Cell death of retinal pigment epithelium (RPE) is characterized as an essential late-stage phenomenon of dry age-related macular degeneration (AMD). The aim of this study was to elucidate the molecular mechanism underlying RPE cell death after exposure to oxidative stress, which occurs often because of the anatomical location of RPE cells. ARPE-19, an established RPE cell line, exhibited necrotic features involving poly (ADP-ribose) polymerase-1 (PARP-1) activation in response to hydrogen peroxide (H2O2). ARPE-19 cells were resistant to H2O2 when PARP-1 was depleted using siRNA or inhibited by a pharmacological inhibitor of PARP-1, olaparib. Our data suggest a causal relationship between PARP-1 activation and ARPE-19 cell death in response to H2O2. Next, we investigated downstream molecular events in PARP-1 activation. Increased mitochondrial depolarization, mitochondrial fission and alterations of the cellular energy dynamics with reduced NAD+ and ATP were observed in H2O2-treated ARPE-19 cells. H2O2-triggered mitochondrial dysfunction was inhibited by olaparib. Nevertheless, translocation of apoptosis-inducing factor (AIF), a biochemical signature for PARP-1-dependent cell death (parthanatos), was not observed in our study. Moreover, the depletion of AIF did not affect the amplitude of cell death, demonstrating the lack of a role for AIF in the death of ARPE-19 cells in response to H2O2. This feature distinguishes the type of death observed in this study from canonical parthanatos. Next, we examined the in vivo role of PARP-1 in a dry AMD animal model system. Histological analysis of the outer nuclear layer in the mouse retina revealed protection against sodium iodate (SI) following treatment with olaparib. Moreover, retina fundus and electroretinograms also confirmed such a protective effect in the SI-treated rabbit. Collectively, we report that AIF-independent PARP-1-dependent necrosis constitutes a major mechanism of RPE cell death leading to retinal degeneration in dry AMD.
Regulated necrosis occurs in various pathophysiological conditions under oxidative stress. Here, we report that receptor-interacting protein kinase 1 (RIPK1), a key player in one type of regulated necrosis (necroptosis), also participates in another type of poly (ADP-ribose) polymerase 1 (PARP1)-dependent regulated necrosis (parthanatos). Various biological signatures of parthanatos were significantly attenuated in Ripk1 mouse embryonic fibroblasts, including PARylation, nuclear translocation of apoptosis-inducing factor, and PARP1-dependent cell death under HO exposure. Hence, we investigated whether RIPK1 regulates the activity of PARP1. RIPK1 activated PARP1 via an interaction with the catalytic domain of PARP1 in the nucleus. Of note, both wild type and kinase-dead mutant RIPK1 induced PARP1 activation and led to PARP1-mediated cell death upon HO insult, demonstrating the kinase-independent regulation of RIPK1 in PARP1 activation. Collectively, our results demonstrate the existence of a kinase-independent role of nuclear RIPK1 in the regulation of PARP1.
IntroductionPrimary congenital glaucoma (PCG), a type of childhood glaucoma, is primarily treated surgically to lower intraocular pressure (IOP). Failure to intervene could result in partial, or even total, blindness. Various surgical intervention types have been proposed for PCG, though the evidence on comparative effectiveness remains limited. The current protocol is an ongoing network meta-analysis enabling comparative investigation of surgical interventions for which randomised controlled trials (RCTs) are available. Our aim is to systematically compare the efficacy of various types of surgical intervention for patients with PCG.Methods and analysisStudies of interest will assess the effects of those surgical interventions on surgery-naïve children (age <18 years) suffering PCG. RCTs regardless of language or publication date will be searched from three electronic databases (Cochrane Central Register of Controlled Trials, Embase and MEDLINE) from 4 April 2022. Two reviewers will screen, first, titles and abstracts, followed by full-text papers, for useful data that they will extract. The primary outcome measure will be the IOP-lowering effect of a given surgical intervention. The two reviewers also will assess the internal validity of studies using the relevant and domain-based risk-of-bias assessment tool. Overall evidence quality will be assessed according to the Confidence in Network Meta-Analysis approach and will be presented in summarised form with network diagrams. For enhanced visualisation of the included interventions’ effects, forest plots will be constructed. Pairwise effect sizes also will be calculated based on the evidence that is available in the network.Ethics and disseminationThis work will synthesise evidence obtained from published studies, and as such, no ethics review or approval will be required. A paper presenting the findings will be submitted to a peer-reviewed scientific journal for publication.PROSPERO registration numberCRD42022313954.
Background Individual with subjective cognitive decline (SCD) complains of cognitive decline on its own while cognitively normal. Current research suggests that SCD can indicate an at‐risk stage of Alzheimer’s disease (AD). In this study, we analyzed neuropsychological factors in SCD patients at a higher risk of progression to MCI. Method This retrospective cohort study included 68 patients who were confirmed with SCD after neuropsychological test. They were classified into progressive SCD group and stable SCD group according to whether they progressed to MCI within the follow‐up period. For both groups, neuropsychological tests including Seoul verbal language test, Boston naming test, Stroop color & word test, Rey complex figure test, and forward and backward digit span test were assessed. Result We collected neuropsychological data of 107 SCD individuals retrospectively, and 68 patients were followed up for a mean of 52.93 months (range 11–113 months). At follow‐up, 35.3% of patients showed cognitive decline to a diagnosis of mild cognitive impairment (MCI) and defined as progressive SCD group (N=24), and the other patients (N=44) were as stable SCD group. Patients with progressive SCD were about 4 years older and more likely to have ischemic heart disease. Furthermore, they showed worse performance on a delayed recall and a recognition task from the Seoul Verbal Learning Test, and Boston naming test compared to those with stable SCD. Conclusion SCD patients with progression of MCI have a tendency of older age, higher rate of ischemic heart disease, and worse decline in memory and language ability. This study suggest that it is worth to consider SCD subtypes based on memory and language ability so that it is possible to detect a high‐risk group of MCI at the early stage.
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