scholarly journals Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction via Inhibition of the Hyperandrogen-Induced IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in PCOS-Like Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yaling Zhang ◽  
Yajing Weng ◽  
Daojuan Wang ◽  
Rong Wang ◽  
Lihui Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Aerobic Exercise ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Oral Intake ◽  
Follicle Development ◽  
Sprague Dawley

Combining diet with exercise can improve health and performance. Exercise can reduce androgen excess and insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients. Curcumin is also presumed to improve the follicle development disorder. Here, we investigated the effects of a combination therapy of oral intake of curcumin and exercise on hyperandrogen-induced endoplasmic reticulum (ER) stress and ovarian granulosa cell (GC) apoptosis in rats with PCOS. We generated a PCOS model via continuous dehydroepiandrosterone subcutaneous injection into the necks of Sprague Dawley rats for 35 days. PCOS-like rats then received curcumin treatment combined with aerobic (treadmill) exercise for 8 weeks. We found that compared to control rats, the ovarian tissue and ovarian GCs of hyperandrogen-induced PCOS rats showed increased levels of ER stress-related genes and proteins. Hyperandrogen-induced ovarian GC apoptosis, which was mediated by excessive ER stress and unfolded protein response (UPR) activation, could cause follicle development disorders. Both curcumin gavage and aerobic exercise improved ovarian function via inhibiting the hyperandrogen-activated ER stress IRE1α-XBP1 pathway. Dihydrotestosterone- (DHT-) induced ER stress was mitigated by curcumin/irisin or 4μ8C (an ER stress inhibitor) in primary GC culture. In this in vitro model, the strongly expressed follicular development-related genes Ar, Cyp11α1, and Cyp19α1 were also downregulated.

scholarly journals Interactions between Endoplasmic Reticulum Stress and Autophagy: Implications for Apoptosis and Neuroplasticity-Related Proteins in Palmitic Acid-Treated Prefrontal Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiangli Xue ◽  
Feng Li ◽  
Ming Cai ◽  
Jingyun Hu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Sprague Dawley ◽  
Related Proteins ◽  
Phenylbutyric Acid

Lipotoxicity of palmitic acid (PA) or high-fat diets has been reported to increase endoplasmic reticulum (ER) stress and autophagy in peripheral tissue as well as apoptotic cell death. It also can lead to an AD-like pathological pattern. However, it has been unknown that PA-induced ER stress and autophagy are involved in the regulation of neuroplastic abnormalities. Here, we investigated the roles of ER stress and autophagy in apoptosis and neuroplasticity-related protein expression in PA-treated prefrontal cells. Prefrontal cells dissected from newborn Sprague-Dawley rats were treated with PA compound with ER stress inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA) or PA alone. PA promoted ER stress and autophagy and also cause apoptosis as well as a decline in the expression of neuroplasticity-related proteins. Inhibition of ER stress decreased the expressions of neuroplasticity-related proteins and reduced autophagy activation and apoptosis in PA-treated prefrontal cells. Inhibition of autophagy exacerbated apoptosis and enhanced ER stress in PA-treated prefrontal cells. The present study illustrated that both ER stress and autophagy could be involved in apoptosis and decreased neuroplasticity-related proteins, and the interaction between ER stress and autophagy may play a critical role in apoptosis in PA-treated prefrontal cells. Our results provide new insights into the molecular mechanisms in vitro of lipotoxicity in obesity-related cognitive dysfunction.

Nogo-A mediated endoplasmic reticulum stress during myocardial ischemic-reperfusion injury in diabetic rats

2021 ◽  
Author(s):  
yonghong xiong ◽  
yan leng ◽  
wei li ◽  
wenyuan li ◽  
rong chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Diabetic Rats ◽  
Myocardial Infarct Size ◽  
Sprague Dawley

Abstract Background: Diabetic myocardial ischemia reperfusion (MI/R) injury is aggravated after myocardial infarction, which leads to myocardial damage. Molecular mechanisms associated with the diabetic ischemia-related cardiac diseases are not yet fully understood. Nogo-A is an endoplasmic reticulum (ER) protein ubiquitously expressed in tissues including in the heart. However, the mechanisms that account for the Nogo-A in MI/R injury remain unknown. Methods: SD (Sprague Dawley) rats were subjected to 45 min of ischemia, followed by 3 h reperfusion. Rats were injection with streptozotocin (60mg/kg), tauroursodeoxycholic acid injection (100mg/kg) or corresponding controls just prior to MI/R. Blood and heart samples were collected at 3 h post-reperfusion. Serum LDH and CK-MB, myocardial infarct size, histopathologic changes, apotosis and ER stress were analyzed to evaluate MI/R injury. Signaling pathways were also investigated in vitro using embryonic rat cardiomyocyte-derived H9c2 cells cultures to identify underlying mechanisms for Nogo-A in diabetic MI/R injury. Results: TUDCA treatment significantly reduced Nogo-A, GRP78 and CHOP levels, diminished myocardial infarct areas, attenuated ER stress and decreased myocardial apoptosis after MI/R. ER stress signaling was significantly decreased in the TUDCA-treated MI/R group compared with controls. The effect of Nogo-A was abrogated by pretreatment with knockdown CHOP. A positive feedback loop between Nogo-A and CHOP was found leading to an enhanced ER stress in diabetic MI/R injure. Conclusions: Our data suggest that Nogo-A mediated ER stress plays a major role in diabetic MI/R injury and Nogo-A might be a key regulator of ER stress.

scholarly journals GnRHa protects the ovarian reserve by reducing endoplasmic reticulum stress during cyclophosphamide-based chemotherapy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaolin Li ◽  
Sixuan Liu ◽  
Xuan Chen ◽  
Run Huang ◽  
Lisi Ma ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Mtor Signaling ◽  
Unfolded Protein ◽  
Hormone Analogs

AbstractChemotherapy-induced ovarian dysfunction is a serious adverse effect in premenopausal patients with cancer. Gonadotrophin-releasing hormone analogs (GnRHa) protect ovarian function, but its molecular mechanisms have not yet been determined. In this study, we attempted to determine the previously unknown molecular mechanism by which such protection occurs. Serum anti-Müllerian hormone (AMH) levels were tested in tumor-bearing nude mice, a series of exploratory experiments were conducted. We discovered that GnRHa protects granulosa cells from chemotherapeutic toxicity in vivo and in vitro. We also showed that CTX-induced endoplasmic reticulum stress inhibits the secretion of AMH, and treatment with GnRHa relieves ER stress and the subsequent unfolded-protein response by modulating mTOR signaling to induce autophagy. The results of mechanistic studies indicated that GnRHa-modulated mTOR signaling to induce autophagy, which alleviated CTX-induced ER stress and promoted the secretion of AMH.

scholarly journals Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Yi-wei Wang ◽  
Qin Zhou ◽  
Xiang Zhang ◽  
Qing-qing Qian ◽  
Jia-wen Xu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Neuronal Loss ◽  
Sprague Dawley ◽  
Neuronal Function ◽  
Microglial Polarization ◽  
Therapeutic Value

Abstract Background Neuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson’s disease. Here, we investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia. Methods Male Sprague–Dawley (SD) rats received the intracerebroventricular injection of the ER stress activator tunicamycin (TM) with or without intraperitoneal injection of the ER stress stabilizer sodium 4-phenylbutyrate (4-PBA) 1 h before LPS administration. The levels of neuroinflammation and memory dysfunction were assessed 24 h after treatment. In addition, the effect of mild ER stress on microglia was determined in vitro. Results Here, we found that low doses of TM led to mild ER stress without cell or organism lethality. We showed that mild ER stress preconditioning reduced microglia activation and neuronal death as well as improved LPS-induced memory impairment in rats. In addition, pre-exposure to nonlethal doses of TM in microglia showed significant protection against LPS-induced proinflammatory cytokine production and M1/2b polarization. However, sodium 4-PBA, a compound that ameliorates ER stress, ablated this protective effect in vivo and in vitro. Conclusions Based on our findings, we conclude that the mild ER stress not only limits the accumulation of misfolded proteins but also protects tissues from harmful endotoxemia insults. Therefore, ER stress preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.

scholarly journals Role of angiotensin in ovarian follicular development and ovulation in mammals: a review of recent advances

Reproduction ◽  
2012 ◽  
Vol 143 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Paulo Bayard Gonçalves ◽  
Rogério Ferreira ◽  
Bernardo Gasperin ◽  
João Francisco Oliveira
Keyword(s):  
Vascular Function ◽  
Ovarian Function ◽  
Ovarian Tissue ◽  
Follicle Development ◽  
Ang Ii ◽  
Paracrine Factor ◽  
Vascular Control

Angiotensin (Ang) II is widely known for its role in the control of systemic blood vessels. Moreover, Ang II acts on the vascular control of ovarian function, corpus luteum formation, and luteolysis. Over the past 10 years, our research group has been studying the new concept of the renin–angiotensin system (RAS) as an autocrine/paracrine factor regulating steroidogenesis and promoting different cellular responses in the ovary, beyond vascular function. We have developed and used differentin vivoandin vitroexperimental models to study the role of RAS in the ovary and a brief overview of our findings is presented here. It is widely accepted that there are marked species differences in RAS function in follicle development. Examples of species-specific functions of the RAS in the ovary include the involvement of Ang II in the regulation of follicle atresia in rats vs the requirement of this peptide for the dominant follicle development and ovulation in rabbits and cattle. More recently, Ang-(1–7), its receptor, and enzymes for its synthesis (ACE2, NEP, and PEP) were identified in bovine follicles, implying that Ang-(1–7) has an ovarian function. Other novel RAS components (e.g. (pro)renin receptor and renin-binding protein) recently identified in the bovine ovary show that ovarian RAS is poorly understood and more complex than previously thought. In the present review, we have highlighted the progress toward understanding the paracrine and autocrine control of ovarian antral follicle development and ovulation by ovarian tissue RAS, focusing onin vivostudies using cattle as a model.

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

scholarly journals Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury

2017 ◽  
Vol 312 (5) ◽  
pp. L586-L598 ◽  
Author(s):  
Ru-Jeng Teng ◽  
Xigang Jing ◽  
Teresa Michalkiewicz ◽  
Adeleye J. Afolayan ◽  
Tzong-Jin Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Saline Control ◽  
Sprague Dawley ◽  
Chemical Chaperone ◽  
Stress Markers ◽  
Rat Pups ◽  
Caffeine Treatment ◽  
Downstream Effectors

Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress.

Impacts of Metformin on Local Ovarian Cell Tissue of Rats with Polycystic Ovary Syndrome and Intestinal Flora Under Aerobic Exercise

2021 ◽  
Vol 11 (12) ◽  
pp. 2381-2388
Author(s):  
Xiao Yan
Keyword(s):  
Growth Factor ◽  
Polycystic Ovary Syndrome ◽  
Aerobic Exercise ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Ovary Syndrome ◽  
Ovarian Cell ◽  
Expression Levels ◽  
Cell Tissue ◽  
Igf I

In order to explore the possible treatment mechanism of metformin on the local ovarian cell tissue of rats with polycystic ovary syndrome (PCOS), 35 female clean sterile rats were selected as the research objects in this study, and randomly divided a PCOS model group (PCOS MG) (25 rats) and a control group (CG) (10 rats). After the modelling was completed, 5 rats were randomly selected to evaluate the modelling effect. When the success rate was higher than 80%, the remaining model rats were divided into two groups randomly, namely the (PCOS MG) (10 rats) and the treatment group (TG) (10 rats). Hematoxylin-eosin (HE) staining was performed on ovarian tissue of the rat, and the ovarian tissue structure was observed under light microscope. Immunohistochemistry was used to detect the distribution and expression levels of tumour necrosis factor-α (TNF-α), insulin-like growth factor-I (IGF-I), and connective tissue growth factor (CTGF) on the ovaries of rats in each group. It was found by observing the vaginal smear under the microscope that the rats in the (PCOS MG) had lost the regular estrous cycle, suggesting that there was no ovulation. The expression levels of TNF-α and CTGF in rats in the (PCOS MG) were greatly higher than those in the CG (P < 0.05); compared with the (PCOS MG), the expression levels of TNF-α and CTGF in the TG were decreased observably (P < 0.05). IGF-I was mainly expressed in granulosa cells (GCs) and follicular membrane cells (FMCs) of the ovarian tissue. The expression level of IGF-I in ovarian GCs in rats in the (PCOS MG) was significantly higher than that in the CG (P < 0.05). The expression level of IGF-I in GCs in the TG was lower significantly than that in the (PCOS MG) (P < 0.05). By comparing with rats in the CG, the rats in the (PCOS MG) had obviously decreased Actinobacteria and Betaproteobacteria in the intestinal tract, and the proportion of Firmicutes in the intestine was significantly increased; the amount of butyric acid in the faeces of rats with aerobic exercise was obviously higher than that in the (PCOS MG), because exercise increased the proportion of intestinal butyric acid-producing bacteria. Conclusion: metformin combined with aerobic exercise can treat the PCOS by regulating serum hormone levels and the expression levels of TNF-α, IGF-I, and CTGF.

Abstract 269: 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) Decreases Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) and Attenuates Endoplasmic Reticulum Stress in Rat Placental Villi Explants

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Christopher T Banek ◽  
Haley E Gillham ◽  
Sarah M Johnson ◽  
Hans C Dreyer ◽  
Jeffrey S Gilbert
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
De Novo ◽  
Vegf Receptor ◽  
Sprague Dawley ◽  
Hypoxic Conditions ◽  
Ampk Phosphorylation ◽  
Angiogenic Balance ◽  
Placental Villi ◽  
Placental Ischemia

Preeclampsia, defined by the onset of de novo hypertension and proteinuria near the 20th week of gestation, is a major contributor to maternal and fetal morbidity and mortality worldwide. Preeclampsia is often preceded by placental ischemia and an imbalance in circulating angiogenic factors (e.g. VEGF - vascular endothelial growth factor, sFlt-1 - soluble VEGF receptor 1). Recent studies also report increased expression of endoplasmic reticulum (ER) stress products in preeclamptic placentas. Our laboratory recently reported 5-aminoimidazole-4-carboxamide-3-ribonuceloside (AICAR) reduces blood pressure and improves angiogenic balance (increased VEGF, decreased sFlt-1) in rats with placental ischemia-induced hypertension, but the mechanism is unclear. We hypothesized AICAR would decrease sFlt-1, increase AMPK phosphorylation, and decrease ER stress in hypoxic placental villous explants. On day 19 of pregnancy, placentas were isolated from four Sprague-Dawley rats and immediately dissected in ice-cold phosphate-buffered saline. Explants were cultured for 12 hours in physiologic normoxic (8% O2) and hypoxic (1.5% O2) conditions. All experiments were performed in triplicate. VEGF secretion was unaffected by AICAR treatment in both normoxic and hypoxic conditions. AICAR decreased sFlt -1 secretion in hypoxic villi (2147±116 vs. *1411±67, P<0.05). Additionally, AMPK activation ratio was increased with AICAR, and was hypoxic-dependent (8%: 2.9±0.3; 8%+A: 3.3±0.1; 1.5%: 3.5±0.1; 1.5%+A: *4.5±0.01;*P<.05). Moreover, markers of ER stress were increased with hypoxia, and decreased with AICAR treatment (BiP 8%: 1.2±0.2; 8%+A: 1.0±0.0; 1.5%: *8.3±0.7; 1.5%+A: 1.9±0.0.3;*P<.05), (CHOP 8%: 0.5±0.0; 8%+A: 0.3±0.1; 1.5%: *1.7±0.1; 1.5%+A: 0.7±0.1;*P<.05). ATF4 was not changed with hypoxia or AICAR treatment. The present data show that AICAR stimulates AMPK phosphorylation and decreases ER stress response proteins in hypoxic placental villi. Further, the present data support the hypothesis that AICAR restores angiogenic balance by decreasing sFlt-1 rather than increasing VEGF secretion from placental villi. These findings suggest AICAR may improve placental function during pregnancies complicated by placental-ischemia.

scholarly journals Biochanin A Alleviates Cerebral Ischemia/Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress-Induced Apoptosis and p38MAPK Signaling Pathway In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Min-min Guo ◽  
Sheng-biao Qu ◽  
Hui-ling Lu ◽  
Wen-bo Wang ◽  
Mu-Liang He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Biochanin A ◽  
Neurological Deficits ◽  
Mapk Phosphorylation ◽  
Cerebral Ischemia Reperfusion

We have previously shown that biochanin A exhibits neuroprotective properties in the context of cerebral ischemia/reperfusion (I/R) injury. The mechanistic basis for such properties, however, remains poorly understood. This study was therefore designed to explore the manner whereby biochanin A controls endoplasmic reticulum (ER) stress, apoptosis, and inflammation within fetal rat primary cortical neurons in response to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury. For the OGD/R in vitro model system, cells were evaluated after a 2 h OGD following a 24 h reoxygenation period, whereas in vivo neurological deficits were evaluated following 2 h of ischemia and 24 h of reperfusion. The expression of proteins associated with apoptosis, ER stress (ERS), and p38 MAPK phosphorylation was evaluated in these samples. Rats treated with biochanin A exhibited reduced neurological deficits relative to control rats following MCAO/R injury. Additionally, GRP78 and CHOP levels rose following I/R modeling both in vitro and in vivo, whereas biochanin A treatment was associated with reductions in CHOP levels but further increases in GRP78 levels. In addition, OGD/R or MCAO/R were associated with markedly enhanced p38 MAPK phosphorylation that was alleviated by biochanin A treatment. Similarly, OGD/R or MCAO/R injury resulted in increases in caspase-3, caspase-12, and Bax levels as well as decreases in Bcl-2 levels, whereas biochanin A treatment was sufficient to reverse these phenotypes. Together, these findings thus demonstrate that biochanin A can alleviate cerebral I/R-induced damage at least in part via suppressing apoptosis, ER stress, and p38 MAPK signaling, thereby serving as a potent neuroprotective agent.

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