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Christina D King, Daljeet Singh, Kyle Holden, Annie B Govan, Scott A Keith, Arjumand Ghazi, Renã A S Robinson
The molecular mechanisms that distinguish immunosenescence from general age-related decline are poorly understood. We addressed this by exposing Day 1 and Day 5 adults of Caenorhabditis elegans to Pseudomonas aeruginosa strain PA01, an opportunistic pathogen. Day 5 adult C. elegans exhibited greater vulnerability to infection as compared to Day 1 C. elegans. Using TMT6 -plex isobaric labeling and reductive dimethylation, we identified 55 proteins whose levels were altered following infection of Day 1 and Day 5 adults...
April 12, 2018: Journal of Proteomics
Madhubanti Mullick, Dwaipayan Sen
Hypoxia-reperfusion (H/R) emblems a plethora of pathological conditions which is potent in contributing to the adversities encountered by human mesenchymal stem cells (hMSCs) in post-transplant microenvironment, resulting in transplant failure. D-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated delta opioid receptor (DOR) activation is well-known for its recuperative properties in different cell types like neuronal and cardiomyocytes. In the current study its effectiveness in assuaging hMSC mortality under H/R-like insult has been delineated...
April 12, 2018: Stem Cell Reviews
Do Yeon Lee, Seung Hyun Hong, Bokyung Kim, Dong-Seok Lee, Kweon Yu, Kyu-Sun Lee
The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. ER stress-associated neuronal cell death pathways play roles in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease. Neuropeptide Y (NPY) has an important role in neuroprotection against neurodegenerative diseases. In this study, we investigated whether NPY has a protective role in ER stress-induced neuronal cell death in SK-N-SH human neuroblastoma cells...
April 6, 2018: European Journal of Cell Biology
Yu-Hong Jing, Ji-Long Yan, Qing-Jun Wang, Hai-Chao Chen, Xue-Zhu Ma, Jie Yin, Li-Ping Gao
Changes in mitochondrial structure and function are the initial factors of cell aging. Spermidine has an antiaging effect, but its effect on neuronal aging and mitochondrial mechanisms is unclear. In this study, mouse neuroblastoma (N2a) cells were treated with d‑galactose (d‑Gal) to establish cell aging to investigate the antiaging effect and mechanisms of spermidine. Changes in the cell cycle and β-galactosidase activity were analyzed to evaluate the extent of cell aging. Stabilities of mitochondrial mRNA and mitochondrial membrane potential (MMP) were evaluated in the process of cell aging under different treatments...
April 9, 2018: Experimental Gerontology
Yasmine Khayyami, Gunnar Lose, Niels Klarskov
INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) reduction is often performed in the preoperative assessment of women before POP surgery. Using urethral pressure reflectometry (UPR), we sought to investigate how POP reduction affects the urethral closure mechanism. METHODS: Women with anterior or posterior vaginal wall prolapse stage ≥II with and without POP reduction were examined with a speculum. We performed prolapse staging according to the Pelvic Organ Prolapse Quantification system, UPR measurements at rest and during squeezing, and standardized stress tests with 300 ml saline...
April 11, 2018: International Urogynecology Journal
Sylvie Callegari, Sven Dennerlein
Mitochondria exist as compartmentalized units, surrounded by a selectively permeable double membrane. Within is contained the mitochondrial genome and protein synthesis machinery, required for the synthesis of OXPHOS components and ultimately, ATP production. Despite their physical barrier, mitochondria are tightly integrated into the cellular environment. A constant flow of information must be maintained to and from the mitochondria and the nucleus, to ensure mitochondria are amenable to cell metabolic requirements and also to feedback on their functional state...
2018: Frontiers in Cell and Developmental Biology
Tingting Zhou, Yanhua Cheng, Wenzhong Yan, Xiaofan Shi, Xin Xu, Jinpei Zhou, Jian Li, Jing Chen, Xu Shen
Activating transcription factor 6α (ATF6α) as a transducer in unfolded protein response (UPR), plays an important role in liver glucose metabolism and insulin resistance. Thus, targeting ATF6α activation has been proposed to be a potential strategy for anti-T2DM drug discovery. Here, we determined that small molecule 2-[5-[1-(4-chlorophenoxy)ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide (TSPA) functioned as an ATF6α translocation inducer effectively promoting ATF6α translocation into nucleus and ameliorating glucose homeostasis on db/db mice...
April 4, 2018: Biochemical and Biophysical Research Communications
A Burgeiro, A C Fonseca, D Espinoza, L Carvalho, N Lourenço, M Antunes, E Carvalho
BACKGROUND: Cardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death...
April 3, 2018: Biochimica et Biophysica Acta
Pavithra M Dedigama-Arachchige, Nuwan P N Acharige, Mary Kay H Pflum
Phosphorylation is a key post-translational modification in cell signaling, which is regulated by the equilibrium activities of kinases and phosphatases. The biological significance of many phosphorylation events remains poorly characterized due to the scarcity of tools to discover phosphatases substrates. In prior work, we established kinase-catalyzed biotinylation where kinases accept the γ-modified ATP analog, ATP-biotin, to label phosphoproteins. Here, we developed a novel method to study substrates of phosphatases using kinase-catalyzed biotinylation termed K-BIPS (Kinase-catalyzed Biotinylation to Identify Phosphatase Substrates)...
April 6, 2018: Molecular omics
Elisabeth Andersen, Maria Eugenia Chollet, Christiane Filion Myklebust, Mirko Pinotti, Francesco Bernardi, Ampaiwan Chuansumrit, Ellen Skarpen, Per Morten Sandset, Grethe Skretting
Congenital factor (F) VII deficiency is a bleeding disorder caused by a heterogeneous pattern of mutations in the F7 gene. Protein misfolding due to mutations is a strong candidate mechanism to produce the highly represented type I FVII deficiency forms, characterized by a concomitant deficiency of FVII antigen and activity. Misfolded proteins can accumulate within the endoplasmic reticulum (ER) causing ER stress with subsequent activation of the unfolded protein response (UPR). So far, there are limited data on this important issue in FVII deficiency...
April 2018: Thrombosis and Haemostasis
Kun Guo, Wei Wang, Weiwei Fan, Zhiying Wang, Manli Zhu, Xiaohan Tang, Wenting Wu, Xue Yang, Xinghua Shao, Yue Sun, Wei Zhang, Xiaofang Li
The function of human Golgi antiapoptotic proteins (GAAPs) resembles that of BAX inhibitor-1, with apoptosis inhibition triggered by intrinsic and extrinsic stimuli. However, little is known about the function of GAAP-related proteins in plants. Here, we studied Arabidopsis GAAP1 and GAAP3 and found that they were localized on the cellular membrane, including the endoplasmic reticulum (ER) membrane. The function of GAAP1/GAAP3 in ER-stress response was tested, and results showed that single or double mutation in GAAP1 and GAAP3 reduced plant survival and enhanced cell death under ER stress...
2018: Frontiers in Plant Science
Kaori Irahara-Miyana, Takanobu Otomo, Hidehito Kondo, Mohammad Arif Hossain, Keiichi Ozono, Norio Sakai
Krabbe disease, one of the autosomal-recessive lysosomal storage disorders (LSDs), is caused by a deficiency of galactocerebrosidase (GALC) activity, resulting in the intracellular accumulation of psychosine, which is cytotoxic for neuronal cells. Genetically pathogenic mutations result in conformational changes in GALC and disrupt the lysosmal trafficking of cargos, which subsequently accumulate in the endoplasmic reticulum (ER). Recently, ER stress together with the activation of the unfolded protein response (UPR) has been suggested to play a key role in the pathogenesis of LSDs...
April 3, 2018: Journal of Human Genetics
Todd McLaughlin, Marek Falkowski, Jae Whan Park, Stephen Keegan, Michael Elliott, Joshua J Wang, Sarah X Zhang
BACKGROUND: Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses...
April 4, 2018: Molecular Neurodegeneration
Francesca Florio, Cinzia Ferri, Cristina Scapin, M Laura Feltri, Lawrence Wrabetz, Maurizio D'Antonio
Schwann cell differentiation and myelination in the peripheral nervous system are the result of fine-tuning of positive and negative transcriptional regulators. As myelination starts, negative regulators are down-regulated whereas positive ones are up-regulated. Fully differentiated Schwann cells maintain an extraordinary plasticity, and can transdifferentiate into "repair" Schwann cells after nerve injury. Reactivation of negative regulators of myelination is essential to generate repair Schwann cells...
April 2, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jaakko Hentilä, Juha P Ahtiainen, Gøran Paulsen, Truls Raastad, Keijo Häkkinen, Antti A Mero, Juha J Hulmi
AIM: Autophagy and unfolded protein response (UPR) appear to be important for skeletal muscle homeostasis and may be altered by exercise. Our aim was to investigate the effects of resistance exercise and training on indicators of UPR and autophagy in healthy untrained young men (n = 12, 27 ± 4 years) and older men (n = 8, 61 ± 6 years) as well as in resistance-trained individuals (n = 15, 25 ± 5 years). METHODS: Indicators of autophagy and UPR were investigated from the muscle biopsies after a single resistance exercise bout and after 21 weeks of resistance training...
April 2, 2018: Acta Physiologica
Chuang Li, Qianqian Fan, Hongyang Quan, Meng Nie, Yunping Luo, Lin Wang
The unfolded protein response (UPR) is widely activated in cancers. The mammalian UPR encompasses three signaling branches, namely inositol-requiring enzyme-1α (IRE1α), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α (ATF6α). The functional significance of each branch in tumorigenesis is incompletely understood, especially in cancer stem cells (CSCs). Here, we report that inhibition and silencing of the three UPR sensors has differential effects on breast cancer growth and the CSC population...
March 27, 2018: Experimental Cell Research
Xiaobin Zheng, Neal Andruska, Michael J Lambrecht, Sisi He, Amadeo Parissenti, Paul J Hergenrother, Erik R Nelson, David J Shapiro
Ovarian cancers often recur and tumors acquire resistance to chemotherapy due to overexpression of the ATP-dependent efflux pump, multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1). Nontoxic small molecule inhibitors targeting MDR1 have remained largely elusive. Instead, in a novel application of our recently described estrogen receptor α (ERα) biomodulator, BHPI, we targeted MDR1's substrate, ATP. BHPI depletes intracellular ATP and nearly blocks MDR1-mediated drug efflux in ovarian cancer cells by inducing toxic hyperactivation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR)...
March 13, 2018: Oncotarget
Olga Oks, Shany Lewin, Irina Langier Goncalves, Amir Sapir
The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway's enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPRmt , can protect yeast, C. elegans, and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins...
March 29, 2018: Genetics
Jongwan Kim, Md Nazmul Haque, Tae-Won Goo, Il Soo Moon
In the brain, endoplasmic reticulum (ER) stress results in synaptic dysfunction and eventually leads to neurodegeneration. Allomyrina dichotoma larvae are a Chinese ethnomedicine and are widely used in East Asia. In the present study, we investigated the ability of ethanol extract of A. dichotoma larvae (ADE) to improve synaptic structure and function by activating unfolded protein response (UPR) under ER stress in animal and neuron culture models. ER stress was induced in obese mice fed a high fat diet (HFD) or by treating dissociated cultures of rat embryonic (E19) hippocampal neurons with tunicamycin (TM)...
March 29, 2018: American Journal of Chinese Medicine
Gerwyn Morris, Basant K Puri, Ken Walder, Michael Berk, Brendon Stubbs, Michael Maes, André F Carvalho
The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression...
March 29, 2018: Molecular Neurobiology
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