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      Pharmacokinetic and nephroprotective benefits of using Schisandra chinensis extracts in a cyclosporine A-based immune-suppressive regime

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          Abstract

          Cyclosporine A (CsA) is a powerful immunosuppressive drug. However, nephrotoxicity resulting from its long-term usage has hampered its prolonged therapeutic usage. Schisandra chinensis extracts (SCE) have previously been used in traditional Chinese medicine and more recently coadministered with Western medicine for the treatment of CsA-induced side effects in the People’s Republic of China. This study aimed to investigate the possible effects of SCE on the pharmacokinetics of CsA in rats and elucidate the potential mechanisms by which it hinders the development of CsA-induced nephrotoxicity. A liquid chromatography/tandem mass spectrometry method was developed and validated for determining the effect of SCE on the pharmacokinetics of CsA. Male Sprague Dawley rats, which were administered with CsA (25 mg/kg/d) alone or in combination with SCE (54 mg/kg/d and 108 mg/kg/d) for 28 days, were used to evaluate the nephroprotective effects of SCE. Our study showed that SCE increased the mean blood concentration of CsA. Furthermore, we found that the concomitant administration of SCE alongside CsA prevented the disruption of catalase activity and reduction in creatinine, urea, renal malondialdehyde, and glutathione peroxidase levels that would have otherwise occurred in the absence of SCE administration. SCE treatment markedly suppressed the expression of 4-hydroxynonenal, Bcl-2-associated X protein, cleaved caspase 3, and autophagy-related protein LC3 A/B. On the other hand, the expression of heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf2), and P-glycoprotein was enhanced by the very same addition of SCE. SCE was also able to increase the systemic exposure of CsA in rats. The renoprotective effects of SCE were thought to be mediated by its antiapoptotic and antioxidant abilities, which caused the attenuation of CsA-induced autophagic cell death. All in all, these findings suggest the prospective use of SCE as an effective adjunct in a CsA-based immunosuppressive regimen.

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          Most cited references 65

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          Pharmacology of Schisandra chinensis Bail.: an overview of Russian research and uses in medicine.

          Schisandra chinensis (Turcz.) Bail. is often referred to as an example of a medicinal plant with use in modern Chinese medicine. However, Schisandra chinensis first gained recognition as an adaptogen in the official medicine of the USSR in the early 1960s, principally as a result of the large number of pharmacological and clinical studies carried out by Russian scientists in the preceding two decades. Schizandra has now secured an established position within the medicine of Russia/USSR as evidenced by the inclusion of the drug in recent editions of the National Pharmacopoeia of the USSR and in the State Register of Drugs. Pharmacological studies on animals have shown that Schizandra increases physical working capacity and affords a stress-protective effect against a broad spectrum of harmful factors including heat shock, skin burn, cooling, frostbite, immobilisation, swimming under load in an atmosphere with decreased air pressure, aseptic inflammation, irradiation, and heavy metal intoxication. The phytoadaptogen exerts an effect on the central nervous, sympathetic, endocrine, immune, respiratory, cardiovascular, gastrointestinal systems, on the development of experimental atherosclerosis, on blood sugar and acid-base balance, and on uterus myotonic activity. Studies on isolated organs, tissues, cells and enzymes have revealed that Schizandra preparations exhibit strong antioxidant activities and affect smooth muscles, arachidonic acid release, biosynthesis of leukotriene B(4) in leukocytes, platelet activating factor activity, carbohydrate-phosphorus metabolism, the formation of heat shock protein and polyamines, tissue respiration and oxygen consumption, and the tolerance of an organism to oxygen intoxication. In healthy subjects, Schizandra increases endurance and accuracy of movement, mental performance and working capacity, and generates alterations in the basal levels of nitric oxide and cortisol in blood and saliva with subsequent effects on the blood cells, vessels and CNS. Numerous clinical trials have demonstrated the efficiency of Schizandra in asthenia, neuralgic and psychiatric (neurosis, psychogenic depression, astheno-depressive states, schizophrenia and alcoholism) disorders, in impaired visual function, hypotension and cardiotonic disorders, in epidemic waves of influenza, in chronic sinusitis, otitis, neuritis and otosclerosis, in pneumonia, radioprotection of the fetoplacental system of pregnant women, allergic dermatitis, acute gastrointestinal diseases, gastric hyper- and hypo-secretion, chronic gastritis, stomach and duodenal ulcers, wound healing and trophic ulcers. This review describes the considerable diversity of pharmacological effects of Schisandra chinensis reported in numerous studies carried out in the former USSR and which have been confirmed over more than 40 years of use of the plant as an official medicinal remedy. Such knowledge can be applied in the expansion of the use of Schizandra in the pharmacotherapy of European and other countries as well as for the further discovery of new drugs based on the lignans that constitute the main secondary metabolites of this plant.
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            The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation.

            The vertebrate cap'n'collar family transcription factor Nrf2 and its invertebrate homologues SKN-1 (in worms) and CncC (in flies) function as master mediators of antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls gene expression programs that defend various tissues against diverse electrophilic stressors and oxidative insults, thus protecting the organism from disorders that are caused or exacerbated by such stresses. Moreover, studies on model organisms implicate the Nrf2 pathway in the prevention of aging-related diseases and suggest that SKN-1-regulated and CncC-regulated gene expression can promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article discusses another aspect of the Nrf2 pathway's function that has not yet received the same degree of attention, but emerges as a topic of increasing interest and potential clinical impact: its role in metabolic regulation and its interaction with central signaling systems that respond to nutritional inputs. Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects of caloric restriction. Nrf2 signaling also crosstalks with metabolic signaling systems such as the insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role in models of diabetic nephropathy. The emerging role of Nrf2 as an effector of metabolic and longevity signals offers new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2 signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.
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              Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging.

              Excessive reactive oxygen species (ROS) generation is as a major cause of oxidative stress and is implicated in cellular dysfunction in aging, cardiovascular disease and other pathologies. As antioxidant trials have largely failed to provide protection in humans, research focus has shifted to activating endogenous antioxidant defenses. In vascular models, activators of the transcription factor NF-E2 related factor 2 (Nrf2) pathway have been shown to restore redox homeostasis by increasing antioxidant/electrophilic response element-mediated (ARE/EpRE) expression of phase II and antioxidant enzymes, including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1) and γ-glutamate cysteine ligase catalytic subunit (GCLC). Nrf2 activators disrupt basal ubiquitin-dependent degradation of Nrf2 by the 26S proteasome, leading to nuclear Nrf2 accumulation and gene induction. This review examines the evidence for crosstalk between Nrf2 and the proteasome, highlighting the mechanisms by which select Nrf2 activators regulate stress-induced proteasomal activity and removal of oxidized proteins. Exploiting the dual action of natural Nrf2 inducers may provide a novel therapeutic strategy for restoring cellular redox homeostasis in aging and cardiovascular related diseases such diabetes, atherosclerosis and stroke. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                28 August 2015
                : 9
                : 4997-5018
                Affiliations
                [1 ]Department of Formulas of Traditional Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
                [2 ]College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
                Author notes
                Correspondence: Yang Yu, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, People’s Republic of China, Tel +86 20 3935 8094, Fax +86 20 3935 8090, Email yuyang@ 123456gzucm.edu.cn
                Article
                dddt-9-4997
                10.2147/DDDT.S89876
                4560515
                © 2015 Lai et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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