Oxidative Stress: A Possible Trigger for Pelvic Organ Prolapse

Marcu, Radu Dragos; Mischianu, Dan; Iorga, Lucian; Diaconu, Camelia Cristina; Surcel, Mihaela; Munteanu, Adriana; Constantin, Carolina; Isvoranu, Gheorghița; Bratu, Ovidiu Gabriel

doi:10.1155/2020/3791934

Cited by 17 publications

(21 citation statements)

References 76 publications

(116 reference statements)

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“…However, when subjected to pathological stresses such as mechanical damage and energy stress, the overloaded ROS accumulates in cells, which can cause tissue oxidative damage 32 . There have been related reports in PFD 14 ; 15 . Lipid peroxidation is considered to be one of the most important mechanisms of cell damage under oxidative stress, and has been shown to be related to the pathology of many diseases.…”

Section: Discussionmentioning

confidence: 95%

“…Normal mechanical strain induces a physiological increase in ROS levels, while excessive mechanical stress will lead to excessive ROS accumulation and ultimately leads to oxidative damage [11][12][13] . Oxidative damage has been reported to be involved in PFD caused by mechanical trauma 14 ; 15 . Ferroptosis is a kind of iron-dependent oxidative cell death, which leads to the dysfunction of the antioxidant system, resulting in the loss of redox homeostasis and cell death 16 ; 17 .…”

Section: Introductionmentioning

confidence: 99%

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Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma

Huang

Hong

et al. 2022

Preprint

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Ferroptosis is a special form of regulated cell death, which is reported to play an important role in a variety of traumatic diseases by promoting lipid peroxidation and devastating cell membrane structure. PFD is a kind of disease affecting the quality and health of many women’s lives, which is closely related to the injury of the pelvic floor muscles. It has been clinically discovered that there is anomalous oxidative damage in the pelvic floor muscles of female patients with PFD, but the specific mechanism is still unclear. In this study, we explored the relationship between ferroptosis and mechanical stretch-induced pelvic floor muscle injury, whether obesity would make the muscles more susceptible to ferroptosis. Our results, in vitro, showed that mechanical stretch could induce oxidative damage to myoblasts and trigger ferroptosis. In addition, GPX4 and 15LOX-1 showed significant changes coinciding with ferroptosis, which was much more obvious in PA-treated myoblasts. Furthermore, ferroptosis induced by mechanical stretch could be rescued by ferroptosis inhibitor (ferrostatin-1). More importantly, in vivo, we found that the mitochondria of pelvic floor muscle shrank, which were consistent with the mitochondrial morphology of ferroptosis, and GPX4 and 15LOX-1 showed the same change observed in cells. In conclusion, our data indicate the intimate relationship between ferroptosis and mechanical injury of pelvic floor muscle, and provide a novel insight for PFD therapy.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma

Huang

Hong

et al. 2022

Preprint

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“…Previous studies have reported that ROS increase in POP ( 33 , 34 ), interfering with multiple cellular processes and favoring POP development. Thus, we speculate that the high level of AGEs in the prolapse tissues could result from increased ROS in POP because the formation of AGEs accelerates under the elevated ROS level in prolapse tissues ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

Sima¹,

Li²,

Xiao³

et al. 2022

Ann Transl Med

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Background: Pelvic organ prolapse (POP) is a common degenerative disease among females. We previously reported that advanced glycation end products (AGEs), compounds derived from nonenzymatic glycoxidation reactions, accumulated in the human vaginal wall and impaired the function of fibroblasts in the pathogenesis of POP. This study investigated the apoptosis induced by AGEs in human uterosacral ligament fibroblasts and the underlying mechanism.Methods: Human uterosacral ligament fibroblasts were cultured and identified. Quantitative real-time polymerase chain reaction (Qrt-PCR) analysis was performed to identify the expression of miR-4429, phosphatase and tensin homolog (PTEN), and caspase-3. Flow cytometric analysis was applied to detect the apoptosis rate of fibroblasts. Dual-luciferase reporter assay was performed to verify the relationship between miR-4429 and PTEN. The overexpression of miR-4429 and the inhibition of PTEN were achieved by cell transfections. Western blot analysis was used to detect the protein levels of PTEN, phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt). Results:The AGEs promoted fibroblast apoptosis both in the POP and the non-POP groups. The expression of PTEN increased in fibroblasts from the POP group or fibroblasts treated with AGEs. It was confirmed that miR-4429 interacted with PTEN messenger RNA (mRNA), and the expression level of miR-4429 was reduced in fibroblasts from the POP group or fibroblasts treated with AGEs. Further, overexpression of miR-4429 alleviated increased PTEN expression and fibroblast apoptosis induced by AGEs. Similarly, inhibition of PTEN expression alleviated increased fibroblast apoptosis induced by AGEs. In addition, the protein expressions of PI3K and phosphorylated Akt were reduced in fibroblasts exposed to AGEs. Conclusions:We proposed that AGEs induced fibroblast apoptosis by regulating the miR-4429/PTEN/ PI3K/Akt pathway in POP. Our results revealed a novel mechanism by which AGEs contributed to the molecular pathological alteration in POP.

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“…Fibroblasts represent the most abundant cell type in the uterosacral ligament and other pelvic connective tissues, which help provide mechanical support to pelvic organs. Primary fibroblasts have been isolated from pelvic connective tissues to investigate the pathogenesis of POP ( 29 , 30 ), as their functional changes under mechanical stress or other pathological conditions contribute to the development of POP ( 8 , 31 ). Fibroblasts have been found to exhibit impaired cell contractility ( 32 ), reduced cell attachment ( 33 ), delayed mechanical responses ( 34 ), increased apoptosis ( 35 ), and altered ECM protein production ( 33 ) in POP compared to fibroblasts in non-POP.…”

Section: Discussionmentioning

confidence: 99%

“…Fibroblasts isolated from the uterosacral ligaments or vaginal wall have been intensively investigated to elucidate the pathophysiology of POP. Pathological changes in fibroblasts, such as an increase in intracellular reactive oxygen species and abnormal ECM production, have been observed under the mechanical stress of POP (7)(8)(9)(10). Fibroblasts are recognized as a heterogeneous population of cells in several organs and tissues (11).…”

Section: Introductionmentioning

confidence: 99%

CD106/VCAM-1 distinguishes a fibroblast subpopulation with high colony-forming capacity and distinct protein expression from the uterosacral ligament

Sima

Xiao

et al. 2022

Ann Transl Med

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Background Pelvic organ prolapse (POP) is a common degenerative disease in women which may diminish quality of life. Investigating the pathological changes of the uterosacral ligament, including the functional changes of fibroblasts, is critical to understanding the pathophysiology of POP. This study was designed to isolate CD106-positive (CD106 + ) fibroblasts from the human uterosacral ligament and assess the function and expression of this subpopulation. Methods We separated CD106 + fibroblasts and CD106 negative (CD106 − ) fibroblasts by fluorescence-activated cell sorting (FACS) and cultured them for subsequent experiments. Flow cytometric analysis was used to test the sorting efficiency, CD106 expression, and typical mesenchymal stem cell (MSC) phenotype marker expression. A colony-forming unit (CFU) assay was applied to evaluate the colony-forming ability of the fibroblasts. Trilineage differentiation capacities were assessed after in vitro induction. The protein levels of vimentin, fibroblast specific protein-1 (FSP-1), collagen I (COL 1), matrix metallopeptidase-1 (MMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot analysis. The expression of CD106 was verified by flow cytometric analysis and immunohistochemistry (IHC) in the POP and non-POP groups. Results The CD106 + fibroblasts were isolated with a purity of (93.50±3.91)%. The CD106 + fibroblasts exhibited higher colony-forming capacity than that of CD106 − fibroblasts, but neither of them showed adipogenic or osteogenic differentiation similar to that of MSCs. The protein levels of MMP-1 and α-SMA were lower, and the level of COL 1 was higher in the CD106 + fibroblasts than in the CD106− fibroblasts. In addition, we observed a decreased expression of CD106 in the POP group compared with the non-POP group. Conclusions Our results suggest that CD106 + fibroblasts possess a high colony-forming capacity and distinct protein expression, and this subpopulation is reduced in POP.

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Oxidative Stress: A Possible Trigger for Pelvic Organ Prolapse

Cited by 17 publications

References 76 publications

Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma

Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma

Advanced glycation end products (AGEs) downregulate the miR-4429/PTEN axis to promote apoptosis of fibroblasts in pelvic organ prolapse

CD106/VCAM-1 distinguishes a fibroblast subpopulation with high colony-forming capacity and distinct protein expression from the uterosacral ligament

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