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Ünlü S, Bozbay N, Akyürek F, Örgül G, Çelik Ç. Comparison of Maternal and Fetal Plasma X Box Binding Protein 1 Levels Between Pregnancies With Fetal Growth Retardation and Healthy Controls. Am J Reprod Immunol 2025; 93:e70094. [PMID: 40344261 DOI: 10.1111/aji.70094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/10/2025] [Accepted: 04/29/2025] [Indexed: 05/11/2025] Open
Abstract
OBJECTIVE This study aimed to compare maternal and cord serum X box binding protein 1 (XBP-1) levels in pregnant women with fetal growth restriction (FGR) with healthy pregnancies. MATERIALS AND METHODS This prospective case-control study was conducted between January 1, 2022, and May 31, 2022, at the Gynecology and Obstetrics Clinic of Selçuk University Faculty of Medicine Hospital. Forty-three pregnant women and fetuses with isolated FGR with abdominal circumference (AC) or estimated fetal weight (EFW) below the 10th percentile according to ultrasonographic measurements constituted the study group; 43 healthy pregnant women and fetuses constituted the control group. Serum XBP-1 levels in prenatal maternal and cord blood were measured by ELISA and compared between the two groups. RESULTS The mean maternal blood XBP-1 level was 1910.22 ± 607.07 ng/L in the FGR group and 1638.89 ± 385.80 ng/L in the control group (p = 0.044). Cord blood XBP-1 levels were 1837.72 ± 942.67 and 1346.14 ± 664.09 ng/L in the study and control groups, respectively (p = 0.006). Maternal XBP-1 levels were found to discriminate FGR with a sensitivity of 80% and specificity of 60% at a value of 1405 ng/L. For cord blood XBP-1, 869.2 ng/L was the best cut-off, with 98% sensitivity and 67% specificity. In ROC analysis, the area under the curve was found to be 0.626 and 0.671, and p values were found to be 0.044 and 0.006 for maternal serum XBP-1 and cord blood XBP-1, respectively. CONCLUSIONS In the study, serum XBP-1 levels in both maternal and fetal umbilical cord blood were found to be higher in patients with FGR. Considering the role of XBP-1 in metabolic pathways and cellular functions, XBP-1 may have an important role in the pathophysiology of FGR.
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Affiliation(s)
- Sena Ünlü
- Department of Obstetrics and Gynecology, Selcuk University Faculty of Medicine, Konya, Turkey
| | - Nizamettin Bozbay
- Department of Perinatology, Selcuk University Faculty of Medicine, Konya, Turkey
| | - Fikret Akyürek
- Department of Biochemistry, Selcuk University Faculty of Medicine, Konya, Turkey
| | - Gökcen Örgül
- Department of Perinatology, Selcuk University Faculty of Medicine, Konya, Turkey
| | - Çetin Çelik
- Department of Gynecologic Oncology, Selçuk University Faculty of Medicine, Konya, Turkey
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Zhou L, Zhu X, Lei S, Wang Y, Xia Z. The role of the ER stress sensor IRE1 in cardiovascular diseases. Mol Cell Biochem 2025; 480:683-691. [PMID: 38717685 DOI: 10.1007/s11010-024-05014-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/18/2024] [Indexed: 02/19/2025]
Abstract
Despite enormous advances in the treatment of cardiovascular diseases, including I/R injury and heart failure, heart diseases remain a leading cause of mortality worldwide. Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor endoplasmic reticulum (ER) transmembrane protein that senses ER stress. It manages ER stress induced by the accumulation of unfolded/misfolded proteins via the unfolded protein response (UPR). However, if the stress still persists, the UPR pathways are activated and induce cell death. Emerging evidence shows that, beyond the UPR, IRE1 participates in the progression of cardiovascular diseases by regulating inflammation levels, immunity, and lipid metabolism. Here, we summarize the recent findings and discuss the potential therapeutic effects of IRE1 in the treatment of cardiovascular diseases.
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Affiliation(s)
- Lu Zhou
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xizi Zhu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shaoqing Lei
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yafeng Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, China.
| | - Zhongyuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
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Zheng Y, Zha X, Zhang B, Elsabagh M, Wang H, Wang M, Zhang H. The interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome†. Biol Reprod 2024; 111:292-311. [PMID: 38678504 DOI: 10.1093/biolre/ioae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 04/12/2024] [Accepted: 04/22/2024] [Indexed: 05/01/2024] Open
Abstract
The endoplasmic reticulum is a complex and dynamic organelle that initiates unfolded protein response and endoplasmic reticulum stress in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia and intrauterine growth retardation are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between endoplasmic reticulum stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signaling pathways while excessive endoplasmic reticulum stress triggers downstream apoptotic signaling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of preeclampsia and intrauterine growth retardation. In addition, this review will elucidate the molecular mechanisms of endoplasmic reticulum stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in preeclampsia and intrauterine growth retardation development. This research seeks to the interplay between endoplasmic reticulum stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications.
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Affiliation(s)
- Yi Zheng
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Xia Zha
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Bei Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Mabrouk Elsabagh
- Department of Animal Production and Technology, Faculty of Agricultural Sciences and Technologies, Niğde Ömer Halisdemir University, Nigde, Turkey
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh University, KafrelSheikh, Egypt
| | - Hongrong Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Mengzhi Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Science, Shihezi, P. R. China
| | - Hao Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
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Wang L, Xie Z, Wu M, Chen Y, Wang X, Li X, Liu F. The role of taurine through endoplasmic reticulum in physiology and pathology. Biochem Pharmacol 2024; 226:116386. [PMID: 38909788 DOI: 10.1016/j.bcp.2024.116386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Taurine is a sulfur-containing amino acid found in many cell organelles that plays a wide range of biological roles, including bile salt production, osmoregulation, oxidative stress reduction, and neuromodulation. Taurine treatments have also been shown to ameliorate the onset and development of many diseases, including hypertension, fatty liver, neurodegenerative diseases and ischemia-reperfusion injury, by exerting antioxidant, anti-inflammatory, and antiapoptotic effects. The endoplasmic reticulum (ER) is a dynamic organelle involved in a wide range of cellular functions, including lipid metabolism, calcium storage and protein stabilization. Under stress, the disruption of the ER environment leads to the accumulation of misfolded proteins and a characteristic stress response called the unfolded protein response (UPR). The UPR protects cells from stress and helps to restore cellular homeostasis, but its activation promotes cell death under prolonged ER stress. Recent studies have shown that ER stress is closely related to the onset and development of many diseases. This article reviews the beneficial effects and related mechanisms of taurine by regulating the ER in different physiological and pathological states, with the aim of providing a reference for further research and clinical applications.
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Affiliation(s)
- Linfeng Wang
- Institute of Microbial Engineering, School of Life Sciences, Henan University, Kaifeng 475004, China; Engineering Research Center for Applied Microbiology of Henan Province, Kaifeng, 475004, China
| | - Zhenxing Xie
- School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Mengxian Wu
- Institute of Microbial Engineering, School of Life Sciences, Henan University, Kaifeng 475004, China; Engineering Research Center for Applied Microbiology of Henan Province, Kaifeng, 475004, China
| | - Yunayuan Chen
- Institute of Microbial Engineering, School of Life Sciences, Henan University, Kaifeng 475004, China; Engineering Research Center for Applied Microbiology of Henan Province, Kaifeng, 475004, China
| | - Xin Wang
- Institute of Microbial Engineering, School of Life Sciences, Henan University, Kaifeng 475004, China; Engineering Research Center for Applied Microbiology of Henan Province, Kaifeng, 475004, China
| | - Xingke Li
- Institute of Microbial Engineering, School of Life Sciences, Henan University, Kaifeng 475004, China; Engineering Research Center for Applied Microbiology of Henan Province, Kaifeng, 475004, China.
| | - Fangli Liu
- College of Nursing and Health, Henan University, Kaifeng 475004, China.
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Barroso E, Díaz M, Reguera AC, Peyman M, Balsinde J, Jurado-Aguilar J, Zhang M, Rostami A, Palomer X, Ibáñez L, Vázquez-Carrera M. CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns. Cell Commun Signal 2023; 21:326. [PMID: 37957724 PMCID: PMC10644500 DOI: 10.1186/s12964-023-01352-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/10/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.
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Affiliation(s)
- Emma Barroso
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Marta Díaz
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Endocrinology, Pediatric Research Institute, Sant Joan de Déu Children's Hospital, Barcelona, Esplugues, Spain
| | - Ana Cristina Reguera
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Mona Peyman
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Jesús Balsinde
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Javier Jurado-Aguilar
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Meijian Zhang
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Adel Rostami
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Xavier Palomer
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Lourdes Ibáñez
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Endocrinology, Pediatric Research Institute, Sant Joan de Déu Children's Hospital, Barcelona, Esplugues, Spain
| | - Manuel Vázquez-Carrera
- Unitat de Farmacologia, Facultat de Farmàcia I Ciències de L'Alimentació, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain.
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain.
- Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
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Li Y, Chen D, Xu J, Wang X, Zhou F. The spatial expression of mTORC2-AKT-IP3R signal pathway in mitochondrial combination of endoplasmic reticulum of maternal fetal interface trophoblast in intrahepatic cholestasis of pregnancy. J Perinat Med 2023; 51:1032-1039. [PMID: 37185229 DOI: 10.1515/jpm-2022-0570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/05/2023] [Indexed: 05/17/2023]
Abstract
OBJECTIVES Intrahepatic cholestasis of pregnancy (ICP) is complicated by adverse fetal outcomes and even fetal death, the mechanism remains unclear. This study aims at evaluating the differential expression of mTORC2-AKT-IP3R signaling pathway, which accurately regulate Ca2+ transfer across mitochondria-associated membranes (MAMs) and determine the stress intensity experienced by endoplasmic reticulum (ER) and mitochondria, in patients diagnosed with ICP. METHODS We combined western blot analysis and placental immunofluorescence co-localization detection to assess the expression and co-localization of the mTORC2-AKT-IP3R signaling pathway in severe (maternal total bile acid (TBA) levels ≥40 μmol/L) and mild (maternal TBA 10-40 μmol/L) ICP. RESULTS Compared with the control and mild ICP groups, phosphorylated protein kinase B (p-AKT) levels were significantly upregulated in the severe ICP group. Placental Rictor levels were lower in the mild ICP group than in the control group and were further downregulated in the severe ICP group. IP3R3 and p-IP3R3 levels were lower in placentas in the severe ICP group than in those in the mild ICP and control groups. Moreover, the co-localization of IP3R3 and p-AKT in patients in the mild and severe ICP groups was significantly elevated compared with that in patients in the control group. CONCLUSIONS In patients with severe ICP, limited expression of Rictor and elevated p-AKT levels would suppress IP3R3/p-IP3R3 levels in MAMs. This inhibition might influence the transportation of Ca2+ from the ER to the mitochondria, thus weaken the stress adaptation associated with MAMs. Our results reveal the possible pathophysiological mechanism of adverse fetal outcomes in ICP.
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Affiliation(s)
- Yaqian Li
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Daijuan Chen
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Jinfeng Xu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Xiaodong Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Fan Zhou
- Department of Medical Genetics/Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
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Li Y, Dong X, Zhang Y, Xiao T, Zhao Y, Wang H. Astragalus polysaccharide improves the growth, meat quality, antioxidant capacity and bacterial resistance of Furong crucian carp (Furong carp♀ × red crucian carp♂). Int J Biol Macromol 2023:124999. [PMID: 37244344 DOI: 10.1016/j.ijbiomac.2023.124999] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/10/2023] [Accepted: 05/19/2023] [Indexed: 05/29/2023]
Abstract
To evaluate the functional effects of APS (Astragalus polysaccharide) on Furong crucian carp, APS-supplemented diets (0.00 %, 0.05 %, 0.10 % and 0.15 %) were prepared and utilized in feeding experiment. The results showed that the 0.05 % APS group has the highest weight gain rate and specific growth rate, and the lowest feed coefficient rate. In addition, 0.05 % APS supplement could improve muscle elasticity, adhesiveness and chewiness. Moreover, the 0.15 % APS group had the highest spleen-somatic index and the 0.05 % group had the maximum intestinal villus length. 0.05 % and 0.10 % APS addition significantly increased T-AOC and CAT activities while MDA contents decreased in all APS groups. The plasma TNF-α levels in all APS groups significantly increased (P<0.05), and the 0.05 % group showed the highest TNF-α level in spleen. In APS addition groups, the tlr8, lgp2 and mda5 gene expressions were significantly elevated, while xbp1, caspase-2 and caspase-9 expressions decreased in uninfected and A. hydrophila-infected fish. Finally, higher survival rate and slower disease outbreak rate were observed in APS-supplemented groups after being infected by A. hydrophila. In conclusion, Furong crucian carp fed by APS-supplemented diets possesses elevated weight gain rate and specific growth rate, and improved meat quality, immunity and disease resistance.
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Affiliation(s)
- Yaoguo Li
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Xiaohu Dong
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Yanling Zhang
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Tiaoyi Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China
| | - Yurong Zhao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China.
| | - Hongquan Wang
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha 410128, China.
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Pharmacological Strategies for Stroke Intervention: Assessment of Pathophysiological Relevance and Clinical Trials. Clin Neuropharmacol 2023; 46:17-30. [PMID: 36515293 DOI: 10.1097/wnf.0000000000000534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The present review describes stroke pathophysiology in brief and discusses the spectrum of available treatments with different promising interventions that are in clinical settings or are in clinical trials. METHODS Relevant articles were searched using Google Scholar, Cochrane Library, and PubMed. Keywords for the search included ischemic stroke, mechanisms, stroke interventions, clinical trials, and stem cell therapy. RESULTS AND CONCLUSION Stroke accounts to a high burden of mortality and morbidity around the globe. Time is an important factor in treating stroke. Treatment options are limited; however, agents with considerable efficacy and tolerability are being continuously explored. With the advances in stroke interventions, new therapies are being formulated with a hope that these may aid the ongoing protective and reparative processes. Such therapies may have an extended therapeutic time window in hours, days, weeks, or longer and may have the advantage to be accessible by a majority of the patients.
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Alanazi AS, Victor F, Rehman K, Khan YH, Yunusa I, Alzarea AI, Akash MSH, Mallhi TH. Pre-Existing Diabetes Mellitus, Hypertension and KidneyDisease as Risk Factors of Pre-Eclampsia: A Disease of Theories and Its Association with Genetic Polymorphism. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:16690. [PMID: 36554576 PMCID: PMC9778778 DOI: 10.3390/ijerph192416690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/25/2022] [Accepted: 12/03/2022] [Indexed: 06/17/2023]
Abstract
Pre-existing diabetes, hypertension and kidney disorders are prominent risk factors of pre-eclampsia (PE). It is a multifactorial pregnancy disorder associated with high blood pressure, proteinuria, and multiorgan failure, which develops after the 20th week of pregnancy. It is one of the most feared pregnancy disorders, as it consumes thousands of fetomaternal lives per annum. According to clinical and pathological studies, the placenta appears to be a key player in the pathogenesis of PE; however, the exact origin of this disorder is still under debate. Defective placentation and angiogenesis are the hallmarks of PE progression. This angiogenic imbalance, together with maternal susceptibility, might determine the severity and clinical presentation of PE. This article comprehensively examines the mechanisms of pathogenesis of PE and current evidence of the factors involved in its progression. Finally, this article will explore the genetic association of PE, various candidate genes, their proposed mechanisms and variants involved in its pathogenesis.
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Affiliation(s)
- Abdullah Salah Alanazi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia
| | - Francis Victor
- Department of Pharmacy, University of Chenab, Gujrat 50700, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan 66000, Pakistan
| | - Yusra Habib Khan
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia
| | - Ismaeel Yunusa
- College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | | | | | - Tauqeer Hussain Mallhi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia
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Capatina N, Burton GJ, Yung HW. Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development. Physiol Rep 2022; 10:e15467. [PMID: 36117391 PMCID: PMC9483615 DOI: 10.14814/phy2.15467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 06/15/2023] Open
Abstract
Hyperhomocysteinemia may arise from folate/vitamin B12 deficiency, genetic polymorphisms, kidney disease, or hypothyroidism. It is associated with an increased risk of early pregnancy loss and placenta-related complications of pregnancy, including pre-eclampsia and fetal growth restriction. While the majority of studies of hyperhomocysteinemia focus on epigenetic changes secondary to metabolic disruption, the effects of homocysteine toxicity on placental development remain unexplored. Here, we investigated the influence of hyperhomocysteinemia on early blastocyst development and trophoblast differentiation. Exposure of cultured blastocysts to high homocysteine levels reduces cell number in the trophectoderm layer, most likely through increased apoptosis. Homocysteine also promotes differentiation of a trophoblast stem cell line. Both effects diminish the stem cell pool, and are mediated in an endoplasmic reticulum (ER) unfolded protein response (UPRER )-dependent manner. Targeted alleviation of UPRER may therefore provide a new therapeutic intervention to improve pregnancy outcome in women with hyperhomocysteinemia.
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Affiliation(s)
- Nadejda Capatina
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast ResearchUniversity of CambridgeCambridgeUK
| | - Graham J. Burton
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast ResearchUniversity of CambridgeCambridgeUK
| | - Hong Wa Yung
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast ResearchUniversity of CambridgeCambridgeUK
- Department of Clinical NeuroscienceUniversity of CambridgeCambridgeUK
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11
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Effect of endoplasmic reticulum stress on human trophoblast cells: Survival triggering or catastrophe resulting in death. Acta Histochem 2022; 124:151951. [PMID: 35998395 DOI: 10.1016/j.acthis.2022.151951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 11/21/2022]
Abstract
Endoplasmic reticulum (ER) stress has been reported to play a role in the pathogenesis of intrauterine growth retardation and preeclampsia, especially implantation failure. Although in vitro ER stress studies in human trophoblast cell line have been conducted in recent years, the influence of Thapsigargin on intracellular dynamics on calcium homeostasis has not been proven. Here, the effects of ER stress and impaired calcium homeostasis on apoptosis, autophagy, cytoskeleton, hypoxia, and adhesion molecules in 2D and spheroid cultures of human trophectoderm cells were investigated at gene expression and protein levels. Thapsigargin caused ER stress by increasing GRP78 gene expression and protein levels. Human trophectoderm cells displayed different characterization properties in 2D and spheroids. While it moves in the pathway of EIF2A and IRE1A mechanisms in 2D, it proceeds in the pathway of EIF2A and ATF6 mechanisms in spheroids and triggers different responses in survival and programmed cell death mechanisms such as apoptosis and autophagy. This led to changes in the cytoskeleton, cell adhesion molecules and cell-cell interactions by affecting the hypoxia mechanism.
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12
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Ma HF, Zheng F, Su LJ, Zhang DW, Liu YN, Li F, Zhang YY, Gong SS, Kou JP. Metabolomic Profiling of Brain Protective Effect of Edaravone on Cerebral Ischemia-Reperfusion Injury in Mice. Front Pharmacol 2022; 13:814942. [PMID: 35237165 PMCID: PMC8882761 DOI: 10.3389/fphar.2022.814942] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/14/2022] [Indexed: 11/18/2022] Open
Abstract
Edaravone (EDA) injection has been extensively applied in clinics for treating stroke. Nevertheless, the metabolite signatures and underlying mechanisms associated with EDA remain unclear, which deserve further elucidation for improving the accurate usage of EDA. Ischemia stroke was simulated by intraluminal occlusion of the right middle cerebral artery for 1 h, followed by reperfusion for 24 h in mice. Brain infarct size, neurological deficits, and lactate dehydrogenase (LDH) levels were improved by EDA. Significantly differential metabolites were screened with untargeted metabolomics by cross-comparisons with pre- and posttreatment of EDA under cerebral ischemia/reperfusion (I/R) injury. The possibly involved pathways, such as valine, leucine, and isoleucine biosynthesis, and phenylalanine, taurine, and hypotaurine metabolisms, were enriched with differential metabolites and relevant regulatory enzymes, respectively. The network of differential metabolites was constructed for the integral exhibition of metabolic characteristics. Targeted analysis of taurine, an important metabolic marker, was performed for further validation. The level of taurine decreased in the MCAO/R group and increased in the EDA group. The inhibition of EDA on cerebral endothelial cell apoptosis was confirmed by TdT-mediated dUTP nick-end labeling (TUNEL) stain. Cysteine sulfinic acid decarboxylase (CSAD), the rate-limiting enzyme of taurine generation, significantly increased along with inhibiting endothelial cell apoptosis after treatment of EDA. Thus, CSAD, as the possible new therapeutic target of EDA, was selected and validated by Western blot and immunofluorescence. Together, this study provided the metabolite signatures and identified CSAD as an unrecognized therapeutic intervention for EDA in the treatment of ischemic stroke via inhibiting brain endothelial cell apoptosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jun-ping Kou
- *Correspondence: Shuai-shuai Gong, ; Jun-ping Kou,
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13
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Huang Z, Su Q, Li W, Ren H, Huang H, Wang A. Suppressed mitochondrial respiration via NOX5-mediated redox imbalance contributes to the antitumor activity of anlotinib in oral squamous cell carcinoma. J Genet Genomics 2021; 48:582-594. [PMID: 34373220 DOI: 10.1016/j.jgg.2021.06.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/19/2021] [Accepted: 06/23/2021] [Indexed: 02/04/2023]
Abstract
Anlotinib, a novel multitarget tyrosine kinase inhibitor, has shown promising results in the management of various carcinomas. This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma (OSCC) and the underlying molecular mechanism. A retrospective clinical study revealed that anlotinib improved the median progression-free survival (mPFS) and median overall survival (mOS) of patients with recurrent and metastatic (R/M) OSCC, respectively. Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patient-derived xenograft models. Mechanistically, RNA-sequencing identified that oxidative stress, oxidative phosphorylation and AKT/mTOR signaling were involved in anlotinib-treated OSCC cells. Anlotinib upregulated NADPH oxidase 5 (NOX5) expression, elevated reactive oxygen species (ROS) production, impaired mitochondrial respiration, and promoted apoptosis. Moreover, anlotinb also inhibited phospho-Akt (p-AKT) expression and elevated p-eIF2α expression in OSCC cells. NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells. Collectively, we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC. The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/eIF2α pathway.
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Affiliation(s)
- Zhexun Huang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Qiao Su
- Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Wuguo Li
- Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Hui Ren
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Huiqiang Huang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China; State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510060, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China
| | - Anxun Wang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
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14
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Chen J, Zhou D, Kang J, Liu C, Huang R, Jiang Z, Liao Y, Liu A, Gao L, Song X, Zhao S, Chen Y, Wang H, Lan Z, Wang W, Guan H, Chen X, Huang J. ER stress modulates apoptosis in A431 cell subjected to EtNBSe-PDT via the PERK pathway. Photodiagnosis Photodyn Ther 2021; 34:102305. [PMID: 33901688 DOI: 10.1016/j.pdpdt.2021.102305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/18/2021] [Accepted: 04/19/2021] [Indexed: 01/01/2023]
Abstract
Photodynamic therapy (PDT) is a promising modality against various cancers including squamous cell carcinoma (SCC) with which the induction of apoptosis is an effective mechanism. Here, we initially describe the preclinical activity of 5-ethylamino-9-diethylaminobenzo [a] phenoselenazinium(EtNBSe)-mediated PDT treatment in SCC. Results of our studies suggest that EtNBSe-PDT provokes a cellular state of endoplasmic reticulum (ER) stress triggering the PERK/ eIF2α signaling pathway and induces the appearance of apoptosis in A431 cells at the meantime. With ER stress inhibitor 4-PBA or eIF2α inhibitor ISRIB, suppressing the EtNBSe-PDT induced ER stress substantially promotes apoptosis of A431 cells. Furthermore, we demonstrate that ATF4, whose expression is ER-stress-inducible and elevated in response to the PERK/eIF2α signaling pathway activation, contributes to cytoprotection against EtNBSe-PDT induced apoptosis. In a mouse model bearing A431 cells, EtNBSe shows intense phototoxicity and when associated with decreased ER stress, EtNBSe-PDT ameliorates tumor growth. Taken together, our study reveals an antagonistic activity of ER stress against EtNBSe-PDT treatment via inhibiting apoptosis in A431 cells. With further development, these results provide a proof-of-concept that downregulation of ER stress response has a therapeutic potential to improve EtNBSe-PDT sensitivity in SCC patients via the promotion of induced apoptosis.
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Affiliation(s)
- Jing Chen
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Dawei Zhou
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Jian Kang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Chenxi Liu
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Roujie Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Zhengqian Jiang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yuxuan Liao
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - An Liu
- Department of Otorhinolaryngology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Lihua Gao
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Xiangzhi Song
- College of Chemistry & Chemical Engineering, Central South University, Changsha, Hunan Province, China
| | - Shuang Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yihui Chen
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Hongyi Wang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Zehao Lan
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Weidong Wang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Haoyu Guan
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
| | - Jinhua Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
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15
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Cao Y, Smith W, Yan L, Kong L. Overview of Cellular Mechanisms and Signaling Pathways of Piceatannol. Curr Stem Cell Res Ther 2020; 15:4-10. [PMID: 30947674 DOI: 10.2174/1574888x14666190402100054] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 12/26/2018] [Accepted: 02/07/2019] [Indexed: 11/22/2022]
Abstract
Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene. However, differences in the nature and position of substituents have made it possible to produce many derivatives. Piceatannol [PT], a hydroxylated derivative from resveratrol, exerts various biological activities ranging from cancer prevention, cardio- protection, neuro-protection, anti-diabetic, depigmentation and so on. Although positive results were obtained in most cell culture and animal studies, the relevant cellular and molecular mechanisms of cytokines and signaling pathway about their biological effects still unclear. Thus, in the current review, we focus on the latest findings of PT on cellular biology in order to better understand the underlying therapeutic mechanisms of PT among various diseases.
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Affiliation(s)
- Yang Cao
- Honghui Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.,Yan'an University Medical School, Yan'an, China
| | - Wanli Smith
- Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland, United States
| | - Liang Yan
- Honghui Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China
| | - Lingbo Kong
- Honghui Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China
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16
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Modulation of Endoplasmic Reticulum Stress Influences Ischemia-Reperfusion Injury After Hemorrhagic Shock. Shock 2020; 52:e76-e84. [PMID: 30499877 DOI: 10.1097/shk.0000000000001298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Impaired function of the endoplasmic reticulum (ER) results in ER stress, an accumulation of proteins in the ER lumen. ER stress is a major contributor to inflammatory diseases and is part of the pathomechanism of ischemia-reperfusion injury (IRI). Since severe traumatic injury is often accompanied by remote organ damage and immune cell dysfunction, we investigated the influence of ER stress modulation on the systemic inflammatory response and liver damage after hemorrhagic shock and reperfusion (HS/R). MATERIAL AND METHODS Male C56BL/6-mice were subjected to hemorrhagic shock with a mean arterial pressure of 30 ± 5 mm Hg. After 90 min mice were resuscitated with Ringer solution. Either the ER stress inductor tunicamycin (TM), its drug vehicle (DV), or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) were added to reperfusion solution. Animals were sacrificed 14 h after shock induction and plasma concentrations of liver transaminases as well as inflammatory cytokines were measured. In addition, liver tissue sections were embedded in paraffin. For the quantification of hepatocellular damage hematoxylin and eosin stained tissue sections were analyzed. Furthermore, the topographic patterns of ER stress marker proteins were evaluated using immunohistochemistry. RESULTS ER stress modulation influenced the topographic pattern of ER stress marker proteins. The alterations were particularly seen in the transition zone between vital liver parenchyma and cell death areas. Furthermore, the application of tunicamycin during reperfusion inhibited the secretion of pro-inflammatory cytokines and increased the hepatocellular damage significantly. However, the injection of TUDCA resulted in a significantly reduced liver damage, as seen by lower transaminases and smaller cell death areas. CONCLUSION ER stress modulation influences post-hemorrhagic IRI. Moreover, the ER stress inhibitor TUDCA diminished the hepatocellular damage following HS/R significantly. This may help to provide a therapeutic target to ameliorate the clinical outcome after trauma-hemorrhage.
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17
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Modi J, Menzie-Suderam J, Xu H, Trujillo P, Medley K, Marshall ML, Tao R, Prentice H, Wu JY. Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model. J Biomed Sci 2020; 27:19. [PMID: 31907023 PMCID: PMC6943893 DOI: 10.1186/s12929-019-0597-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 11/27/2019] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress. METHODS Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 μg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting. RESULTS G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA. CONCLUSIONS G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.
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Affiliation(s)
- Jigar Modi
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, USA
| | - Janet Menzie-Suderam
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Hongyuan Xu
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Paola Trujillo
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Kristen Medley
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | | | - Rui Tao
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Howard Prentice
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA.
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, USA.
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA.
| | - Jang-Yen Wu
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA.
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, USA.
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA.
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18
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Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia. Proc Natl Acad Sci U S A 2019; 116:18109-18118. [PMID: 31439814 PMCID: PMC6731647 DOI: 10.1073/pnas.1907548116] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Preeclampsia endangers the lives and well-being of mother and baby. The syndrome is associated with placental dysfunction. High demand for energy to support active nutrient transport and hormone production increases placental susceptibility to mitochondrial stress. Here, we investigate mitochondrial activity and explore stress-response pathways in preeclamptic placentas. We demonstrate activation of noncanonical mitochondrial unfolded protein response (UPRmt) pathways associated with reduced CLPP, a key protease in UPRmt signalling, that compromises mitochondrial respiration. The changes can be recapitulated in trophoblast cells by hypoxia–reoxygenation. Either activation of UPRmt or knockdown of CLPP can sufficiently reduce mitochondrial respiration. Translation of CLPP is negatively regulated by the endoplasmic reticulum UPR pathway. Understanding mitochondrial stress provides new insights into the pathophysiology of early-onset preeclampsia. Preeclampsia (PE) is a dangerous complication of pregnancy, especially when it presents at <34 wk of gestation (PE < 34 wk). It is a major cause of maternal and fetal morbidity and mortality and also increases the risk of cardiometabolic diseases in later life for both mother and offspring. Placental oxidative stress induced by defective placentation sits at the epicenter of the pathophysiology. The placenta is susceptible to activation of the unfolded protein response (UPR), and we hypothesized this may affect mitochondrial function. We first examined mitochondrial respiration before investigating evidence of mitochondrial UPR (UPRmt) in placentas of PE < 34 wk patients. Reduced placental oxidative phosphorylation (OXPHOS) capacity measured in situ was observed despite no change in protein or mRNA levels of electron transport chain complexes. These results were fully recapitulated by subjecting trophoblast cells to repetitive hypoxia–reoxygenation and were associated with activation of a noncanonical UPRmt pathway; the quality-control protease CLPP, central to UPRmt signal transduction, was reduced, while the cochaperone, TID1, was increased. Transcriptional factor ATF5, which regulates expression of key UPRmt genes including HSP60 and GRP75, showed no nuclear translocation. Induction of the UPRmt with methacycline reduced OXPHOS capacity, while silencing CLPP was sufficient to reduce OXPHOS capacity, membrane potential, and promoted mitochondrial fission. CLPP was negatively regulated by the PERK-eIF2α arm of the endoplasmic reticulum UPR pathway, independent of ATF4. Similar changes in the UPRmt pathway were observed in placentas from PE < 34 wk patients. Our results identify UPRmt as a therapeutic target for restoration of placental function in early-onset preeclampsia.
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19
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Zhou X, Chen Z, Zhong W, Yu R, He L. Effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. Hum Exp Toxicol 2019; 38:833-845. [PMID: 30977402 DOI: 10.1177/0960327119842273] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In the development of dental fluorosis, oxidative stress is considered as the key mechanism. Endoplasmic reticulum (ER) stress can induce oxidative stress and activate the important antioxidative factor nuclear factor erythroid 2-related factor 2 (Nrf2) in a PKR-like ER kinase (PERK)-dependent manner, but combining ER stress and oxidative stress, the role of PERK-Nrf2 signaling pathway involved in fluoride-regulated ameloblasts is not fully defined. Here, we studied the effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. We found that low-dose and continuous fluoride exposure increased binding immunoglobulin protein expression and activated PERK-activating transcription factor 4 signaling pathway. Meanwhile, the expression of Nrf2 and its target genes (glutamylcysteine synthetase and glutathione S-transferase-P1) enhanced following ER stress. Tunicamycin increased the expression of PERK, leading to Nrf2 nuclear import, and tauroursodeoxycholate suppressed Nrf2 activation through PERK during ER stress, indicating that PERK activation is required for Nrf2 nuclear entry. Furthermore, tert-butylhydroquinone triggered the overexpression of Nrf2 to reduce ER stress, but luteolin inhibited Nrf2 nuclear localization to elevate ER stress. In summary, this study proved that fluoride under certain dose can induce ER stress and promote Nrf2 nuclear import via PERK activation and suggested that antioxidation mechanism mediated by PERK-Nrf2 can alleviate fluoride-induced ER stress effectively.
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Affiliation(s)
- X Zhou
- 1 Department of Dental Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- 2 Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
- 3 Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, Guangzhou, China
| | - Z Chen
- 2 Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - W Zhong
- 2 Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - R Yu
- 2 Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - L He
- 1 Department of Dental Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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20
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Mochan S, Dhingra MK, Gupta SK, Saxena S, Arora P, Yadav V, Rani N, Luthra K, Dwivedi S, Bhatla N, Dhingra R. Status of VEGF in preeclampsia and its effect on endoplasmic reticulum stress in placental trophoblast cells. Eur J Obstet Gynecol Reprod Biol X 2019; 4:100070. [PMID: 31517301 PMCID: PMC6728727 DOI: 10.1016/j.eurox.2019.100070] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/18/2019] [Accepted: 06/11/2019] [Indexed: 11/19/2022] Open
Abstract
Objective To explore the role of VEGF in attenuating endoplasmic reticulum stress in placental trophoblast cells. Study design Study was divided into following parts: 1. Serum Analysis of GRP78 and VEGF using sandwich ELISA. 2. Expression of VEGF and GRP78 in placentae by immunohistochemistry (IHC). 3. In Vitro experiments. Status of ER stress markers (GRP78, eIF2α, XBP1, ATF6 and CHOP) was assessed at various time points (8 h, 14 h, 24 h) when trophoblast cells were treated with varying concentration(s) of VEGF and also by adding recombinant VEGF at protein (Immunofluorescence, Western blot) and transcript levels (qRT-PCR). Results Increased GRP78 and decreased VEGF protein levels in sera and placentae of preeclamptic pregnant women and reduced expression of various ER stress markers at both transcript and protein levels was observed in trophoblast cells when they were exposed to recombinant VEGF thereby indicating positive role of VEGF in alleviating ER stress. Conclusions Reduced expression of ER stress markers in trophoblast cells against increased VEGF highlighted a new window to explore prospective drugs that can be designed to modulate the activities of various ER stress sensors in order to alleviate ER stress in pregnant women with preeclampsia.
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Affiliation(s)
- Sankat Mochan
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
- Corresponding authors.
| | - Manoj Kumar Dhingra
- Department of Community Medicine, NC Medical college and hospital, Israna, Panipat, Haryana, 132107, India
| | - Sunil Kumar Gupta
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Shobhit Saxena
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Pallavi Arora
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Vineeta Yadav
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Neerja Rani
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Sadanand Dwivedi
- Department of Biostatistics, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Neerja Bhatla
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| | - Renu Dhingra
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
- Corresponding authors.
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21
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Lojpur T, Easton Z, Raez-Villanueva S, Laviolette S, Holloway AC, Hardy DB. Δ9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts. Reprod Toxicol 2019; 87:21-31. [PMID: 31054322 DOI: 10.1016/j.reprotox.2019.04.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/05/2019] [Accepted: 04/30/2019] [Indexed: 02/07/2023]
Abstract
While studies have demonstrated that the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) alone induces placental insufficiency and fetal growth restriction, the underlying mechanisms remain elusive. Given that both (i) endoplasmic reticulum (ER) stress in pregnancy and (ii) gestational exposure to Δ9-THC leads to placental deficiency, we hypothesized that Δ9-THC may directly induce placental ER stress, influencing trophoblast gene expression and mitochondrial function. BeWo human trophoblast cells treated with Δ9-THC (3-30 μM) led to a dose-dependent increase in all ER stress markers and CHOP; these effects could be blocked with CB1R/CB2R antagonists. Moreover, expression of ER stress-sensitive genes ERRγ, VEGFA, and FLT-1 were increased by Δ9-THC, and abrogated with the ER stress inhibitor TUDCA. Δ9-THC also diminished mitochondrial respiration and ATP-coupling due to decreased abundance of mitochondrial chain complex proteins. Collectively, these findings indicate that Δ9-THC can directly augment ER stress resulting in aberrant placental gene expression and impaired mitochondrial function.
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Affiliation(s)
- Tina Lojpur
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada
| | - Zachary Easton
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada
| | | | - Steven Laviolette
- Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada
| | - Alison C Holloway
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Daniel B Hardy
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada.
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22
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Abstract
Complications of pregnancy remain key drivers of morbidity and mortality, affecting the health of both the mother and her offspring in the short and long term. There is lack of detailed understanding of the pathways involved in the pathology and pathogenesis of compromised pregnancy, as well as a shortfall of effective prognostic, diagnostic and treatment options. In many complications of pregnancy, such as in preeclampsia, there is an increase in uteroplacental vascular resistance. However, the cause and effect relationship between placental dysfunction and adverse outcomes in the mother and her offspring remains uncertain. In this review, we aim to highlight the value of gestational hypoxia-induced complications of pregnancy in elucidating underlying molecular pathways and in assessing candidate therapeutic options for these complex disorders. Chronic maternal hypoxia not only mimics the placental pathology associated with obstetric syndromes like gestational hypertension at morphological, molecular and functional levels, but also recapitulates key symptoms that occur as maternal and fetal clinical manifestations of these pregnancy disorders. We propose that gestational hypoxia provides a useful model to study the inter-relationship between placental dysfunction and adverse outcomes in the mother and her offspring in a wide array of examples of complicated pregnancy, such as in preeclampsia.
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23
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Maamoun H, Abdelsalam SS, Zeidan A, Korashy HM, Agouni A. Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes. Int J Mol Sci 2019; 20:ijms20071658. [PMID: 30987118 PMCID: PMC6480154 DOI: 10.3390/ijms20071658] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/25/2019] [Accepted: 03/29/2019] [Indexed: 12/12/2022] Open
Abstract
Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.
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Affiliation(s)
- Hatem Maamoun
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Abbaseyya, Cairo 11566, Egypt.
| | - Shahenda S Abdelsalam
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Asad Zeidan
- Department of Basic Sciences, College of Medicine, QU health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, P.O. Box 2713, Doha, Qatar.
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24
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Affiliation(s)
- Sarosh Rana
- From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL (S.R.)
| | - Elizabeth Lemoine
- Harvard Medical School, Boston, MA (E.L.)
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (E.L., S.A.K.)
| | - Joey P. Granger
- Department of Physiology, University of Mississippi Medical Center, Jackson (J.P.G.)
| | - S. Ananth Karumanchi
- Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (S.A.K.)
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (E.L., S.A.K.)
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25
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Lorenzon-Ojea AR, Yung HW, Burton GJ, Bevilacqua E. The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165386. [PMID: 30776414 DOI: 10.1016/j.bbadis.2019.01.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 12/17/2018] [Accepted: 01/08/2019] [Indexed: 11/24/2022]
Abstract
Endoplasmic reticulum (ER) stress occurs when the protein folding machinery in the cell is unable to cope with newly synthesized proteins, which results in an accumulation of misfolded proteins in the ER lumen. In response, the cell activates a cellular signaling pathway known as the Unfolded Protein Response (UPR), aiming to restore cellular homeostasis. Activation and exacerbation of the UPR have been described in several human pathologies, including cancer and neurological disorders, and in some gestational diseases such as preeclampsia and gestational diabetes. This review explores the participation of stromal cell-derived factor 2 (SDF2) in UPR pathways, shows new information and discusses its exacerbation regarding protein expression in severe preeclampsia and labor, both of which are associated with ER stress.
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Affiliation(s)
- Aline R Lorenzon-Ojea
- Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, SP, Brazil.
| | - Hong Wa Yung
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Graham J Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Estela Bevilacqua
- Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, SP, Brazil.
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Abstract
INTRODUCTION Cell-free "fetal" DNA is released from the placenta. Because the fetal membranes also arise from the trophectoderm layer of the blastocyst, these studies sought to test the hypothesis that the membranes also release cell-free DNA (cfDNA). METHODS Fetal membranes were harvested from pregnant CD-1 mice and cultured in 12-well plates containing media alone or with staurosporine and thapsigargin (apoptosis stimulators), Q-VD-OPh (caspase inhibitor), Trolox (vitamin E analog), and lipopolysaccharide and tumor necrosis factor α (TNFα; inflammatory mediators). The cfDNA in the media was extracted, quantified, and normalized for tissue weight. Media was used for a lactate dehydrogenase (LDH) assay. Membrane homogenates were used to assess activated caspase levels and the expression of DNA fragmentation factor B (DFFB) and BAX proteins. 5-Methylcytosine was assessed using a 5-mC DNA enzyme-linked immunosorbent assay. The cfDNA was used to stimulate interleukin 6 (IL6) release by J774A.1 mouse macrophage cells. RESULTS Increased cfDNA release at 6 and 21 hours occurred in parallel with increasing LDH levels. The cfDNA concentrations were significantly suppressed by Q-VD-OPh and Trolox and increased by thapsigargin and TNFα. Increased caspase activity was suppressed by Q-VD-OPh and increased by TNFα, thapsigargin, and staurosporine. The expression of BAX and DFFB proteins significantly increased by 21 hours. 5-Methylcytosine levels were significantly lower in fetal membranes and placentas and below detectable in the cfDNA released by the explants. The cfDNA-stimulated IL6 release by macrophage cells was suppressed by chloroquine, a Toll-like receptor 9 (TLR9) inhibitor. CONCLUSIONS These studies have confirmed cfDNA release by the mouse fetal membranes; cfDNA was markedly hypomethylated and a robust stimulator of TLR9.
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Affiliation(s)
- Michala R Sawyer
- Division of Maternal-Fetal Medicine and the Vincent Center for Reproductive Biology, Department of Obstetrics & Gynecology, Massachusetts General Hospital, 55 Fruit Street, Thier Bldg. 9-911, Boston, MA, 02114, USA
| | - Sharareh Adeli
- Division of Maternal-Fetal Medicine and the Vincent Center for Reproductive Biology, Department of Obstetrics & Gynecology, Massachusetts General Hospital, 55 Fruit Street, Thier Bldg. 9-911, Boston, MA, 02114, USA
| | - Mark Phillippe
- Division of Maternal-Fetal Medicine and the Vincent Center for Reproductive Biology, Department of Obstetrics & Gynecology, Massachusetts General Hospital, 55 Fruit Street, Thier Bldg. 9-911, Boston, MA, 02114, USA.
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Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:467-478. [PMID: 30448406 PMCID: PMC6360351 DOI: 10.1016/j.ajpath.2018.10.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/19/2018] [Accepted: 10/23/2018] [Indexed: 01/09/2023]
Abstract
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 proinflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether proinflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast before exploring potential regulatory mechanisms. There was increased immunoreactivity of heat shock 70-kDa protein 5, also known as 78-kDa glucose regulated protein, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared with normotensive controls. Treating EVT-like JEG-3 and HTR8/SVneo cells with ER stress inducers (tunicamycin and thapsigargin) suppressed MMP2 mRNA and protein expression, secretion, and activity and reduced their invasiveness. A cocktail of proinflammatory cytokines (IL-1β, tumor necrosis factor-α, and interferon-γ) suppressed MMP-2 activity in JEG-3 cells and was accompanied by activation of the PKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2A (EIF2A) arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which proinflammatory cytokines may modulate trophoblast invasion through ER stress pathways.
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Skórzyńska-Dziduszko KE, Kimber-Trojnar Ż, Patro-Małysza J, Stenzel-Bembenek A, Oleszczuk J, Leszczyńska-Gorzelak B. Heat Shock Proteins as a Potential Therapeutic Target in the Treatment of Gestational Diabetes Mellitus: What We Know so Far. Int J Mol Sci 2018; 19:ijms19103205. [PMID: 30336561 PMCID: PMC6213996 DOI: 10.3390/ijms19103205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/14/2018] [Accepted: 10/15/2018] [Indexed: 12/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a complex condition that involves a variety of pathological mechanisms, including pancreatic β-cell failure, insulin resistance, and inflammation. There is an increasing body of literature suggesting that these interrelated phenomena may arise from the common mechanism of endoplasmic reticulum (ER) stress. Both obesity-associated nutrient excess and hyperglycemia disturb ER function in protein folding and transport. This results in the accumulation of polypeptides in the ER lumen and impairs insulin secretion and signaling. Exercise elicits metabolic adaptive responses, which may help to restore normal chaperone expression in insulin-resistant tissues. Pharmacological induction of chaperones, mimicking the metabolic effect of exercise, is a promising therapeutic tool for preventing GDM by maintaining the body's natural stress response. Metformin, a commonly used diabetes medication, has recently been identified as a modulator of ER-stress-associated inflammation. The results of recent studies suggest the potential use of chemical ER chaperones and antioxidant vitamins as therapeutic interventions that can prevent glucose-induced ER stress in GDM placentas. In this review, we discuss whether chaperones may significantly contribute to the pathogenesis of GDM, as well as whether they can be a potential therapeutic target in GDM treatment.
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Affiliation(s)
| | - Żaneta Kimber-Trojnar
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Jolanta Patro-Małysza
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Agnieszka Stenzel-Bembenek
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, W. Chodźki 1 Street, 20-093 Lublin, Poland.
| | - Jan Oleszczuk
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Bożena Leszczyńska-Gorzelak
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
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Kim H, Moon JY, Burapan S, Han J, Cho SK. Induction of ER Stress-Mediated Apoptosis by the Major Component 5,7,4'-Trimethoxyflavone Isolated from Kaempferia parviflora Tea Infusion. Nutr Cancer 2018; 70:984-996. [PMID: 30273054 DOI: 10.1080/01635581.2018.1491607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Kaempferia parviflora (KP) is a famous medicinal plant from Thailand, and is a rich source of various kinds of methoxyflavones (MFs). Many kinds of food products such as tea, capsule, and liquor are manufactured from the rhizomes of KP. In this study, KP infusions were prepared with different brewing conditions, and the amounts of three major methoxylflavones, 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF), were analyzed. The antiproliferative activities of DMF, TMF, and PMF isolated from the brewed tea samples were evaluated. TMF was discovered to be significantly effective at inhibiting proliferation of SNU-16 human gastric cancer cells in a concentration dependent manner. TMF induced apoptosis, as evidenced by increments of sub-G1 phase, DNA fragmentation, annexin-V/PI staining, the Bax/Bcl-xL ratio, proteolytic activation of caspase-3,-7,-8, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Furthermore, it was found that TMF induced apoptosis via ER stress, verified by an increase in the level of C/EBP homologous protein (CHOP), glucose regulated protein 78 (GRP78), inositol-requiring enzyme 1 α (IRE1α), activating transcription factor-4 (ATF-4), and the splice isoform of X-box-binding protein-1 (XBP-1) mRNA.
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Affiliation(s)
- Hyeonji Kim
- a Faculty of Biotechnology, College of Applied Life Sciences , SARI, Jeju National University , Jeju , Republic of Korea
| | - Jeong Yong Moon
- b Subtropical/Tropical Organism Gene Bank, Jeju National University , Jeju , Republic of Korea
| | - Supawadee Burapan
- c Metalloenzyme Research Group and Department of Integrative Plant Science , Chung-Ang University , Anseong , Republic of Korea
| | - Jaehong Han
- c Metalloenzyme Research Group and Department of Integrative Plant Science , Chung-Ang University , Anseong , Republic of Korea
| | - Somi Kim Cho
- a Faculty of Biotechnology, College of Applied Life Sciences , SARI, Jeju National University , Jeju , Republic of Korea.,b Subtropical/Tropical Organism Gene Bank, Jeju National University , Jeju , Republic of Korea
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30
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Li ZR, Yang L, Zhen J, Zhao Y, Lu ZN. Nobiletin protects PC12 cells from ERS-induced apoptosis in OGD/R injury via activation of the PI3K/AKT pathway. Exp Ther Med 2018; 16:1470-1476. [PMID: 30116396 DOI: 10.3892/etm.2018.6330] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 06/05/2018] [Indexed: 12/12/2022] Open
Abstract
Nobiletin (NOB) possesses multiple pharmacological effects, but its anti-apoptotic property has acquired a great deal of attention. Endoplasmic reticulum (ER) stress (ERS)-induced apoptosis acts as the pivotal aetiology in neuronal oxygen-glucose deprivation and reoxygenation (OGD/R) injury. The aim of this study focused on whether NOB exerts neuro-protective effects on OGD/R injury by repressing ERS-induced apoptosis. The PC12 neuronal cell line was subjected to 4 h OGD and 24 h reoxygenation following NOB treatment. A PI3K/AKT inhibitor (LY294002) was added during the mechanistic experiments. Cell viability, lactate dehydrogenase (LDH) release and apoptosis were determined. Western blotting was used to measure protein expression levels. The results showed that OGD/R caused neuronal damageas exhibited by the increase in LDH release and the reduction of cellular viability. Moreover, ERS-induced apoptosis was markedly stimulated by OGD/R in PC12 cells, as evidenced by the elevation in the apoptotic rate and protein levels of C/EBP homologous protein/glucose-regulated protein-78. However, NOB administration significantly reversed neuronal damage and the ERS-induced apoptosis in response to OGD/R injury. Mechanistic detections showed that the neuron-favorable and ERS-repressing contributions of NOB were, in part, a result of the activation of the PI3K/AKT pathway, which was validated by a specific PI3K/AKT inhibitor (LY294002). Therefore, NOB protects PC12 cells from ERS-induced apoptosis in OGD/R injury mainly through enhancement of the PI3K/AKT pathway, which may provide a novel therapeutic avenue for the prevention of cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Zi-Ru Li
- Department of Internal Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lei Yang
- Department of Internal Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jin Zhen
- Department of Internal Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yan Zhao
- Department of Internal Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zu-Neng Lu
- Department of Internal Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Suh KS, Chon S, Choi EM. Protective effects of piceatannol on methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblastic cells. Free Radic Res 2018; 52:712-723. [DOI: 10.1080/10715762.2018.1467010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Kwang Sik Suh
- Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, Dongdaemun-gu, Republic of Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, Dongdaemun-gu, Republic of Korea
| | - Eun Mi Choi
- Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, Dongdaemun-gu, Republic of Korea
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Su CM, Chen CY, Lu T, Sun Y, Li W, Huang YL, Tsai CH, Chang CS, Tang CH. A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress. Oncotarget 2018; 7:83530-83543. [PMID: 27835579 PMCID: PMC5347786 DOI: 10.18632/oncotarget.13171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/19/2016] [Indexed: 12/15/2022] Open
Abstract
Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.
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Affiliation(s)
- Chen-Ming Su
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.,Graduate Institute of Basic Medical Science, China Medical University, Taichung Taiwan
| | - Chien-Yu Chen
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Tingting Lu
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Yi Sun
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Weimin Li
- Department of Cardiology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Yuan-Li Huang
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Chun-Hao Tsai
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Shiang Chang
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.,Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
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33
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Hung TH, Hsieh TT, Wu CP, Li MJ, Yeh YL, Chen SF. Mammalian target of rapamycin signaling is a mechanistic link between increased endoplasmic reticulum stress and autophagy in the placentas of pregnancies complicated by growth restriction. Placenta 2017; 60:9-20. [PMID: 29208245 DOI: 10.1016/j.placenta.2017.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 10/01/2017] [Accepted: 10/06/2017] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Increased endoplasmic reticulum (ER) stress and autophagy have been noted in the placentas of pregnancies complicated by idiopathic intrauterine growth restriction (IUGR); however, the cause of these phenomena remains unclear. We surmised that oxygen-glucose deprivation (OGD) may increase ER stress and autophagy and that mammalian target of rapamycin (mTOR) signaling is involved in regulating placental ER stress and autophagy in pregnancies complicated by IUGR. METHODS We obtained placentas from women with normal term pregnancies and pregnancies complicated by IUGR to compare ER stress, mTOR signaling, and levels of autophagy-related proteins between the two groups and used primary cytotrophoblast cells treated with or without salubrinal (an ER stress inhibitor), MHY1485 (an mTOR activator), or rapamycin (an mTOR inhibitor) to investigate the effects of OGD on ER stress, mTOR activity, and autophagy levels in vitro. RESULTS Women with pregnancies complicated by IUGR displayed higher placental ER stress and autophagy levels but lower mTOR activity than women with normal pregnancies. Furthermore, OGD increased ER stress, regulated in development and DNA damage responses-1 (REDD1), phosphorylated tuberous sclerosis complex 2 (TSC2), and autophagy levels and decreased mTOR activity compared to the standard culture condition; however, the salubrinal treatment attenuated these changes. Moreover, the administration of MHY1485 or rapamycin to OGD-treated cells decreased or increased autophagy levels, respectively. DISCUSSION Based on our results, mTOR is a mechanistic link between OGD-induced ER stress and autophagy in cytotrophoblast cells; thus, mTOR plays an essential role in the pathogenesis of pregnancies complicated by IUGR.
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Affiliation(s)
- Tai-Ho Hung
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan; Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - T'sang-T'ang Hsieh
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology and Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Meng-Jen Li
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yi-Lin Yeh
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Szu-Fu Chen
- Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan
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Abstract
Although suggested that “fetal” cell-free DNA (cfDNA) is derived from trophoblast cells, the exact origin is unclear. The studies in this report sought to demonstrate that placental tissue releases cfDNA in parallel with cell death, that the size range of cfDNA is similar to that found in maternal plasma, and that the cfDNA fragments are able to stimulate a proinflammatory cytokine response. Placentas were harvested from near term pregnant CD-1 mice and cultured in DMEM/Ham’s F12/FBS media in 8% or 21% O2. After centrifugation to remove cells and cellular debris, the cfDNA was extracted from the media and quantified by DNA spectrophotometry. The cfDNA fragments were sized using a 1.5% TAE gel. Cell death was quantified by lactate dehydrogenase assay; and tissue homogenates were used to quantify caspase activity and BAX expression. Cultured RAW-264.7 macrophage cells were used to determine IL6 stimulation by cfDNA. The cfDNA levels released in 8% O2 (placental normoxia) were not significantly different from explants cultured in 21% O2 (placental hyperoxia). The cfDNA fragments ranged in size from < 100 –< 400 bp. The cfDNA release increased when cultured with LPS, whereas it decreased with trolox (vitamin E analog). Explant release of cfDNA increased in parallel with cell death. The cfDNA release and cell death of trophoblast appears to involve components of the apoptosis signaling pathway as suggested by LPS enhancement of placental caspase activity, suppression of cfDNA release by a pan-caspase inhibitor and the trend toward increased Bax protein expression. Studies with cultured macrophage cells confirmed the ability of cfDNA to stimulate an IL6 response. In summary, these studies have confirmed the ability of placental tissue to release significant amounts of cfDNA, a phenomenon that appears to be mediated, at least in part, by apoptosis; and that the cfDNA released by the placental explants is able to stimulate a significant proinflammatory response. Thus, these studies provide support for the hypothesis that cell-free fetal DNA released by placental tissue potentially plays a mechanistically important role during the events leading to the onset of parturition.
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Affiliation(s)
- Mark Phillippe
- Vincent Center for Reproductive Biology, Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA
- * E-mail:
| | - Sharareh Adeli
- Vincent Center for Reproductive Biology, Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA
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Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SGE, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol 2017; 19:568-577. [PMID: 28394884 PMCID: PMC5410172 DOI: 10.1038/ncb3516] [Citation(s) in RCA: 462] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 03/16/2017] [Indexed: 02/07/2023]
Abstract
In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium as the site of implantation and nutritional support for the conceptus, there are no long-term culture systems that recapitulate endometrial function in vitro. We adapted conditions used to establish human adult stem cell-derived organoid cultures to generate 3D cultures of normal and decidualised human endometrium. These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones. Single cells from both endometrium and decidua can generate a fully functional organoid. Transcript analysis confirmed great similarity between organoids and the primary tissue of origin. On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy. We also derived organoids from malignant endometrium, and so provide a foundation to study common diseases, such as endometriosis and endometrial cancer, as well as the physiology of early gestation.
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Affiliation(s)
- Margherita Y Turco
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.,Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
| | - Lucy Gardner
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.,Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
| | - Jasmine Hughes
- Department of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2SP, UK
| | - Tereza Cindrova-Davies
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - Maria J Gomez
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK
| | - Lydia Farrell
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.,Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
| | | | - Steven G E Marsh
- Anthony Nolan Research Institute, Royal Free Hospital, London, NW3 2QU, UK
| | - Jan J Brosens
- Division of Reproductive Health, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Hilary O Critchley
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Benjamin D Simons
- Gurdon Institute and Department of Physics, University of Cambridge, Cambridge CB2 1QN, UK.,Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK
| | - Myriam Hemberger
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.,Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
| | - Bon-Kyoung Koo
- Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.,Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK
| | - Ashley Moffett
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.,Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
| | - Graham J Burton
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
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36
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Lim W, Yang C, Park S, Bazer FW, Song G. Inhibitory Effects of Quercetin on Progression of Human Choriocarcinoma Cells Are Mediated Through PI3K/AKT and MAPK Signal Transduction Cascades. J Cell Physiol 2016; 232:1428-1440. [PMID: 27714811 DOI: 10.1002/jcp.25637] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 10/05/2016] [Indexed: 01/05/2023]
Abstract
As a major dietary flavonol, quercetin mitigates proliferation and progression of cancer due to its anti-angiogenic, anti-inflammatory, anti-oxidant, and apoptotic biological effects on cells. Although its apoptotic effects have been reported for various cancers, little is known of the functional role of quercetin in gestational choriocarcinoma. Results of the present study indicated that quercetin reduced proliferation and induced cell death in two choriocarcinoma cell lines, JAR and JEG3 cells, with an increase in the sub-G1 phase of the cell cycle. In addition, quercetin induced mitochondrial dysfunction significantly reduced mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in both JAR and JEG3 cells. Further, quercetin inhibited phosphorylation of AKT, P70S6K and S6 proteins whereas, it increased phosphorylation of ERK1/2, P38, JNK and P90RSK proteins in JAR and JEG3 cells. The decrease in viability of choriocarcinoma cells treated with quercetin was confirmed by using combinations of quercetin and pharmacological inhibitors of the PI3K and MAPK signaling pathways. Classical chemotherapeutic agents, cisplatin (a platinum-based drug) and paclitaxel (a taxene-based drug), inhibited proliferation of JAR and JEG3 cells, and when combined with quercetin, the antiproliferative effects of cisplatin and paclitaxel were enhanced for both choriocarcinoma cell lines. Collectively, these results suggest that quercetin prevents development of choriocarcinoma and may be a valuable therapeutic agent for treatment of choriocarcinoma through its regulation of PI3K and MAPK signal transduction pathways. J. Cell. Physiol. 232: 1428-1440, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Whasun Lim
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Changwon Yang
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Sunwoo Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Fuller W Bazer
- Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, Texas
| | - Gwonhwa Song
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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37
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The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. J Mol Cell Cardiol 2016; 100:43-53. [DOI: 10.1016/j.yjmcc.2016.09.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 11/22/2022]
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38
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Yung HW, Alnæs-Katjavivi P, Jones CJP, El-Bacha T, Golic M, Staff AC, Burton GJ. Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants. Diabetologia 2016; 59:2240-50. [PMID: 27406815 PMCID: PMC5016560 DOI: 10.1007/s00125-016-4040-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 06/10/2016] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS The aim of this work was to determine whether placental endoplasmic reticulum (ER) stress may contribute to the pathophysiology of gestational diabetes mellitus (GDM) and to test the efficacy of chemical chaperones and antioxidant vitamins in ameliorating that stress in a trophoblast-like cell line in vitro. METHODS Placental samples were obtained from women suffering from GDM and from normoglycaemic controls and were frozen immediately. Women with GDM had 2 h serum glucose levels > 9.0 mmol/l following a 75 g oral glucose tolerance test and were treated with diet and insulin when necessary. Western blotting was used to assess markers of ER stress. To test the effects of hyperglycaemia on the generation of ER stress, a new trophoblast-like cell line, BeWo-NG, was generated by culturing in a physiological glucose concentration of 5.5 mmol/l (over 20 passages) before challenging with 10 or 20 mmol/l glucose. RESULTS All GDM patients were well-controlled (HbA1c 5.86 ± 0.55% or 40.64 ± 5.85 mmol/mol, n = 11). Low-grade ER stress was observed in the placental samples, with dilation of ER cisternae and increased phosphorylation of eukaryotic initiation factor 2 subunit α. Challenge of BeWo-NG with high glucose activated the same pathways, but this was as a result of acidosis of the culture medium rather than the glucose concentration per se. Addition of chemical chaperones 4-phenylbutyrate and tauroursodeoxycholic acid and vitamins C and E ameliorated the ER stress. CONCLUSIONS/INTERPRETATION This is the first report of placental ER stress in GDM patients. Chemical chaperones and antioxidant vitamins represent potential therapeutic interventions for GDM.
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Affiliation(s)
- Hong-Wa Yung
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Patji Alnæs-Katjavivi
- Department of Obstetrics and Gynecology, Oslo University Hospital, Ullevål and Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Carolyn J P Jones
- Centre for Maternal and Fetal Health, Institute of Human Development, University of Manchester, Manchester, UK
| | - Tatiana El-Bacha
- Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Michaela Golic
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Obstetrics and Gynecology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Anne-Cathrine Staff
- Department of Obstetrics and Gynecology, Oslo University Hospital, Ullevål and Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Graham J Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
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39
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Lorenzon-Ojea AR, Guzzo CR, Kapidzic M, Fisher SJ, Bevilacqua E. Stromal Cell-Derived Factor 2: A Novel Protein that Interferes in Endoplasmic Reticulum Stress Pathway in Human Placental Cells. Biol Reprod 2016; 95:41. [PMID: 27335075 PMCID: PMC5029474 DOI: 10.1095/biolreprod.115.138164] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 06/02/2016] [Indexed: 12/24/2022] Open
Abstract
Endoplasmic reticulum (ER) stress results from changes in ER homeostasis and folding of proteins. ER stress initiates cellular adaptive mechanisms to rescue cell homeostasis or, if that does not work, to elicit apoptosis. We have previously shown that mouse SDF2 is sublocalized in the ER, is ubiquitously expressed, and shows strong similarities with stromal cell-derived factor (SDF) 2L1 and SDF2-like from Arabidopsis, ER proteins involved in chaperone network and protein folding. Thus, we hypothesized that SDF2 plays a role in the ER stress and unfolded protein response. In this study, we investigated the possible role of SDF2 in the human placenta. Expression of SDF2 was present throughout gestation and was expressed by several cell types. Second-trimester cytotrophoblast cells (CTBs) in the differentiation process, monitored through chorionic gonadotropin production, showed upregulation of SDF2 protein. SDF2 expression, however, was significantly diminished in placentas from neonates small for gestational age and in hypoxic in vitro conditions (P ≤ 0.001, 2% O2), suggesting a link with cellular stress. ER stress-induced cells-CTB and BeWo-also showed SDF2 downregulation in different time points, emphasizing this relationship. SDF2 downregulation was also followed by an increase in binding immunoglobulin protein (BiP) expression, an ER protein-associated chaperone acting as a sensor for misfolded proteins and an ER stress cell survival marker. In line with this, SDF2 siRNA resulted in significant anticipation of BiP expression. Downregulation of SDF2 also interfered with C/EBP homologous protein expression, one of the highest inducible genes during ER stress. These findings suggest that SDF2 may be an important regulatory factor by which trophoblast cells can control cell survival under ER stress. In conclusion, this study identifies a novel factor with the ability to interfere with ER stress proteins, which may contribute to the understanding of ER stress associated with placental-related diseases of pregnancy.
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Affiliation(s)
- Aline R Lorenzon-Ojea
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California San Francisco, San Francisco, California
| | - Cristiane R Guzzo
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mirhan Kapidzic
- Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California San Francisco, San Francisco, California
| | - Susan J Fisher
- Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California San Francisco, San Francisco, California
| | - Estela Bevilacqua
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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40
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Grootjans J, Lenaerts K, Buurman WA, Dejong CHC, Derikx JPM. Life and death at the mucosal-luminal interface: New perspectives on human intestinal ischemia-reperfusion. World J Gastroenterol 2016; 22:2760-2770. [PMID: 26973414 PMCID: PMC4777998 DOI: 10.3748/wjg.v22.i9.2760] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/24/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
Intestinal ischemia is a frequently observed phenomenon. Morbidity and mortality rates are extraordinarily high and did not improve over the past decades. This is in part attributable to limited knowledge on the pathophysiology of intestinal ischemia-reperfusion (IR) in man, the paucity in preventive and/or therapeutic options and the lack of early diagnostic markers for intestinal ischemia. To improve our knowledge and solve clinically important questions regarding intestinal IR, we developed a human experimental intestinal IR model. With this model, we were able to gain insight into the mechanisms that allow the human gut to withstand short periods of IR without the development of severe inflammatory responses. The purpose of this review is to overview the most relevant recent advances in our understanding of the pathophysiology of human intestinal IR, as well as the (potential) future clinical implications.
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41
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Mizuuchi M, Cindrova-Davies T, Olovsson M, Charnock-Jones DS, Burton GJ, Yung HW. Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6β: implications for the pathophysiology of human pregnancy complications. J Pathol 2016; 238:550-61. [PMID: 26648175 PMCID: PMC4784173 DOI: 10.1002/path.4678] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/21/2015] [Accepted: 11/27/2015] [Indexed: 01/05/2023]
Abstract
Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early-onset pre-eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high-risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early-onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down-regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6α and ATF6β in the syncytiotrophoblast of placentae from PE patients. Transcript analysis showed a decrease of PlGF mRNA, and an increase from genes encoding those UPR transcription factors in placentae from cases of early-onset PE, but not of late-onset (>34 weeks) PE, compared to term controls. Further investigations indicated a strong correlation between ATF4 and PlGF mRNA levels only (r = - 0.73, p < 0.05). These results could be recapitulated in trophoblast-like cells exposed to chemical inducers of ER stress or hypoxia-reoxygenation. The stability of PlGF transcripts was unchanged. The use of small interfering RNA specific for transcription factors in the UPR pathways revealed that ATF4 and ATF6β, but not ATF6α, modulate PlGF transcription. To conclude, ATF4 and ATF6β act synergistically in the negative regulation of PlGF mRNA expression, resulting in reduced PlGF secretion by the trophoblast in response to stress. Therefore, these results further support the targeting of placental ER stress as a potential new therapeutic intervention for these pregnancy complications.
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Affiliation(s)
- Masahito Mizuuchi
- Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, UK
| | - Tereza Cindrova-Davies
- Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, UK
| | - Matts Olovsson
- Department of Women's and Children's Health, Uppsala University, Sweden
| | - D Stephen Charnock-Jones
- Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, UK
- Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, UK
- National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK
| | - Graham J Burton
- Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, UK
| | - Hong Wa Yung
- Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, UK
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Wong MK, Holloway AC, Hardy DB. Nicotine Directly Induces Endoplasmic Reticulum Stress Response in Rat Placental Trophoblast Giant Cells. Toxicol Sci 2016; 151:23-34. [PMID: 26803847 DOI: 10.1093/toxsci/kfw019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Nicotine exposure during pregnancy leads to placental insufficiency impairing both fetal and neonatal development. Previous studies from our laboratory have demonstrated that in rats, nicotine augmented endoplasmic reticulum (ER) stress in association with placental insufficiency; however, the underlying mechanisms remain elusive. Therefore, we sought to investigate the possible direct effect of nicotine on ER stress in Rcho-1 rat placental trophoblast giant (TG) cells during differentiation. Protein and/or mRNA expression of markers involved in ER stress (eg, phosphorylated PERK, eIF2α, CHOP, and BiP/GRP78) and TG cell differentiation and function (eg, Pl-1, placental growth factor [Pgf], Hsd11b1, and Hsd11b2) were quantified via Western blot or real-time polymerase chain reaction. Nicotine treatment led to dose-dependent increases in the phosphorylation of PERK[Thr981] and eIF2α[Ser51], whereas pretreatment with a nicotinic acetylcholine receptor (nAChR) antagonist (mecamylamine hydrochloride) blocked the induction of PERK phosphorylation, verifying the direct involvement of nicotine and nAChR binding. We next investigated select target genes known to play essential roles in placental TG cell differentiation and function (Pl-1, Pgf, Hsd11b1, and Hsd11b2), and found that nicotine significantly augmented the mRNA levels of Hsd11b1 in a dose-dependent manner. Furthermore, using tauroursodeoxycholic acid, a safe bile acid known to improve protein chaperoning and folding, we were able to prevent nicotine-induced increases in both PERK phosphorylation and Hsd11b1 mRNA levels, revealing a potential novel therapeutic approach to reverse the deleterious effects of nicotine exposure in pregnancy. Collectively, these results implicate that nicotine, acting through its receptor, can directly augment ER stress and impair placental function.
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Affiliation(s)
- Michael K Wong
- *Department of Physiology and Pharmacology, Western University, London, Ontario, Canada N6A 5C1
| | - Alison C Holloway
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada L8S 4K1
| | - Daniel B Hardy
- *Department of Physiology and Pharmacology, Western University, London, Ontario, Canada N6A 5C1 Departments of Obstetrics and Gynecology, Children's Health Research Institute, Lawson, Health Research Institute, Western University, London, Ontario, Canada N6A 5C1
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Matheson H, Veerbeek JHW, Charnock-Jones DS, Burton GJ, Yung HW. Morphological and molecular changes in the murine placenta exposed to normobaric hypoxia throughout pregnancy. J Physiol 2015; 594:1371-88. [PMID: 26278110 PMCID: PMC4771784 DOI: 10.1113/jp271073] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 08/04/2015] [Indexed: 11/22/2022] Open
Abstract
Key points
Exposure of pregnant mice to chronic hypoxia at 13% O2 induces fetal growth restriction but increases placental weight. Sex dimorphism induces differential responses in placental weight to hypoxia. The male placenta is heavier than the female and is associated with less severe fetal growth restriction. Increases in maternal arterial/venous blood spaces and higher protein kinase B (Akt)‐mechanistic target of rapamycin growth signalling could contribute to the heavier hypoxic placenta. Placental endoplasmic reticulum stress is elevated equally in both sexes in response to hypoxia. In comparison, oxidative stress is only apparent in female placentas. Chronic hypoxia induces down‐regulation of placental mitochondrial electron transport chain complexes protein subunits but does not cause intracellular energy depletion. Abstract Chronic hypoxia is a common complication of pregnancy, arising through malperfusion of the placenta or pregnancy at high altitude. The present study investigated the effects of hypoxia on the growth of the placenta, which is the organ that interfaces between the mother and her fetus. Mice were housed in an hypoxic environment for the whole of gestation. An atmosphere of 13% oxygen induced fetal growth restriction (1182 ± 9 mg, n = 90 vs. 1044 ± 11 mg, n = 62, P < 0.05) but enhanced placental weight (907 ± 11 mg, n = 90 vs. 998 ± 15 mg, n = 62,P < 0.05). Stereological analyses revealed an increase in the volume of maternal blood spaces in the placenta, consistent with increased flow. At the molecular level, we observed activation of the protein kinase B (Akt)‐mechanistic target of rapamycin growth and proliferation pathway. Chronic hypoxia also triggered mild endoplasmic reticulum stress, a conserved homeostatic response that mediates translational arrest through phosphorylation of eukaryotic initiation factor 2 subunit α. Surprisingly, although subunits of the mitochondrial electron transport chain complexes were reduced at the protein level, there was no evidence of intracellular energy depletion. Finally, we demonstrated sex‐specific placental responses to chronic hypoxia. Placentas from male fetuses were heavier (1082 ± 2 mg, n = 30 vs. 928 ± 2 mg, n = 34, P < 0.05) and less susceptible to hypoxia‐induced oxidative stress than those from females. Their capacity to adapt may explain why male fetuses were significantly less growth restricted at embryonic day 18.5 than their female counterparts. These findings are consistent with the concept that male fetuses are more aggressive with respect to their nutrient demands, which may place them at greater risk of adverse outcomes under limiting conditions.
Exposure of pregnant mice to chronic hypoxia at 13% O2 induces fetal growth restriction but increases placental weight. Sex dimorphism induces differential responses in placental weight to hypoxia. The male placenta is heavier than the female and is associated with less severe fetal growth restriction. Increases in maternal arterial/venous blood spaces and higher protein kinase B (Akt)‐mechanistic target of rapamycin growth signalling could contribute to the heavier hypoxic placenta. Placental endoplasmic reticulum stress is elevated equally in both sexes in response to hypoxia. In comparison, oxidative stress is only apparent in female placentas. Chronic hypoxia induces down‐regulation of placental mitochondrial electron transport chain complexes protein subunits but does not cause intracellular energy depletion.
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Affiliation(s)
- Hannah Matheson
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Jan H W Veerbeek
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.,Birth Center and the Division of Woman and Baby, University Medical Center Utrecht, Utrecht, The Netherlands
| | - D Stephen Charnock-Jones
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.,Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, UK.,National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK
| | - Graham J Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Hong Wa Yung
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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44
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Tung WF, Chen WJ, Hung HC, Liu GY, Tung JN, Huang CC, Lin CL. 4-Phenylbutyric Acid (4-PBA) and Lithium Cooperatively Attenuate Cell Death during Oxygen-Glucose Deprivation (OGD) and Reoxygenation. Cell Mol Neurobiol 2015; 35:849-59. [PMID: 25776137 PMCID: PMC11486266 DOI: 10.1007/s10571-015-0179-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 03/11/2015] [Indexed: 11/24/2022]
Abstract
Hypoxia is an important cause of brain injury in ischemic stroke. It is known that endoplasmic reticulum (ER) stress is an important determinant of cell survival or death during hypoxia. However, the signaling pathways and molecular mechanisms involved remain to be studied in more detail. To investigate whether inhibition of ER stress promotes neuroprotection pathways, we applied an in vitro oxygen-glucose deprivation (OGD) followed by reoxygenation model of human SK-N-MC neuronal cell cultures in this study. Our results showed that neuronal cell death was induced in this model during the OGD reoxygenation by the sustained ER stress, but not during OGD phase. However, treatment of the cultures with lithium with the OGD reoxygenation insult did not result in neuroprotection, whereas concomitant treatment of chemical chaperon 4-phenylbutyric acid (4-PBA) provides protective effects in ER stress-exposed cells. Moreover, 4-PBA rescued ER stress-suppressed Akt protein biosynthesis, which works cooperatively with lithium in the activation of Akt downstream signaling by inhibition of autophagy-induced cell death. Taken together, our finding provides a possible mechanism by which 4-PBA and lithium contribute to mediate neuroprotection cooperatively. This result may potentially be a useful therapeutic strategy for ischemic stroke.
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Affiliation(s)
- Wai-Fai Tung
- Section of Neurology, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Wei-Jen Chen
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Hui-Chih Hung
- Department of Life Sciences and Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
| | - Guang-Yaw Liu
- Institute of Microbiology & Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Jai-Nien Tung
- Section of Neurosurgery, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Chien-Chih Huang
- Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, Taiwan
| | - Chih-Li Lin
- Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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45
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Comparison between single and combined post-treatment with S-Methyl-N,N-diethylthiolcarbamate sulfoxide and taurine following transient focal cerebral ischemia in rat brain. Neuroscience 2015; 300:460-73. [DOI: 10.1016/j.neuroscience.2015.05.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 05/15/2015] [Accepted: 05/18/2015] [Indexed: 01/22/2023]
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Burton GJ, Yung HW. Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. Pregnancy Hypertens 2015; 1:72-8. [PMID: 22242213 PMCID: PMC3252240 DOI: 10.1016/j.preghy.2010.12.002] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent data have provided molecular evidence of high levels of endoplasmic reticulum stress in non-laboured placentas from cases of early-onset pre-eclampsia. Endoplasmic reticulum stress is intricately linked to oxidative stress, and the two often share the same aetiology. In the case of pre-eclampsia this is likely to be placental malperfusion, secondary to deficient conversion of the spiral arteries. Endoplasmic reticulum stress activates a number of signalling pathways aimed at restoring homeostasis, but if these attempts fail then the apoptotic machinery may be activated. The potential consequences for placental development and function are numerous and diverse. Inhibition of protein synthesis results in lower levels of many kinases, growth factors and regulatory proteins involved in cell cycle control, and experiments in vitro reveal that endoplasmic reticulum stress slows cell proliferation. Chronic, low levels of stress during the second and third trimesters may therefore result in a growth restricted phenotype. Higher levels of endoplasmic reticulum stress lead to activation of pro-inflammatory pathways, a feature of pre-eclampsia that may contribute to maternal endothelial cell activation. These findings emphasise the complexity of cellular responses to stress, and the need to approach these in a holistic fashion when considering therapeutic interventions.
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Affiliation(s)
- Graham J Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
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47
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Lin X, Peng Z, Su C. Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Int J Mol Sci 2015; 16:10888-906. [PMID: 25984608 PMCID: PMC4463681 DOI: 10.3390/ijms160510888] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 04/10/2015] [Accepted: 04/22/2015] [Indexed: 12/31/2022] Open
Abstract
Costunolide (CE) and dehydrocostuslactone (DE) are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application.
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Affiliation(s)
- Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
| | - Zhangxiao Peng
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
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48
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Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta. PLoS One 2015; 10:e0122295. [PMID: 25811377 PMCID: PMC4374683 DOI: 10.1371/journal.pone.0122295] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/17/2015] [Indexed: 12/16/2022] Open
Abstract
Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation—a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health.
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Hou X, Liu Y, Liu H, Chen X, Liu M, Che H, Guo F, Wang C, Zhang D, Wu J, Chen X, Shen C, Li C, Peng F, Bi Y, Yang Z, Yang G, Ai J, Gao X, Zhao S. PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation. Sci Rep 2015; 5:9065. [PMID: 25761777 PMCID: PMC4356960 DOI: 10.1038/srep09065] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/09/2015] [Indexed: 12/14/2022] Open
Abstract
Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.
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Affiliation(s)
- Xu Hou
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Yaohua Liu
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Huailei Liu
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Xin Chen
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Min Liu
- College of Basic Medicine, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Hui Che
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Fei Guo
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chunlei Wang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Daming Zhang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Jianing Wu
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Xiaofeng Chen
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chen Shen
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chenguang Li
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Fei Peng
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Yunke Bi
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Zhuowen Yang
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Guang Yang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Jing Ai
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Xin Gao
- Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia
| | - Shiguang Zhao
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
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50
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Jiang T, Wang L, Li X, Song J, Wu X, Zhou S. Inositol-requiring enzyme 1-mediated endoplasmic reticulum stress triggers apoptosis and fibrosis formation in liver cirrhosis rat models. Mol Med Rep 2014; 11:2941-6. [PMID: 25434505 DOI: 10.3892/mmr.2014.3020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 09/12/2014] [Indexed: 01/12/2023] Open
Abstract
Long‑term and advanced cirrhosis is usually irreversible and often coincides with variceal hemorrhage or development of hepatocellular carcinoma; therefore, liver cirrhosis is a major cause of morbidity and mortality globally. The aim of the present study was to investigate the specific mechanism behind the formation of fibrosis or cirrhosis using rat models of hepatic fibrosis. The cirrhosis model was established by intraperitoneally administering dimethylnitrosamine to the rats. Hematoxylin and eosin staining was performed on the hepatic tissues of the rats to observe the fibrosis or cirrhosis, and western blot analysis was employed to detect α‑smooth muscle actin and desmin protein expression. Flow cytometric analysis was used to examine early and late apoptosis, and the protein and mRNA expression of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) pathway proteins and apoptotic proteins [C/EBP homologous protein (CHOP) and caspase‑12] was detected by western blotting and the reverse-transcription polymerase chain reaction, respectively. The results indicated that the cirrhosis model was established successfully and that fibrosis was significantly increased in the cirrhosis model group compared with that in the normal control group. Flow cytometric analysis showed that early and late apoptosis in the cirrhosis model was significantly higher compared with that in the control group. The expression of the UPR pathway protein inositol-requiring enzyme (IRE) 1, as well as the expression of CHOP, was increased significantly in the cirrhotic rat tissues compared with that in the control group tissues (P<0.05). In conclusion, apoptosis was clearly observed in the hepatic tissue of cirrhotic rats, and the apoptosis was caused by activation of the ER stress-mediated IRE1 and CHOP.
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Affiliation(s)
- Tianpeng Jiang
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Lizhou Wang
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Xing Li
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Jie Song
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Xiaoping Wu
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Shi Zhou
- Department of Radiology, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
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