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Sara K Young-Baird, Byung-Sik Shin, Thomas E Dever
The heterotrimeric eukaryotic translation initiation factor (eIF) 2 plays critical roles in delivering initiator Met-tRNAiMet to the 40S ribosomal subunit and in selecting the translation initiation site. Genetic analyses of patients with MEHMO syndrome, an X-linked intellectual disability syndrome, have identified several unique mutations in the EIF2S3 gene that encodes the γ subunit of eIF2. To gain insights into the molecular consequences of MEHMO syndrome mutations on eIF2 function, we generated a yeast model of the human eIF2γ-I259M mutant, previously identified in a patient with MEHMO syndrome...
December 4, 2018: Nucleic Acids Research
Tamás Gáll, Dávid Pethő, Annamária Nagy, Zoltán Hendrik, Gábor Méhes, László Potor, Magnus Gram, Bo Åkerström, Ann Smith, Péter Nagy, György Balla, József Balla
Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress...
2018: Frontiers in Physiology
Miaoting Yang, Zhijuan Chen, Chunxin Xiao, Waijiao Tang, Beijie Zhou
OBJECTIVE: To investigate the effects of sera from rats fed with Huganqingzhi tablets (HGT) on endoplasmic reticulum (ER) stress in a steatotic hepatocyte model of free fatty acids (FFAs)-induced nonalcoholic fatty liver disease (NAFLD) and explore the possible mechanism. METHODS: FFAs prepared by mixing oleic acid and palmitic acid at the ratio of 2:1. HepG2 cells were treated with the sera from rats fed with low-, moderate-or high-dose HGT (HGT sera) or sera of rats fed with fenofibrate (fenofibrate sera), followed by treatment with 1 mmol/L FFAs for 24 h to induce hepatic steatosis...
November 30, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Wei Liu, Tianyao Yang, Zhaofa Xu, Bin Xu, Yu Deng
Methyl-mercury (MeHg) is a dangerous environmental contamination biotransformed from mercury or inorganic mercury compounds in waterways, which induces severe toxic effects in central nervous system. Oxidative stress is involved in various ways of intracellular physiological or pathological processes including neuronal apoptosis. For understanding the ways that oxidative stress participating in MeHg-induced apoptosis, the current study attempted to explore the effects of oxidative stress on endoplasmic reticulum (ER) and mitochondria function, especially focussing on ER stress followed by unfold protein response (UPR), as well as mitochondrial apoptosis pathways activation in primary cultured cortical neurons...
December 4, 2018: Free Radical Research
Dusana Majera, Zdenek Skrott, Jan Bouchal, Jirina Bartkova, Dana Simkova, Mariam Gachechiladze, Jana Steigerova, Daniela Kurfurstova, Jan Gursky, Gabriela Korinkova, Karel Cwiertka, Zdenek Hodny, Martin Mistrik, Jiri Bartek
BACKGROUND: Castration-resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically-supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol-abuse drug Antabuse) and its copper-chelating metabolite CuET that inhibit protein turnover. METHODS: Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio-resistant stem-cell like derived cells...
November 29, 2018: Prostate
Fangfang Di, Jiansheng Liu, Shang Li, Guangxin Yao, Yan Hong, Zi-Jiang Chen, Weiping Li, Yanzhi Du
Ovulatory disorder is common in patients with hyperprolactinemia or polycystic ovary syndrome (PCOS). Previous studies have shown that ATF4 plays critical role in apoptosis and glucose homeostasis, but its role in regulating reproductive function was not explored. The present study investigated the role of ATF4 in ovarian ovulatory function. Human granulosa cells (hGCs) from 48 women newly diagnosed with PCOS and 37 controls were used to determine ATF4 expression. In vitro cultured hGCs were used to detect the upstream and downstream genes of ATF4...
2018: Frontiers in Endocrinology
Yingxin Zhang, Jie Ding, Cong Xu, Hongli Yang, Peng Xia, Shengjun Ma, Haiying Chen
Background and Objectives: Previous studies have shown that integrins alpha5beta1 (ITGA5B1) gene-modified rat bone marrow mesenchymal stem cells (rBMSCs) could prevent cell anoikis and increase the nitric oxide (NO) production. Here we examined the capability of rBMSCs/ITGA5B1 on the phenotype modulation of Human Pulmonary Artery Smooth Muscle Cell (HPASMC) in vitro. Methods and Results: The synthetic (dedifferentiated) phenotype of HPASMC was induced by monocrotaline (MCT, 1 μ M) for 24 h and then co-cultured with rBMSCs/ITGA5B1 in a transwell culture system...
November 30, 2018: International Journal of Stem Cells
Chong Shen, Tongmeng Jiang, Bo Zhu, Yiguan Le, Jianwei Liu, Zainen Qin, Haimin Chen, Gang Zhong, Li Zheng, Jinmin Zhao, Xingdong Zhang
In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and an eventual therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were involved in transformation of MSCs induced by in vitro culture based on the comparative profiling of in vitro cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs...
2018: Journal of Biological Engineering
Mayra Diosa-Toro, Berit Troost, Denise van de Pol, Alexander Martin Heberle, Silvio Urcuqui-Inchima, Kathrin Thedieck, Jolanda M Smit
Dengue is the most common arboviral disease worldwide with 96 million symptomatic cases annually. Despite its major impact on global human health and huge economic burden there is no antiviral drug available to treat the disease. The first tetravalent dengue virus vaccine was licensed in 2015 for individuals aged 9 to 45, however, most cases are reported in infants and young children. This, together with the limited efficacy of the vaccine to dengue virus (DENV) serotype 2, stresses the need to continue the search for compounds with antiviral activity to DENV...
November 20, 2018: Antiviral Research
Yaojing Jiang, Zhihong Wang, Bo Ma, Linling Fan, Na Yi, Bin Lu, Qinghua Wang, Rui Liu
Glucagon-like peptide 1 (GLP-1) improves insulin resistance of adipose tissue in obese humans. However, the mechanism of this effect is unclear. Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin signaling. We hypothesized that GLP-1 could directly improve insulin signaling in ER-stressed adipocytes. Here, we examined the effects of GLP-1 on ER stress response in fat cells in an obese and insulin-resistant murine model. We found that GLP-1 analog liraglutide reduced ER stress related gene expression in visceral fat cells accompanied by improved systemic insulin tolerance...
2018: Frontiers in Pharmacology
Jingmei Liu, Ping Han, Jin Gong, Yunwu Wang, Bingxin Chen, Jiazhi Liao, Dean Tian
Accumulating evidence indicates that KIAA1199 plays a vital role in tumor progression. However, the role of KIAA1199 in hepatocellular carcinoma (HCC) still remains unknown. In this study, we found that KIAA1199 was upregulated in human HCC tissues and in highly metastatic HCC cell lines. Furthermore, the expression of KIAA1199 was significantly correlated with tumor size and metastasis in HCC. Knockdown of KIAA1199 inhibited cell proliferation and migration in vitro, and suppressed tumorigenicity and lung metastasis in vivo...
2018: Cell Death Discovery
Na Ma, Chang-Cheng Zhang, Qian Chen, Qiong-Yan Ma, Xu You, Si-Qi Yang, Ding Yuan, Hai-Xia Zhao
To study the protective effects of Wuzi Yanzong recipe on testis germ cell apoptosis in natural ageing rats through endoplasmic reticulum stress (ERS), 16-month-old male SPF grade SD rats were randomly divided into three groups: ageing model group, and low and high-dose Wuzi Yanzong recipe groups (WZ, 1 and 4 g·kg⁻¹), with 10 rats in each group. In addition, 2-month-old SD male rats were used as adult control group. The ageing model group and the adult control group were fed with normal diet for 4 months...
October 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Xiaoming Hu, Jiali Deng, Tianming Yu, Shanghai Chen, Yadong Ge, Ziheng Zhou, Yajie Guo, Hao Ying, Qiwei Zhai, Yan Chen, Feixiang Yuan, Yuguo Niu, Weigang Shu, Huimin Chen, Caiyun Ma, Zhanju Liu, Feifan Guo
BACKGROUND & AIMS: Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBD) and mice with enterocolitis. METHODS: We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of colon from 21 patients with active CD, 22 patients with active UC, and 38 individuals without IBD (controls), and of ileum from 19 patients with active CD and 8 individuals without IBD in China...
November 16, 2018: Gastroenterology
Akio Miyoshi, Sachie Koyama, Masayo Sasagawa-Monden, Manabu Kadoya, Kosuke Konishi, Takuhito Shoji, Masaaki Inaba, Yasuhiko Yamamoto, Hidenori Koyama
Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological regulation and underlying mechanisms are scarcely understood. In endothelium-specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF-α level. Treatment with TNF-α also significantly increased serum sRAGE...
November 19, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Cheuk-Lun Lee, Jan H W Veerbeek, Tirtha K Rana, Bas B van Rijn, Graham J Burton, Hong Wa Yung
Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by pro-inflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether pro-inflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast, before exploring potential regulatory mechanisms...
November 15, 2018: American Journal of Pathology
Siyao Li, Zhixin Jiang, Wenjie Chai, Yuanyuan Xu, Yi Wang
Emerging evidence indicates that nonylphenol (NP), a widely diffused and stable environmental contaminant, causes damage to the central nervous system (CNS). Although NP could cross the blood-brain barrier (BBB) and accumulate in key brain regions, little is known about the direct effects of NP on neurons. In this study, we aimed to investigate the direct effects of NP exposure on induction of apoptosis and autophagy in primary cortical neurons. Results showed that exposure to NP decreased the cell viability in a concentration-dependent manner...
November 14, 2018: Neurochemistry International
Chiara Paganini, Luca Monti, Rossella Costantini, Roberta Besio, Silvia Lecci, Marco Biggiogera, Kun Tian, Jean-Marc Schwartz, Céline Huber, Valérie Cormier-Daire, Beth G Gibson, Katarzyna A Pirog, Antonella Forlino, Antonio Rossi
Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed...
November 12, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Xiang Zhu, Hongqi Li, Yuanbo Wu, Jian Zhou, Guangwei Yang, Weidong Wang
MicroRNA (miR)‑214 has been demonstrated to suppress gluconeogenesis by targeting activating transcription factor 4 (ATF4), which regulates gluconeogenesis by affecting the transcriptional activity of forkhead box protein O1 (FoxO1). Our previous study revealed that the upregulation of maternally expressed gene 3 (MEG3), a long noncoding RNA, enhanced hepatic insulin resistance via increased FoxO1 expression. The present study aimed to explore whether miR‑214 and ATF4 were involved in the MEG3‑mediated increase of FoxO1 expression...
January 2019: International Journal of Molecular Medicine
Yong Zhou, Xiaoxia Liu, Wenjuan Li, Xiaoyan Sun, Zhenwei Xie
OBJECTIVE: To investigate the relationship between endoplasmic reticulum stress (ERS) and the pathogenesis of stress urinary incontinence (SUI) in postmenopausal women. METHODS: Anterior vaginal wall tissue was collected from postmenopausal women with SUI and control subjects. Western blotting was performed for glucose-regulated protein (GRP78), inositol-requiring enzyme 1(IRE1), protein kinase-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP), and B-cell lymphoma 2 (Bcl-2)...
November 14, 2018: Journal of International Medical Research
Leah Persaud, Jason Mighty, Xuelin Zhong, Ashleigh Francis, Marifer Mendez, Hilal Muharam, Stephen M Redenti, Dibash Das, Bertal Huseyin Aktas, Moira Sauane
Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action...
November 12, 2018: International Journal of Molecular Sciences
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