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Jinmi Lee, Seok-Woo Hong, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee
Lipin-1 performs dual function during lipid metabolism, i.e., it functions as a transcriptional coactivator and as a phosphatidate phosphatase during triglyceride biosynthesis. We investigated whether exendin-4 prevented endoplasmic reticulum (ER) stress-induced hepatic steatosis and whether the protective effects of exendin-4 were associated with lipin-1 signaling. Tunicamycin and thapsigargin, ER stress inducers, increased triglycerides (TG) content and expression of genes encoding lipid droplet surface proteins...
June 22, 2018: Cell Stress & Chaperones
Johannes Laengle, Judith Stift, Agnes Bilecz, Brigitte Wolf, Andrea Beer, Balazs Hegedus, Stefan Stremitzer, Patrick Starlinger, Dietmar Tamandl, Dietmar Pils, Michael Bergmann
Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear. Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33)...
2018: Theranostics
Yapei Li, Yang-Fan PengZhou, Chunle Wang, Le Li, Yiping Leng, Ruifang Chen, Hong Yuan, Shenghua Zhou, Zhen Zhang, Alex F Chen
Endothelial cell senescence is regarded as a vital characteristic of cardiovascular diseases (CVDs). Elevated palmitate (PA) is an independent risk factor of CVDs, but its role in the endothelial cell senescence is currently unknown. During the course of studying pro-senescent role of PA, we discovered a key role of double-stranded RNA-dependent protein kinase PKR in endothelial senescence. Exposure of human umbilical vein endothelial cells (HUVECs) to PA induced cell senescence, characterized by increased levels of senescence-associated β-galactose glucosidase (SA-β-gal) activity, excessive reactive oxygen species (ROS) production, impaired cellular proliferation, and G1 phase arrest...
June 15, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Uilst Bat-Erdene, Eric Quan, Kelvin Chan, Brianna-Marie Lee, Wejdan Matook, Ki-Young Lee, Jesusa L Rosales
A proliferation-inducing ligand (APRIL), which induces survival and migration signals and tumor growth, is commonly observed in breast cancer tissues but is not often expressed in breast cancer cells themselves. Here, we examined whether breast cancer cells induce APRIL secretion from neutrophils, which are frequently recruited into the breast tumor microenvironment. We found that breast cancer cells do stimulate neutrophils to secrete APRIL through their glycosaminoglycans. Breast cancer cells depleted of heparan sulfate or chondroitin sulfate glycosaminoglycans lose their ability to induce APRIL secretion from neutrophils, and heparan sulfate and chondroitin sulfate can induce secretion that is comparable to that of breast cancer cell-induced secretion...
June 15, 2018: Oncogenesis
Guo Liu, Wenhao Zhang
Excessive exposure to ultraviolet (UV) rays can cause damage of the skin and may induce cancer, immunosuppression, photoaging, and inflammation. The long non-coding RNA (lncRNA) HOX antisense intergenic RNA (HOTAIR) is involved in multiple human biological processes. However, its role in UVB-induced keratinocyte injury is unclear. This study was performed to investigate the effects of HOTAIR in UVB-induced apoptosis and inflammatory injury in human keratinocytes (HaCaT cells). Quantitative real-time polymerase chain reaction was performed to analyze the expression levels of HOTAIR, PKR, TNF-α, and IL-6...
June 11, 2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Hannah M Burgess, Aldo Pourchet, Cristina H Hajdu, Luis Chiriboga, Alan B Frey, Ian Mohr
Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts...
March 30, 2018: Molecular Therapy Oncolytics
Anna Maria Melzer, Navaneethan Palanisamy
The human protein kinase R (PKR) recognizes invading RNA viruses and mediates the antiviral immune response by phosphorylating the eukaryotic translation initiation factor 2α (eIF-2α), thus blocking protein translation in infected cells and thus preventing viral replication. The observation that individuals show different degrees of susceptibility to viral infections gives rise to the hypothesis that single nucleotide polymorphisms (SNPs) in the protein kinase R may alter the response to an infection. Using different available servers (e...
June 4, 2018: Molecular Immunology
Judit Gervain
INTRODUCTION: Hepatitis C virus (HCV) shows great structural variability. Based on genome sequencing and phylogenetical analysis, 7 types and 67 subtypes can be differentiated with varying geographical distribution. It is very important to determine the HCV type/subtype prior to starting direct antiviral therapy (DAA), which has been available since 2014, because the type, dose and optimal length of medication depends on these. AIM: In Hungary, the treatment of chronic HCV patients started in 1992 with the relevant special diagnostic tests being carried out in our Molecular Diagnostic Laboratory...
May 2018: Orvosi Hetilap
Qin Xu, Chuanben Chen, Guilin Chen, Wei Chen, Dongmei Zhou, Yunqing Xie
In patients with endometrial cancer, the expression and prognostic significance of calreticulin (CRT) remains to be fully elucidated. To investigate the role of CRT in endometrial cancer, the present study compared its expression status with clinicopathological characteristics and evaluated its prognostic significance. The expression of CRT, PKR-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), and Ki67 were assessed by immunohistochemistry and/or western blotting in endometrial cancer patients...
June 2018: Oncology Letters
Robert F Hillary, Una FitzGerald
BACKGROUND: Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER)-localised protein and member of the leucine zipper family of transcription factors. Best known for its role in transducing signals linked to stress to the endoplasmic reticulum, the 50 kDa activated form of ATF6 is now emerging as a major regulator of organogenesis and tissue homeostasis. Responsible for the correct folding, secretion and membrane insertion of a third of the proteome in eukaryotic cells, the ER encompasses a dynamic, labyrinthine network of regulators, chaperones, foldases and cofactors...
May 25, 2018: Journal of Biomedical Science
Mariko Taga, François Mouton-Liger, Malha Sadoune, Sarah Gourmaud, Jenny Norman, Marion Tible, Sylvie Thomasseau, Claire Paquet, James A R Nicoll, Delphine Boche, Jacques Hugon
Metabolic disorders including obesity and type 2 diabetes are known to be associated with chronic inflammation and are obvious risk factors for Alzheimer's disease. Recent evidences concerning obesity and diabetes suggest that the metabolic inflammasome ("metaflammasome") mediates chronic inflammation. The double-stranded RNA-dependent protein kinase (PKR) is a central component of the metaflammasome. In wild type (WT) and PKR-/- mice, blood glucose, insulin and lipid levels and the brain expression of the phosphorylated components of the metaflammasome-PKR, JNK, IRS1 and IKKbeta-were studied after the induction of obesity by a high fat diet (HFD)...
2018: PloS One
Hannah M Burgess, Ian Mohr
In response to virus-induced shut-off of host protein synthesis, dynamic aggregates containing mRNA, RNA-binding proteins and translation factors termed stress granules (SGs) often accumulate within the cytoplasm. SGs typically form following phosphorylation and inactivation of the eukaryotic translation initiation factor 2 alpha, a substrate of the double-stranded (ds) RNA-activated kinase PKR. The detection of innate immune sensors and effectors like PKR at SGs is suggestive of role in pathogen nucleic acid sensing...
May 23, 2018: Journal of Virology
Andrey Ivanov, Xionghao Lin, Tatiana Ammosova, Andrey V Ilatovskiy, Namita Kumari, Hatajai Lassiter, Nowah Afangbedji, Xiaomei Niu, Michael G Petukhov, Sergei Nekhai
BACKGROUND: HIV-1 transcription activator protein Tat is phosphorylated in vitro by CDK2 and DNA-PK on Ser-16 residue and by PKR on Tat Ser-46 residue. Here we analyzed Tat phosphorylation in cultured cells and its functionality. RESULTS: Mass spectrometry analysis showed primarily Tat Ser-16 phosphorylation in cultured cells. In vitro, CDK2/cyclin E predominantly phosphorylated Tat Ser-16 and PKR-Tat Ser-46. Alanine mutations of either Ser-16 or Ser-46 decreased overall Tat phosphorylation...
May 23, 2018: Retrovirology
Shu Wu, Jinpiao Lin, Ya Fu, Qishui Ou
BACKGROUND: IFN-α is widely used for the treatment of chronic hepatitis B (CHB) infection due to its high HBsAg loss. However, IFN-α treatment has a number of side effects. Thus, identification of molecular biomarkers to predict IFN-α therapeutic effect would be useful in the clinic. In this study, we aim to study the role of RIG-I in prediction of IFN-α curative effect of CHB patients. METHODS: A total of 65 CHB patients treated with PegIFN-αweekly for 48 weeks were enrolled...
May 23, 2018: Antiviral Therapy
Jie An, Joshua J Woodward, Weinan Lai, Mark Minie, Xizhang Sun, Lena Tanaka, Jessica M Snyder, Tomikazu Sasaki, Keith B Elkon
OBJECTIVE: Type I interferon (IFN-I) is strongly implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE) as well as rare monogenic 'interferonopathies' such as Aicardi-Goutieres Syndrome (AGS) caused by mutations in the DNA exonuclease, TREX1. The DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), is linked to subsets of AGS and lupus. We identified inhibitors of DNA-cGAS interaction and tested lead candidate, X6, in a mouse model of AGS. METHODS: Trex1-/- mice were treated orally from birth with either X6 or HCQ for 8 weeks...
May 21, 2018: Arthritis & Rheumatology
Huy-Dung Hoang, Tyson E Graber, Tommy Alain
In the early stages of infection, gaining control of the cellular protein synthesis machinery including its ribosomes is the ultimate combat objective for a virus. To successfully replicate, viruses unequivocally need to usurp and redeploy this machinery for translation of their own mRNA. In response, the host triggers global shutdown of translation while paradoxically allowing swift synthesis of antiviral proteins as a strategy to limit collateral damage. This fundamental conflict at the level of translational control defines the outcome of infection...
May 7, 2018: Journal of Molecular Biology
Xing Liu, David Main, Yijie Ma, Bin He
The Us11 protein of herpes simplex virus 1 (HSV-1) is an accessory factor with multiple functions. In virus-infected cells, it inhibits double-stranded RNA dependent protein kinase PKR, 2',5'-oligoadenylate synthetase, RIG-I and MDA-5. However, its precise role is incompletely defined. By screening human cDNA library, we show that the Us11 protein targets heat shock protein 90 (Hsp90), which inactivates TANK binding kinase 1 (TBK1) and antiviral immunity. When ectopically expressed, HSV-1 Us11 precludes the access of TBK1 to Hsp90 and IFN promoter activation...
May 9, 2018: Journal of Virology
Shun Chen, Chao Yang, Wei Zhang, Suresh Mahalingam, Mingshu Wang, Anchun Cheng
Infections with viruses in the Flaviviridae family have a vast global and economic impact because of the high morbidity and mortality. The pathogenesis of Flaviviridae infections is very complex and not fully understood because these viruses can inhibit multiple immune pathways including the complement system, NK cells, and IFN induction and signalling pathways. The non-structural (NS) 5 and 5A proteins of Flaviviridae viruses are highly conserved and play an important role in resisting host immunity through various evasion mechanisms...
May 6, 2018: Pharmacology & Therapeutics
Nousheen Aslam, Muhammad Harris Shoaib, Rabia Bushra, Faraz Ahmed Farooqi, Farya Zafar, Huma Ali, Saima Saleem
Pakistan is categorized to below to middle income countries where two third of the national annual health expenditure is in the form of out of pocket (OOP) cost. A prevalence based study was conducted to determine the OOP cost treatment of hypertension in Karachi by interviewing 350 hypertensive patients aged >30 years through a validated questionnaire. Hypertension (HTN) was classified into stage 1 and stage 2 and was found to be common in females (53.42%) than males (46.57%). The total costs of stage 1and stage 2 HTN were calculated to be 217869...
May 2018: Pakistan Journal of Pharmaceutical Sciences
S W F Middleton, P J Schranz, V I Mandalia, A D Toms
BACKGROUND: The surgical management of isolated medial compartment degenerative disease of the knee causes debate. Unicompartmental arthroplasty options include fixed and mobile bearing implant designs with fixed bearing becoming increasingly popular. We present the largest cohort of a fixed bearing single radius design, Stryker Triathlon Partial Knee Replacement (PKR). METHODS: We prospectively collected demographic data and patient reported outcome measures (PROMs) on our cohort of PKR implants since its adoption in our unit, 2009 until March 2015...
May 3, 2018: Knee
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