172 research outputs found

    Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

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    Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio

    Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms

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    A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits

    New-generation synthetic implants for the surgical correction of pelvic organ prolapse and stress urinary incontinence: design and testing

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    Introduction. Up to 50.0% of postpartum women experience stress urinary incontinence (SUI) and pelvic organ prolapse (POP). One of the most common and pathogenetically substantiated methods for surgical correction of severe SIU and POP is prosthetic reconstruction of the pelvic floor, involves the use of monofilament polypropylene surgical meshes through vaginal or laparoscopic access.. However, this way is associated with specific problems, i.e., primarily mucosal erosions, and pelvic pain. This has served as a trigger for the development of new materials that reduce the likelihood of such side effects.Objective. To develop the new-generation synthetic implants for surgical correction of stress urinary incontinence and pelvic organ prolapse.Materials and methods. The main development stages: 1. design of an experimental sample of a synthetic implant (evaluation of basic, physical and mechanical properties). 2. test of an experimental sample obtained in vitro.Results. A bioresorbable polypropylene ligature delivery system was developed and manufactured in two variants: for the POP correction (mesh tape with a width of 13 – 15 mm) and for the SUI correction (mesh tape with a width of 10 – 11 mm).Conclusion. Based on the results of the in vitro tests, we can conclude that the synthetic implants developed are able to provide physiological longitudinal (axial) support of the necessary pelvic floor sections and reduce the risk of postoperative complications. Further in vivo studies are required to assess the response of living tissue to the implantation of this type of synthetic implants

    Сomparison of biomechanical properties of non-absorbable and partially absorbable mesh implants used in surgery for urinary incontinence and genital prolapse: experimental study

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    Introduction. The amount of non-absorbable synthetic material used in the surgical treatment of pelvic organ prolapse and stress urinary incontinence has been shown to directly correlate with the risks of mesh-associated complications. Previously, we developed a partially absorbable implant. Currently, there are insufficient data on the use of partially absorbable implants in female pelvic floor reconstruction, which requires comparative biomechanical and pathomorphological studies.Objective. To compare the biomechanical properties of a new generation partially absorbable implants and nonabsorbable polypropylene mesh implants during animal model.Materials & methods. Thirty-nine rabbits weighing 3200 ± 250 g were randomised into three groups depending on the implanted endoprosthesis: group 1 (n = 15) — “Axilen” implant (polydioxanone 98%, polypropylene 2%), group 2 (n = 15) — “Axilen Rapid” implant (polyglycapron 98%, polypropylene 2%), group 3 (n = 9) — “Urosling 1” implant. After implantation, rabbits of all 3 groups were divided into 3 subgroups according to the withdrawal period from the experiment: 14 days, 60 days, and 180 days. The biomaterial obtained was subjected to two studies: evaluation of the macroscopic view of the explanted mesh endoprosthesis with the formed capsule and the surrounding tissues, study of the biomechanical properties of the formed connective tissue capsule with the implant.Results. According to macroscopic evaluation, there was a less significant tissue reaction to partially absorbed implants. A comparative analysis of biomechanical indices revealed no statistically significant difference in rupture elongation at all follow-up periods among the presented groups. Tensile strength, at 60 and 180 days, was not statistically different between the groups described. At 14 days, there was a statistically significant difference in tensile strength between groups 1 and 3 (p = 0.003).Conclusion. During biomechanical animal experiments, the connective tissue capsule formed on the partially absorbable implant was not inferior to the similar parameter of the non-absorbable sample in its tensile strength, which explains a great potential for the use of partially absorbable implants in reconstructive surgery of pelvic organ prolapse and stress urinary incontinence
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