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      Therapeutics and Clinical Risk Management (submit here)

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      Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-κB/PUMA signal in rats


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          Triptolide, an active compound extracted from the Chinese herb thunder god vine ( Tripterygium wilfordii Hook F.), has potent antitumor activity. Recently, triptolide was found to have protective effects against acute cerebral ischemia/reperfusion (I/R) injury through inhibition of cell apoptosis. However, the regulatory mechanism of the effect remains unclear. We hypothesize that the regulatory mechanisms of triptolide are mediated by nuclear factor κB (NF-κB) and p53-upregulated-modulator-of-apoptosis signal inhibition. To verify this hypothesis, we occluded the middle cerebral artery in male rats to establish focal cerebral I/R model. The rats received triptolide or vehicle at the onset of reperfusion following middle cerebral artery occlusion. At 24 hours after reperfusion, neurological deficits, infarct volume, and cell apoptosis were evaluated. The expression levels of NF-κBp65, PUMA, and caspase-3 were determined by Western blot. Real-time polymerase chain reaction was used to determine the levels of NF-κBp65 mRNA, PUMA mRNA, and caspase-3 mRNA. NF-κB activity was determined by electrophoretic mobility shift assay. Apoptotic cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In I/R group, neurological deficit scores, cerebral infarct volume, expression of NF-κBp65, PUMA, caspase-3, NF-κB activity, and TUNEL-positive cells were found to be increased at 24 hours after I/R injury. The I/R/triptolide rats showed significantly better neurological deficit scores, decreased neural apoptosis, and reduced cerebral infarct volume. In addition, the expression of NF-κBp65, PUMA, caspase-3, and NF-κB activity was suppressed in the I/R/triptolide rats. These results indicate that the neuroprotective effects of triptolide during acute cerebral I/R injury are possibly related to the inhibition of apoptosis through suppression of NF-κB/PUMA signaling pathway.

          Most cited references33

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          PUMA induces the rapid apoptosis of colorectal cancer cells.

          Through global profiling of genes that were expressed soon after p53 expression, we identified a novel gene termed PUMA (p53 upregulated modulator of apoptosis). The protein encoded by PUMA was found to be exclusively mitochondrial and to bind to Bcl-2 and Bcl-X(L) through a BH3 domain. Exogenous expression of PUMA resulted in an extremely rapid and profound apoptosis that occurred much earlier than that resulting from exogenous expression of p53. Based on its unique expression patterns, p53 dependence, and biochemical properties, PUMA may be a direct mediator of p53-associated apoptosis.
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            PUMA, a potent killer with or without p53.

            J. Yu, L. Zhang (2008)
            PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a critical mediator of p53-dependent and -independent apoptosis induced by a wide variety of stimuli, including genotoxic stress, deregulated oncogene expression, toxins, altered redox status, growth factor/cytokine withdrawal and infection. It serves as a proximal signaling molecule whose expression is regulated by transcription factors in response to these stimuli. PUMA transduces death signals primarily to the mitochondria, where it acts indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members. It directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. PUMA ablation or inhibition leads to apoptosis deficiency underlying increased risks for cancer development and therapeutic resistance. Although elevated PUMA expression elicits profound chemo- and radiosensitization in cancer cells, inhibition of PUMA expression may be useful for curbing excessive cell death associated with tissue injury and degenerative diseases. Therefore, PUMA is a general sensor of cell death stimuli and a promising drug target for cancer therapy and tissue damage.
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              To be, or not to be: NF-kappaB is the answer--role of Rel/NF-kappaB in the regulation of apoptosis.

              During their lifetime, cells encounter many life or death situations that challenge their very own existence. Their survival depends on the interplay within a complex yet precisely orchestrated network of proteins. The Rel/NF-kappaB signaling pathway and the transcription factors that it activates have emerged as critical regulators of the apoptotic response. These proteins are best known for the key roles that they play in normal immune and inflammatory responses, but they are also implicated in the control of cell proliferation, differentiation, apoptosis and oncogenesis. In recent years, there has been remarkable progress in understanding the pathways that activate the Rel/NF-kappaB factors and their role in the cell's decision to either fight or surrender to apoptotic challenge. Whereas NF-kappaB is most commonly involved in suppressing apoptosis by transactivating the expression of antiapoptotic genes, it can promote programmed cell death in response to certain death-inducing signals and in certain cell types. This review surveys our current understanding of the role of NF-kappaB in the apoptotic response and focuses on many developments since this topic was last reviewed in Oncogene 4 years ago. These recent findings shed new light on the activity of NF-kappaB as a critical regulator of apoptosis in the immune, hepatic, epidermal and nervous systems, on the mechanisms through which it operates and on its role in tissue development, homoeostasis and cancer.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                24 May 2016
                : 12
                : 817-824
                [1 ]Department of Neurology, The Third Hospital of Liaocheng, Liaocheng, Shandong, People’s Republic of China
                [2 ]Department of Neurology, The Third Hospital of Changsha, Changsha, Hunan, People’s Republic of China
                Author notes
                Correspondence: Weibing Fan, Department of Neurology, The Third Hospital of Changsha, No 23, Weishan Road, Changsha, Hunan, People’s Republic of China, Tel +86 139 4302 7748, Email thirdcsneuro@ 123456sina.com
                © 2016 Zhang 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.

                Original Research

                ischemia/reperfusion, apoptosis, triptolide, neuroprotection


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