High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors

<p>Abstract</p> <p>Background</p> <p>High glucose can induce apoptosis in vascular endothelial cells, which may contribute to the development of vascular complications in diabetes. We evaluated the role of the death receptor pathway of apoptotic signaling in high glucose-induced apoptosis in human coronary artery endothelial cells (HCAECs).</p> <p>Methods</p> <p>HCAECs were treated with media containing 5.6, 11.1, and 16.7 mM of glucose for 24 h in the presence or absence of tumor necrosis factor (TNF)-α. For detection of apoptosis, DNA fragmentation assay was used. HCAEC expression of death receptors were analyzed by the PCR and flow cytometry methods. Also, using immunohistochemical techniques, coronary expression of death receptors was assessed in streptozotocin-nicotinamide-induced type 2 diabetic mice.</p> <p>Results</p> <p>Exposure of HCAECs to high glucose resulted in a significant increase in TNF-R1 and Fas expression, compared with normal glucose. High glucose increased TNF-α production by HCAECs and exogenous TNF-α up-regulated TNF-R1 and Fas expression in HCAECs. High glucose-induced up-regulation of TNF-R1 and Fas expression was undetectable in the presence of TNF-α. Treatment with TNF-R1 neutralizing peptides significantly inhibited high glucose-induced endothelial cell apoptosis. Type 2 diabetic mice displayed appreciable expression of TNF-R1 and Fas in coronary vessels.</p> <p>Conclusions</p> <p>In association with increased TNF-α levels, the death receptors, TNF-R1 and Fas, are up-regulated in HCAECs under high glucose conditions, which could in turn play a role in high glucose-induced endothelial cell apoptosis.</p

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

Selective autophagy contributes to the degradation of condensates, such as sequestosome 1-bodies, also called p62/SQSTM1-bodies. We showed that endogenous p62 forms gel-like structures, which serve as platforms for autophagosome formation and nuclear factor erythroid 2-related factor 2 (NRF2) activation. Further, p62-mediated NRF2 activation is not cytotoxic, but combination of NRF2 activation with impaired bulk and selective autophagy causes liver injury

Three-Axis Model for Atg Recruitment in Autophagy against Salmonella

Salmonella enterica serovar Typhimurium enter epithelial cells and take up residence there. Within epithelial cells, a portion of the bacteria are surrounded by an autophagosome-like double-membrane structure, and they are still residing within the Salmonella-containing vacuole (SCV). In this paper, we will discuss how the autophagy machinery is recruited in proximity to Salmonella. The formation of this double membrane requires Atg9L1 and FIP200; these proteins are important for autophagy-specific recruitment of the PI3-kinase complex. In the absence of Atg9L1, FIP200, and PI3-kinase activity, LC3 is still recruited to the vicinity of Salmonella. We propose a novel model in which the mechanism of LC3 recruitment is separate from the generation of the isolation membrane. There exist at least three axes in Atg recruitment: ULK1 complex, Atg9L1, and Atg16L complex

p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress. Liquid-liquid phase separation of p62/SQSTM1 has been previously described, although the significance in vivo remains unclear. Here the authors show p62 droplets contain ubiquitin, autophagy-related proteins and Keap1 to serve as platform of not only autophagosome formation but also Nrf2 activation.Peer reviewe

Defining the museum of the 21st century: evolving multiculturalism in museums in the United States

This publication brings together a selection of papers presented at the online symposium organized by ICOFOM under the general theme Defining the Museum of the 21st Century, with Southern New Hampshire University in the United States on September 14, 2018.Chung, S.S.C., Leshchenko, A, & Soares, B.B. (Eds.). (2019). Defining the museum of the 21st century: evolving multiculturalism in museums in the United States. Retrieved from http://academicarchive.snhu.ed

p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress

Two-zero Textures of the Majorana Neutrino Mass Matrix and Current Experimental Tests

In view of the latest T2K and MINOS neutrino oscillation data which hint at a relatively large theta_13, we perform a systematic study of the Majorana neutrino mass matrix M_nu with two independent texture zeros. We show that three neutrino masses (m_1, m_2, m_3) and three CP-violating phases (delta, rho, sigma) can fully be determined from two neutrino mass-squared differences (delta m^2, Delta m^2) and three flavor mixing angles (theta_12, theta_23, theta_13). We find that seven patterns of M_nu (i.e., A_{1,2}, B_{1,2,3,4} and C) are compatible with current experimental data at the 3-sigma level, but the parameter space of each pattern is more strictly constrained than before. We demonstrate that the texture zeros of M_nu are stable against the one-loop quantum corrections, and there exists a permutation symmetry between Patterns A_1 and A_2, B_1 and B_2 or B_3 and B_4. Phenomenological implications of M_nu on the neutrinoless double-beta decay and leptonic CP violation are discussed, and a realization of those texture zeros by means of the Z_n flavor symmetries is illustrated.Comment: 41 pages, including 4 tables and 14 figures, more discussions added, to appear in JHE

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

Selective autophagy contributes to the degradation of condensates, such as sequestosome 1-bodies, also called p62/SQSTM1-bodies. We showed that endogenous p62 forms gel-like structures, which serve as platforms for autophagosome formation and nuclear factor erythroid 2-related factor 2 (NRF2) activation. Further, p62-mediated NRF2 activation is not cytotoxic, but combination of NRF2 activation with impaired bulk and selective autophagy causes liver injury