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Hye-Bin Park, Mi-Jeong Kim, Bae-Dong Jung, Seunghyung Lee, Choon-Keun Park, Boo-Keun Yang, Hee-Tae Cheong
We investigate the effect of endoplasmic reticulum (ER) stress inhibitor treatment during parthenogenetic activation of oocytes on the ER stress generation, apoptosis, and in vitro development of parthenogenetic porcine embryos. Porcine in vitro matured oocytes were activated by 1) electric stimulus (E) or 2) E+10 μM Ca-ionophore (A23187) treatment (EC). Oocytes were then treated by ER stress inhibitors such as salubrinal (200 nM) and tauroursodeoxychloic acid (TUDCA, 100 μM) for 3 h prior to in vitro culture...
September 2018: Balsaeng'gwa Saengsig
Ying Zhang, Xue Liu, Lu Zhang, Xuelian Li, Zhongqiu Zhou, Lei Jiao, Yingchun Shao, Mengmeng Li, Bing Leng, Yuhong Zhou, Tianyi Liu, Qiushuang Liu, Hongli Shan, Zhimin Du
Ischemia-reperfusion (I/R) injury is a major side effect of the reperfusion treatment of the ischemic heart. Few therapies are available for the effective prevention of this injury caused by the oxidative stress-induced cardiomyocyte apoptosis. Metformin was shown to have a potential cardiac protective effect and ability to reduce cardiac events, but the exact mechanism remains unclear. Here, we aimed to confirm and investigate the mechanisms underlying potential metformin activity against I/R injury in response to oxidative stress...
September 6, 2018: Molecular Therapy. Nucleic Acids
Virginia Andreani, Senthilkumar Ramamoorthy, Abhinav Pandey, Ekaterina Lupar, Stephen L Nutt, Tim Lämmermann, Rudolf Grosschedl
Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1 -/- Prdm1 +/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
Chhanda Biswas, Sheila Rao, Katharine Slade, David Hyman, Devin Dersh, Adriana R Mantegazza, Philip W Zoltick, Michael S Marks, Yair Argon, Edward M Behrens
Toll like receptors (TLRs) share a conserved structure comprising the N-terminal ectodomain, a transmembrane segment and a C-terminal cytoplasmic Toll/IL-1 receptor (TIR) domain. Proper assembly of the TIR domain is crucial for signal transduction; however, the contribution of individual motifs within the TIR domain to TLR trafficking and signaling remains unclear. We targeted a highly conserved tyrosine (Y870) located in the box 1 region of the TIR domain of most TLRs, including TLR9, previously described to be a critical site of phosphorylation in TLR4...
2018: PloS One
Elisa Landucci, Irene L Llorente, Berta Anuncibay-Soto, Domenico E Pellegrini-Giampietro, Arsenio Fernández-López
We previously demonstrated that the non-steroidal anti-inflammatory agent meloxicam has neuroprotective effects in an oxygen and glucose deprivation model (OGD) of rat organotypic hippocampal slice cultures. We wondered if GABAergic transmission changed the neuroprotective effects of meloxicam and if meloxicam was able to modulate endoplasmic reticulum stress (ER stress) in this model. Mortality was measured using propidium iodide. Western blot assays were performed to measure levels of cleaved and non-cleaved caspase-3 to quantify apoptosis, while levels of GRP78, GRP94 and phosphorylated eIF2α were used to detect unfolded protein response (UPR)...
August 21, 2018: Neuroscience
Xian-Qiang Ni, Wei-Wei Lu, Jin-Sheng Zhang, Qing Zhu, Jin-Ling Ren, Yan-Rong Yu, Xiu-Ying Liu, Xiu-Jie Wang, Mei Han, Qing Jing, Jie Du, Chao-Shu Tang, Yong-Fen Qi
Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII...
October 2018: Endocrine
Sonam Grover, Tarina Sharma, Yadvir Singh, Sakshi Kohli, Manjunath P, Aditi Singh, Torsten Semmler, Lothar H Wieler, Karsten Tedin, Nasreen Z Ehtesham, Seyed E Hasnain
The genome of Mycobacterium tuberculosis , the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS)...
June 19, 2018: MBio
Shuyue Wang, Xu Li, Tingting Li, Huizhen Wang, Xiangchao Zhang, Jiarun Lou, Qiang Xing, Xiaoli Hu, Zhenmin Bao
The 94-kDa glucose-regulated protein (GRP94) belonging to the HSP90 family is an endoplasmic reticulum (ER) chaperone. It plays critical roles in ER quality control, and has been implicated as a specialized immune chaperone to regulate both innate and adaptive immunity. In this study, we identified and characterized a GRP94 gene (PyGRP94) from Yesso scallop (Patinopecten yessoensis). The protein sequence of PyGRP94 is highly conserved with its homologs in vertebrates, with a signal sequence in N-terminal, an ER retrieval signal sequence in C-terminal and a HATPase_c domain...
September 2018: Fish & Shellfish Immunology
María-José Barrera, Sergio Aguilera, Isabel Castro, Sergio González, Patricia Carvajal, Claudio Molina, Marcela A Hermoso, María-Julieta González
For many years, researchers in the field of autoimmunity have focused on the role of the immune components in the etiopathogenesis of autoimmune diseases. However, some studies have demonstrated the importance of target tissues in their pathogenesis and the breach of immune tolerance. The immune system as well as target tissue cells (plasmatic, β-pancreatic, fibroblast-like synoviocytes, thyroid follicular and epithelial cells of the lachrymal glands, salivary glands, intestine, bronchioles and renal tubules) share the characteristic of secretory cells with an extended endoplasmic reticulum (ER)...
August 2018: Autoimmunity Reviews
Pedro Buc Calderon, Anne-Laure Sennesael, Christophe Glorieux
Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown. Since many tumors display high Grp94 levels, we investigated the effects of tumor microenvironment on the regulation of this chaperone expression. First, we found out that hypoxia did not change Grp94 expression in the human tumor cell lines MCF-7 (breast cancer) and HepG2 (liver cancer). Second, glucose deprivation significantly increased Grp94 protein levels...
September 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Abdullah Hoter, Mahdi Amiri, Mohamad Warda, Hassan Y Naim
Endoplasmin, or GRP94, is an ER-located stress inducible molecular chaperone implicated in the folding and assembly of many proteins. The Arabian one-humped camel lives in an environment of thermal stress, nevertheless is able to encounter the risk of misfolded proteins. Here, the cDNA encoding camel GRP94 was isolated by rapid amplification of cDNA ends. The isolated cDNA contained an open reading frame of 2412 bp encoding a protein of 803 amino acids with predicted molecular mass of 92.5 kDa. Nucleotide and protein BLAST analysis of cGRP94 revealed strong conservation between camel and other domestic mammals...
October 1, 2018: International Journal of Biological Macromolecules
Alessandra Stacchiotti, Gaia Favero, Antonio Lavazza, Maria Monsalve, Luigi Fabrizio Rodella, Rita Rezzani
Taurine (TAU) is a sulfur-containing beta amino acid that is not involved in protein composition and anabolism, conditionally essential in mammals provided through diet. Growing evidence supports a protective role of TAU supply in osmoregulation, calcium flux, and reduction of inflammation and oxidant damage in renal diseases like diabetes. Endoplasmic reticulum (ER) stress, due to abnormal proteostasis, is a contributor to nephrotic syndrome and related renal damage. Here, we investigated the effect of dietary TAU (1...
May 29, 2018: Nutrients
Jing Fang, Panpan Zhu, Zhuangzhi Yang, Xi Peng, Zhicai Zuo, Hengmin Cui, Ping Ouyang, Gang Shu, Zhengli Chen, Chao Huang, Wentao Liu
Aflatoxin B1 (AFB1 ) can cause hepatotoxicity, genotoxicity, and immunosuppressive effects for a variety of organisms. Selenium (Se), as an essential nutrient element, plays important protective effects against cell apoptosis induced by AFB1 . This research aimed to reveal the ameliorative effects of selenium on AFB1 -induced excess apoptosis in chicken splenocytes through death receptor and endoplasmic reticulum pathways in vivo. Two hundred sixteen neonatal chickens, randomized into four treatments, were fed with basal diet (control treatment), 0...
May 16, 2018: Biological Trace Element Research
Meetali Singh, Divya Beri, Rishi Kumar Nageshan, Leena Chavaan, Darshak Gadara, Mukta Poojary, Suraj Subramaniam, Utpal Tatu
Trichomonas vaginalis is a causative agent of Trichomoniasis, a leading non-viral sexually transmitted disease worldwide. In the current study, we show Heat shock protein 90 is essential for its growth. Upon genomic analysis of the parasite, it was found to possess seven ORFs which could potentially encode Hsp90 isoforms. We identified a cytosolic Hsp90 homolog, four homologs which can align to truncated cytosolic Hsp90 gene products along with two Grp94 homologs (ER isoform of Hsp90). However, both Grp94 orthologs lacked an ER retention motif...
May 2018: PLoS Neglected Tropical Diseases
Beibei Zhang, Pilar Ayuda Durán, Laure Piechaczyk, Yngvar Fløisand, Mireia Mayoral Safont Safont, Ida Tveit Karlsen, Zina Fandalyuk, Dagim Tadele, Pepijn van Mierlo, Alexander D Rowe, Joseph M Robertson, Bjørn Tore Gjertsen, Emmet McCormack, Jorrit M Enserink
Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response, leading to increased expression of GRP94/HSP90B1...
May 10, 2018: Haematologica
Lipeng Xiong, Wenwen Yan, Emmanuel Zubia, Yanqing Zhou, Yang Zhang, Qianqian Duan, Mahesh Narayan, Guoqiang Xu
A Disintegrin And Metalloproteinase 12 (ADAM12) is highly expressed in multiple cancers such as breast and cervical cancers and its high expression reduces the overall patient survival rate. ADAM12 has two major splicing variants, the long membrane-anchored form ADAM12L and the short secreted form ADAM12S. However, how they are regulated and whether they are modulated similarly or differently in cells are not clear. Here, we use affinity purification and mass spectrometry to identify the ADAM12S-interacting proteins...
June 30, 2018: Journal of Proteomics
Magdalena Kusaczuk, Rafał Krętowski, Monika Naumowicz, Anna Stypułkowska, Marzanna Cechowska-Pasko
Introduction: Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors. Materials and methods: Here, we explored the effects of 5-15 nm SiNPs in the human glioblastoma cell line LN229...
2018: International Journal of Nanomedicine
Madeline Y Wong, Ngoc Duc Doan, Andrew S DiChiara, Louis J Papa, Jaime H Cheah, Christian K Soule, Nicki Watson, John D Hulleman, Matthew D Shoulders
Collagen overproduction is a feature of fibrosis and cancer, while insufficient deposition of functional collagen molecules and/or the secretion of malformed collagen is common in genetic disorders like osteogenesis imperfecta. Collagen secretion is an appealing therapeutic target in these and other diseases, as secretion directly connects intracellular biosynthesis to collagen deposition and biological function in the extracellular matrix. However, small molecule and biological methods to tune collagen secretion are severely lacking...
May 15, 2018: Biochemistry
Alex B Addinsall, Craig R Wright, Chris S Shaw, Natasha L McRae, Leonard G Forgan, Chia-Heng Weng, Xavier A Conlan, Paul S Francis, Zoe M Smith, Sofianos Andrikopoulos, Nicole Stupka
Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/- heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1-/- knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype...
August 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Paul Lebeau, Khrystyna Platko, Ali A Al-Hashimi, Jae Hyun Byun, Šárka Lhoták, Nicholas Holzapfel, Gabriel Gyulay, Suleiman A Igdoura, David R Cool, Bernardo Trigatti, Nabil G Seidah, Richard C Austin
The proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low-density lipoprotein receptor (LDLR). As such, loss-of-function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase hepatic LDLR levels and lower the risk of developing CVD. The retention of misfolded protein in the ER can cause ER stress and activate the unfolded protein response (UPR). In this study, we investigated whether a variety of LOF PCSK9 variants that are retained in the ER can cause ER stress and hepatic cytotoxicity...
May 11, 2018: Journal of Biological Chemistry
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