P3485Autophagy insufficiency participates in hyperhomocysteinemia-induced cardiac aging

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
W Wang ◽  
Y Zhou ◽  
J Xu ◽  
S Zhang ◽  
Y Meng
Keyword(s):  
Cardiac Function ◽  
Rat Model ◽  
Natural Aging ◽  
Autophagic Flux ◽  
Cardiac Aging ◽  
Transmission Electron ◽  
Injured Myocardium ◽  
Underlying Mechanisms ◽  
Fdg Pet Ct ◽  
Related Proteins

Abstract Background The elevated plasma homocysteine (Hcy) level can lead to severe cardiovascular injuries, which participates in the progression of atherosclerosis, heart failure and so on. Except cardiovascular diseases, accumulated researches further revealed that hyperhomocystenemia (HHcy) can also induce aging-related diseases, including Alzheimer's disease, Parkinson's disease, diabetic cardiomyopathy, etc. Though some researches had revealed that Hcy stimulation would lead to endothelial cells senescence, whether cardiac aging could be induced by HHcy still remain unknown. Purpose This study aimed to reveal whether HHcy can induce cardiac aging and the underlying mechanisms. Methods SD rats were utilized to establish HHcy rat model and natural aging rat model. The cardiac function were determined by Echocardiography. Transmission electron microscope were used to detect mitochondria injuries of myocardium. 18F-FDG PET/CT was used to detect the state of glucose metabolism in myocardial cells. Agilent mRNA Array was used to detect possible altered pathways in myocardium of HHcy rats. The autophagy level was determined by detection of both autophagy-related proteins expressions with Western Blot and autophagic flux with mRFP-GFP-LC3. Results HHcy rats showed overall aging phenotypes, which were consistent with natural aging rats. The impaired cardiac function and severely injured myocardium morphology were observed in HHcy rats. Aging-related markers were increased significantly in HHcy rats and Hcy-treated cells, presented as increased p16, p21 and p53 expressions and increased senescence-associated beta-galactosidase (SA-β-gal) activity. Mitochondria dysfunction and morphology injuries were also detected in HHcy rats. Moreover, decreased serum Beclin-1 level was tested in CHD patients with HHcy. The decreased autophagy level was further verified in HHcy rats and Hcy-treated cells. Furthermore, the over-expression of Atg5 could attenuate Hcy induced cellular senescence. Conclusion HHcy can reduce autophagy level, which leading to severe mitochondria injuries, and resulted in cardiac aging eventually. Acknowledgement/Funding Natural Science Foundation of China (81671382,91839107)

scholarly journals Inhibition of Cathepsin S Induces Mitochondrial Apoptosis in Glioblastoma Cell Lines Through Mitochondrial Stress and Autophagosome Accumulation

2020 ◽  
Vol 10 ◽  
Author(s):  
Maoxing Fei ◽  
Li Zhang ◽  
Handong Wang ◽  
Yihao Zhu ◽  
Wenhao Niu ◽  
...  
Keyword(s):  
Cathepsin S ◽  
Autophagic Flux ◽  
Mitochondrial Apoptosis ◽  
Mitochondrial Stress ◽  
Calcium Uniporter ◽  
Mitochondrial Functions ◽  
Lysosomal Cysteine Protease ◽  
Underlying Mechanisms ◽  
High Level ◽  
Related Proteins

Cathepsin S (CTSS), a lysosomal cysteine protease, is overexpressed in various cancers, including glioblastoma (GB). A high level of CTSS is associated with tumor progression and poor outcome in GB. However, the underlying mechanisms of its role in the biological characteristics of G5B remain to be elucidated. Here, we uncovered a potential role of CTSS in the lysosomes and mitochondria of GB cells (GBCs). Downregulation of CTSS in GBCs could increase the expression of autophagy-related proteins; however, there was no significant change in p62, suggesting autophagy blockade. Moreover, inhibition of CTSS increased the expression of mitochondrial calcium uniporter (MCU) and enhanced mitochondrial Ca2+ uptake ability, causing mitochondrial Ca2+ overload, the generation of copious reactive oxygen species (ROS) and eventual mitochondrial apoptosis. Additionally, elevated damage to mitochondria exacerbated the burden of autophagy. Finally, we found that silence of MCU could alleviate the inhibition of CTSS-induced autophagosome accumulation and mitochondrial stress. Collectively, these results demonstrate that CTSS plays an important role in the process of autophagic flux and mitochondrial functions in GBCs.

scholarly journals Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43266-283 in Glioblastoma Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4262
Author(s):  
Sara G. Pelaz ◽  
Claudia Ollauri-Ibáñez ◽  
Concepción Lillo ◽  
Arantxa Tabernero
Keyword(s):  
Stem Cells ◽  
Autophagic Flux ◽  
Antitumor Effects ◽  
Glioblastoma Stem Cells ◽  
Src Inhibitor ◽  
Transmission Electron ◽  
Nutrient Environment ◽  
Related Proteins ◽  
First Time ◽  
Potential Use

Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43266-283 effect. TAT-Cx43266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43266-283 as a therapy for this type of cancer.

scholarly journals Non-Coding RNAs in Cardiac Aging

2015 ◽  
Vol 36 (5) ◽  
pp. 1679-1687 ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Junjie Xiao ◽  
Xiangqing Kong
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Function ◽  
Cardiac Aging ◽  
Molecular Changes ◽  
General Overview ◽  
Increased Risk ◽  
Wide Range ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
Impaired Cardiac Function

Aging has a remarkable impact on the function of the heart, and is independently associated with increased risk for cardiovascular diseases. Cardiac aging is an intrinsic physiological process that results in impaired cardiac function, along with lots of cellular and molecular changes. Non-coding RNAs include small transcripts, such as microRNAs and a wide range of long non-coding RNAs (lncRNAs). Emerging evidence has revealed that non-coding RNAs acted as powerful and dynamic modifiers of cardiac aging. This review aims to provide a general overview of non-coding RNAs implicated in cardiac aging, and the underlying mechanisms involved in maintaining homeo-stasis and retarding aging.

scholarly journals Dislocation-mediated shear amorphization in boron carbide

2021 ◽  
Vol 7 (8) ◽  
pp. eabc6714 ◽  
Author(s):  
Kolan Madhav Reddy ◽  
Dezhou Guo ◽  
Shuangxi Song ◽  
Chun Cheng ◽  
Jiuhui Han ◽  
...  
Keyword(s):  
Boron Carbide ◽  
Structural Transition ◽  
Activation Volume ◽  
Structural Evolution ◽  
Dislocation Nucleation ◽  
Superhard Materials ◽  
Rate Dependent ◽  
Transmission Electron ◽  
Lower Activation ◽  
Underlying Mechanisms

The failure of superhard materials is often associated with stress-induced amorphization. However, the underlying mechanisms of the structural evolution remain largely unknown. Here, we report the experimental measurements of the onset of shear amorphization in single-crystal boron carbide by nanoindentation and transmission electron microscopy. We verified that rate-dependent loading discontinuity, i.e., pop-in, in nanoindentation load-displacement curves results from the formation of nanosized amorphous bands via shear amorphization. Stochastic analysis of the pop-in events reveals an exceptionally small activation volume, slow nucleation rate, and lower activation energy of the shear amorphization, suggesting that the high-pressure structural transition is activated and initiated by dislocation nucleation. This dislocation-mediated amorphization has important implications in understanding the failure mechanisms of superhard materials at stresses far below their theoretical strengths.

scholarly journals Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms

2015 ◽  
Vol 764 ◽  
pp. 195-201 ◽  
Author(s):  
Saeed Ghofrani ◽  
Mohammad-Taghi Joghataei ◽  
Simin Mohseni ◽  
Tourandokht Baluchnejadmojarad ◽  
Maryam Bagheri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Rat Model ◽  
Underlying Mechanisms

LncRNA Prostate Cancer Gene Expression Marker 1 (PCGEM1) Down-Regulation Inhibits the Development of Osteoarthritis by Modulating miR-152-3p

2022 ◽  
Vol 12 (2) ◽  
pp. 306-315
Author(s):  
Jie Song ◽  
Cheng Chen ◽  
Hui Zhang
Keyword(s):  
Cell Model ◽  
Luciferase Reporter ◽  
Down Regulation ◽  
Protein Levels ◽  
Diphenyltetrazolium Bromide ◽  
Proliferation And Apoptosis ◽  
Underlying Mechanisms ◽  
Commercial Kits ◽  
Related Proteins

Osteoarthritis (OA) is a chronic and inflammatory disease, leading to pain or even disability in severe cases. LncRNA PCGEM1 (PCGEM1) is reported to be dysregulated, serving as critical regulators in various human diseases, including OA. However, the biological role of PCGEM1 and its underlying mechanisms during OA remained unclear. In the present study, CHON-001 cells were exposed to interleukin (IL)-1β to construct the OA cell model. Expression of PCGEM1 and miR-152-3p in cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Corresponding commercial kits were used to measure the expressions of lactate dehydrogenase (LDH), inter-leukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α. Protein levels of apoptosis-related proteins, cleaved-Caspase3 and Caspase3, were detected by Western blotting. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) tetrazolium (MTT) and flow cytometry assays were utilized for the determination of cell proliferation and apoptosis. The association between PCGEN1 and miR-152-3p was confirmed by a dual-luciferase reporter assay. From the results, PCGEM1 expression was significantly increased while miR-152-3p was inhibited in CHON-001 cells after IL-1β treatment. In addition, silencing of PCGEM1 could promote proliferation, inhibit the apoptosis, suppress LDH level and alleviate inflammation response caused by IL-1β in CHON-001 cells by sponging miR-152-3p. In a word, PCGEM1 down-regulation suppressed OA progression by the regulation of miR-152-3p expression, functioning as a potential therapeutic target for OA clinical treatment.

Abstract 123: SUMO1 Modification Regulates SR Calcium ATPase Pump, SERCA2a in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Ahyoung Lee ◽  
Dongtak Jeong ◽  
Jae Gyun Oh ◽  
Antoine Chaanine ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Calcium Atpase ◽  
Post Translational Modifications ◽  
Beneficial Effects ◽  
Protein Levels ◽  
In Trans ◽  
Underlying Mechanisms ◽  
Hemodynamic Performance ◽  
Reduced Activity

Background: The cardiac calcium ATPase, SERCA2a, is a critical pump responsible for Ca2+ re-uptake during excitation-contraction coupling. Impaired Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. However, the underlying mechanisms of SERCA2a’s dysfunction remain incompletely understood. Methods and Results: In this study, we show that SERCA2a is modified by SUMO1 at lysine sites 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. SUMO1 and SERCA2a SUMOylation levels were both decreased in mouse and pig models of heart failure and failing human left ventricles. To determine whether reduced SUMO1 levels are responsible for reduced SERCA2a protein levels and reduced cardiac function, we used an adenovirus associated virus-mediated gene delivery approach to up-regulate SUMO1 in trans aortic constriction-induced mouse model of heart failure. We found that increasing SUMO1 levels led to a restoration of SERCA2a levels, improved hemodynamic performance, and reduced mouse mortality. By contrast, down-regulation of SUMO1 using small hairpin RNA accelerated cardiac functional deterioration and was accompanied by decreased SERCA2a function. Conclusion: In this study, we study a new mechanism for modulation of SERCA2a activity and beneficial effects of SUMO1 in the setting of heart failure. It suggests that changes in post-translational modifications of SERCA2a could negatively affect cardiac function in heart failure. Our data may provide a new platform for the design of therapeutic strategies for heart failure.

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