scholarly journals Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

2014 ◽  
Vol 290 (7) ◽  
pp. 4202-4214 ◽  
Author(s):  
Daniela Volonte ◽  
Huafei Zou ◽  
Janine N. Bartholomew ◽  
Zhongmin Liu ◽  
Penelope A. Morel ◽  
...  
2013 ◽  
Vol 24 (12) ◽  
pp. 1852-1862 ◽  
Author(s):  
Daniela Volonte ◽  
Zhongmin Liu ◽  
Paul M. Musille ◽  
Elena Stoppani ◽  
Nobunao Wakabayashi ◽  
...  

Reactive oxygen species (ROS) can induce premature cellular senescence, which is believed to contribute to aging and age-related diseases. The nuclear erythroid 2 p45–related factor-2 (Nrf2) is a transcription factor that mediates cytoprotective responses against stress. We demonstrate that caveolin-1 is a direct binding partner of Nrf2, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82–101) to the caveolin-binding domain of Nrf2 (amino acids 281–289). Biochemical studies show that Nrf2 is concentrated into caveolar membranes in human and mouse fibroblasts, where it colocalizes with caveolin-1, under resting conditions. After oxidative stress, caveolin-1 limits the movement of Nrf2 from caveolar membranes to the nucleus. In contrast, Nrf2 is constitutively localized to the nucleus before and after oxidative stress in caveolin-1–null mouse embryonic fibroblasts (MEFs), which do not express caveolin-1. Functional studies demonstrate that caveolin-1 acts as an endogenous inhibitor of Nrf2, as shown by the enhanced up-regulation of NQO1, an Nrf2 target gene, in caveolin-1–null MEFs and the activation or inhibition of a luciferase construct carrying an antioxidant responsive element (ARE) after down-regulation of caveolin-1 by small interfering RNA or overexpression of caveolin-1, respectively. Expression of a mutant form of Nrf2 that cannot bind to caveolin-1 (Φ→A-Nrf2) hyperactivates ARE and inhibits oxidative stress–induced activation of the p53/p21Waf1/Cip1 pathway and induction of premature senescence in fibroblasts. Finally, we show that overexpression of caveolin-1 in colon cancer cells inhibits oxidant-induced activation of Nrf2-dependent signaling, promotes premature senescence, and inhibits their transformed phenotype. Thus, by inhibiting Nrf2-mediated signaling, caveolin-1 links free radicals to the activation of the p53/senescence pathway.


2013 ◽  
Vol 305 (8) ◽  
pp. E951-E963 ◽  
Author(s):  
Milad S. Bitar ◽  
Samy M. Abdel-Halim ◽  
Fahd Al-Mulla

A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated β-galactosidase activity and phospho-γ-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes.


2019 ◽  
Vol 15 (2) ◽  
pp. 207-212
Author(s):  
Vinita Verma ◽  
Hina Oza ◽  
Riddhi Thaker ◽  
Sunil Kumar

Background: Preterm Birth (PTB) is one of the main causes of neonatal death and infant mortality and morbidity. The pro-inflammatory cytokine interleukin-6 (IL-6) is a major proinflammatory mediator of the host response to infection and malondialdehyde (MDA) is a marker of oxidative stress. Objective : To evaluate potential associations between IL-6 and MDA levels in women with preterm birth. Method: A total of 150 women (66 with full-term and 84 with PTB) were enrolled in this case-control study. Predesigned performas were filled through questionnaire interviews to collect data on personal, demographic, occupational, lifestyle and reproductive history. Blood samples were collected within 36 hours of delivery. Serum concentrations of IL-6 and MDA were determined in mothers with full-term and preterm birth. Results: The mean age was marginally higher; whereas BMI was slightly lower in cases (PTB) as compared to controls (full-term) subjects. Serum IL-6 and MDA levels were significantly higher in subjects with PTB than full-term birth. The data were further analyzed with respect to underweight, normal and overweight/obese BMI. In all the BMI categories, the levels of IL-6 and MDA were higher in PTB cases. Among the PTB categories, the levels of IL-6 and MDA were highest in moderate to late preterm birth. A significant positive correlation was found between IL-6 and MDA levels. There was a weak negative correlation between either IL-6 or MDA and the number of gestational weeks. Conclusion : Elevated maternal serum levels of Interleukin-6 and Malondialdehyde in preterm as compared to full-term birth might suggest that inflammation and oxidative stress play a critical role in PTB.


2021 ◽  
Vol 505 ◽  
pp. 1-12
Author(s):  
Silvia Codenotti ◽  
Francesco Marampon ◽  
Luca Triggiani ◽  
Marco Lorenzo Bonù ◽  
Stefano Maria Magrini ◽  
...  

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 626
Author(s):  
Li Xiao ◽  
Nobuhiko Miwa

Reactive oxygen species (ROS)-induced oxidative stress in adipose tissue is associated with inflammation and the development of obesity-related metabolic disorders. The aim of this study is to investigate the effects of hydrogen nano-bubble water (HW) on ROS generation, adipogenesis, and interleukin-6 (IL-6) secretion in hydrogen peroxide (H2O2) or phorbol 12-myristate 13-acetate (PMA)-stimulated OP9 adipocytes, and three-dimensional (3D) subcutaneous adipose equivalents. Nanoparticle tracking analysis showed that fresh HW contains 1.17 × 108/mL of nano-sized hydrogen bubbles. Even after 8 to 13 months of storage, approximately half of the bubbles still remained in the water. CellROX® staining showed that HW could diminish H2O2- or PMA-induced intracellular ROS generation in human keratinocytes HaCaT and OP9 cells. We discovered that PMA could markedly increase lipid accumulation to 180% and IL-6 secretion 2.7-fold in OP9 adipocytes. Similarly, H2O2 (5 µM) also significantly stimulated lipid accumulation in OP9 cells and the 3D adipose equivalents. HW treatment significantly repressed H2O2- or PMA-induced lipid accumulation and IL-6 secretion in OP9 adipocytes and the 3D adipose equivalents. In conclusion, HW showed a possibility of repressing oxidative stress, inflammatory response, and adipogenesis at cellular/tissue levels. It can be used for preventing the development of metabolic disorders amongst obese people.


2008 ◽  
Vol 1 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Vicky Lahaie-Collins ◽  
Julie Bournival ◽  
Marilyn Plouffe ◽  
Julie Carange ◽  
Maria-Grazia Martinoli

Oxidative stress is regarded as a mediator of nerve cell death in several neurodegenerative disorders, such as Parkinson's disease. Sesamin, a lignan mainly found in sesame oil, is currently under study for its anti-oxidative and possible neuroprotective properties. We used 1-methyl-4-phenyl-pyridine (MPP+) ion, the active metabolite of the potent parkinsonism-causing toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, to produce oxidative stress and neurodegeneration in neuronal PC12 cells, which express dopamine, as well as neurofilaments. Our results show that picomolar doses of sesamin protected neuronal PC12 cells from MPP+-induced cellular death, as revealed by colorimetric measurements and production of reactive oxygen species. We also demonstrated that sesamin acted by rescuing tyrosine hydroxylase levels from MPP+-induced depletion. Sesamin, however, did not modulate dopamine transporter levels, and estrogen receptor-alpha and -beta protein expression. By examining several parameters of cell distress, we found that sesamin also elicited a strong increase in superoxide dismutase activity as well as protein expression and decreased catalase activity and the MPP+stimulated inducible nitric oxide synthase protein expression, in neuronal PC12 cells. Finally, sesamin possessed significant anti-inflammatory properties, as disclosed by its potential to reduce MPP+-induced interleukin-6 mRNA levels in microglia. From these studies, we determined the importance of the lignan sesamin as a neuroprotective molecule and its possible role in complementary and/or preventive therapies of neurodegenerative diseases.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Antonio Macciò ◽  
Sara Oppi ◽  
Clelia Madeddu

AbstractImproving early diagnosis along with timely and effective treatment of COVID-19 are urgently needed. However, at present, the mechanisms underlying disease spread and development, defined prognosis, and immune status of patients with COVID-19 remain to be determined. Patients with severe disease state exhibit a hyperinflammatory response associated with cytokine storm syndrome, hypercoagulability, and depressed cell-mediated immunity. These clinical manifestations, sharing similar pathogenesis, have been well-studied in patients with advanced ovarian cancer. The present review suggests treatment approaches for COVID-19 based on strategies used against ovarian cancer, which shares similar immunopathology and associated coagulation disorders.The chronicization of the hyperinflammatory cytokine storm in patients with severe COVID-19 highlights a defective resistance phase that leads to aspecific chronic inflammation, associated with oxidative stress, which impairs specific T-cell response, induces tissue and endothelial damage, and thrombosis associated with systemic effects that lead to severe multi-organ failure and death. These events are similar to those observed in advanced ovarian cancer which share similar pathogenesis mediated primarily by Interleukin-6, which is, as well demonstrated in ovarian cancer, the key cytokine driving the immunopathology, related systemic symptoms, and patient prognosis.Consistent with findings in other disease models with similar immunopathology, such as advanced ovarian cancer, treatment of severe COVID-19 infection should target inflammation, oxidative stress, coagulation disorders, and immunodepression to improve patient outcome. Correctly identifying disease stages, based on available laboratory data, and developing a specific protocol for each phase is essential for effective treatment.


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