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unfolded protein response

Chuandong Zhu, Lixue Wang, Yang Cai, Guoxiang Wang, Hanfeng Xu, Yuan Wan, Qin Zheng
The high atomic number of gold nanoparticles (GNPs) enables them to offer potential as practical and efficient radiosensitizing agents for cancer radiotherapy applications. In the present study, it was demonstrated that GNPs can significantly modulate the irradiation response of hepatocellular carcinoma (HCC) cells in vitro and in vivo , of which the underlying mechanisms were investigated. Cetuximab (C225) is a targeting agent, which binds to the extracellular domain of epidermal growth factor receptor (EGFR)...
April 2018: Oncology Letters
Yingfeng Deng, Zhao V Wang, Ruth Gordillo, Yi Zhu, Aktar Ali, Chen Zhang, Xiaoding Wang, Mengle Shao, Zhuzhen Zhang, Puneeth Iyengar, Rana K Gupta, Jay D Horton, Joseph A Hill, Philipp E Scherer
OBJECTIVE: The spliced transcription factor Xbp1 (Xbp1s), a transducer of the unfolded protein response (UPR), regulates lipolysis. Lipolysis is stimulated by fasting when uridine synthesis is also activated in adipocytes. METHODS: Here we have examined the regulatory role Xbp1s in stimulation of uridine biosynthesis in adipocytes and triglyceride mobilization using inducible mouse models. RESULTS: Xbp1s is a key molecule involved in adipocyte uridine biosynthesis and release by activation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD), the rate-limiting enzyme for UMP biosynthesis...
March 2, 2018: Molecular Metabolism
Camila Rubio-Patiño, Jozef P Bossowski, Gian Marco De Donatis, Laura Mondragón, Elodie Villa, Lazaro E Aira, Johanna Chiche, Rana Mhaidly, Cynthia Lebeaupin, Sandrine Marchetti, Konstantinos Voutetakis, Aristotelis Chatziioannou, Florence A Castelli, Patricia Lamourette, Emeline Chu-Van, François Fenaille, Tony Avril, Thierry Passeron, John B Patterson, Els Verhoeyen, Béatrice Bailly-Maitre, Eric Chevet, Jean-Ehrland Ricci
Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet...
March 1, 2018: Cell Metabolism
Muhammad Mosaraf Hossain, David Barua, Vahid Arabkari, Nahidul Islam, Ananya Gupta, Sanjeev Gupta
Nuclear receptor coactivators (NCOAs) function as coactivators for nuclear receptors as well as several other transcription factors and potentiate their transcriptional activity. NCOAs play an important role in biology of hormone-dependent and -independent cancers. MCB-613 is a recently described, small molecule stimulator of NCOAs and anti-neoplastic compound that leads to the death of tumour cells due to increased cellular stress. In the present study we investigated the molecular mechanism of MCB-613-induced cell death...
February 20, 2018: Oncotarget
Jianrong Li, Qilin Yu, Bing Zhang, Chenpeng Xiao, Tianyu Ma, Xiao Yi, Chao Liang, Mingchun Li
Cellular stresses could activate several response processes, such as the unfolded protein response (UPR), autophagy and oxidative stress response to restore cellular homeostasis or render cell death. Herein, we identified the Candida albicans stress-associated endoplasmic reticulum protein 1 (SERP1), also known as Ysy6, which was involved in endoplasmic reticulum (ER) stress response. We found that deletion of both SERP1/YSY6 and ATG8 led to hypersensitivity to tunicamycin (TN), and resulted in severe mitochondrial dysfunction under this stress...
March 6, 2018: International Journal of Medical Microbiology: IJMM
Wenlong Zhou, Yan Yang, Liang Tang, Kai Cheng, Changkun Li, Huimin Wang, Minzhi Liu, Wei Wang
Acrolein (Acr) was used as a selection agent to improve the glutathione (GSH) overproduction of the prototrophic strain W303-1b/FGPPT . After two rounds of adaptive laboratory evolution (ALE), an unexpected result was obtained wherein identical GSH production was observed in the selected isolates. Then, a threshold selection mechanism of Acr-stressed adaption was clarified based on the formation of an Acr-GSH adduct, and a diffusion coefficient (0.36 ± 0.02 μmol·min-1 ·OD600 -1 ) was calculated. Metabolomic analysis was carried out to reveal the molecular bases that triggered GSH overproduction...
March 14, 2018: Scientific Reports
Anna Maria Fratta Pasini, Chiara Stranieri, Anna Maria Rigoni, Sergio De Marchi, Denise Peserico, Chiara Mozzini, Luciano Cominacini, Ulisse Garbin
AIM: Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression...
March 13, 2018: Journal of Atherosclerosis and Thrombosis
Justine Lebeau, Jaclyn M Saunders, Vivian W R Moraes, Aparajita Madhavan, Nicole Madrazo, Mary C Anthony, R Luke Wiseman
Endoplasmic reticulum (ER) stress is transmitted to mitochondria and is associated with pathologic mitochondrial dysfunction in diverse diseases. The PERK arm of the unfolded protein response (UPR) protects mitochondria during ER stress through the transcriptional and translational remodeling of mitochondrial molecular quality control pathways. Here, we show that ER stress also induces dynamic remodeling of mitochondrial morphology by promoting protective stress-induced mitochondrial hyperfusion (SIMH). ER-stress-associated SIMH is regulated by the PERK arm of the UPR and activated by eIF2α phosphorylation-dependent translation attenuation...
March 13, 2018: Cell Reports
Marilena Lepretti, Stefania Martucciello, Mario Alberto Burgos Aceves, Rosalba Putti, Lillà Lionetti
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been suggested to play a key role in insulin resistance development. Reactive oxygen species (ROS) production and lipid accumulation due to mitochondrial dysfunction seemed to be important mechanisms leading to cellular insulin resistance. Moreover, mitochondria are functionally and structurally linked to ER, which undergoes stress in conditions of chronic overnutrition, activating the unfolded protein response, which in turn activates the principal inflammatory pathways that impair insulin action...
March 14, 2018: Nutrients
Denisse Sepúlveda, María-José Barrera, Isabel Castro, Sergio Aguilera, Patricia Carvajal, Carolina Lagos, Sergio González, Nicolás Albornoz, Verónica Bahamondes, Andrew F G Quest, Ulises Urzúa, Claudio Molina, Cecilia Leyton, Marcela A Hermoso, María-Julieta González
Objectives: Labial salivary glands (LSGs) of SS patients show alterations related to endoplasmic reticulum stress. Glandular dysfunction could be partly the consequence of an altered inositol-requiring enzyme 1α (IRE1α)/X box-binding protein 1 (XBP-1) signalling pathway of the unfolded protein response, which then regulates genes involved in biogenesis of the secretory machinery. This study aimed to determine the expression, promoter methylation and localization of the IRE1α/XBP-1 pathway components in LSGs of SS patients and also their expression induced by IFN-γ in vitro...
March 9, 2018: Rheumatology
Myungchul Song, Kyunghee Song, Sunghee Kim, Jinyoung Lee, Sueyun Hwang, Chingtack Han
Caenorhabditis elegans C09F5.1 is a nematode-specific gene that encodes a type II transmembrane protein containing the BRICHOS domain. The gene was isolated as a heat-sensitive mutant, but the function of the protein remained unclear. We examined the expression pattern and subcellular localization of C09F5.1 as well as its roles in thermotolerance and chaperone function. Expression of C09F5.1 under heat shock conditions was induced in a heat shock factor 1 (HSF-1)-dependent manner. However, under normal growth conditions, most cells types exposed to mechanical stimuli expressed C09F5...
March 13, 2018: Genes
Ping Fan, Amit K Tyagi, Fadeke A Agboke, Rohit Mathur, Niranjana Pokharel, V Craig Jordan
Stress responses are critical for estrogen (E2 )-induced apoptosis in E2 -deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2 -deprived breast cancer cells is unknown. Here, we demonstrated that E2 differentially modulates NF-κB activity according to treatment time. E2 initially has significant potential to suppress NF-κB activation; it completely blocks tumor necrosis factor alpha (TNFα)-induced activation of NF-κB...
December 2018: Cell Death Discovery
Iglika G Ivanova, Catherine V Park, Adrian I Yemm, Niall S Kenneth
HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation...
February 26, 2018: Nucleic Acids Research
Maria S Yusseppone, Iara Rocchetta, Sebastian E Sabatini, Carlos M Luquet, Maria Del Carmen Ríos de Molina, Christoph Held, Doris Abele
Hypoxia in freshwater ecosystems is spreading as a consequence of global change, including pollution and eutrophication. In the Patagonian Andes, a decline in precipitation causes reduced lake water volumes and stagnant conditions that limit oxygen transport and exacerbate hypoxia below the upper mixed layer. We analyzed the molecular and biochemical response of the North Patagonian bivalve Diplodon chilensis after 10 days of experimental anoxia (<0.2 mg O2 /L), hypoxia (2 mg O2 /L), and normoxia (9 mg O2 /L)...
2018: Frontiers in Physiology
Parismita Kalita, Harish Shukla, Rohit Shukla, Timir Tripathi
The thiol-disulfide redox metabolism in platyhelminth parasites depends entirely on a single selenocysteine (Sec) containing flavoenzyme, thioredoxin glutathione reductase (TGR) that links the classical thioredoxin (Trx) and glutathione (GSH) systems. In the present study, we investigated the catalytic and structural properties of different variants of Fasciola gigantica TGR to understand the role of Sec. The recombinant full-length Sec containing TGR (FgTGRsec), TGR without Sec (FgTGR) and TGRsec without the N-terminal glutaredoxin (Grx) domain (∆NTD-FgTGRsec) were purified to homogeneity...
March 8, 2018: Biochimica et Biophysica Acta
M Forouhan, K Mori, R P Boot-Handford
Whilst the role of ATF6α in modulating the unfolded protein response (UPR) has been well documented, the function of its paralogue ATF6β is less well understood. Using knockdown in cell culture and gene ablation in mice we have directly compared the roles of ATF6α & β in responding to the increased ER stress induced by mutant forms of type X collagen that cause the ER stress-associated metaphyseal chondrodysplasia type Schmid (MCDS). ATF6α more efficiently deals with the disease-associated ER stress in the absence of ATF6β and conversely, ATF6β is less effective in the absence of ATF6α...
March 6, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
I De, N Dogra, S Singh
Mitochondria are the sole semiautonomous organelle of human cell and plays very important role in not only energy production but also in apoptosis, metabolism and cell signaling. It is also known to be major producer of ROS and RNS free radicals during ATP production. These free radicals in excessive amounts may damage the mitochondrial DNA as well as proteome resulting in accumulation of misfolded proteins which may prove deleterious to its functioning and is known to be involved in disease pathology. To maintain healthy proteome, mitochondria has developed as quality control machinery in semiautonomous manner, where cellular proteins such as proteases and heat shock proteins are used for quality control...
March 7, 2018: Current Molecular Medicine
Kyle S Cole, Julia M D Grandjean, Kenny Chen, Collin H Witt, Johanna O'Day, Matthew D Shoulders, R Luke Wiseman, Eranthie Weerapana
Protein disulfide isomerase A1 (PDIA1) is an endoplasmic reticulum (ER)-localized thiol-disulfide oxidoreductase that is an important folding catalyst for secretory pathway proteins. PDIA1 contains two active-site domains (a and a'), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. The two active-site domains share 37% sequence identity, and function independently to perform disulfide-bond reduction, oxidation and isomerization. Numerous inhibitors for PDIA1 have been reported, yet the selectivity of these inhibitors toward the a and a' sites are poorly characterized...
March 9, 2018: Biochemistry
Zhi-Chuan Zhu, Ji-Wei Liu, Kui Li, Jing Zheng, Zhi-Qi Xiong
The nuclear import receptor karyopherin β1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest...
March 9, 2018: Oncogene
Prashanth K B Nagesh, Elham Hatami, Pallabita Chowdhury, Vivek K Kashyap, Sheema Khan, Bilal B Hafeez, Subhash C Chauhan, Meena Jaggi, Murali M Yallapu
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine the ER stress mediated UPR pathway in prostate cancer cells...
March 7, 2018: Cancers
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