scholarly journals N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Benxu Cheng ◽  
Pinki Anand ◽  
Anxiu Kuang ◽  
Feroz Akhtar ◽  
Virginia L. Scofield
Keyword(s):  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Free Radical Scavenger ◽  
Parp Cleavage ◽  
Radical Scavenger ◽  
Nuclear Condensation ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome ◽  
Induced Apoptosis ◽  
Human Neuronal Cells

Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson’s disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration.

scholarly journals Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-18
Author(s):  
I-Cheng Chen ◽  
Kuo-Hsuan Chang ◽  
Yi-Jing Chen ◽  
Yi-Chun Chen ◽  
Guey-Jen Lee-Chen ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Caspase 3 ◽  
Neurodegenerative Disorder ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Pueraria Lobata ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

scholarly journals Ubiquitin-Proteasome System Stress Sensitizes Ovarian Cancer to Proteasome Inhibitor–Induced Apoptosis

2006 ◽  
Vol 66 (7) ◽  
pp. 3754-3763 ◽  
Author(s):  
Martina Bazzaro ◽  
Michael K. Lee ◽  
Alessia Zoso ◽  
Wanda L.H. Stirling ◽  
Antonio Santillan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Induced Apoptosis

Targeting the Ubiquitin-proteasome System for the Treatment of Multiple Myeloma and Other Human Diseases

2010 ◽  
Vol 2 ◽  
pp. CMT.S2889
Author(s):  
Klaus Podar ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Human Diseases ◽  
Cellular Functions ◽  
Adverse Side Effects ◽  
Ubiquitin Proteasome ◽  
Novel Approaches

The ubiquitin-proteasome-degradation system plays a key role in multiple cellular functions. Its deregulation is associated with the initiation and progression of human diseases including not only solid and hematologic malignancies but also neurologic and autoimmune disorders. This article discusses several novel mechanistic aspects of the ubiquitin-proteasome system. Moreover, it focuses on the development, mechanisms of action, and clinical experience with Bortezomib, the first in-class-proteasome inhibitor to enter the clinics. Finally, it summarizes novel approaches to specifically target distinct components within the highly complex and dynamic ubiquitin-proteasome machinery to ultimately further increase drug activity, as well as reduce drug resistance and adverse side effects.

scholarly journals Melatonin protects the mouse testis against heat-induced damage

2020 ◽  
Vol 26 (2) ◽  
pp. 65-79 ◽  
Author(s):  
Pengfei Zhang ◽  
Yi Zheng ◽  
Yinghua Lv ◽  
Fuyuan Li ◽  
Lihong Su ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heat Stress ◽  
Male Fertility ◽  
Reactive Oxygen Species Generation ◽  
Free Radical Scavenger ◽  
Testicular Atrophy ◽  
Therapeutic Drug ◽  
Radical Scavenger ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Abstract Spermatogenesis, an intricate process occurring in the testis, is responsible for ongoing production of spermatozoa and thus the cornerstone of lifelong male fertility. In the testis, spermatogenesis occurs optimally at a temperature 2–4°C lower than that of the core body. Increased scrotal temperature generates testicular heat stress and later causes testicular atrophy and spermatogenic arrest, resulting in a lower sperm yield and therefore impaired male fertility. Melatonin (N-acetyl-5-methoxytryptamine), a small neuro-hormone synthesized and secreted by the pineal gland and the testis, is widely known as a potent free-radical scavenger; it has been reported that melatonin protects the testis against inflammation and reactive oxygen species generation thereby playing anti-inflammatory, -oxidative and -apoptotic roles in the testis. Nevertheless, the role of melatonin in the testicular response to heat stress has not been studied. Here, by employing a mouse model of testicular hyperthermia, we systematically investigated the testicular response to heat stress as well as the occurrence of autophagy, apoptosis and oxidative stress in the testis. Importantly, we found that pre-treatment with melatonin attenuated heat-induced apoptosis and oxidative stress in the testis. Also, post-treatment with melatonin promoted recovery of the testes from heat-induced damage, probably by maintaining the integrity of the Sertoli cell tight-junction. Thus, we for the first time provide the proof of concept that melatonin can protect the testis against heat-induced damage, supporting the potential future use of melatonin as a therapeutic drug in men for sub/infertility incurred by various testicular hyperthermia factors.

scholarly journals UbiHub: a data hub for the explorers of ubiquitination pathways

2019 ◽  
Vol 35 (16) ◽  
pp. 2882-2884 ◽  
Author(s):  
Lihua Liu ◽  
David R Damerell ◽  
Leonidas Koukouflis ◽  
Yufeng Tong ◽  
Brian D Marsden ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Phylogenetic Trees ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Protein Target ◽  
Protein Ubiquitination ◽  
Online Resource ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease

Abstract Motivation Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. Results We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. Availability and implementation https://ubihub.thesgc.org.

Bortezomib - A Potential Therapeutic Approach in B Chronic Lymphocytic Leukaemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5007-5007
Author(s):  
A. Sarmento-Ribeiro ◽  
M. Dourado ◽  
C. Gonçalves ◽  
C. Geraldes ◽  
E. Cortesão ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Mononuclear Cells ◽  
Lymphocytic Leukaemia ◽  
Marked Decrease ◽  
Single Agent ◽  
Ubiquitin Proteasome System ◽  
The Other ◽  
Average Difference ◽  
Apoptotic Effect ◽  
Ubiquitin Proteasome

Abstract B-cell lymphocytic leukaemia (B-CLL) is an indolent non-Hodgkin’s lymphoma and the most frequent leukaemia. Even though the capacity of B-CLL leukemic cells to proliferate has been underestimated until recently, the accumulation of tumor cells mostly results from a defect in the apoptotic program. The ubiquitin/proteasome system is important in the turnover of regulatory proteins and as regulator of cell proliferation and apoptosis. This critical link between the apoptotic machinery and the ubiquitin/proteasome system led to an increased interest in designing inhibitory agents that target these pathways. A promising new drug, bortezomib (BZ), a dipeptidyl boronic acid proteasome inhibitor, was approved for treatment of relapsed multiple myeloma. Extensive preclinical data are being developed to study the potential application of this new drug in other cancers. Our preliminary results show that BZ induces a marked decrease in LLC-B cell viability by increasing the percentage of apoptosis. The aim of this study is to evaluate the potential therapeutic value of BZ in B-CLL patients studying the cytotoxicity mechanisms induced by this proteasome inhibitor. For this purpose, mononuclear cells isolated from 22 patients with B-CLL (14 without and 8 with conventional therapy) were cultured in absence and presence of bortezomib (BZ) (ranging concentration from 0.01 μM to 10 μM), as single agent, or plus 75 or 150 μM fludarabine (FDN), during 24 hours. Directly conjugated monoclonal antibodies to CD5 and CD19 was used to identify LLC-B cells. Cell death was evaluated by annexin V incorporation and detected by flow cytometry. The expression of the proteins involved in apoptosis regulation, namely the proapoptotic proteins, Bax and p53, and the antiapoptotic protein Bcl-2 was determined by flow cytometry using monoclonal antibodies. Our results show that BZ induces a marked decrease in B-CLL cell viability by increasing the percentage of apoptosis in a dose dependent manner (20 to 80% apoptosis). However, in concentrations higher than 1 mM a saturable effect is observed. On the other hand, a lesser sensitivity to BZ was observed in normal mononuclear cells (≤ 30% apoptosis). BZ apoptotic effect seems to be independent of previous therapy. We observed higher levels of apoptosis in B-CLL cells treated with BZ compared with cells not treated or in response to treatment with FDN, which may relate with the increase in Bax expression (average difference of 37.3 ± 18%). However, we observe identical apoptosis levels in B-CLL cells, as opposed to others (Duechler, M. et al., 2005), and an increase in apoptotic T cells levels in the presence of treatment with BZ plus FDN compared with those observed in cells treated with BZ alone. On the other hand, when compared with the results obtained with FDN alone (in 150 μM), an increase in apoptosis levels was detected (average difference of 69.5 ± 28% increase in apoptosis, for B-CLL cells and 33.6 ± 11.6%, for T cells). Our results support that bortezomib induces apoptosis as a single agent in a Bax-dependent way. The apoptotic effect show some selectivity for the transformed cells (B-CLL). These results suggests that this proteasome inhibitor may be useful as a therapeutic approach in B-CLL patients.

scholarly journals Free Radical Scavenger Edaravone Suppresses X-ray-induced Apoptosis through p53 Inhibition in MOLT-4 Cells

2007 ◽  
Vol 48 (6) ◽  
pp. 495-503 ◽  
Author(s):  
Nakashi SASANO ◽  
Atsushi ENOMOTO ◽  
Yoshio HOSOI ◽  
Yosuke KATSUMURA ◽  
Yoshihisa MATSUMOTO ◽  
...  
Keyword(s):  
Free Radical ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
X Ray ◽  
Induced Apoptosis

Edaravone, a known free radical scavenger, enhances X-ray-induced apoptosis at low concentrations

2010 ◽  
Vol 293 (1) ◽  
pp. 52-57 ◽  
Author(s):  
N. Sasano ◽  
A. Enomoto ◽  
Y. Hosoi ◽  
Y. Katsumura ◽  
Y. Matsumoto ◽  
...  
Keyword(s):  
Free Radical ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
X Ray ◽  
Low Concentrations ◽  
Induced Apoptosis

scholarly journals mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy

2015 ◽  
Vol 112 (52) ◽  
pp. 15790-15797 ◽  
Author(s):  
Jinghui Zhao ◽  
Bo Zhai ◽  
Steven P. Gygi ◽  
Alfred Lewis Goldberg
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Cholesterol Biosynthesis ◽  
Mammalian Target Of Rapamycin ◽  
Ubiquitin Proteasome System ◽  
Mtor Inhibition ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome

Growth factors and nutrients enhance protein synthesis and suppress overall protein degradation by activating the protein kinase mammalian target of rapamycin (mTOR). Conversely, nutrient or serum deprivation inhibits mTOR and stimulates protein breakdown by inducing autophagy, which provides the starved cells with amino acids for protein synthesis and energy production. However, it is unclear whether proteolysis by the ubiquitin proteasome system (UPS), which catalyzes most protein degradation in mammalian cells, also increases when mTOR activity decreases. Here we show that inhibiting mTOR with rapamycin or Torin1 rapidly increases the degradation of long-lived cell proteins, but not short-lived ones, by stimulating proteolysis by proteasomes, in addition to autophagy. This enhanced proteasomal degradation required protein ubiquitination, and within 30 min after mTOR inhibition, the cellular content of K48-linked ubiquitinated proteins increased without any change in proteasome content or activity. This rapid increase in UPS-mediated proteolysis continued for many hours and resulted primarily from inhibition of mTORC1 (not mTORC2), but did not require new protein synthesis or key mTOR targets: S6Ks, 4E-BPs, or Ulks. These findings do not support the recent report that mTORC1 inhibition reduces proteolysis by suppressing proteasome expression [Zhang Y, et al. (2014) Nature 513(7518):440–443]. Several growth-related proteins were identified that were ubiquitinated and degraded more rapidly after mTOR inhibition, including HMG-CoA synthase, whose enhanced degradation probably limits cholesterol biosynthesis upon insulin deficiency. Thus, mTOR inhibition coordinately activates the UPS and autophagy, which provide essential amino acids and, together with the enhanced ubiquitination of anabolic proteins, help slow growth.

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