Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

Khan, Shafaat Yar; Awad, Ezzat M.; Oszwald, André; Mayr, Manuel; Yin, Xiaoke; Waltenberger, Birgit; Stuppner, Hermann; Lipovac, Markus; Uhrín, Pavel; Breuss, Johannes M.

doi:10.1038/srep39501

Cited by 107 publications

(79 citation statements)

References 68 publications

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“…Expression of p16 Ink4a and p21 Cip1 was greatest in the aorta of the aged mice ( p16 Ink4a ~ 25‐fold; p < .01; p21 Cip1 ~ 10‐fold; p < .01). This is consistent with prior reports that endothelial cells readily undergo senescence (Khan et al, ; Zhu, Tchkonia, Pirtskhalava, et al, ). Skeletal muscle (quadriceps) and heart were the only tissues where both p16 Ink4a and p21 Cip1 were not significantly elevated in aged WT mice.…”

Section: Resultssupporting

confidence: 93%

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

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Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.

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Section: Resultssupporting

confidence: 93%

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

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“…Previous studies have shown that co-incubation of HUVEC with TNF-α and TGF-β1 induces cellular senescence and injury (Khan et al, 2017). Indeed, in our co-culture studies, gene expression of p16 and p21 was upregulated.…”

Section: Discussionsupporting

confidence: 51%

“…Briefly, commercially available human umbilical vein endothelial cells (HUVEC, Cell Applications, San Diego, CA, United States; Cat.# 200K-05f) were grown in endothelial cell growth medium (EGM TM -Plus Endothelial Cell Growth Media-Plus Bulletkit TM Medium, Lonza, Cohasset, MN, United States; Cat.# CC-5035), seeded at a density of 3.5 × 10 5 cells/well in a transwell plate (VWR, Radnor, PA, United States, Cat.# 2944-076), and divided into four groups. Group 1 cells were cultured under normal conditions, while group 2-4 cells were co-incubated with tumor necrosis factor-α (TNF-α, 10 ng/mL) and transforming growth factor-β1 (TGF-β1, 5 ng/mL) for 3 days to induce cellular injury (Khan et al, 2017). This medium was then replaced with fresh growth medium.…”

Section: Co-culture Of Msc and Senescent Endothelial Cellsmentioning

confidence: 99%

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Conley

Hickson

Kellogg

et al. 2020

Front. Cell Dev. Biol.

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Background: Chronic inflammatory conditions like obesity may adversely impact the biological functions underlying the regenerative potential of mesenchymal stromal/stem cells (MSC). Obesity can impair MSC function by inducing cellular senescence, a growth-arrest program that transitions cells to a pro-inflammatory state. However, the effect of obesity on adipose tissue-derived MSC in human subjects remains unclear. We tested the hypothesis that obesity induces senescence and dysfunction in human MSC. Methods: MSC were harvested from abdominal subcutaneous fat collected from obese and age-matched non-obese subjects (n = 40) during bariatric or kidney donation surgeries, respectively. MSC were characterized, their migration and proliferation assessed, and cellular senescence evaluated by gene expression of cell-cycle arrest and senescence-associated secretory phenotype markers. In vitro studies tested MSC effect on injured human umbilical vein endothelial cells (HUVEC) function. Results: Mean age was 59 ± 8 years, 66% were females. Obese subjects had higher body-mass index (BMI) than non-obese. MSC from obese subjects exhibited lower proliferative capacities than non-obese-MSC, suggesting decreased function, whereas their migration remained unchanged. Senescent cell burden and phenotype, manifested as p16, p53, IL-6, and MCP-1 gene expression, were significantly upregulated in obese subjects' MSC. BMI correlated directly with expression of p16, p21, and IL-6. Furthermore, co-incubation with non-obese, but not with obese-MSC, restored VEGF expression and tube formation that were blunted in injured HUVEC. Conclusion: Human obesity triggers an early senescence program in adipose tissue-derived MSC. Thus, obesity-induced cellular injury may alter efficacy of this endogenous repair system and hamper the feasibility of autologous transplantation in obese individuals.

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“…Woodson (Apocynaceae) have been traditionally used in South America as anti-inflammatory, antitumor, analgesic, and antiulcer agents. 17 Therefore, in order to evaluate the therapeutical potential of plumericin in IBDs, we investigated the effects of this natural product on intestinal inflammation, oxidative stress, and colon injury, both in vitro and in vivo. Moreover, it has been shown to potentlynhibit the NF-κB pathway 15 and to possess antiproliferative properties in the vasculature 16 and it has been characterized as inhibitor of the TNF-α-induced senescence of endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Plumericin prevents intestinal inflammation and oxidative stress in vitro and in vivo

et al. 2019

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Inflammatory bowel diseases (IBDs) are characterized by an inflammatory and oxidative stress condition in the intestinal tissue. In this study, we evaluated the effect of plumericin, one of the main bioactive components of Himatanthus sucuuba (Woodson) bark, on intestinal inflammation and oxidative stress, both in vitro and in vivo. The effect of plumericin (0.5‐2 µM) in vitro was evaluated in rat intestinal epithelial cells (IEC‐6) treated with lipopolysaccharides from E. coli (10 μg/mL) plus interferon‐γ (10 U/mL). Moreover, a 2,4,6‐dinitrobenzene sulfonic acid (DNBS)‐induced colitis model was used to evaluate the anti‐inflammatory and antioxidant activity of plumericin (3 mg/kg) in vivo. The results showed that plumericin significantly reduces intestinal inflammatory factors such as tumor necrosis factor‐α, cyclooxygenase‐2 and inducible nitric oxide synthase expression, and nitrotyrosine formation. Plumericin also inhibited nuclear factor‐κB translocation, reactive oxygen species (ROS) release, and inflammasome activation. Moreover, plumericin activated the nuclear factor erythroid‐derived 2 pathway in IEC‐6. Using the DNBS‐induced colitis model, a significant reduction in the weight loss and in the development of the macroscopic and histologic signs of colon injury, together with a reduced inflammatory and oxidative stress state, were observed in plumericin‐treated mice. These results indicate that plumericin exerts a strong anti‐inflammatory and antioxidant activity. Thus, it might be a candidate for the development of a new pharmacologic approach for IBDs treatment.

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Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

Cited by 107 publications

References 68 publications

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Plumericin prevents intestinal inflammation and oxidative stress in vitro and in vivo

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