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      Corilagin induces human glioblastoma U251 cell apoptosis by impeding activity of (immuno)proteasome

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          Abstract

          Glioma is a type of common primary intracranial tumor, which is difficult to treat. It has been confirmed by research that corilagin (the primary active constituent of the matsumura leafflower herb) has significant antitumor effect. In particular, our previous research demonstrated that corilagin effectively promotes apoptosis of glioma U251 cells and has a synergistic effect when used with temozolomide. However, the mechanism by which corilagin causes apoptosis in U251 cells has yet to be investigated. Proteasomes are catalytic centers of the ubiquitin-proteasome system, which is the major protein degradation pathway in eukaryotic cells; they are primarily responsible for the degradation of signal molecules, tumor suppressors, cyclins and apoptosis inhibitors and serve an important role in tumor cell proliferation and apoptosis. The present study investigated the pro-apoptotic effect of corilagin on glioma U251 cells and confirmed that decreased proteasome activity and expression levels serve an important role in corilagin-induced U251 cell apoptosis.

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          Most cited references43

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          Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            Structure and Function of the 26S Proteasome.

            As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.
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              Glioma epigenetics: From subclassification to novel treatment options

              Gliomas are the most common malignant primary brain tumors, of which glioblastoma is the most malignant form (WHO grade IV), and notorious for treatment resistance. Over the last decade mutations in epigenetic regulator genes have been identified as key drivers of subtypes of gliomas with distinct clinical features. Most characteristic are mutations in IDH1 or IDH2 in lower grade gliomas, and histone 3 mutations in pediatric high grade gliomas that are also associated with characteristic DNA methylation patterns. Furthermore, in adult glioblastoma patients epigenetic silencing of the DNA repair gene MGMT by promoter methylation is predictive for benefit from alkylating agent therapy. These epigenetic alterations are used as biomarkers and play a central role for classification of gliomas (WHO 2016) and treatment decisions. Here we review the pivotal role of epigenetic alterations in the etiology and biology of gliomas. We summarize the complex interactions between "driver" mutations, DNA methylation, histone post-translational modifications, and overall chromatin organization, and how they inform current efforts of testing epigenetic compounds and combinations in preclinical and clinical studies.
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                Author and article information

                Journal
                Oncol Rep
                Oncol Rep
                Oncology Reports
                D.A. Spandidos
                1021-335X
                1791-2431
                April 2021
                19 February 2021
                19 February 2021
                : 45
                : 4
                : 34
                Affiliations
                [1 ]Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
                [2 ]Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA
                [3 ]Department of Neurosurgery, Affiliated Hospital of Jining Medical University and Shandong Provincial Key Laboratory of Stem Cells and Neuro-Oncology, Jining, Shandong 272029, P.R. China
                [4 ]Department of Hematology Laboratory, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
                Author notes
                Correspondence to: Professor Feng Jin, Department of Neurosurgery, Affiliated Hospital of Jining Medical University and Shandong Provincial Key Laboratory of Stem Cells and Neuro-Oncology, 89 Guhuai Road, Jining, Shandong 272029, P.R. China, E-mail: jinfengsdjn@ 123456163.com
                [*]

                Contributed equally

                Article
                OR-0-0-7985
                10.3892/or.2021.7985
                7905533
                33649855
                dfe9d176-833e-42dd-8cd1-1ce928ba4ae6
                Copyright: © Qin et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 04 September 2020
                : 28 January 2021
                Funding
                Funded by: Project of Scientific Developmental Program of Shandong Provincial Administration of Traditional Chinese Medicine
                Award ID: 2019-0479
                Funded by: Project of Health and Family Planning Commission of Shandong Province
                Award ID: 2019WS362
                Award ID: 2019WS361
                Funded by: Jining Medical University
                Award ID: JYFC2018FKJ107
                Funded by: General Project of Jining Science and Technology Bureau
                Award ID: 2016-56-60
                Funded by: Scientific Research Project of Jining Medical University
                Award ID: JY2015KJ022
                Funded by: Nursery Research Program of Affiliated Hospital of Jining Medical University
                Award ID: MP-2015-003
                Award ID: MP-2018-012
                The present study was supported by Project of Scientific Developmental Program of Shandong Provincial Administration of Traditional Chinese Medicine (grant no. 2019-0479), Project of Health and Family Planning Commission of Shandong Province (grant nos. 2019WS362 and 2019WS361), Teacher Support Fund of Jining Medical University (grant no. JYFC2018FKJ107), General Project of Jining Science and Technology Bureau (grant no. 2016-56-60), Scientific Research Project of Jining Medical University (grant no. JY2015KJ022) and Nursery Research Program of Affiliated Hospital of Jining Medical University (grant nos. MP-2015-003 and MP-2018-012).
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                corilagin,u251,apoptosis,proteasome,inhibitors
                corilagin, u251, apoptosis, proteasome, inhibitors

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