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- Ghavami, Saeid, 1965-, et al.
(författare)
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Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders
- 2014
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Ingår i: Progress in Neurobiology. - Kidlington, Oxford, United Kingdom : Pergamon Press. - 0301-0082 .- 1873-5118. ; 112, s. 24-49
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Forskningsöversikt (refereegranskat)abstract
- Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.
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| 2. |
- Hombach-Klonisch, Sabine, et al.
(författare)
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Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response
- 2018
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Ingår i: Pharmacology and Therapeutics. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0163-7258 .- 1879-016X. ; 184, s. 13-41
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Forskningsöversikt (refereegranskat)abstract
- Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15 months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.
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| 3. |
- Likus, Wirginia, et al.
(författare)
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Could drugs inhibiting the mevalonate pathway also target cancer stem cells?
- 2016
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Ingår i: Drug resistance updates. - : CHURCHILL LIVINGSTONE. - 1368-7646 .- 1532-2084. ; 25, s. 13-25
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Forskningsöversikt (refereegranskat)abstract
- Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell sternness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity related cardiovascular diseases. Its prominent role in regulation of cell growth and sternness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in sternness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells. (C) 2016 The Authors. Published by Elsevier Ltd.
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| 4. |
- Rollano Penaloza, Oscar M., et al.
(författare)
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Apoptins : selective anticancer agents
- 2014
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Ingår i: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914 .- 1471-499X. ; 20:9, s. 519-528
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Forskningsöversikt (refereegranskat)abstract
- Therapies that selectively target cancer cells for deathhave been the center of intense research recently. Onepotential therapy may involve apoptin proteins, whichare able to induce apoptosis in cancer cells leavingnormal cells unharmed. Apoptin was originally discoveredin the Chicken anemia virus (CAV); however, humangyroviruses (HGyV) have recently been found that alsoharbor apoptin-like proteins. Although the cancer cellspecific activity of these apoptins appears to be wellconserved, the precise functions and mechanisms ofaction are yet to be fully elucidated. Strategies for bothdelivering apoptin to treat tumors and disseminating theprotein inside the tumor body are now being developed,and have shown promise in preclinical animal studies.
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| 5. |
- Yeganeh, Behzad, et al.
(författare)
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Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease
- 2014
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Ingår i: Pharmacology and Therapeutics. - : Elsevier. - 0163-7258 .- 1879-016X. ; 143:1, s. 87-110
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Forskningsöversikt (refereegranskat)abstract
- The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA.Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate.The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering.In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.
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