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• Research Paper Volume 13, Issue 17 pp 21547-21570

  HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

  Relevance score: 12.145832

  Dan-Dan Chen, Xuyan Peng, Yuxuan Wang, Mingjun Jiang, Mengjiao Xue, Guohui Shang, Xuhui Liu, Xiaolin Jia, Baixue Liu, Yingwei Lu, Hongmei Mu, Fengyan Zhang, Yanzhong Hu

  Keywords: HSP90, senotheray, NF-kb, HIF1α, β-galactosidase

  Published in Aging on September 8, 2021

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  The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro. Using H₂O₂-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5–5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro. In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal’s protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.

• Research Paper Volume 6, Issue 8 pp 661-674

  Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

  Relevance score: 10.567659

  Roman A. Zinovkin, Valeria P. Romaschenko, Ivan I. Galkin, Vlada V. Zakharova, Olga Yu. Pletjushkina, Boris V. Chernyak, Ekaterina N. Popova

  Keywords: mitochondrial reactive oxygen species, endothelium, TNF, NF-kB, cell adhesion molecules

  Published in Aging on August 13, 2014

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  Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium.

  

  (A) ICAM1; (B) VCAM; (C) TNF; (D) MCP-1. The animals were treated as indicated on Fig. 1. Data are represented as mean +/− SEM. n = 10. ** p < 0.001.

  
  
  

  

  (A) TNF; (B) IL-6. Data are represented as mean +/− SEM. n = 10.

  
  
  

  

  (A, B) Expression of ICAM1 mRNA in TNF-induced (4 h, 50 pg/ml) endothelial cells. (C) Cell-surface ICAM1 expression and IL-6 and IL-8 cytokine secretion in TNF-induced (8 h, 5 ng/ml) endothelial cells (n = 3). (D) Neutrophil adhesion to endothelium monolayer stimulated with TNF (8 h, 5 ng/ml). c, control. Data are represented as mean +/− SEM; n = 3 except for 0.2 nM SkQ1 data on Figs. 3A-3C, where n ≥ 15. * p ≤ 0.05, ** p < 0.001,*** p < 0.0001.

  
  
  

  

  (A) ICAM1; (B) E-selectin; (C) VCAM. Data are represented as mean +/− SEM. n = 3. * p ≤ 0.05.

  
  
  

  

  (A) Effect of inhibitors of NF-κB (50 mkM Bay 117082), p38 (5 mkM SP 600125) and JNK (20 mkM SB 203580) on TNF-induced ICAM1 mRNA expression. (B) Effect of SkQ1 on TNF-induced p38 phosphorylation. (C) Effect of SkQ1 on TNF-induced IκBα phosphorylation and proteolysis and p65 phosphorylation. (D) Effect of N-acetylcysteine (1 mM) on TNF-induced IκBα phosphorylation. (E) Densitometric analysis of protein bands in Figs. 5C and 5D. (F) TNF-induced p65 translocation into the nucleus. (G) Effect of SkQ1 on p65 content in nuclear and cytoplasmic fractions. Data are represented as mean +/− SEM; n = 3 except for SkQ1 data on Fig. 5E, where n = 5. * p ≤ 0.05, *** p < 0.0001.

  
  
  

• News Volume 1, Issue 3 pp 275-277

  Partners in death: a role for p73 and NF-kB in promoting apoptosis

  Relevance score: 13.398487

  Karen H. Vousden

  Keywords: p73, NF-kB, NOXA, genotoxic stress

  Published in Aging on March 28, 2009

• Research Paper pp undefined-undefined

  Huangqi Guizhi Wuwu Decoction can prevent and treat oxaliplatin induced neuropathic pain by TNFα/IL-1β/IL-6/MAPK/NF-kB pathway

  Relevance score: 10.649425

  Mingzhu Li, Zheng Li, Xiande Ma, Shengbo Jin, Yang Cao, Xuebing Wang, Jian Zhao, Jianbo Wang, Xin Wang, Jian Xu

  Keywords: Huangqi Guizhi Wuwu Decoction, oxaliplatin, CINP, MAPK/NF-kB Pathway

  Published in Aging on Invalid Date

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  Objective: This study explored the effects and mechanisms of Huangqi Guizhi Wuwu Decoction on chemotherapy-induced neuropathic pain (CINP).

  Methods: Bodyweight and related behavioral testing of the rat model were utilized to investigate the effects of Huangqi Guizhi Wuwu Decoction on CINP. ELISA was used to measure the levels of TNF-α, IL-1β, and IL-6, in the serum of chronic CINP rats. Immunohistochemistry and Western blot analysis were performed to detect the expression of MAPK pathway related-proteins namely ERK1/2, p38, and JNK, and the expression of downstream essential proteins such as c-Fos, CREB, and NF-κB.

  Results: Body weight and related behavioral testing of the rat model suggests that Huangqi Guizhi Wuwu Decoction can improve the slow weight gain of oxaliplatin-induced chronic CINP model rats and effectively prevent and treat oxaliplatin-induced regular CIPN rat model of hyperalgesia. It can also oppress the mechanical pain threshold, cold pain threshold, and heat pain threshold decreased. Furthermore, by ELISA, immunohistochemistry, and western blot analysis, we found that Huangqi Guizhi Wuwu Decoction can down-regulate the levels of TNF-α, IL-1β, and IL-6 in the serum of chronic CINP rats induced by oxaliplatin. It also suppresses the expression of MAPK pathway related-proteins ERK1/2, p38, and JNK. This results in a decrease in the expression of downstream essential proteins, c-Fos, CREB, and Nf-κB.

  Conclusions: In conclusion, we found that Huangqi Guizhi Wuwu Decoction can combat nerve cell injury, reduce pain sensitization, and prevent and repair the damage of nerve cells in the oxaliplatin CINP model rats via TNFα/IL-1β/IL-6/MAPK/NF-kB pathway.