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      The protective mechanism of Ginkgolides and Ginkgo flavonoids on the TNF-α induced apoptosis of rat hippocampal neurons and its mechanisms in vitro

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          Abstract

          Objective

          To explore the neuroprotective mechanism of Ginkgolides or Ginkgo flavonoids on the TNF-α induced apoptosis of cultured rat hippocampal neurons.

          Materials and methods

          Primary hippocampal neurons were isolated from rat brains and cultured with (model group) or without (control group) addition of tumor necrosis factor-α (TNF-α, final concentration of 40 ng/ml) to induce apoptosis. TNF-α induced cultures were divided into model group, Ginkgolides pre-treatment group (20 μg/ml) and Ginkgo flavonoids pre-treatment group (12 μg/ml). CCK8 was used to assess cell viability while Hoechst 33258 staining, Flow cytometry and TUNEL kits were all employed to determine apoptotic neurons. Expression levels of Bcl-2, Bax, Caspase-3, Caspase-7, Caspase-8, Caspase-9 and Cytc were estimated by qRT-PCR.

          Results

          Cell viability was significantly improved in Ginkgolides pre-treatment group or Ginkgo flavonoids pre-treatment group compared with that in model group. Apoptotic neurons were significantly less in Ginkgolides pre-treatment group or Ginkgo flavonoids pre-treatment group than those in model group. Transcription levels of caspase-7, caspase-8, caspase-3, caspase-9, Bax and Cytc were down-regulated, while transcription levels of Bcl-2 was up-regulated in Ginkgolides pre-treatment or Ginkgo flavonoids pre-treatment group than those in model group.

          Conclusions

          Ginkgolides and Ginkgo flavonoids might protect against apoptosis of hippocampal neurons through inhibiting death receptor pathway or mitochondrial pathway under TNF-α background.

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          Most cited references 39

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          Old, new and emerging functions of caspases.

          Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.
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            Caspases at the crossroads of immune-cell life and death.

             Erin Siegel (2006)
            Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death.
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              Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients.

              Ginkgo biloba is among the most favourite and best explored herbal drugs. Standardized extracts of Ginkgo biloba represent the only herbal alternative to synthetic antidementia drugs in the therapy of cognitive decline and Alzheimer's diseases. The clinical efficiency of such standardized Ginkgo biloba extracts (GBE) is still controversial, but authors of numerous international clinical studies recommended the use of GBE in the described therapies.Extracts of Ginkgo biloba are a mixture of substances with a wide variety of physical and chemical properties and activities. Numerous pharmacological investigations lead to the conclusion that the terpene trilactones (TTL) and the flavonoids of GBE are responsible for the main pharmacological effects of the extract in the therapy of cognitive decline. Therefore, the quality of GBE products must be oriented on a defined quantity of TTL and flavonoids. Furthermore, because of their toxic potential the amount of ginkgolic acid should be less than 5 ppm.However, data on pharmacokinetics and bioavailability, especially related to the central nervous system (CNS), which is the target tissue, are relatively rare. A few investigations characterize the TTL and flavonoids of Ginkgo biloba pharmacokinetically in plasma and in the brain. Recent investigations show that significant levels of TTL and Ginkgo biloba flavonoids cross the blood-brain barrier and enter the CNS of rats after oral application of GBE. Knowledge about the pharmacokinetic behaviour of these substances is necessary to discuss the pharmacological results on a more realistic basis.
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                Author and article information

                Contributors
                Journal
                Heliyon
                Heliyon
                Heliyon
                Elsevier
                2405-8440
                21 September 2015
                September 2015
                21 September 2015
                : 1
                : 1
                Affiliations
                School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
                Author notes
                [* ]Corresponding author. Tel.: +86 22 59596287 xijuanjiang@ 123456foxmail.com
                [1]

                These authors have contributed equally to this work.

                Article
                S2405-8440(15)30066-9 e00020
                10.1016/j.heliyon.2015.e00020
                4939806
                27441214
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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