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Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury
Ren-Dong Tian1, Yi-Qun Chen1, Yi-Huai He
Corresponding author
993565989@qq.com

Corresponding author at: Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical College, No. 201 Dalian Street, Zunyi 563003, Guizhou, China.
, Yong-Jing Tang, Gui-Mei Chen, Fang-Wan Yang, Ying Li, Wen-Ge Huang, Huan Chen, Xia Liu, Shi-De Lin
Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical College, ZunyiGuizhou, China
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including apoptosis&#44; autophagy&#44; necrosis&#44; necroptosis&#44; and cornification <a class="elsevierStyleCrossRef" href="#bib0265">&#91;4&#93;</a>&#46; Therefore&#44; controlling hepatocyte death can be an effective strategy to improve liver injury&#46; Necroptosis&#44; a newly discovered form of cell death&#44; is an inflammatory form of necrotic cell death that resembles the morphological features of necrosis&#44; yet the process is tightly regulated like apoptosis <a class="elsevierStyleCrossRef" href="#bib0270">&#91;5&#93;</a>&#46; Hepatocyte necroptosis has been implicated in the pathogenesis of various liver diseases <a class="elsevierStyleCrossRefs" href="#bib0255">&#91;2&#44;3&#44;6&#44;7&#93;</a>&#44; such as liver injury caused by nonalcoholic fatty liver disease &#40;NAFLD&#41; or nonalcoholic steatohepatitis &#40;NASH&#41;&#44; alcohol <a class="elsevierStyleCrossRefs" href="#bib0285">&#91;8&#44;9&#93;</a>&#44; carbon tetrachloride <a class="elsevierStyleCrossRef" href="#bib0295">&#91;10&#93;</a>&#44; drug-induced liver injury&#44; hypoxia-induced liver injury <a class="elsevierStyleCrossRef" href="#bib0300">&#91;11&#93;</a>&#44; pyrazinamide&#44; and paracetamol-induced liver injury <a class="elsevierStyleCrossRef" href="#bib0305">&#91;12&#93;</a>&#46; Necroptotic signaling is mediated by death receptors&#44; such as tumor necrosis factor-alpha &#40;TNF-&#945;&#41;&#44; TNF receptor 1 &#40;TNFR1&#41;&#44; and toll-like receptors &#40;TLR&#41; that phosphorylates the receptor-interacting protein 3 &#40;RIP3&#41;&#44; which in turn recruits and phosphorylates the mixed lineage kinase domain-like pseudokinase &#40;MLKL&#41;&#46; Phosphorylation of MLKL increases the permeabilization of the cell membrane <a class="elsevierStyleCrossRef" href="#bib0310">&#91;13&#93;</a>&#46; Therefore&#44; RIP3 and MLKL are considered to be key modulators of necroptosis&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The endoplasmic reticulum &#40;ER&#41; is an organelle that plays critical roles in the synthesis and folding of proteins <a class="elsevierStyleCrossRef" href="#bib0315">&#91;14&#93;</a>&#46; In addition&#44; the ER maintains the calcium homeostasis of cells&#44; as well as it mediates the biosynthesis of phospholipids and cholesterols&#46; Disruption the function of the ER leads to the accumulation of unfolded or misfolded proteins in the ER lumen&#44; which in return&#44; induces ER stress <a class="elsevierStyleCrossRef" href="#bib0280">&#91;7&#93;</a>&#46; ER stress has been shown to induce necroptosis <a class="elsevierStyleCrossRefs" href="#bib0320">&#91;15&#44;16&#93;</a> through activation of the pro-apoptotic signaling cascade <a class="elsevierStyleCrossRef" href="#bib0330">&#91;17&#93;</a>&#46; ER stress causes the glucose-regulated protein 78 &#40;GRP78&#41; to competitively bind unfolded or misfolded proteins <a class="elsevierStyleCrossRef" href="#bib0335">&#91;18&#93;</a>&#46; In turn&#44; this leads to the phosphorylation of protein kinase R-like ER kinase &#40;PERK&#41; and inositol-requiring enzyme 1 alpha &#40;IRE1&#945;&#41;&#44; along with the cleavage of activating transcription factor 6 &#40;ATF6&#41; <a class="elsevierStyleCrossRef" href="#bib0340">&#91;19&#93;</a>&#46; Subsequently&#44; activated PERK can phosphorylate the alpha subunit of eukaryotic initiation factor 2 &#40;eIF2&#945;&#41; at serine 51 <a class="elsevierStyleCrossRef" href="#bib0345">&#91;20&#93;</a>&#46; eIF2 is a 126<span class="elsevierStyleHsp" style=""></span>kDa protein composed of &#945;&#44; &#946; and &#947; subunits that are essential for mRNA translation and subsequent protein synthesis <a class="elsevierStyleCrossRef" href="#bib0350">&#91;21&#93;</a>&#46; The phosphorylated eIF2&#945; attenuates protein synthesis and thus relieves the protein folding load in the ER <a class="elsevierStyleCrossRef" href="#bib0355">&#91;22&#93;</a>&#46; Simultaneously&#44; phosphorylated eIF2&#945; activates another cascade that leads to the dephosphorylation of eIF2&#945;&#44; which creates a negative feedback mechanism to restore protein synthesis <a class="elsevierStyleCrossRef" href="#bib0360">&#91;23&#93;</a>&#46; Briefly&#44; phosphorylated eIF2&#945; up-regulates the translation of activating transcription factor 4 &#40;ATF4&#41;&#44; which in turn induces the expression of growth arrest and DNA damage 34 &#40;GADD34&#41; as well as GRP78 and C&#47;EBP homologous protein &#40;CHOP&#41; <a class="elsevierStyleCrossRef" href="#bib0365">&#91;24&#93;</a>&#46; GADD34 binds with protein phosphatase 1 &#40;PP1&#41;&#44; thereby facilitating the dephosphorylation of eIF2&#945; <a class="elsevierStyleCrossRef" href="#bib0370">&#91;25&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">ER stress can also be relieved by several chemical reagents&#46; For example&#44; 4-phenylbutyric acid &#40;PBA&#41; is a chemical chaperone that has been shown to alleviate ER stress in different cell models <a class="elsevierStyleCrossRefs" href="#bib0375">&#91;26&#8211;28&#93;</a>&#46; Salubrinal selectively reduces the dephosphorylation of eIF2&#945; by suppressing the activity of PP1&#44; therefore maintaining the phosphorylated eIF2&#945; levels and inhibiting the expression of eIF2 as and minimizing ER stress <a class="elsevierStyleCrossRefs" href="#bib0390">&#91;29&#44;30&#93;</a>&#46; Furthermore&#44; PERK&#44; ATF6&#44; and IRE1&#945; can also activate ER-related degradation and promoting cell survival <a class="elsevierStyleCrossRef" href="#bib0400">&#91;31&#93;</a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Tunicamycin is a nucleoside antibiotic that can be used as a pharmacological inducer of ER stress <a class="elsevierStyleCrossRefs" href="#bib0405">&#91;32&#44;33&#93;</a>&#46; <span class="elsevierStyleSmallCaps">d</span>-Galactosamine is a hepatotoxic agent that causes the inhibition of transcription and protein synthesis&#44; which leads to cell death <a class="elsevierStyleCrossRef" href="#bib0415">&#91;34&#93;</a>&#46; TNF-&#945; and ER stress are involved in the pathogenesis of several liver diseases <a class="elsevierStyleCrossRef" href="#bib0420">&#91;35&#93;</a>&#46; Previous studies demonstrated that tunicamycin could induce acute kidney injury by inducing ER stress <a class="elsevierStyleCrossRefs" href="#bib0425">&#91;36&#44;37&#93;</a>&#46; Furthermore&#44; tunicamycin can be used to induce acute liver injury <a class="elsevierStyleCrossRef" href="#bib0435">&#91;38&#93;</a>&#46; In this study&#44; we used tunicamycin and d-galactosamine-induced acute liver injury mouse models and tunicamycin-induced ER stress cell models to investigate the regulatory functions of eIF2&#945; phosphorylation in hepatocyte necroptosis in acute liver injury&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Animal</span><p id="par0025" class="elsevierStylePara elsevierViewall">A total of 400 male BALB&#47;c mice &#40;6&#8211;8 weeks old&#44; 18<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>g&#41; were obtained from the Animal Center of Zunyi Medical College &#40;Guizhou&#44; China&#41;&#46; The animals were housed in a specific pathogen-free facility with the temperature maintained between 20 and 24<span class="elsevierStyleHsp" style=""></span>&#176;C and an automatic 12-h light&#47;dark cycle with food and water available <span class="elsevierStyleItalic">ad libitum</span>&#46; The study protocol was approved by the Animal Care and Use Committee of the Affiliated Hospital of Zunyi Medical College &#40;Guizhou Province&#44; China&#41; in accordance with Guidelines of China Animal Care and Research&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Experimental design</span><p id="par0030" class="elsevierStylePara elsevierViewall">Mice were allowed one week to acclimatize before commencing the experimental procedures&#46; Next&#44; the mice were randomly divided into different experimental groups&#46; The control group mice &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice&#41; received an intraperitoneal injection of phosphate buffer saline &#40;PBS&#44; 10<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#41;&#46; To induce acute liver injury&#44; mice either received an intraperitoneal injection of tunicamycin &#40;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; Sigma&#41; in the tunicamycin group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice&#41; or d-galactosamine &#40;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; Sigma&#41; in the d-galactosamine-treated mice &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice&#41;&#46; To pharmacologically alleviate the ER stress&#44; mice were pretreated with an intraperitoneal injection of PBA &#40;150<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; Sigma&#41; or salubrinal &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; Sigma&#41; for 2<span class="elsevierStyleHsp" style=""></span>h&#46; Subsequently&#44; the mice were administered tunicamycin resulting in PBA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin&#44; and salubrinal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin treatment groups &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; Alternatively&#44; the PBS&#44; PBA&#44; and salubrinal treated mice were given a PBS injection to serve as control and PBA or salubrinal groups&#44; respectively &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">Cell culture and ER stress induction</span><p id="par0035" class="elsevierStylePara elsevierViewall">The human hepatocyte LO2 cell line was obtained from the Cell Bank of the Type Culture Collection of the Chinese Academy of Sciences &#40;Shanghai&#44; China&#41;&#46; LO2 cells were cultured in RPMI-1640 supplemented with 10&#37; fetal bovine serum and 1&#37; penicillin&#47;streptomycin&#46; To investigate the impact of tunicamycin on ER stress and necroptosis&#44; LO2 cells were treated with PBS or tunicamycin &#40;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; Sigma&#41; for 12&#44; 24&#44; or 48<span class="elsevierStyleHsp" style=""></span>h&#46; Similarly&#44; PBA and salubrinal were used to alleviate ER stress&#46; Briefly&#44; LO2 cells were pretreated with PBA &#40;10<span class="elsevierStyleHsp" style=""></span>mM&#41; or salubrinal &#40;20<span class="elsevierStyleHsp" style=""></span>&#956;M&#44; Sigma&#41; for 2<span class="elsevierStyleHsp" style=""></span>h and then incubated with PBS &#40;control&#41; or tunicamycin &#40;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; Sigma&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Western blot</span><p id="par0040" class="elsevierStylePara elsevierViewall">Mice were sacrificed&#44; and the livers were dissected and homogenized in immunoprecipitation assay lysis buffer &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#44; R0010&#44; Solarbio&#44; Beijing&#44; China&#41;&#46; Following centrifugation&#44; individual liver lysates &#40;40<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; were separated on 10&#37; sodium dodecyl sulfate polyacrylamide gels by electrophoresis &#40;SDS-PAGE&#41; and transferred to polyvinylidene fluoride &#40;PVDF&#41; membranes &#40;Millipore&#44; Billerica&#44; MA&#44; USA&#41;&#46; Membranes were blocked with 5&#37; skim milk in TBS and probed with the following mouse monoclonal antibodies against &#946;-actin &#40;sc-58673&#44; 1&#58;10000&#44; sc&#58; Santa Cruz Biotechnology&#41;&#44; CHOP &#40;ab11419&#44; 1&#58;10000&#41;&#44; eIF2&#945; &#40;sc-133132&#44; 1&#58;10000&#41;&#44; GRP78 &#40;sc-376768&#44; 1&#58;10000&#41;&#44; phosphorylated PERK &#40;p-PERK&#44; MA5-15033&#44; 1&#58;10000&#44; Thermo Fisher Scientific&#44; USA&#41;&#44; PERK &#40;sc-377400&#44; 1&#58;10000&#41;&#44; RIP3 &#40;sc-374639&#44; 1&#58;10000&#41; and TNFR1 &#40;sc-374186&#44; 1&#58;10000&#41; or rabbit monoclonal antibodies against cleaved caspase-3 &#40;9664&#44; 1&#58;10000&#44; Cell Signaling Technology&#41; and phosphorylated eIF2&#945; &#40;p-eIF2&#945;&#44; 3398&#44; 1&#58;10000&#44; Cell Signaling Technology&#41; at 4<span class="elsevierStyleHsp" style=""></span>&#176;C overnight&#46; Next&#44; the bound antibodies were detected with horseradish peroxidase &#40;HRP&#41;-conjugated anti-mouse or anti-rabbit IgG and visualized using enhanced chemiluminescence&#46; The relative level of each target protein was calculated by densitometric analysis using the Quantity One software &#40;Bio-Rad&#44; Hercules&#44; CA&#44; USA&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Cell viability assay</span><p id="par0045" class="elsevierStylePara elsevierViewall">Cell viability was assessed using the MTS &#91;3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-5-&#40;3-carboxymethoxyphenyl&#41;-2-&#40;4-sulfophenyl&#41;-2H-tetrazolium&#93; method with the Cell Titer 96 AQueous One Solution Cell Proliferation Assay kit &#40;Promega Corporation&#44; Madison&#44; WI&#44; USA&#41; according to the manufacturer&#39;s protocol&#46; Briefly&#44; the LO2 cells were incubated with 20<span class="elsevierStyleHsp" style=""></span>&#956;L of MTS solution for 3<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; and the absorbance was measured at 490<span class="elsevierStyleHsp" style=""></span>nm on a microplate reader &#40;Bio-Rad model 680&#59; Bio-Rad&#44; Hercules&#44; CA&#44; United States&#41;&#46; LO2 cell viability was normalized as a percentage of the control&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0070">Histology and immunohistochemistry</span><p id="par0050" class="elsevierStylePara elsevierViewall">Liver tissues were fixed in 10&#37; formalin&#44; embedded in paraffin&#44; and sectioned at 5<span class="elsevierStyleHsp" style=""></span>&#956;m thickness on a microtome &#40;Leica&#41;&#46; Following deparaffinization and rehydration&#44; the tissue sections were stained with hematoxylin and eosin &#40;H&#38;E&#41; according to the standard protocols&#46; Alternatively&#44; the sections were blocked and subsequently immunostained using monoclonal antibodies against RIP3 &#40;sc-374639&#44; 1&#58;200&#41; and TNFR1 &#40;sc-374186&#44; 1&#58;200&#41;&#46; The signal was visualized using the DAB reagent under a light microscope&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0075">Serum alanine aminotransferase level</span><p id="par0055" class="elsevierStylePara elsevierViewall">Following euthanasia&#44; sera samples were obtained from the blood of each mouse&#46; Serum alanine aminotransferase &#40;ALT&#41; levels were determined using the rate method with the Beckman Coulter Auto Analyzer &#40;Model AU5800&#44; USA&#41; according to the standard protocols&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">The differences between the examined groups were calculated using Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#46; Numerical data were expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41;&#46; Survival rate was estimated using the Kaplan&#8211;Meier method and the log-rank test&#46; A <span class="elsevierStyleItalic">p</span>-value &#60;0&#46;05 was considered to be statistically significant&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0090">Tunicamycin and <span class="elsevierStyleSmallCaps">d</span>-galactosamine induces ER stress and necroptosis in mice</span><p id="par0065" class="elsevierStylePara elsevierViewall">Tunicamycin disrupts protein folding in the ER&#44; resulting in ER stress and hepatocyte injury&#46; TNF-&#945; induces necroptosis through binding of TNFR1&#46; Therefore&#44; we challenged male BALB&#47;c mice with tunicamycin or d-galactosamine injections to induce acute liver injury and analyzed the relative protein levels of intrahepatic TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL&#46; In the livers of tunicamycin-treated mice&#44; the expression of TNFR1&#44; GRP78&#44; and RIP3&#44; and phosphorylated levels of eIF2&#945; and MLKL were increased &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>a&#41;&#46; Similarly&#44; signs of hepatocyte necrosis were confirmed by H&#38;E staining especially at 24 and 48<span class="elsevierStyleHsp" style=""></span>h post-injection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>b&#41;&#46; Compared to the control group&#44; the intrahepatic expression of TNFR1 and RIP3 were upregulated in the tunicamycin-treated mice&#44; especially around the central vein of a hepatic lobule at 24 and 48<span class="elsevierStyleHsp" style=""></span>h post tunicamycin injection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>c&#41;&#46; These results clearly demonstrate that tunicamycin administration induces ER stress&#44; hepatocyte TNFR1 expression&#44; eIF2&#945; phosphorylation&#44; and necroptosis in mice&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Similarly&#44; <span class="elsevierStyleSmallCaps">d</span>-galactosamine administration increased RIP3 and GRP78 expression&#44; as well as phosphorylated eIF2&#945; and MLKL levels in mice &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>d&#41;&#46; Nevertheless&#44; <span class="elsevierStyleSmallCaps">d</span>-galactosamine treatment reduced the intrahepatic expression of TNFR1 compared to the control mice &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>d&#41;&#46; These data demonstrate that <span class="elsevierStyleSmallCaps">d</span>-galactosamine induces ER stress and necroptosis in mice without up-regulating hepatic TNFR1 expression&#46; Therefore&#44; it is plausible to speculate that hepatocyte necroptosis can be mediated by TNFR1-independent pathways&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0095">Tunicamycin treatment induces ER stress and necroptosis while reducing TNFR1 expression in LO2 cells</span><p id="par0075" class="elsevierStylePara elsevierViewall">The results outlined above suggest that hepatocyte necroptosis can be mediated via TNF-&#945;&#47;TNFR1-independent pathways&#46; Therefore&#44; we treated LO2 cells with tunicamycin to investigate the impact of ER stress on TNFR1 expression and necroptosis&#46; Next&#44; we examined the relative expression of TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3 and p-MLKL by Western blot&#46; Tunicamycin treatment increased GRP78 and RIP3 expression&#44; as well as phosphorylated eIF2&#945; and MLKL levels when compared with the control cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46; Additionally&#44; tunicamycin treatment significantly down-regulated the TNFR1 protein expression at 12 and 24<span class="elsevierStyleHsp" style=""></span>h&#44; then increased its expression at 48<span class="elsevierStyleHsp" style=""></span>h&#46; It also reduced the LO2 cell viability at 24 and 48<span class="elsevierStyleHsp" style=""></span>h as compared to the control cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#41;&#46; These data demonstrate that tunicamycin treatment can induce ER stress and hepatocyte necroptosis via TNFR1-independent pathways in LO2 cells&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0100">PBA pretreatment moderates tunicamycin-induced ER stress and necroptosis</span><p id="par0080" class="elsevierStylePara elsevierViewall">PBA alleviates ER stress&#44; which produces hepatoprotective effects&#46; To confirm this hypothesis&#44; male BALB&#47;c mice were pretreated with PBS or PBA and injected with tunicamycin or PBS&#46; Compared with the tunicamycin-treated mice&#44; the cumulative survival was significantly improved in mice pretreated with PBA before tunicamycin injection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a&#41;&#46; However&#44; PBA treatment did not significantly affect the mortality rate in the control mice &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a&#41;&#46; Tunicamycin treatment significantly increased serum ALT levels when compared with the control or PBA treated mice&#46; Tunicamycin with PBA pretreatment significantly reduced the serum ALT levels in mice &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>b&#41;&#46; Similarly&#44; tunicamycin with PBA pretreatment improved the hepatic necrosis as revealed by H&#38;E staining &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>c&#41;&#46; Interestingly&#44; PBA treatment did not significantly change eIF2&#945; phosphorylation levels or RIP3 expression levels in mice when compared with the control group without ER stress &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>d&#41;&#46; On the other hand&#44; PBA pretreatment before tunicamycin significantly reduced TNFR1&#44; RIP3 and GRP78 expression&#44; as well as eIF2&#945; and MLKL phosphorylation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>e&#41;&#46; Similarly&#44; PBA pretreatment before tunicamycin decreased the expression of TNFR1 and RIP3 in the liver samples as compared to the tunicamycin-treated mice &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>f&#41;&#46; These data clearly demonstrate that PBA pretreatment alleviates tunicamycin-induced liver injury&#44; hepatocyte ER stress&#44; necroptosis&#44; while also down-regulating TNFR1 expression in mice&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">To further confirm our hypothesis&#44; the LO2 cells were pretreated with PBS or PBA&#44; and then incubated with tunicamycin or PBS&#46; PBA treatment did not change eIF2&#945; phosphorylation or RIP3 expression in LO2 cells compared to the control LO2 without ER stress &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>g&#41;&#46; However&#44; tunicamycin incubation increased eIF2&#945;phosphorylation and RIP3 expression in LO2 cells&#46; Interestingly&#44; PBA pretreatment before tunicamycin incubation significantly reduced GRP78 and RIP3 expression&#44; as well as eIF2&#945; and MLKL phosphorylation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>h&#41;&#46; In contrast&#44; it significantly restored the TNFR1 expression in LO2 cells&#46; In addition&#44; LO2 viability was significantly enhanced in the tunicamycin&#47;PBA pretreated group compared to the tunicamycin group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>i&#41;&#46; These results demonstrate that PBA pretreatment can moderate tunicamycin-induced ER stress and hepatocyte necroptosis in a manner independent of TNF-&#945;&#47;TNFR1 signaling in LO2 cells&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0105">Salubrinal pretreatment elevates tunicamycin-induced eIF2&#945; phosphorylation and reduces ER stress and necroptosis</span><p id="par0090" class="elsevierStylePara elsevierViewall">In cells&#44; ER stress triggers eIF2&#945; phosphorylation&#46; Therefore&#44; we used salubrinal to selectively inhibit eIF2&#945; dephosphorylation and reduce ER stress to investigate the role of eIF2&#945; phosphorylation in hepatocyte necroptosis and ER stress in an acute liver injury model&#46; To this end&#44; male BALB&#47;c mice were pretreated with PBS or salubrinal before they were injected with tunicamycin or PBS&#46; Compared to the tunicamycin treatment group&#44; the cumulative survival was significantly improved in mice pretreated with salubrinal before tunicamycin injection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>a&#41;&#46; Tunicamycin treatment significantly increased serum ALT levels compared to the control or PBA treated&#44; while tunicamycin with salubrinal pretreatment significantly reduced serum ALT levels &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>b&#41;&#46; Salubrinal pretreatment before tunicamycin administration significantly reduced hepatocyte necrosis as verified by H&#38;E staining &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>c&#41;&#46; Importantly&#44; salubrinal-alone did not change the cumulative mortality &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>a&#41;&#46; Similarly&#44; salubrinal treatment-alone did not change the serum ALT levels &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>b&#41; or eIF2&#945; phosphorylation and RIP3 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>d&#41; when compared to the control mice without liver injury&#46; In contrast&#44; salubrinal pretreatment before tunicamycin administration significantly increased intrahepatic eIF2&#945; phosphorylation&#44; and reduced TNFR1&#44; RIP3&#44; GRP78 expression&#44; as well as MLKL phosphorylation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>e&#41;&#44; when compared to the tunicamycin-treated mice&#46; In agreement&#44; compared with tunicamycin-treatment&#44; the relative expression levels of TNFR1 and RIP3 were reduced in the tunicamycin&#47;salubrinal pretreatment group as verified by immunohistochemical staining &#40;34&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;39&#37; vs 22&#46;53<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;18&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>f&#41;&#46; These data indicate that enhanced eIF2&#945; phosphorylation mitigates tunicamycin-induced hepatocyte ER stress&#44; TNFR1 expression&#44; and necroptosis in mice&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Next&#44; we repeated the same model in LO2 cells to further investigate the impact of eIF2&#945; phosphorylation on ER stress and necroptosis <span class="elsevierStyleItalic">in vitro</span>&#46; LO2 cells were pretreated with PBS or salubrinal&#44; and then incubated with tunicamycin or PBS&#46; Salubrinal treatment-alone did not change the eIF2&#945; phosphorylation or RIP3 expression in LO2 cells without ER stress &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>g&#41;&#46; However&#44; salubrinal pretreatment before tunicamycin significantly increased eIF2&#945; phosphorylation and reduced the CHOP and RIP3 expression &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; as well as MLKL phosphorylation levels&#44; as compared to tunicamycin-treated cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>h&#41;&#46; In addition&#44; it partially restored TNFR1 expression and LO2 cell viability &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>i&#41;&#46; These data confirm that eIF2&#945; phosphorylation mitigated tunicamycin-induced ER stress and necroptosis in LO2 cells&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">In the present study&#44; we demonstrated that tunicamycin and <span class="elsevierStyleSmallCaps">d</span>-galactosamine successfully induced ER stress and hepatocyte necroptosis&#44; as well as eIF2&#945; phosphorylation&#44; in BALB&#47;c mice and LO2 cells&#46; Moreover&#44; <span class="elsevierStyleSmallCaps">d</span>-galactosamine could induce ER stress and necroptosis without up-regulating TNFR1 expression&#44; indicating that ER stress and necroptosis can be mediated via TNF&#945;&#47;TNFR1-independent pathways in hepatocytes&#46; Pretreatment with PBA mitigated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells by alleviating ER stress&#44; while salubrinal pretreatment mitigated tunicamycin-induced ER stress and hepatocyte necroptosis by inhibiting eIF2&#945; dephosphorylation and increasing p-eIF2&#945; levels&#46; In addition&#44; PBA and salubrinal pretreatment alleviated ER stress and necroptosis&#44; but it partially restored TNFR1 expression in LO2 cells challenged with tunicamycin&#46; Together&#44; these results demonstrate the crucial role of eIF2&#945; phosphorylation in mitigating ER stress and necroptosis independent of TNFR1 signaling in an acute liver injury model&#46; To the best of our knowledge&#44; this is the first study that reveals the beneficial role of eIF2&#945; phosphorylation in alleviating hepatocyte necroptosis and ER stress in an acute liver injury&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">TNF-&#945; is a pleiotropic cytokine involved in inflammation and cell injury <a class="elsevierStyleCrossRef" href="#bib0440">&#91;39&#93;</a>&#46; TNF-&#945; function is mediated by TNFR1 signaling <a class="elsevierStyleCrossRefs" href="#bib0395">&#91;30&#44;40&#93;</a>&#46; TNFR1 mediates cell injury via the &#8220;death domain&#8221; and up-regulates the TNFR1 expression may enhance the cell sensitivity to TNF-&#945;-induced cell injury&#46; Effective control of ER stress can mitigate liver injury <a class="elsevierStyleCrossRef" href="#bib0450">&#91;41&#93;</a>&#46; Our results demonstrate that ER stress inhibits TNFR1 expression in tunicamycin-incubated LO2 cells and <span class="elsevierStyleSmallCaps">d</span>-galactosamine-treated mice&#44; suggesting that TNFR1 signaling may not be necessary to trigger hepatocyte necrosis&#46; Moreover&#44; tunicamycin or <span class="elsevierStyleSmallCaps">d</span>-galactosamine administration significantly induced hepatocyte ER stress and necroptosis in mice&#46; PBA pretreatment significantly mitigated the tunicamycin-induced hepatocyte ER stress and necroptosis in mice&#46; In addition&#44; tunicamycin treatment induced ER stress and necroptosis&#44; and reduced LO2 cells viability&#46; These effects were moderated by PBA pretreatment&#46; These results not only support that ER stress mediates hepatocyte necroptosis&#44; but also suggest that ER stress can induce necroptosis independent of TNFR1 signaling in acute liver injury <a class="elsevierStyleCrossRef" href="#bib0320">&#91;15&#93;</a>&#46; Moreover&#44; our data showed that ER stress affects TNFR1 expression differently&#44; indicating that ER stress may have multiple ways to regulate TNFR1 expression&#46; Future investigations should focus on dissecting the underlying molecular mechanism&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">eIF2&#945; phosphorylation can inhibit protein synthesis and up-regulate ATF4 expression <a class="elsevierStyleCrossRef" href="#bib0455">&#91;42&#93;</a>&#46; Inhibition of protein synthesis can reduce the protein folding load in the ER <a class="elsevierStyleCrossRef" href="#bib0460">&#91;43&#93;</a>&#46; In this study&#44; tunicamycin and <span class="elsevierStyleSmallCaps">d</span>-galactosamine significantly induced hepatocyte ER stress and eIF2&#945; phosphorylation&#46; Interestingly&#44; pretreatment with salubrinal significantly elevated eIF2&#945; phosphorylation and reduced tunicamycin-induced ER stress&#44; as well as necroptosis&#44; in mice and LO2 cells&#46; On the other hand&#44; PBA pretreatment decreased eIF2&#945; phosphorylation and necroptosis&#46; These data suggest that eIF2&#945; phosphorylation does not directly modulate hepatocyte necroptosis&#44; but it indirectly mitigates tunicamycin-induced ER stress and regulates hepatocyte necroptosis&#46; This discrepancy can be attributed to the fact that PBA acts as a chemical molecular chaperone that reduces ER stress by reducing the need for eIF2&#945; phosphorylation <a class="elsevierStyleCrossRef" href="#bib0465">&#91;44&#93;</a>&#46; Previously&#44; Wang <span class="elsevierStyleItalic">et al</span>&#46; demonstrated that up-regulating phosphorylated eIF2&#945; by salubrinal administration attenuated ER stress and improved necroptosis <a class="elsevierStyleCrossRef" href="#bib0470">&#91;45&#93;</a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Hepatocyte necroptosis has been implicated in different acute and chronic pathological conditions&#44; including NAFLD or NASH&#44; alcohol-induced liver injury&#44; drug-induced liver injury&#44; as well as hepatitis B and C viral infections <a class="elsevierStyleCrossRef" href="#bib0475">&#91;46&#93;</a>&#46; ER stress also has been implicated in a variety of liver diseases&#44; including NAFLD&#44; alcohol-induced liver injury&#44; drug-induced liver injury&#44; hepatic insulin resistance&#44; ischemia-reperfusion injury and hepatitis viral infections <a class="elsevierStyleCrossRefs" href="#bib0480">&#91;47&#8211;49&#93;</a>&#46; However&#44; whether ER stress is directly regulated to necroptosis has not been fully elucidated&#46; Our data shows that inhibition of ER stress can reduce hepatocyte necroptosis by up-regulating eIF2&#945; phosphorylation&#44; thus decreasing liver injury&#46; This mechanism may also explain the relationship of ER stress and necroptosis in other liver diseases besides liver injury&#44; which may be a therapeutic target for the treatment of liver diseases&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Taken together&#44; we observed that the selective elevation of eIF2&#945; phosphorylation could regulate ER stress through a feedback mechanism&#44; which consequently reduces hepatocyte necroptosis&#44; thus mitigating the acute liver injury&#46; These results provide new insights into the underlying molecular mechanisms that regulate acute liver injury&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">List of abbreviations</span><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDefList"><span class="elsevierStyleDefTerm">ATF4</span><span class="elsevierStyleDefDescription"><p id="par0130" class="elsevierStylePara elsevierViewall">activating transcription factor 4</p></span><span class="elsevierStyleDefTerm">ATF6</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">activating transcription factor 6</p></span><span class="elsevierStyleDefTerm">ALT</span><span class="elsevierStyleDefDescription"><p id="par0140" class="elsevierStylePara elsevierViewall">alanine aminotransferase</p></span><span class="elsevierStyleDefTerm">CHOP</span><span class="elsevierStyleDefDescription"><p id="par0145" class="elsevierStylePara elsevierViewall">C&#47;EBP homologous protein</p></span><span class="elsevierStyleDefTerm">ER</span><span class="elsevierStyleDefDescription"><p id="par0150" class="elsevierStylePara elsevierViewall">endoplasmic reticulum</p></span><span class="elsevierStyleDefTerm">eIF2&#945;</span><span class="elsevierStyleDefDescription"><p id="par0155" class="elsevierStylePara elsevierViewall">eukaryotic initiation factor 2 alpha</p></span><span class="elsevierStyleDefTerm">GADD34</span><span class="elsevierStyleDefDescription"><p id="par0160" class="elsevierStylePara elsevierViewall">growth arrest and DNA damage 34</p></span><span class="elsevierStyleDefTerm">GRP78</span><span class="elsevierStyleDefDescription"><p id="par0165" class="elsevierStylePara elsevierViewall">glucose-regulated protein 78</p></span><span class="elsevierStyleDefTerm">HRP</span><span class="elsevierStyleDefDescription"><p id="par0170" class="elsevierStylePara elsevierViewall">horseradish peroxidase</p></span><span class="elsevierStyleDefTerm">H&#38;E</span><span class="elsevierStyleDefDescription"><p id="par0175" class="elsevierStylePara elsevierViewall">hematoxylin and eosin</p></span><span class="elsevierStyleDefTerm">IRE1&#945;</span><span class="elsevierStyleDefDescription"><p id="par0180" class="elsevierStylePara elsevierViewall">inositol-requiring enzyme 1 alpha</p></span><span class="elsevierStyleDefTerm">MLKL</span><span class="elsevierStyleDefDescription"><p id="par0185" class="elsevierStylePara elsevierViewall">mixed lineage kinase domain-like pseudokinase</p></span><span class="elsevierStyleDefTerm">PP1</span><span class="elsevierStyleDefDescription"><p id="par0190" class="elsevierStylePara elsevierViewall">protein phosphatase 1</p></span><span class="elsevierStyleDefTerm">PVDF</span><span class="elsevierStyleDefDescription"><p id="par0195" class="elsevierStylePara elsevierViewall">polyvinylidene fluoride</p></span><span class="elsevierStyleDefTerm">PERK</span><span class="elsevierStyleDefDescription"><p id="par0200" class="elsevierStylePara elsevierViewall">protein kinase R-like ER kinase</p></span><span class="elsevierStyleDefTerm">PBS</span><span class="elsevierStyleDefDescription"><p id="par0205" class="elsevierStylePara elsevierViewall">phosphate buffer saline</p></span><span class="elsevierStyleDefTerm">PBA</span><span class="elsevierStyleDefDescription"><p id="par0210" class="elsevierStylePara elsevierViewall">4-phenylbutyric acid</p></span><span class="elsevierStyleDefTerm">RIP3</span><span class="elsevierStyleDefDescription"><p id="par0215" class="elsevierStylePara elsevierViewall">receptor-interacting protein 3</p></span></span></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Financial support</span><p id="par0220" class="elsevierStylePara elsevierViewall">This study was partially supported by the <span class="elsevierStyleGrantSponsor" id="gs1">National Natural Science Foundation of China</span> &#40;81560110&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs2">Tian Qing Liver Disease Research Fund Project of Chinese Foundation for Hepatitis Prevention and Control</span> &#40;TQGB20170050&#41;&#44; as well as <span class="elsevierStyleGrantSponsor" id="gs3">The Science and Technology Planning Projects of Guizhou Province</span> &#40;QKH&#183;LH &#91;2017&#93; 7093&#44; QKH&#183;ZC&#91;2019&#93; 2803&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Introduction and objectives"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Experimental design"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Cell culture and ER stress induction"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Western blot"
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              "identificador" => "sec0035"
              "titulo" => "Cell viability assay"
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              "titulo" => "Histology and immunohistochemistry"
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              "titulo" => "Serum alanine aminotransferase level"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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              "titulo" => "Tunicamycin and d-galactosamine induces ER stress and necroptosis in mice"
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              "identificador" => "sec0065"
              "titulo" => "Tunicamycin treatment induces ER stress and necroptosis while reducing TNFR1 expression in LO2 cells"
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              "identificador" => "sec0070"
              "titulo" => "PBA pretreatment moderates tunicamycin-induced ER stress and necroptosis"
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              "identificador" => "sec0075"
              "titulo" => "Salubrinal pretreatment elevates tunicamycin-induced eIF2&#945; phosphorylation and reduces ER stress and necroptosis"
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          "titulo" => "Discussion"
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          "titulo" => "List of abbreviations"
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          "titulo" => "Financial support"
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            0 => "Eukaryotic initiation factor 2&#945;"
            1 => "Endoplasmic reticulum stress"
            2 => "Necroptosis"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Necroptosis and endoplasmic reticulum &#40;ER&#41; stress has been implicated in acute and chronic liver injury&#46; Activated eukaryotic initiation factor 2 alpha &#40;eIF2&#945;&#41; attenuates protein synthesis and relieves the load of protein folding in the ER&#46; In this study&#44; we aimed to analyze the impact of eIF2&#945; phosphorylation on hepatocyte necroptosis in acute liver injury&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Male BALB&#47;c mice were injected with tunicamycin or d-galactosamine&#44; and LO2 cells were incubated with tunicamycin to induce acute liver injury&#46; 4-Phenylbutyric acid &#40;PBA&#41; and salubrinal were used to inhibit ER stress and eIF2&#945; dephosphorylation&#44; respectively&#46; We analyzed the eIF2&#945; phosphorylation&#44; ER stress&#44; and hepatocyte necroptosis in mice and cells model&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Tunicamycin or d-galactosamine significantly induced ER stress and necroptosis&#44; as well as eIF2&#945; phosphorylation&#44; in mice and LO2 cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; ER stress aggravated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Elevated eIF2&#945; phosphorylation significantly mitigated hepatocyte ER stress &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and hepatocyte necroptosis in mice &#40;34&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;39&#37; vs 22&#46;53<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;18&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and LO2 cells &#40;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 vs 0&#46;33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Interestingly&#44; tumor necrosis factor receptor &#40;TNFR&#41; 1 protein levels were not completely synchronized with necroptosis&#46; TNFR1 expression was reduced in d-galactosamine-treated mice &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and cells incubated with tunicamycin for 12 and 24<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; ER stress partially restored TNFR1 expression and increased necroptosis in tunicamycin-incubated cells &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">These results imply that ER stress can mediate hepatocyte necroptosis independent of TNFR1 signaling and elevated eIF2&#945; phosphorylation can mitigate ER stress during acute liver injury&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Ren-Dong Tian and Yi-Qun Chen contributed equally to this work&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Tunicamycin or <span class="elsevierStyleSmallCaps">d</span>-galactosamine administration induces ER stress and hepatocyte necroptosis in mice&#46; Male BALB&#47;c mice were injected with either PBS &#40;control group&#41;&#44; tunicamycin &#40;tunicamycin group&#41;&#44; or <span class="elsevierStyleSmallCaps">d</span>-galactosamine &#40;<span class="elsevierStyleSmallCaps">d</span>-galactosamine group&#41;&#46; &#40;a&#41; The relative expression of intrahepatic TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL were determined by Western blot at 12&#44; 24 and 48<span class="elsevierStyleHsp" style=""></span>h post tunicamycin injection &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;b&#41; Hepatocyte necrosis was detected by in H&#38;E staining in paraffin-embedded sections&#46; &#40;c&#41; Immunohistochemical staining of intrahepatic TNFR1 and RIP3 expression in mice &#40;magnification 100&#215;&#41;&#46; &#40;d&#41; The relative expression of intrahepatic TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL was determined by Western blot at 12&#44; 24 and 48<span class="elsevierStyleHsp" style=""></span>h post <span class="elsevierStyleSmallCaps">d</span>-galactosamine administration &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01 versus the control group&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Tunicamycin treatment induces hepatocyte ER stress and necroptosis in LO2 cells&#46; LO2 cells were treated with PBS &#40;control group&#41; or tunicamycin &#40;tunicamycin group&#41;&#46; &#40;a&#41; The relative expression of intrahepatic TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL were determined by Western blot in LO2 cells at 12&#44; 24 and 48<span class="elsevierStyleHsp" style=""></span>h post incubation with tunicamycin&#46; &#40;b&#41; Viability of LO2 cells was determined by MTS assay&#46; Histograms represent mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD of five independent experiments&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01 versus the control group&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">PBA pretreatment moderates tunicamycin-induced ER stress and hepatocyte necroptosis in mice and LO2 cells&#46; Male BALB&#47;c mice were pretreated with PBS or PBA for 2<span class="elsevierStyleHsp" style=""></span>h&#44; and then injected with PBS or tunicamycin for 24<span class="elsevierStyleHsp" style=""></span>h&#46; LO2 cells were pretreated with PBS or PBA for 2<span class="elsevierStyleHsp" style=""></span>h&#44; and then injected with PBS or tunicamycin&#46; &#40;a&#41; The cumulative survival of each mouse group was investigated at 0&#44; 12&#44; 24&#44; 36 and 48<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;b&#41; Serum ALT levels were detected using the rate method in the control &#40;PBS and PBS&#41;&#44; PBA &#40;PBA pretreatment and PBS injection&#41;&#44; tunicamycin &#40;PBS and tunicamycin injection&#41;&#44; and the PBA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;PBA pre-treatment and tunicamycin injection&#41; groups &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;c&#41; Histological examination of hepatocyte necrosis in the mice livers of tunicamycin and tunicamycin&#47;PBA pretreated group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;d&#41; The relative expression intrahepatic p-eIF2&#945;&#44; eIF2&#945;&#44; and RIP3 post-PBA treatment in mice compared to the control mice&#46; &#40;e&#41; The relative expression of intrahepatic TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL were determined by Western blot in the tunicamycin group and the tunicamycin&#47;PBA pretreated mice&#46; &#40;f&#41; Immunohistochemical analysis of intrahepatic TNFR1 and RIP3 expression in the paraffin-embedded liver tissues &#40;magnification 100&#215;&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;g&#41; The relative expression of p-eIF2&#945;&#44; eIF2&#945;&#44; and RIP3 were determined by Western blot in the untreated&#44; control &#40;PBS and PBS incubation&#41;&#44; and tunicamycin &#40;PBS and tunicamycin incubation&#41; LO2 cells&#46; &#40;h&#41; The relative expression of TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL were determined by Western blot in the tunicamycin group and the tunicamycin&#47;PBA pretreated LO2 cells&#46; Protein samples were electrophoresed in duplicate lanes&#46; &#40;i&#41; Viability of LO2 cells as determined by MTS assay in the control &#40;PBS and PBS incubation&#41;&#44; PBA &#40;PBA pretreatment and PBS incubation&#41;&#44; tunicamycin &#40;PBS and tunicamycin incubation&#41;&#44; and the PBA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;PBA pretreatment and tunicamycin incubation&#41; groups&#46; Histograms represent mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD of four independent experiments &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; <span class="elsevierStyleSup">&#8224;</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 versus the tunicamycin group&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Salubrinal pretreatment elevates tunicamycin-induced eIF2&#945; phosphorylation and mitigates hepatocyte ER stress and necroptosis&#46; Male BALB&#47;c mice were pretreated with PBS or salubrinal for 2<span class="elsevierStyleHsp" style=""></span>h&#44; and then injected with PBS or tunicamycin for 24<span class="elsevierStyleHsp" style=""></span>h&#46; LO2 cells were pretreated with PBS or salubrinal for 2<span class="elsevierStyleHsp" style=""></span>h&#44; and then incubated with PBS or tunicamycin&#46; &#40;a&#41; The cumulative survival of each mice group was investigated at 0&#44; 12&#44; 24&#44; 36 and 48<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;b&#41; Serum ALT levels were detected using the rate method in the control &#40;PBS and PBS&#41;&#44; salubrinal &#40;salubrinal pretreatment and PBS injection&#41;&#44; tunicamycin &#40;PBS and tunicamycin injection&#41; and the salubrinal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;salubrinal pretreatment and tunicamycin injection&#41; groups&#46; &#40;c&#41; Histological examination of hepatocyte necrosis in the livers of tunicamycin and tunicamycin&#47;salubrinal pretreated group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 mice per group&#41;&#46; &#40;d&#41; The relative expression of intrahepatic p-eIF2&#945;&#44; eIF2&#945; and RIP3 in the untreated&#44; tunicamycin &#40;PBS and tunicamycin injection&#41;&#44; control &#40;PBS and PBS injection&#41;&#44; and salubrinal &#40;salubrinal pretreatment and PBS injection&#41; mice&#46; &#40;e&#41; The relative expression of intrahepatic TNFR1&#44; phosphorylated eIF2&#945;&#44; total eIF2&#945;&#44; GRP78&#44; RIP3&#44; and phosphorylated MLKL in the salubrinal &#40;salubrinal pretreatment and PBS injection&#41; and the salubrinal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;salubrinal pretreatment and tunicamycin injection&#41; mice&#46; Protein samples were electrophoresed in duplicate lanes&#46; &#40;f&#41; Immunohistochemical analysis of intrahepatic TNFR1 and RIP3 expression in the livers of salubrinal &#40;salubrinal pretreatment and PBS injection&#41; and the salubrinal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;salubrinal pretreatment and tunicamycin injection&#41; groups &#40;magnification 100&#215;&#41;&#46; &#40;g&#41; The relative expression of p-eIF2&#945;&#44; eIF2&#945; and RIP3 in the control &#40;PBS and PBS incubation&#41;&#44; tunicamycin &#40;PBS and tunicamycin incubation&#41; and salubrinal &#40;salubrinal pretreatment and PBS incubation&#59; duplicate lanes are presented&#41; LO2 cells&#46; &#40;h&#41; The relative levels of TNFR1&#44; p-eIF2&#945;&#44; eIF2&#945;&#44; GRP78&#44; RIP3&#44; and p-MLKL expression in the tunicamycin &#40;PBS and tunicamycin incubation&#41; and salubrinal&#47;tunicamycin &#40;salubrinal pretreatment and tunicamycin incubation&#41; LO2 cells&#46; Protein samples were electrophoresed in duplicate lanes&#46; &#40;i&#41; Viability of LO2 cells determined by MTS assay in the control &#40;PBS and PBS incubation&#41;&#44; salubrinal &#40;salubrinal pretreatment and PBS incubation&#41;&#44; tunicamycin &#40;PBS and tunicamycin incubation&#41; and the salubrinal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tunicamycin &#40;salubrinal pretreatment and tunicamycin incubation&#41; groups&#46; Histograms represent mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD of four independent experiments&#46; <span class="elsevierStyleSup">&#8224;</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 versus the tunicamycin group&#46;</p>"
        ]
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      "titulo" => "References"
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                      "titulo" => "Apoptosis and necroptosis in the liver&#58; a matter of life and death"
                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;F&#46; Schwabe"
                            1 => "T&#46; Luedde"
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                          "etal" => false
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                            1 => "H&#46;M&#46; Ni"
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Article information
ISSN: 16652681
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos