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https://www.readbyqxmd.com/read/28440280/targeting-asic3-for-relieving-mice-fibromyalgia-pain-roles-of-electroacupuncture-opioid-and-adenosine
#1
Liang-Ta Yen, Ching-Liang Hsieh, Hsin-Cheng Hsu, Yi-Wen Lin
Many scientists are seeking better therapies for treating fibromyalgia (FM) pain. We used a mouse model of FM to determine if ASIC3 and its relevant signaling pathway participated in FM pain. We demonstrated that FM-induced mechanical hyperalgesia was attenuated by electroacupuncture (EA). The decrease in fatigue-induced lower motor function in FM mice was also reversed by EA. These EA-based effects were abolished by the opioid receptor antagonist naloxone and the adenosine A1 receptor antagonist rolofylline...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28440222/dual-leucine-zipper-kinase-dependent-perk-activation-contributes-to-neuronal-degeneration-following-insult
#2
Martin Larhammar, Sarah Huntwork-Rodriguez, Zhiyu Jiang, Hilda Solanoy, Arundhati Sengupta Ghosh, Bei Wang, Joshua S Kaminker, Kevin Huang, Jeffrey Eastham-Anderson, Michael Siu, Zora Modrusan, Madeline M Farley, Marc Tessier-Lavigne, Joseph W Lewcock, Trent A Watkins
The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4)...
April 25, 2017: ELife
https://www.readbyqxmd.com/read/28439080/ets-related-gene-mediated-androgen-receptor-aggregation-and-endoplasmic-reticulum-stress-in-prostate-cancer-development
#3
Taduru L Sreenath, Shiela S Macalindong, Natallia Mikhalkevich, Shashwat Sharad, Ahmed Mohamed, Denise Young, Talaibek Borbiev, Charles Xavier, Rishita Gupta, Muhammad Jamal, Kevin Babcock, Shyh-Han Tan, Marja T Nevalainen, Albert Dobi, Gyorgy Petrovics, Isabell A Sesterhenn, Inger L Rosner, Charles J Bieberich, Peter Nelson, Valeri Vasioukhin, Shiv Srivastava
Mechanistic studies of deregulated ERG in prostate cancer and other cancers continue to enhance its role in cancer biology and its utility as a biomarker and therapeutic target. Here, we show that ERG, through its physical interaction with androgen receptor, induces AR aggregation and endoplasmic reticulum stress in the prostate glands of ERG transgenic mice. Histomorphological alterations and the expression of ER stress sensors Atf6, Ire1α, Perk, their downstream effectors Grp78/BiP and eIF2α in ERG transgenic mouse prostate glands indicate the presence of chronic ER stress...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28433684/activating-transcription-factor-6-dependent-sestrin-2-induction-ameliorates-er-stress-mediated-liver-injury
#4
Kyung Hwan Jegal, Sang Mi Park, Sam Seok Cho, Sung Hui Byun, Sae Kwang Ku, Sang Chan Kim, Sung Hwan Ki, Il Je Cho
Endoplasmic reticulum (ER) stress is characterized by an accumulation of misfolded proteins, and ER stress reduction is essential for maintaining tissue homeostasis. However, the molecular mechanisms that protect cells from ER stress are not completely understood. The present study investigated the role of sestrin 2 (SESN2) on ER stress and sought to elucidate the mechanism responsible for the hepatoprotective effect of SESN2 in vitro and in vivo. Treatment with tunicamycin (Tm) increased SESN2 protein and mRNA levels and reporter gene activity...
April 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28432299/tangluoning-a-traditional-chinese-medicine-attenuates-in-vivo-and-in-vitro-diabetic-peripheral-neuropathy-through-modulation-of-perk-nrf2-pathway
#5
Xinwei Yang, Weijie Yao, Haolong Liu, Yanbin Gao, Renhui Liu, Liping Xu
Prolonged hyperglycemia-induced oxidative stress and endoplasmic reticulum stress have been demonstrated to play a key role in progression of diabetic peripheral neuropathy (DPN). PERK/ Nrf2 pathway plays a predominant role in oxidative and endoplasmic reticulum (ER) stress which is associated with cell survival. This study examined the modulation of the PERK/Nrf2 pathway and apoptosis by a traditional Chinese medicine Tangluoning (TLN) in streptozotocin-induced DPN rat models and the effects of serum TLN on the PERK/Nrf2 pathway, apoptosis, intracellular reactive oxygen species and mitochondrial membrane potential in Schwann cells cultured in 150 mM glucose...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431342/discovery-of-tetrahydrocarbazoles-as-dual-perk-and-prb-inhibitors
#6
Mahesh R Kulkarni, Madhav S Mane, Usha Ghosh, Rajiv Sharma, Nitin P Lad, Ankita Srivastava, Asha Kulkarni-Almeida, Prashant S Kharkar, Vijay M Khedkar, Shivaji S Pandit
The extracellular signal-regulated kinase (ERK) is one of the most important molecular targets for cancer that controls diverse cellular processes such as proliferation, survival, differentiation and motility. Similarly, the Rb (retinoblastoma protein) is a tumor suppressor protein and its function is to prevent excessive cell growth by inhibiting cell cycle progression. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. Herein, we discovered a new series of tetrahydrocarbazoles as dual inhibitors of pERK and pRb phosphorylation...
March 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#7
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28426781/tauroursodeoxycholic-acid-tudca-attenuates-pressure-overload-induced-cardiac-remodeling-by-reducing-endoplasmic-reticulum-stress
#8
Shilpa Rani, Pradeep Kumar Sreenivasaiah, Jin Ock Kim, Mi Young Lee, Wan Seok Kang, Yong Sook Kim, Youngkeun Ahn, Woo Jin Park, Chunghee Cho, Do Han Kim
Pressure overload in the heart induces pathological hypertrophy and is associated with cardiac dysfunction. Apoptosis and fibrosis signaling initiated by the endoplasmic reticulum stress (ERS) is known to contribute to these maladaptive effects. The aim of this study was to investigate whether reduction of ERS by a known chemical chaperone, tauroursodeoxycholic acid (TUDCA) can attenuate pressure overload-induced cardiac remodeling in a mouse model of transverse aortic constriction (TAC). Oral administration of TUDCA at a dose of 300 mg/kg body weight (BW) in the TUDCA-TAC group reduced ERS markers (GRP78, p-PERK, and p-eIf2α), compared to the Vehicle (Veh)-TAC group...
2017: PloS One
https://www.readbyqxmd.com/read/28424060/effects-of-a-combination-treatment-of-kd5040-and-l-dopa-in-a-mouse-model-of-parkinson-s-disease
#9
Sora Ahn, Taek-Jin Song, Seong-Uk Park, Songhee Jeon, Jongpil Kim, Joo-Young Oh, Jaehwan Jang, Sanhwa Hong, Min-A Song, Hye-Seoung Shin, Young-Rim Jung, Hi-Joon Park
BACKGROUND: Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( l -dopa) remains the gold standard pharmacological therapy for patients with Parkinson's disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l -dopa and antidyskinetic effects caused by l -dopa as well...
April 19, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28423691/predicting-clinical-benefit-from-everolimus-in-patients-with-advanced-solid-tumors-the-cpct-03-study
#10
Fleur Weeber, Geert A Cirkel, Marlous Hoogstraat, Sander Bins, Christa G M Gadellaa-van Hooijdonk, Salo Ooft, Erik van Werkhoven, Stefan M Willems, Marijn van Stralen, Wouter B Veldhuis, Nicolle J M Besselink, Hugo M Horlings, Neeltje Steeghs, Maja J de Jonge, Marlies H G Langenberg, Lodewyk F A Wessels, Edwin P J G Cuppen, J H Schellens, Stefan Sleijfer, Martijn P Lolkema, Emile E Voest
BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK...
March 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423496/mtor-inhibitors-activate-perk-signaling-and-favor-viability-of-gastrointestinal-neuroendocrine-cell-lines
#11
Patricia Freis, Julien Bollard, Justine Lebeau, Patrick Massoma, Joëlle Fauvre, Cécile Vercherat, Thomas Walter, Serge Manié, Colette Roche, Jean-Yves Scoazec, Carole Ferraro-Peyret
mTOR and Unfolded Protein Response (UPR) are two signaling pathways frequently activated in cancer cells. The mTOR pathway has been shown to be up-regulated in most gastroenteropancreatic neuroendocrine tumors. In contrast, little is known about the UPR status in neoplastic neuroendocrine cells. However, these hormone-producing cells are likely to present distinctive adaptations of this pathway, as other secretory cells. We therefore analyzed the status of the three axes of UPR and their relation to mTOR pathway in two gastrointestinal neuroendocrine tumors (GI-NET) cell lines STC-1 and GluTag...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28421170/porcine-reproductive-and-respiratory-syndrome-virus-infection-induces-stress-granule-formation-depending-on-protein-kinase-r-like-endoplasmic-reticulum-kinase-perk-in-marc-145-cells
#12
Yanrong Zhou, Liurong Fang, Dang Wang, Kaimei Cai, Huanchun Chen, Shaobo Xiao
Stress granules (SGs) are sites of mRNA storage that are formed in response to various conditions of stress, including viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. In this study, we found that infection of PRRSV strain WUH3 (genotype 2 PRRSV) induced stable formation of robust SGs in MARC-145 cells, as demonstrated by the recruitment of marker proteins of SGs, including TIA1, G3BP1, and eIF3η...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28420192/thioredoxin-interacting-protein-mediates-apoptosis-in-early-brain-injury-after-subarachnoid-haemorrhage
#13
Qing Zhao, Xudong Che, Hongxia Zhang, Guanping Tan, Liu Liu, Dengzhi Jiang, Jun Zhao, Xiang Xiang, Xiaochuan Sun, Zhaohui He
Early brain injury (EBI) is considered to be the major factor associated with high morbidity and mortality after subarachnoid haemorrhage (SAH). Apoptosis is the major pathological mechanism of EBI, and its pathogenesis has not been fully clarified. Here, we report that thioredoxin-interacting protein (TXNIP), which is induced by protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), participates in EBI by promoting apoptosis. By using adult male Sprague-Dawley rats to establish SAH models, as well as Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, immunofluorescence, and western blot, we found that TXNIP expression significantly increased after SAH in comparison to the sham group and peaked at 48 h (up to 3...
April 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28419216/lav-bpifb4-isoform-modulates-enos-signaling-through-ca2-pkc-alpha-dependent-mechanism
#14
Chiara Carmela Spinelli, Albino Carrizzo, Anna Ferrario, Francesco Villa, Antonio Damato, Mariateresa Ambrosio, Michele Madonna, Giacomo Frati, Sergio Fucile, Miriam Sciaccalunga, Mario Capunzo, Gaetano Calì, Luciano Milanesi, Anna Maciag, Annibale Alessandro Puca, Carmine Vecchione
Aims: Aging is associated with impairment of endothelial nitric oxide synthase (eNOS) and progressive reduction in endothelial function. A genetic study on long-living individuals - who are characterized by delays in aging and in the onset of cardiovascular disease - previously revealed I229V ( rs2070325 ) in BPIFB4 as a longevity-associated variant (LAV); the LAV protein enhanced endothelial NO production and vasorelaxation through a PERK/14-3-3/HSP90 signal. Here, we further characterize the molecular mechanisms underlying LAV-BPIFB4-dependent enhancement of vascular function...
April 13, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28418119/endoplasmic-reticulum-stress-pathway-perk-eif2%C3%AE-confers-radioresistance-in-oropharyngeal-carcinoma-by-activating-nf-%C3%AE%C2%BAb
#15
Qiao Qiao, Chaonan Sun, Chuyang Han, Ning Han, Miao Zhang, Guang Li
Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis and development of malignant tumours, as well as in the regulation of radio- and chemoresistance in many malignancies. ERS signalling pathway protein kinase RNA-like endoplasmic reticulum kinase (PERK) -eukaryotic initiation factor-2 (eIF2α) may induce aberrant activation of nuclear factor-κB (NF-κB). Our previous study showed that NF-κB confered radioresistance in lymphoma cells. However, whether PERK-eIF2α regulates radioresistance in oropharyngeal carcinoma through NF-κB activation is unknown...
April 18, 2017: Cancer Science
https://www.readbyqxmd.com/read/28416388/human-grp78-affinity-towards-its-signaling-partners-ire1%C3%AE-and-perk-is-differently-modulated-by-an-unfolded-protein-client
#16
Razvan C Stan, Raissa L Silva, Maristela M de Camargo
Protein-folding stress is characteristic of specialized secretory cells and plays a dominant role in a multitude of diseases. The unfolded protein response (UPR) thus triggered is a proteostatic signaling network that adapts the protein-folding capacity of the endoplasmic reticulum to the cellular demands. We have measured the binding affinities between human GRP78, an essential chaperone located in ER, and two transmembrane UPR sensors (human PERK and Ire1α), with or without the addition of an unfolded protein client...
April 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28415755/mitochondrial-matrix-chaperone-and-c-myc-inhibition-causes-enhanced-lethality-in-glioblastoma
#17
Chiaki Tsuge Ishida, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Dario C Altieri, Georg Karpel-Massler, Markus David Siegelin
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415630/resveratrol-alleviates-ffa-and-ccl4-induced-apoptosis-in-hepg2-cells-via-restoring-endoplasmic-reticulum-stress
#18
Fenghua Li, Yang Yang, Lili Yang, Kai Wang, Xing Zhang, Yunlong Zong, Yixin Ding, Changhong Wang, Li Zhang, Guang Ji
Cell apoptosis often induces inflammation and injury in the liver, with endoplasmic reticulum (ER) stress as the most possible reason. Resveratrol (RSV) has been shown to prevent hepatic steatosis and alleviate apoptosis, however, the exact mechanisms underlying the effects still need to be explored. Here we co-cultured HepG2 cells with free fatty acid (FFA) solution (oleic acid: palmitic acid = 2:1) and then exposed to a carbon tetrachloride (CCl4) solution to induce apoptosis. To evaluate the therapeutic effects, RSV (2...
March 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405686/long-non-coding-rna-meg3-induces-cell-apoptosis-in-esophageal-cancer-through-endoplasmic-reticulum-stress
#19
Zhen-Lun Huang, Rui-Pei Chen, Xiao-Tao Zhou, Hao-Lian Zhan, Min-Min Hu, Bin Liu, Guan-Di Wu, Ling-Fei Wu
Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA MEG3 has been identified in several cancers, little is known about its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to detect MEG3 expression in clinical ESCC tissues, investigate its biological functions and the endoplasmic reticulum (ER) stress-relative mechanism. MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 28 ESCC patients...
May 2017: Oncology Reports
https://www.readbyqxmd.com/read/28400912/impact-on-autophagy-and-ultraviolet-b-induced-responses-of-treatment-with-the-mtor-inhibitors-rapamycin-everolimus-torin-1-and-pp242-in-human-keratinocytes
#20
Song Xu, Li Li, Min Li, Mengli Zhang, Mei Ju, Xu Chen, Heng Gu
The mechanistic target of Rapamycin (MTOR) protein is a crucial signaling regulator in mammalian cells that is extensively involved in cellular biology. The function of MTOR signaling in keratinocytes remains unclear. In this study, we detected the MTOR signaling and autophagy response in the human keratinocyte cell line HaCaT and human epidermal keratinocytes treated with MTOR inhibitors. Moreover, we detected the impact of MTOR inhibitors on keratinocytes exposed to the common carcinogenic stressors ultraviolet B (UVB) and UVA radiation...
2017: Oxidative Medicine and Cellular Longevity
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