Formulations (GEN-F and GEN-L) were characterized by transmission electron microscopy. Drug content analysis, including entrapment efficiency (EE%), drug loading (DL%), and the cumulative amount of genistein released from the micelles, was performed using HPLC. The permeability of optimum formulation was measured in Caco-2 cell monolayers, and the oral bioavailability was evaluated in SD rats.

          Results: The solutions of GEN-F and GEN-L were observed to be transparent and colorless. GEN-F had a lower EE% of 80.79±0.55% and a DL% of 1.69±0.24% compared to GEN-L, which had an EE% 83.40±1.36% and a DL% 2.26±0.18%. TEM results showed that the morphology of GEN-F and GEN-L was homogeneous and resembled a spherical shape. The dilution and storage conditions had no significant effect on particle size and EE%. Genistein demonstrated a sustained release behavior when encapsulated in micelles. Pharmacokinetics study showed that the relative oral bioavailability of GEN-F and GEN-L increased by 2.23 and 3.46 fold while also enhancing the permeability of genistein across a Caco-2 cell monolayer compared to that of raw genistein.

          Conclusion: GEN-F and GEN-L as a drug delivery system provide an effective strategy for enhancing and further realizing the potential value of GEN.

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          Most cited references 47

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          Genistein and cancer: current status, challenges, and future directions.

          Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety.
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            Genistein: Its role in metabolic diseases and cancer.

            Genistein is an isoflavone present in soy and is known to have multiple molecular effects, such as the inhibition of inflammation, promotion of apoptosis, and modulation of steroidal hormone receptors and metabolic pathways. Since these molecular effects impact carcinogenesis, cancer propagation, obesity, osteoporosis, and metabolic syndromes, genistein plays an important role in preventing and treating common disorders. The role of genistein has not been adequately evaluated in all these clinical settings. This review summarizes some of the known molecular effects of genistein and its potential role in health maintenance and treatment.
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              Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic β-cell function.

              Type 2 diabetes is a result of chronic insulin resistance and loss of functional pancreatic β-cell mass. Strategies to preserve β-cell mass and a greater understanding of the mechanisms underlying β-cell turnover are needed to prevent and treat this devastating disease. Genistein, a naturally occurring soy isoflavone, is reported to have numerous health benefits attributed to multiple biological functions. Over the past 10 years, numerous studies have demonstrated that genistein has anti-diabetic effects, in particular, direct effects on β-cell proliferation, glucose-stimulated insulin secretion and protection against apoptosis, independent of its functions as an estrogen receptor agonist, antioxidant, or tyrosine kinase inhibitor. Effects are structure-specific and not common to all flavonoids. While there are limited data on the effects of genistein consumption in humans with diabetes, there are a plethora of animal and cell-culture studies that demonstrate a direct effect of genistein on β-cells at physiologically relevant concentrations (<10 μM). The effects appear to involve cAMP/PKA signaling and there are some studies that suggest an effect on epigenetic regulation of gene expression. This review focuses on the anti-diabetic effects of genistein in both in vitro and in vivo models and potential mechanisms underlying its direct effects on β-cells.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                07 June 2019
                : 13
                : 1947-1956
                [1 ]Department of Pharmaceutical Analysis and Metabolomics, Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine , Nanjing, People’s Republic of China
                [2 ]Department of Pharmaceutical Analysis and Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing, People’s Republic of China
                [3 ]School of Holistic Integrative Medicine, Nanjing University of Chinese Medicine , Nanjing, People’s Republic of China
                [4 ]Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, People’s Republic of China
                [5 ]Department of Marine Pharmacy, China Pharmaceutical University , Nanjing, People’s Republic of China
                Author notes
                Correspondence: Jianming JuJiangsu Province Academy of Traditional Chinese Medicine , NO. 100, Shizi Street, Hongshan Road, Qixia District, Nanjing210028, People’s Republic of ChinaEmail jjm405@ 123456sina.com
                Weiguang LiDepartment of Marine Pharmacy, China Pharmaceutical University , NO.639, Longmian Avenue, Jiangning District, Nanjing210009, People’s Republic of ChinaEmail welllwg@ 123456163.com

                These authors contributed equally to this work

                © 2019 Ding et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 4, References: 47, Pages: 10
                Original Research


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