Insulin-Like Growth Factor I Prevents Cellular Aging via Activation of Mitophagy

Mitochondrial dysfunction is a hallmark of cellular aging. Mitophagy is a critical mitochondrial quality control mechanism that removes dysfunctional mitochondria and contributes to cell survival. Insulin-like growth factor 1 (IGF-1) promotes survival of smooth muscle cells (SMCs), but its potential effect on cellular aging is unknown yet. We found that IGF-1 decreased cell senescence, prevented DNA telomere shortening, increased mitochondrial membrane potential, activated cytochrome C oxidase, and reduced mitochondrial DNA damage in long-term cultured (aged) aortic SMC, suggesting an antiaging effect. IGF-1 increased mitophagy in aged cells, and this was associated with decreased expression of cyclin-dependent kinase inhibitors p16 and p21 and elevated levels of Nrf2 and Sirt3, regulators of mitophagy and mitochondrial biogenesis. SiRNA-induced inhibition of either Nrf2 or Sirt3 blocked IGF-1-induced upregulation of mitophagy, suggesting that the Nrf2/Sirt3 pathway was required for IGF-1’s effect on mitophagy. PINK1 is a master regulator of mitophagy. PINK1 silencing suppressed mitophagy and inhibited IGF-1-induced antiaging effects in aged SMC, consistent with an essential role of mitophagy in IGF-1’s effect on cellular aging. Thus, IGF-1 inhibited cellular aging via Nrf2/Sirt3-dependent activation of mitophagy. Our data suggest that activation of IGF-1 signaling is a novel potential strategy to activate mitophagy and slow cellular aging

Polymorphism -433 C>T of the Osteopontin Gene is Associated with the Susceptibility to Develop Gliomas and their Prognosis in a Chinese Cohort

Aim: To investigate role of the Osteopontin (OPN) genetic polymorphisms in the susceptibility to gliomas and their prognosis. Methods: A total of 248 Chinese glioma patients and 281 age and sex matched healthy controls were recruited. The genetic polymorphisms at three loci, namely, -156 GG>G, -443 C>T and -66T>G, were determined. The log-rank test and Kaplan- Meier analysis were introduced to assess the effect of OPN gene polymorphisms on patient survival. Results: We found that the genotype frequencies of OPN -443 C>T polymorphism were significantly different between glioma patients and controls. Multivariable analyses showed a higher risk for gliomas in -443 CC genotype carriers compared to -443TT carriers (PT polymorphism was closely related to the gliomas' tumor grade. The -443 C>T polymorphism also affected the tumor OPN expression level, but not the serum OPN level. More importantly, the -443 C>T polymorphism was significantly associated with the prognosis of these patients regardless of their treatment status. The patients with -443CC genotype had a poorer prognosis than those with -443TT and -443CT genotypes. In contrast, the -156 G>GG and -66T>G polymorphisms were not associated with risk, clinical characteristics, or prognosis of gliomas. Conclusion: This study suggests that the -443C>T gene polymorphisms may be used as a molecular marker for glioma occurrence and clinical outcome in glioma patients. © 2014 S. Karger AG, Base

Polymorphisms of Receptor for Advanced Glycation end Products and Risk of Epithelial Ovarian Cancer in Chinese Patients

Background: Given the roles of receptor for advanced glycation end products (RAGE) in the pathogenesis of carcinogenesis, we propose that RAGE polymorphisms may be associated with risk of epithelial ovarian carcinoma (EOC). Method: This case-control study included 190 women over 40 years of age who were diagnosed with primary EOC and 210 healthy control subjects. RAGE gene polymorphisms, including 82G>S,-374T>A,-429C>T,and 1704G>T were determined. Results: We found that only the frequencies of the 82G>S polymorphisms were significantly different between the EOC cases and controls. The 82SS genotype was significantly higher in EOC patients than in controls (37.89% vs. 23.33%,PT,-374T>A and -429C>T did not affect the EOC risk. Conclusion: This result suggests that the 82G>S polymorphism of RAGE gene may be associated with the susceptibility of EOC

Microstructure and compressive behavior of lamellar Al2O3p/Al composite prepared by freeze-drying and mechanical-pressure infiltration method

Infiltrated molten Al matrix by mechanical-pressure infiltration method into the ceramic scaffold prepared by freeze-drying technology could prepare dense lamellar Al matrix composites without damage of the biomimetic microstructure of the scaffold. However, the investigation of lamellar Al matrix composites prepared by freeze-drying and mechanical-pressure infiltration method has not been fully understood yet. In the present work, the Al2O3 scaffold with pearl layer structure was prepared by freezing-dry method, and eventually the lamellar Al2O3p/Al composite was fabricated by mechanical-pressure infiltration method. The Al matrix was infiltrated well into the large pores of the Al2O3 scaffold, and the lamellar structure of the Al2O3 was well preserved. The hardness of the lamellar Al2O3p/Al composite was isotropic in transvers and perpendicular directions. However, the compressive strengths of the lamellar Al2O3p/Al composite were significant anisotropic while the compressive strength in transvers direction was 127.7% higher than that in the perpendicular direction, indicating the integrality of the lamellae microstructure (especially the bridging layers). Due to the mismatched deformability, weak debonding was observed between Al and Al2O3p/Al layers in the fracture surface of the lamellar Al2O3p/Al composite. It indicates that the interfacial bonding between Al and Al2O3p/Al layers is rather strong, which is beneficial for higher strength in transvers direction but lead to lower strength in perpendicular direction

Role of Osteoprotegerin and Its Gene Polymorphisms in the Occurrence of Left Ventricular Hypertrophy in Essential Hypertensive Patients

Overall view from N. Grand Avenue, looking southwest; Dorothy Chandler Pavilion at left; A 739-seat thrust stage at the Los Angeles Music Center designed by Welton Becket and Associates. The smallest of the three venues, the Taper is flanked by the Dorothy Chandler Pavilion and the Ahmanson Theatre on the Music Center Plaza. Mr. Becket designed the center in the style of New Formalism, which emphasized geometric shapes. The perfectly circular Taper is considered one of his best works, featuring a distinctive decorated drum of a design with its exterior wrapped in a lacy precast relief by Jacques Overhoff. The lobby has a curving, abalone wall by Tony Duquette. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 7/29/2013

Polymorphism of the RAGE Affects the Serum Inflammatory Levels and Risk of Ischemic Stroke in a Chinese Population

Background: Increasing evidence shows that inflammation plays an important role in the occurrence and progression of acute ischemic stroke. The receptor for advanced glycation end products (RAGE) has been documented to involve in the pathogenic mechanisms of a variety of neurological diseases, including ischemic stroke (IS). However, the impact of RAGE gene polymorphisms on the susceptibility to IS has not been reported. We thus explored the association between RAGE gene polymorphisms and the susceptibility to IS. Method: A total of 384 patients with IS and 425 healthy controls were enrolled in this study. Three genetic polymorphisms of RAGE gene (82G/S, -429T/C and -374T/A) were determined. The serum levels of soluble RAGE (sRAGE), intetleukin-6 (IL-6), high sensitivity-C reaction protein (hsCRP) and plasminogen activator inhibitor-1 (PAT-1) were detected. Results: Among the studied polymorphisms, only the polymorphism at 82G/S of RAGE gene was associated with the risk for ischemic stroke irrespective of the stroke subtypes. The 82S/S homozygote carriers had a significantly increased risk for ischemic stroke [adjusted odds ratio (OR): 2.297; p<0.001]. The haplotype analyses showed that the C 429S821- 374 and T 429SuA 374 had higher risk to develop IS (OR=1.864 and 1.931, respectively, all p <0.01), while the C 429G82T 374showed a protective effect against IS susceptibility (OR=0.568, p=0.001). In addition, the 82S/S homozygote carriers had a higher inflammatory level compared with 82G/S and 82G/G genotypes, indicated by lower serum sRAGE level, higher serum IL-6, hs-CRP and PAT-1 levels. The polymorphisms at -374 and -429 loci did not influence the stroke risk and the above mentioned inflammation cytokines. Conclusion: Our results showed a close correlation between the 82G/S polymorphism and the susceptibility to IS, suggesting the 82G/S polymorphism may be used as a genetic marker for the prediction of stroke occurrence in high risk subjects. Copyright (C) 2013 S. Karger AG, Base

Myocardial Injection of Apelin-Overexpressing Bone Marrow Cells Improves Cardiac Repair via Upregulation of Sirt3 after Myocardial Infarction

<div><p>Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. <i>In vitro</i>, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ⁺/c-kit⁺/Sca1⁺ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.</p></div