Long term high glucose exposure induces premature senescence in retinal endothelial cells

Bertelli, Pietro Maria; Pedrini, Edoardo; Hughes, David W.; McDonnell, Shannon K.; Pathak, Varun; Peixoto, Elisa; Guduric-Fuchs, Jasenka; Stitt, Alan W.; Medina, Reinhold J.

doi:10.3389/fphys.2022.929118

Cited by 25 publications

(17 citation statements)

References 34 publications

(38 reference statements)

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“…Hyperglycemia is a proximal trigger for many downstream molecular disorders in diabetes, including cellular senescence. The excessive production of reactive oxygen species (ROS) and the extensive oxidative attack on multicellular targets, including mitochondrial structures, establish a perpetuating cycle [ 49 , 50 ]. We believe it is plausible to hypothesize that senescence explains why high glucose-induced cells are resistant to ferroptosis and have altered iron homeostasis protein expression.…”

Section: Discussionmentioning

confidence: 99%

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Wei¹,

Liu²,

Zheng³

et al. 2023

Cell Death Discov.

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Cellular senescence describes a state of permanent proliferative arrest in cells. Studies have demonstrated that diabetes promotes the pathological accumulation of senescent cells, which in turn impairs cell movement and proliferation. Historically, senescence has been perceived to be a detrimental consequence of chronic wound healing. However, the underlying mechanism that causes senescent cells to remain in diabetic wounds is yet to be elucidated. Ferroptosis and ferritinophagy observed in diabetes are due to iron metabolism disorders, which are directly associated with the initiation and progression of diabetes. Herein, we reveal that senescent fibroblasts in diabetic wounds are resistant to ferroptosis and that impaired ferritinophagy may be a contributing cause. Further, the expression of NCOA4, a key factor that influences ferritinophagy, is decreased in both diabetic wound tissue and high glucose-induced senescent fibroblasts. Moreover, NCOA4 overexpression could render senescent fibroblasts more vulnerable to ferroptosis. A faster wound healing process was also linked to the induction of ferroptosis. Thus, resistance to ferroptosis impedes the removal of senescent fibroblasts; promoting ferritinophagy could reverse this process, which may have significant implications for the management of diabetic wounds.

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Section: Discussionmentioning

confidence: 99%

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Wei¹,

Liu²,

Zheng³

et al. 2023

Cell Death Discov.

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“…Moreover, we used medium with a higher glucose concentration compared to other groups (Ferretti & Brockes, 1988; Ferretti & Kumar, 2015; Strand et al, 2021). Thus, we speculated that long‐term culturing of cells in medium with high glucose levels may induce senescence (Bertelli et al, 2022; Liu et al, 2020). Ferretti and Brockes (1988) reported no signs of senescence in cells from eastern newt limbs based on the doubling time of cells.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo expansion of primary cells from limb tissue of Pleurodeles waltl

Hasan

Sekiya

2023

Dev Growth Differ

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Pleurodeles waltl is coming to light as a model animal, especially in regeneration studies, but deep studies on the molecular mechanisms have been limited due to the absence of primary tissue cells for wide usage. Therefore, we aimed to grow primary cells from limb tissue of P. waltl for in vitro experiments. Limb tissues were cut into small pieces and seeded as “explants” on culture dishes coated with fibronectin and gelatin. Compared to the control without coating, both fibronectin and gelatin supported quicker outgrowth of cells from explants and faster cell adhesion, and fibronectin showed significantly better performance than gelatin. Interestingly, the doubling time of cells on fibronectin‐ and gelatin‐coated surfaces was almost the same (42.39 ± 2.79 h vs. 42.91 ± 3.69 h) and was not significantly different from that on non‐coated plates (49.64 ± 3.63 h). The cryopreserved cells were successfully recovered and showed a multiplication capacity that was similar to that of fresh cells. Senescent cells were barely detected even after long‐term sub‐culture (>15 passages). Moreover, enhanced fluorescence of MitoSOX™ Red in cells under H2O2 exposure confirmed the respondence to chemical stimuli. Collectively, our results show that we are able to grow enough good‐quality cells from P. waltl limb tissue for in vitro experiments, and fibronectin coating provides the best biocompatible environment for cell outgrowth and attachment.

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“…The current perspective indicates that age is the most critical risk factor for prostate tumorigenesis. According to the Hayflick limit, most somatic cells divide naturally up to 40–60 times and eventually undergo cellular senescence, a state that imposes stable cell cycle arrest ( 15 ). As an essential biological behavior, senescence works like a safeguard to eliminate abnormal and dysfunctional cells, thereby maintaining the organism’s homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer

Han

Deng²,

Yang³

et al. 2023

Front. Immunol.

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BackgroundProstate cancer (PCa) is an age-associated malignancy with high morbidity and mortality rate, posing a severe threat to public health. Cellular senescence, a specialized cell cycle arrest form, results in the secretion of various inflammatory mediators. In recent studies, senescence has shown an essential role in tumorigenesis and tumor development, yet the extensive effects of senescence in PCa have not been systematically investigated. Here, we aimed to develop a feasible senescence-associated prognosis model for early identification and appropriate management in patients with PCa.MethodThe RNA sequence results and clinical information available from The Cancer Genome Atlas (TCGA) and a list of experimentally validated senescence-related genes (SRGs) from the CellAge database were first obtained. Then, a senescence-risk signature related with prognosis was constructed using univariate Cox and LASSO regression analysis. We calculated the risk score of each patient and divided them into high-risk and low-risk groups in terms of the median value. Furthermore, two datasets (GSE70770 and GSE46602) were used to assess the effects of the risk model. A nomogram was built by integrating the risk score and clinical characteristics, which was further verified using ROC curves and calibrations. Finally, we compared the differences in the tumor microenvironment (TME) landscape, drug susceptibility, and the functional enrichment among the different risk groups.ResultsWe established a unique prognostic signature in PCa patients based on eight SRGs, including CENPA, ADCK5, FOXM1, TFAP4, MAPK, LGALS3, BAG3, and NOX4, and validated well prognosis-predictive power in independent datasets. The risk model was associated with age and TNM staging, and the calibration chart presented a high consistency in nomogram prediction. Additionally, the prognostic signature could serve as an independent prediction factor due to its high accuracy. Notably, we found that the risk score was positively associated with tumor mutation burden (TMB) and immune checkpoint, whereas negatively correlated with tumor immune dysfunction and exclusion (TIDE), suggesting that these patients with risk scores were more sensitive to immunotherapy. Drug susceptibility analysis revealed differences in the responses to general drugs (docetaxel, cyclophosphamide, 5-Fluorouracil, cisplatin, paclitaxel, and vincristine) were yielded between the two risk groups.ConclusionIdentifying the SRG-score signature may become a promising method for predicting the prognosis of patients with PCa and tailoring appropriate treatment strategies.

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Long term high glucose exposure induces premature senescence in retinal endothelial cells

Cited by 25 publications

References 34 publications

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Ex vivo expansion of primary cells from limb tissue of Pleurodeles waltl

Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer

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