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Weizhuo Wang, Jinsong Chen, Yigeng Hui, Mengdi Huang, Puwei Yuan
Emerging evidence indicates that microRNAs (miRNAs) are crucial regulators of osteoblast differentiation. A previous study has reported that miR-193a-3p expression is altered during the induction of osteoblast differentiation. However, the precise biological function and regulatory mechanism of miR-193a-3p during osteoblast differentiation remains unclear. In this study, we aimed to investigate the precise role and underlying mechanism of miR-193a-3p in regulating osteoblast differentiation. The results showed that miR-193a-3p expression was significantly down-regulated during the induction of osteoblast differentiation...
August 9, 2018: Biochemical and Biophysical Research Communications
L A Frank, R D Rose, M R Anastasi, T C Y Tan, M F Barry, J G Thompson, H M Brown
Blastocoel expansion during embryo development is known to be reliant on the Na+/K+-ATPase pump, but little is known about the relative contribution of active (Na+/K+-ATPase pump) and facilitated diffusion (aquaporins) water transport during blastocoel re-expansion after vitrification. The aims of this study were to examine potential effects of artificial blastocoel collapse (ABC) on markers of embryo stress and the contribution of active and facilitated diffusion water transport mechanisms to blastocoel re-expansion...
August 13, 2018: Reproduction, Fertility, and Development
Adrien Nougarède, Chloé Tesnière, Jarkko Ylanko, Ruth Rimokh, Germain Gillet, David W Andrews
In response to a variety of insults the unfolded protein response (UPR) is a major cell program quickly engaged to promote either cell survival or if stress levels cannot be relieved, apoptosis. UPR relies on three major pathways, named from the endoplasmic reticulum (ER) resident proteins IRE1α, PERK, and ATF6 that mediate response. Current tools to measure the activation of these ER stress response pathways in mammalian cells are cumbersome and not compatible with high-throughput imaging. In this study, we present IRE1α and PERK sensors with improved sensitivity, based on the canonical events of xbp1 splicing and ATF4 translation at ORF3...
August 8, 2018: Assay and Drug Development Technologies
Blanca Algarra, Verónica Maillo, Manuel Avilés, Alfonso Gutiérrez-Adán, Dimitrios Rizos, Maria Jimenez-Movilla
Previously, our group demonstrated that recombinant porcine oviductin (pOVGP1) binds to the zona pellucida (ZP) of in vitro-matured (IVM) porcine oocytes with a positive effect on in vitro fertilization (IVF). The fact that pOVGP1 was detected inside IVM oocytes suggested that this protein had a biological role during embryo development. The aim of this study was to evaluate the effects of pOVGP1 on bovine in vitro embryo development. We applied 10 or 50 µg/ml of pOVGP1 during IVF, embryonic in vitro culture (IVC), or both, to evaluate cleavage and embryo development...
August 6, 2018: Journal of Reproduction and Development
Miaojuan Qiu, Suchun Li, Lizi Jin, Pinning Feng, Yonglun Kong, Xiaoduo Zhao, Yu Lin, Yunyun Xu, Chunling Li, Weidong Wang
BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells...
July 31, 2018: Lipids in Health and Disease
Caroline Demangel, Stephen High
Infection with Mycobacterium ulcerans results in a necrotizing skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesized membrane and secretory proteins into and across the ER membrane...
July 28, 2018: Biology of the Cell
Mohammed N A Siddiquey, Hongbo Zhang, Christopher C Nguyen, Anthony J Domma, Jeremy P Kamil
Eukaryotic cells are equipped with three sensors that respond to the accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR), which functions to resolve proteotoxic stresses involving the secretory pathway. Here, we identify UL148, a viral ER resident glycoprotein from human cytomegalovirus (HCMV), as an inducer of the UPR. Metabolic labeling results indicate that global mRNA translation is decreased when UL148 expression is induced in uninfected cells...
July 25, 2018: Journal of Virology
Andreas Petry, Zuwen Zhang, Benjamin Trautz, Florian Riess, Agnes Görlach
BACKGROUND: Cardiovascular diseases have been associated with stress in the endoplasmic reticulum (ER) and accumulation of unfolded proteins leading to the unfolded protein response (UPR). Reactive oxygen species (ROS) such as superoxide and H2O2 derived from NADPH oxidases have been implicated in the pathogenesis of cardiovascular diseases. ROS have also been associated with ER stress. The role NADPH oxidases in the UPR is, however, not completely resolved yet. AIM: In this study we investigated the role of p22phox, an essential component of most NADPH oxidases, in the UPR of endothelial cells...
July 25, 2018: Antioxidants & Redox Signaling
Chiaki Tsuge Ishida, Yiru Zhang, Elena Bianchetti, Chang Shu, Trang Tt Nguyen, Giulio Kleiner, Maria Sanchez-Quintero, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Varun Vijay Prabhu, Joshua E Allen, Markus D Siegelin
PURPOSE: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma. EXPERIMENTAL DESIGN: Gene set enrichment, LC/MS and extracellular flux analysis were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. RESULTS: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo...
July 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kumar Abhishek, Sushmita Das, Ashish Kumar, Ajay Kumar, Vinod Kumar, Savita Saini, Abhishek Mandal, Sudha Verma, Manjay Kumar, Pradeep Das
BACKGROUND: Endoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation. METHODOLOGY: Infected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody...
July 2018: PLoS Neglected Tropical Diseases
Nianxiu Tian, Yanbin Gao, Xiaolei Wang, Xiaoming Wu, Dawei Zou, Zhiyao Zhu, ZheJi Han, Tao Wang, Yimin Shi
Background: Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown. Aim: This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK-eIF2α pathway...
2018: Drug Design, Development and Therapy
James W Foster, Vishal Shinde, Uri S Soiberman, Gajanan Sathe, Sheng Liu, Julius Wan, Jiang Qian, Yassine Dauoud, Akhilesh Pandey, Albert S Jun, Shukti Chakravarti
Purpose: Keratoconus (KC) is a multifactorial disease where progressive thinning and weakening of the cornea leads to loss of visual acuity. Although the underlying etiology is poorly understood, a major endpoint is a dysfunctional stromal connective tissue matrix. Using multiple individual KC corneas, we determined that matrix production by keratocytes is severely impeded due to an altered stress response program. Methods: KC and donor (DN) stromal keratocytes were cultured in low glucose serum-free medium containing insulin, selenium and transferrin...
June 1, 2018: Investigative Ophthalmology & Visual Science
Pei Li, Luming Liu, Guoyu Zhou, Zhiyuan Tian, Chen Luo, Tao Xia, Jingwen Chen, Qiang Niu, Lixin Dong, Qian Zhao, Aiguo Wang, Shun Zhang
Brominated flame retardant 2,2',4,4'‑tetrabromodiphenyl ether (PBDE-47) is known to induce developmental neurotoxicity by disturbing thyroid hormones (THs). Evidence shows that maternal THs are crucial for brain development and growth of fetuses and infants. However, little is known about the effects of PBDE-47 on maternal thyroid status and its mode of action. Here, using female Sprague-Dawley rats orally exposed to low doses of PBDE-47 (0.1, 1.0, 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we show that perigestational exposure to PBDE-47 elevated serum triiodothyronine and thyroxine levels in mother rats...
July 16, 2018: Science of the Total Environment
Jiwei Wang, Qichao Qi, Wenjing Zhou, Zichao Feng, Bin Huang, Anjing Chen, Di Zhang, Wenjie Li, Qing Zhang, Zheng Jiang, Rolf Bjerkvig, Lars Prestegarden, Frits Thorsen, Xinyu Wang, Xingang Li, Jian Wang
Flavokawain B (FKB), a natural kava chalcone, displays potent antitumor activity in various types of cancer. The mechanism of action, however, remains unclear. Here, we evaluated the efficacy of FKB in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its inhibitory effects in cancer. Approximately 60% of GBM cells, U251, U87, and T98, became senescent after treatment with FKB (3 μg/mL for 48 h) as assessed in the senescence-associated (SA)-GLB1/SA-β-galactosidase assay...
July 19, 2018: Autophagy
Juan Jin, Li Zhao, Wenli Zou, Wei Shen, Hongjuan Zhang, Qiang He
BACKGROUND/AIMS: Autophagy plays an essential role in lupus nephritis (LN)-induced kidney injury, although the mechanism of action remains obscure. We investigated the role of cyclooxygenase-2 (COX-2) and the ATF4 endoplasmic reticulum (ER) stress pathway in LN-induced podocyte autophagy. METHODS: We evaluated podocyte autophagy in a mouse model of LN. Protein levels of COX-2 and ATF4, and markers of autophagy, were evaluated by immunofluorescence and western blotting...
July 19, 2018: Cellular Physiology and Biochemistry
Cheng Wang, Zhijia Tan, Ben Niu, Kwok Yeung Tsang, Andrew Tai, Wilson C W Chan, Rebecca L K Lo, Keith K H Leung, Nelson W F Dung, Nobuyuki Itoh, Michael Q Zhang, Danny Chan, Kathryn Song Eng Cheah
The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9 ...
July 19, 2018: ELife
Yan Xin, Bin Wan, Yu Yang, Xue-Jing Cui, Yi-Chun Xie, Liang-Hong Guo
Wide application of perfluoroalkyl acids (PFAAs) has raised great concerns on their side-effects on human health. PFAAs have been shown to accumulate mainly in the liver and cause hepatotoxicity. However, PFAAs can also deposit in lung tissues through air-borne particles and cause serious pulmonary toxicity. But the underlying mechanisms are still largely unknown. Autophagy is a type of programmed cell death parallel to necrosis and apoptosis, and may be involved in the lung toxicity of PFAAs. In this study, lung cancer cells, A549, were employed as the model to investigate the effects of three PFAAs with different carbon chain lengths on cell autophagy...
July 18, 2018: Archives of Toxicology
Ha-Na Gil, Dongsoo Koh, Yoongho Lim, Young Han Lee, Soon Young Shin
The synthetic chalcone derivative 2-hydroxy-3',5,5'-trimenthoxyochalcone (named DK-139) exhibits anti-inflammatory and anti-tumor invasion properties. However, effects of DK-139 on tumor cell growth remain unknown. In the present study, we evaluated the inhibitory activity of DK-139 against human lung cancer cells. Treatment with DK-139 inhibited clonogenicity in various lung cancers and stimulated the caspase cascade, leading to the apoptosis of A549 lung cancer cells. To investigate the mode of action of DK-139-induced apoptosis, we analyzed the effect of DK-139 on the endoplasmic reticulum (ER) stress response...
July 4, 2018: Bioorganic & Medicinal Chemistry Letters
Xiaozhen Chen, Yinglin Wang, Xiang Xie, Hongfei Chen, Qiqi Zhu, Zhidong Ge, Hua Wei, Jingshong Deng, Zhengyuan Xia, Qingquan Lian
Background: Sepsis leads to severe acute lung injury/acute respiratory distress syndrome (ALI/ARDS) that is associated with enhanced endoplasmic reticulum (ER) stress. Heme oxygenase-1 (HO-1), an ER-anchored protein, exerts antioxidant and protective functions under ALI. However, the role of HO-1 activation in the development of endoplasmic reticulum (ER) stress during sepsis remains unknown. Methods: Cecal ligation and puncture (CLP) model was created to induce septic ALI...
2018: Mediators of Inflammation
Adrián González-González, Esperanza Muñoz-Muela, Juan A Marchal, Francisca Elvira Cara, Maria Pilar Molina, Marina Cruz-Lozano, Gema Jiménez, Akanksha Verma, Alberto Ramírez, Wei Qian, Wen Chen, Anthony J Kozielski, Olivier Elemento, M Dolores Martin-Salvago, Rafael Jesús Luque, Carmen Rosa-Garrido, David Landeira, María Quintana-Romero, Roberto R Rosato, María A García, César L Ramírez-Tortosa, Hanna Kim, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K Sood, José A Lorente, Pedro Sánchez-Rovira, Jenny C Chang, Sergio Granados-Principal
PURPOSE: Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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